April 2023

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    Overview of Hepatitis

    • Acute liver injury - Most patients will recover completely once the offending medication is stopped. In the setting of cholestatic injury, jaundice can take weeks to months to resolve.
    • Chronic liver injury - Resolution usually occurs when offending drug is stopped, but this pattern of liver injury may progress to cirrhosis and liver failure.
    • Acetaminophen: Educate patients about not exceeding maximum doses of 3000 mg and measuring pediatric doses accurately. The injury to the liver is due to a direct, toxic effect of high doses of acetaminophen. Hepatotoxicity most commonly arises after a suicide attempt using more than 7.5 grams (generally more than 15 grams) as a single overdose. Hepatic injury generally starts 24 to 72 hours after ingestion.
    • Methotrexate: prevent liver injury with folic acid as well as frequent liver function tests. Methotrexate is well known to cause serum aminotransferase elevations. Long term therapy has been linked to development of fatty liver disease, fibrosis and even cirrhosis. Administration of folic acid (1 mg daily) has been shown to decrease the rate of liver test abnormalities on therapy without affecting the efficacy of methotrexate.
    • Duloxetine (Cymbalta®): should not be administered to patients with substantial alcohol use or any hepatic insufficiency. Duloxetine can induce liver damage in patients with a medical history of chronic liver disease or alcohol consumption, as well as patients with major depressive disorder.
    • Isoniazid: Blacks and Hispanics are more susceptible to toxicity by this drug. Even with monitoring, isoniazid remains a major cause of acute liver failure due to idiosyncratic reactions and is associated with several instances of acute liver failure and death, or emergency liver transplantation in the United States each year.
    • Kava kava: an herb used for anxiety, and has an FDA warning for hepatotoxicity, was withdrawn from the German market.
    • Hepatitis C meds: (Epclusa, Harvoni, Zepatier) may cause liver damage especially in patients who also have hepatitis B. These meds now require a black box warning.
    • Alcohol: Persons who abuse alcohol are susceptible to drug toxicity because alcohol induces liver injury and cirrhotic changes that alter drug metabolism. Alcohol causes depletion of glutathione (hepatoprotective) stores that make the person more susceptible to toxicity by drugs (especially acetaminophen).
    • Amiodarone: Liver injury can be severe and lead to liver failure and death. The acute injury with intravenous infusions can cause an acute liver failure but is usually transient and reverses rapidly. Amiodarone causes liver damage ranging from asymptomatic serum aminotransferase elevation to hepatic failure requiring liver transplantation.

    Hepatitis-A—the basics: Hepatitis-A is typically acquired through ingestion (through fecal-oral transmission) and replicates in the liver. The virus that causes Hepatitis-A is a Picornavirus (RNA) which is stable at low pH and is inactivated by temperature of 185°F or higher, formalin, chlorine.

    After ten to twelve days virus is present in blood and is excreted via the biliary system into the feces. Incubation period ranges from fifteen to fifty days with about a 28-day average. Viruses are present in blood and feces 10 to 12 days after infection. Virus excretion may continue for up to 3 weeks after onset of symptoms. Patients are most infectious 1 to 2 weeks before onset of illness.

    Symptoms of Hepatitis-A : Abrupt onset of fever, malaise, anorexia, nausea, abdominal discomfort, dark urine, jaundice. Most children are asymptomatic. Older kids and adults are symptomatic. Clinical illness I usually limited to two months.

    Humans are the only sources of Hepatitis-A. There are no insect or animal reservoirs. Spread is oral-fecal with contaminated food or water. Although it is spread throughout the world, it is highly endemic in some areas, particularly Central and South America, Africa, the Middle East, Asia, and the Western Pacific. Most vaccinations are given as “travel vaccines”.

    In the United States the rate of Hepatitis-A declined 95.5% since vaccination initiation in 1996 to 2011. From 2016-2021, over 37,000 outbreak-associated cases were reported from 35 states. Before vaccination most cases occurred in the western states.

    Hepatitis A vaccine - Havrix® & Vaqta®:
    • Who gets it?
      • Initially it was recommended for men having sex with men, injection drug users and children living in states with a high disease rate.
      • In 2020, ACIP recommended vaccination of all children and adolescents aged 2 through 18 years who have not previously received Hepatitis-A vaccine and routine vaccination of all persons with HIV age 1 year or older.
      • My daughter, Dr. Gretchen Garofoli tells all her students to get the Hepatitis-A vaccine if they eat out frequently in restaurants.
    • Havrix: available as:
      • 360EL.U/0.5ml (pediatric)
      • 720EL.U/0.5ml (pediatric)
      • 1440 EL.U/1ml (adult formulation)
    • Vaqta available as:
      • 25u/ 0.5ml (pediatric, adolescent)
      • 50u/ 1ml (adult)

    Children 1-18VaccineDose# of DosesSchedule in Months
    Havrix720elu20, 6-12 months later
    Vaqta25u20, 6-18 months later
    Adults Over 19VaccineDose# of DosesSchedule in Months
    Havrix1440elu20, 6-12 months later
    Vaqta50u20, 6-18 months later
    • Generally given between 1st and 2nd birthdays.
    • Both formulations are available in pediatric and adult formulations.
    • Both vaccines use different potency measurements. Both volume and scheduled doses are the same.
    • Hepatitis A is an inactivated vaccine.
    • Give IM in the deltoid, not ID, IV, or SQ.
    Vaccine Efficacy:
    • Highly immunogenic
    • More than 95% of adults develop protective antibody within 4 weeks of a single dose.
    • More than 97% of children and adolescents will be seropositive within 1 month of the first dose.

    Reference: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from: https://www.ncbi.nlm.Snih.gov/books/NBK547852/

    I can’t think of Hepatitis-A without thinking of my childhood. My oldest brother was in 6th grade and was extremely ill. The rest of the Kreckel kids were in 5th, 3rd and 2nd grade. He was diagnosed with hepatitis the day before Christmas in 1967. He spent a week in the hospital in isolation. I remember going to the hospital on Christmas day with my family and waving to him through the glass window. Any toys he got that Christmas given to him while he was in the hospital had to be destroyed!

    On Christmas Eve we had to go to our family doctor’s office to get a shot of gamma globulin. We were joined by our three cousins and 6 family friends at his office, all of us getting the gamma globulin. My Mom was a wonderful baker, and she frequently shared her homemade bread. Because of her generosity, 12 little kids from the ages of 2 to 14 got shots that day.

    Of course, I was the problem patient. I didn’t want a shot in the buttocks and squeezed my gluteal muscles as tight as possible. The doctor told me to relax, and I refused. He smacked my rear end, and I yelled, causing my muscles to relax and he injected me. How things have changed in healthcare!

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    Vaccination Overview: Diphtheria & Pertussis

    Diphtheria is another communicable disease that has been virtually eliminated, thanks to vaccination. It was first described by Hippocrates in the 5th century BC. December 2022: 154 cases of diphtheria have been reported by eight EU/EEA countries: Germany (64), Austria (42), Belgium (18), France (14), Norway (7), the Netherlands (5), Italy (3), and Spain (1). Most of these cases were brought in by refugees. From 1996 to 2018, the United States averaged less than one case per year, due to consistently high vaccination (over 93%),

    The causative agent for diphtheria is Corynebacterium diphtheriae or C. diphtheriae which is a Gram-positive aerobic bacillus. The primary mechanism of transmission consists of close contact with respiratory secretions (direct or via airborne droplets) or skin lesions. Diphtheria can also be spread from human to human by fomites such as towels, handkerchiefs, and used tissues. Humans are believed to be the only known reservoir for C. Diphtheriae. Diphtheria has an R-naught value of 2.6 and is highly contagious.

    TYPICAL COURSE: The normal incubation period is 2-5 days. C. diphtheriae has four biotypes: gravis, intermedius, mitis, and belfanti but all biotypes can become toxigenic and cause severe disease. Toxigenic diphtheria bacilli acquired in the nasopharynx produce an exotoxin that inhibits cellular protein synthesis, destroys local tissue, and forms a pseudo membrane. There are four major complications including myocarditis, polyneuropathies, nephritis, and thrombocytopenia. Non-toxin-producing C. diphtheriae strains cause mild to severe exudative pharyngitis and sometimes lesions, endocarditis, bacteremia, and septic arthritis.

    Before we had vaccines, diphtheria was a major cause of morbidity and mortality worldwide, primarily affecting children under the age of 15. Until the beginning of the 20th century, as many as 10 percent of American children developed diphtheria, and 5-10% died from its complications. By adolescence so many kids were exposed to diphtheria, 70 to 80 percent of the urban population was immune from natural infection. 100,000-200,000 cases and 13,000-15,000 deaths were reported annually in the 1920s before vaccines were available.

    There are four major types of diphtheria:
    • Pharyngeal and Tonsillar Diphtheria: The most common sites of diphtheria are the pharynx and the tonsils. A thick gray membrane covers the throat and tonsils. Infection at these sites is usually associated with substantial systemic absorption of the toxin.
    • Anterior Nasal Diphtheria: This looks much like the common cold, due to low absorption of the toxin.
    • Cutaneous Diphtheria: This may be manifested by a scaling rash or by ulcers with clearly demarcated edges. This type of diphtheria is most seen in the tropics.
    • Other sites: mucous membranes of the conjunctiva and vulvovaginal area, as well as the external auditory canal

    Antitoxin: Diphtheria antitoxin is a hyperimmune antiserum produced in horses that binds to and inactivates the diphtheria toxin. In 1898 a trial showed that the antitoxin reduced mortality from 7 to 2.5 percent. It must be administered early because it is only effective when the toxin has not entered the cells yet. The antitoxin is only available through CDC and it is only used for respiratory and cutaneous diphtheria.

    Antibiotics: erythromycin (Ery-Tab®), procaine penicillin-G (Wycillin®), and oral penicillin VK (Veetids®)are effective treatments for diphtheria and must be administered for 14 days. By killing off the bacteria, toxin release is attenuated.

    VACCINATION: Diphtheria toxoid was developed in the early 1920s but was not widely used until the early 1930s. It was incorporated with the tetanus toxoid and pertussis vaccine and became routinely used in the 1940s. Vaccination does not prevent colonization, but reduces transmission by 60%, likely through reduced symptomatic shedding.

    Diphtheria toxoid is produced by growing toxigenic C. diphtheriae in a liquid medium. Diphtheria toxoid is combined with tetanus toxoid as diphtheria and tetanus toxoid (DT) vaccine or tetanus and diphtheria toxoid: Td (Tenivac®) and (Tdvax®) vaccine. Diphtheria toxoid is also combined with both tetanus toxoid and acellular pertussis vaccine as DTaP (Infanrix®) and (Daptacel®) or Tdap (Boostrix®) and (Adacel®) vaccines. Td contains reduced amounts of diphtheria toxoid compared with DT. More than 95% of recipients develop protective antibody levels after 3 doses and booster for infants or 3 doses for adults.

    I have had quite a few older patients come into the pharmacy, and said “Hey doc, what vaccine am I supposed to get now that my daughter is going to have a baby next month.” First off, I congratulate them on the new bundle of joy, followed by the information about TDaP. EVERYONE who gets to have direct contact with a newborn SHOULD (OK, MUST) have an up-to-date Tdap!

    Bordetella pertussis is a small, aerobic gram-negative rod. A toxin produced by the bacteria causes most of the pathogenesis of the disease. The bacteria attached to the cilia of the respiratory epithelial cells produce toxins that paralyze the cilia and cause inflammation of the respiratory tract, which interferes with the clearing of pulmonary secretions.

    The incubation period is quite long, ranging from 4-21 days, and starts with symptoms similar to the common cold. Once the disease enters the paroxysmal stage it becomes evident that the patient is infected with pertussis. Characteristically, the patient might have bursts of numerous, rapid coughs due to difficulty expelling thick mucus from the tracheobronchial tree. At the end of the paroxysms, a long inspiratory effort is usually accompanied by a characteristic high-pitched whoop or barking sound.

    Between these attacks, the patient usually does not appear to be very ill. When an attack occurs, the patient becomes very distressed and can turn cyanotic and possibly vomit. These attacks are more frequent at night, with up to fifteen attacks in 24 hours. Seizures and encephalopathy, which are more commonly seen in infants, may occur as a result of hypoxia from coughing, or possibly from pertussis toxin.

    • Pediatrics
      • azithromycin (Z-pak®),
      • clarithromycin (Biaxin®) or
      • trimethoprim-sulfamethoxazole (Bactrim®)
    • Adults:
      • azithromycin (Z-pak®):
        • Day-1: 500mg
        • Days 2-5: 250mg
      • trimethoprim-sulfamethoxazole DS (Bactrim DS®): twice daily
      • clarithromycin (Biaxin®) 500mg twice daily
    VACCINATION: Whole-cell pertussis vaccines were first licensed in the United States in 1914 and were available as a combined vaccine with diphtheria and tetanus toxoids (as DTP) in 1948. In the 20th century, pertussis was one of the most common childhood diseases and a major cause of childhood mortality in the United States, primarily due to secondary bacterial pneumonia. Before the availability of the pertussis vaccine in the 1940s, more than 200,000 cases of pertussis were reported annually. Since the widespread use of the vaccine began, the incidence has decreased by more than 75% compared with the pre-vaccine era.

    DTwP versus DTaP: “What is acellular” pertussis?

    The acellular pertussis vaccine (aP) has three or more antigens which provided around 85% efficacy. Its efficacy is similar to the whole-cell pertussis vaccine; however, it declines faster compared to the whole-cell pertussis vaccine. The value of acellular vaccines is in their fewer side effects compared to whole-cell vaccines.

    Pertussis is still a problem in that between 2000 and 2017. There were 307 deaths from pertussis reported to the CDC with which children younger than age 2 months accounted for 84.0% of these deaths. Tdap products
    • Boostrix®:
      • This was approved in 2005.
      • Indications: one dose in adults then use Td for subsequent doses; may be used if over age 65
    • Adacel®:
      • Its safety and efficacy have not been established for geriatrics (65+), however, do not hesitate to use it if only Adacel® is available.
    • Recommended once after the age of 19 and then Td is recommended every 10 years
    Tdap vaccine can protect adolescents and adults from tetanus, diphtheria, and pertussis. One dose of Tdap is routinely given at age 11 or 12. People who did not get Tdap at that age should get it as soon as possible.

    Tdap is especially important for healthcare professionals and anyone having close contact with a baby younger than 12 months. Pregnant women should get a dose of Tdap during every pregnancy, during the third trimester, to protect the newborn from pertussis. Infants are most at risk for severe, life-threatening complications from pertussis.

    One of the most significant demonstrations of the importance of diphtheria antitoxin was its use in the 1925 diphtheria epidemic in Nome, Alaska. Coordinated emergency delivery of this life-saving antitoxin by the dog-sled relay in the harshest of conditions has left a profound legacy in the annals of vaccinology and public health.

    This adventure crossed 674 miles, using 20 mushers and 150 sled dogs, and ran from January 27th to February 1st. Airplanes were not reliable at that time, and the nearest port to Nome was frozen shut. Lead dogs Balto and Togo, and the dog-led antitoxin run of 1925 represents a dynamic illustration of the contribution made by non-human species towards mass immunization in the history of vaccinology. This unique example of cooperative interspecies fellowship and collaboration highlights the importance of the human-animal bond in the one-health initiative. [The 1925 Diphtheria Antitoxin Run to Nome - Alaska: A Public Health Illustration of Human-Animal Collaboration - PubMed (nih.gov)]

    You can meet the mushers and sled dogs on Wikipedia. Look up “1925 Serum Run to Nome.” Better yet, there are some short YouTube videos that are enlightening… especially for you dog lovers!

    Have a Great Day on the Bench!!

    March 2023

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    A Broad Look at Childhood Immunizations: Haemophilus Influenzae Type-B & Tetanus

    Haemophilus influenzae type-b

    H. influenzae type b was the leading cause of invasive bacterial disease among children in the United States prior to licensing of Haemophilus b conjugate vaccines in 1987. The bacterium also causes pneumonia, meningitis, epiglottitis arthritis, cellulitis, and blood infections. Centers for Disease Control and Prevention (CDC) now estimate that H influenzae type b disease in children under the age of 5 years has been reduced by 95%.

    The organism was given the name Haemophilus by Charles-Edward Winslow, et al. in 1920. It was not until 1933 that it was established that influenza was caused by a virus and that H. influenzae was a cause of secondary infection. Haemophilus influenzae is an aerobic gram-negative bacteria with a polysaccharide capsule with six different serotypes (a-f) of polysaccharide capsule.

    H. influenzae enters the body through the nasopharynx. Organisms colonize the nasopharynx and may remain only transiently or for several months in the absence of symptoms (asymptomatic carrier). This bacterium does not survive on inanimate surfaces. Hib could be isolated from the nasopharynx of 0.5% to 3% of healthy infants and children but was uncommon in adults.

    Before effective vaccines were introduced, it was estimated that one in 200 children developed invasive H influenzae type b disease by the age of 5 years. In children less than 5 years of age, the mortality rate for invasive H influenzae type b disease ranged between 3% and 6%.

    Meningitis: In more than 60% of these children, meningitis was the clinical syndrome and permanent sequelae ranging from mild hearing loss to mental retardation affecting 20% to 30% of all survivors.

    Epiglottitis (a swelling of the cartilage covering the windpipe, which can block the flow of air into the lungs): The demographics, causative organisms, and natural history of epiglottitis have changed substantially in the Hib vaccination era. Routine Hib vaccination for infants has made epiglottitis rare in children. It's now more common in adults. Truly an example of “herd immunity”

    Vaccine history:
    • A pure polysaccharide vaccine was licensed for use in the United States in 1985 and was used until 1988. The vaccine had low efficacy and is no longer available in the United States.
    • The first Hib conjugate vaccine was licensed in 1987. Conjugation is the process of chemically bonding a polysaccharide to a more effective protein carrier. This process changes the polysaccharide from a T-independent to a T-dependent antigen and greatly improves immunogenicity, particularly in young children.
    Dosage of available vaccines:
      • ActHIB®:4-dose series (3 dose primary series at age 2, 4, and 6 months, followed by a booster dose* at age 12–15 months)
      • Hiberix®:4-dose series (3 dose primary series at age 2, 4, and 6 months, followed by a booster dose* at age 12–15 months)
      • PedvaxHIB®: 3-dose series (2-dose primary series at age 2 and 4 months, followed by a booster dose at age 12–15 months
      • Pentacel® (DTaP-IPV/Hib) 4-dose series (3 dose primary series at age 2, 4, and 6 months, followed by a booster dose* at age 12–15 months)
      • Vaxelis® (DTaP-IPV-Hib-HepB): 4-dose series (3 dose primary series at age 2, 4, and 6 months, followed by a booster dose* at age 12–15 months)
      • *Vaxelis® ((DTaP-IPV-Hib-HepB): is not recommended for use as a booster dose. A different Hib-containing vaccine should be used for the booster dose.
    • Vaccines are interchangeable and should follow a 3-dose schedule if more than 1 brand is used
    • Hib vaccines should be given at the same visit as other recommended vaccines.
    Rates of vaccination: Among children born during 2016–2017, 92.2% had received the Hib vaccine primary series (at least 2 or 3 doses, depending on product) and 79.9% had received the full series (primary series and booster; at least 3 or 4 doses, depending on product type) by age 24 months.

    Are the vaccines working? You betcha!!
    Hib Secular Trends in the United States
    • About 20,000 cases of Hib annually before vaccine
    • Incidence of Hib has declined 99% since the pre-vaccine era.
    • Clinical efficacy has been estimated at 95% to 100%. Invasive Hib disease is uncommon in children who are fully vaccinated.
    • From 2009-2018, 36 reported cases of Hib in patients younger than age 5 years
    • Secondary cases of Hib are rare (illness occurring 1-60 days following contact with an ill person)

    Tetanus is caused by bacteria known as Clostridium tetani, which is an anaerobic bacteria found in the soil. Clostridium tetani resides in the gut of mammals. C. tetani spores can survive autoclaving at 249.8°F (121°C) for 10 to 15 minutes. When the bacteria invade the body, they produce a toxin called tetanospasmin, that causes painful muscle contractions and stiffness, usually all over the body. This occurs by the tetanus toxin entering adjacent inhibitory interneurons, where it blocks neurotransmission by its cleaving action on the membrane proteins involved in exocytosis of the nerve cell. One of the cardinal features of tetanus: intense, painful spasms of the masseter muscles, and an inability to open the mouth, known as trismus or more commonly, “lockjaw”.

    It can lead to tightening of muscles in the head and neck, so you can’t open your mouth, swallow, or sometimes even breathe. Patients have facial paralysis called “Risus Sardonicus” known as “the smile of the devil.” Tetanus kills about 1 out of 10 people who are infected even after receiving the best medical care. Is rare in the US, thanks to our vaccine efforts.

    “Help I stepped on a rusty nail” A clean nail will cause tetanus just as efficiently as a rusty nail. Other opportunities for entry of tetanus includes gunshot wounds, compound fractures, burns, and unsterile intramuscular or subcutaneous injections (that often occur in injection drug users). What needs to happen for tetanus to occur is:
    • Any injury that penetrates the skin, that results in the inoculation of C. tetani spores. Any foreign body increases the risk.
    • Other bacteria present creating a mixed wound infection
    • Tissue breakdown
    • Localized ischemia
    • The incubation period is usually about 8 days, with a usual range of 1 to 3 weeks.
    Other opportunities for tetanus infection includes:
    • Infection of the umbilical stump in neonates
    • Obstetric patients (after septic abortions)
    • Bowel flora growth in post op patients
    • Animal or insect bites
    • Dental abscesses
    • Diabetics with mixed wound infections on the extremities
    • Injection drug users. C. tetani spores can be found in contaminated heroin.
    Clostridium family reunion:

    Clostridium are gram positive anaerobic bacilli. The grow best when there is no oxygen. We health care practitioners are very familiar with the “star” of the clostridium family, C. difficile. However, there are other members of this family we need to avoid as well:
    • Clostridium botulinum: can produce botulinum toxin in food or wounds and can cause botulism. Can cause muscle paralysis. Clostridium botulinum can form spores that are very, very heat resistant. Even hours in the boiling water canner will not kill it. (source: www.foodsafety. gov)
    • Clostridiodes difficile can flourish when other gut flora bacteria are killed during antibiotic therapy, leading to superinfection and potentially fatal pseudomembranous colitis (a severe necrotizing disease of the large intestine).
    • Clostridium perfringens causes a wide range of symptoms, from food poisoning to cellulitis, fasciitis, and gas gangrene.
    • Clostridium sordellii can cause a fatal infection in exceptionally rare cases after medical abortions. no oxygen.
    TREATMENT: Tetanus immune globulin (TIG) is recommended for persons with tetanus to remove unbound tetanus toxin. Toxin bound to nerve endings is unaffected by TIG. A single intramuscular dose of 500 units is generally recommended for children and adults, with part of the dose infiltrated around the wound if it can be identified. Intravenous immune globulin (IVIG) contains tetanus antitoxin and may be used if TIG is not available. Antibiotic therapy is of little value, unless debridement is done in an aggressive manner.

    VACCINATION: The development of tetanus toxoid occurred in 1924. It was first widely used during World War II. After the 1940s, tetanus declined steadily. Since the mid-1970s, about 50 to 100 cases have been reported annually in the United States. More recently, from 2009–2018, an average of 29 cases were reported per year, thanks to our vaccination efforts.

    WaTcH YoUr ShIfT KeY !!!
    When discussing Tetanus vaccines
    • Td contains reduced amounts of diphtheria toxoid compared with DT.
    • DTaP and Tdap contain the same acellular pertussis components, but Tdap contains a reduced quantity of some pertussis antigens and diphtheria toxoid. Boostrix® contains a reduced quantity of tetanus toxoid compared to Infanrix®.
    • Children younger than age 7 years should receive DTaP vaccine or DT vaccine (if not covering pertussis)
    • Persons age 7 years or older should receive Td vaccine or Tdap vaccine, even if they have not completed a series of DTaP or DT (Tdap would be off-label for children age 7 through 9 years, but is still recommended by ACIP).
    • Tdap (Boostrix® by GSK) is approved for persons age 10 years or older to any age
    • Tdap (Adacel® by Sanofi-Pasteur) is approved for persons age 10 through 64 years.
      • Note: Either vaccine administered to a person age 65 years or older is immunogenic and would provide protection. A dose of either vaccine would be considered valid.
    • For complete immunization schedule consult CDC
    • Tetanus antitoxin levels decrease with time, so boosters are recommended every 10 years
    • Small percentage of individuals are unprotected before 10 years, so booster for wound needed if more than 5 years have elapsed since last dose.

    Further reading:https://www.cdc.gov/vaccines/pubs/pinkbook/tetanus.html#epi

    My sister Mary Kreckel Fritz is a registered nurse who graduated from Philipsburg State Hospital School of Nursing in 1980 has vast experience in the area of pediatrics. In regard to this topic, she had this to offer:

    “We had several kids with epiglottitis, they were either intubated or had a tracheotomy. They were one-on-one nursing care because if they pulled out their tubes you lost their airway. The endo tube and trach tube stayed for a few days until the swelling in the epiglottis went down.

    These kids were easily diagnosed because they would lean forward with constant drooling with respiratory distress. I would have to comfort them by hugging them while they were restrained from pulling out their tubes. When parents in the pediatrician’s office were reluctant to give vaccines, I always told them how epiglottitis has been eradicated because of the vaccines.”

    Have a Great Day on the Bench!!

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    Overview of Polio

    Polio – The History of the Vaccine

    Polio is another vaccine preventable disease that many in my parents’ generation grew to fear. Polio was probably the first disease where science and research, and not just serendipity (like smallpox), brought a dreaded disease under control.

    Jonas Salk\: Jonas Edward Salk was born October 28, 1914 in New York City, the eldest of three sons to Russian-Jewish immigrants. In 1942, Salk went to the University of Michigan on a research fellowship to develop an influenza vaccine. In 1947, Salk was appointed director of the Virus Research Laboratory at the University of Pittsburgh School of Medicine. In 1963, he founded the Salk Institute for Biological Studies in La Jolla, California, thanks to support from the March of Dimes. Salk spent his last years searching for a vaccine against AIDS. He died at the age of 80 on June 23, 1995 in La Jolla, California.
    • Salk created his inactivated polio vaccine (IPV) during 1952–1953 while a researcher at the University of Pittsburgh.
    • The vaccine contained wild polioviruses of all 3 serotypes that had been killed by means of formaldehyde; when injected intramuscularly, the vaccine elicited the production of antibodies, rendering recipients immune to the disease.
    • In 1954, Dr. Salk began a placebo-controlled study on 1.3 million children. By 1955, Dr. Salk announced that the vaccine was safe and effective, and a nationwide campaign began to inoculate our nation. On April 12, 1955, it was proclaimed that the battle against poliomyelitis had potentially been won thanks to Salk’s vaccine.
    • When asked about the patent for his vaccine Dr Salk responded: "Who owns this patent? Well, the people, I would say. There is no patent. Could you patent the sun?"
    Albert Sabin: Dr. Sabin was born Abram Saperstejn on August 26, 1906, in Bialystok, Poland. He imigrated to the United States with his parents in 1921 to avoid the persecutions directed against people of Jewish lineage. He received his M.D. from New York University in 1931 and immediately began research on polio. After World War II broke out, he joined the U.S. Army Epidemiological Board’s Virus Committee and accepted assignments in Europe, Africa, the Middle East, and the Pacific. During this phase of his career, Dr. Sabin developed vaccines for encephalitis (sleeping sickness), sand-fly fever, and dengue fever. Dr Sabin died March 3, 1993, and is buried in Arlington National Cemetery.
    • In the middle of the 1930s, Sabin was studying poliovirus at the University of Cincinnati. In 1939, he realized that it was not a respiratory virus but an enteric virus that lived and multiplied in the intestine.
    • Sabin was able to demonstrate that contagion occurred through both the respiratory route from coughing and sneezing and the enteric route from fecal contamination.
    • In the late 1950’s, the mass vaccination campaign in the Soviet Union demonstrated high vaccine effectiveness and resulted in licensure of the oral polio vaccine (OPV) in the United States in 1961. Subsequently, OPV rapidly replaced IPV as the vaccine of choice in the US. OPV was preferred over IPV because it induced both systemic and intestinal immunity, was easier to administer, and was less expensive than IPV.
    • The main drawback of OPV is that, very rarely (in 1 case out of ≈750,000), Sabin viruses can mutate back to a more neurovirulent form and cause vaccine-associated paralytic polio.
    • Dr. Sabin did not patent his vaccine because he wanted it to be used as broadly as possible. “It’s my gift to all the world’s children”, he said.
    Cutter Incident
    A defective polio vaccine that was manufactured by Cutter Labs in Berkley California was used in the Western and Mid-Western states. Over 200,000 kids were injected. Because of this defective vaccine, thousands of cases were reported, 192 kids were left severely paralyzed, and 11 kids died.

    The government temporarily suspended the vaccination program until it was determined that Cutter vaccine should be permanently withdrawn and IPV from other manufacturers could be reinitiated safely. The jury found that Cutter was not negligent in producing the vaccine but had breached an implied warranty that their product was safe.

    Dr. Paul A. Offit, MD, is the Director of the Vaccine Education Center and an attending physician in the Division of Infectious Diseases at Children's Hospital of Philadelphia. He wrote a book that outlines a series of events that contributed to the vaccine that contained live virus to be released from Cutter Laboratories. These included the use of a highly virulent strain (Mahoney), deficiencies in the inactivation of vaccine virus, inadequate safety tests, and poor communication with other scientists and the government (Carapetis J, 2006).

    The Cutter Incident still impacts vaccine administration 60 years later, according to Dr. Offit’s book “The Cutter Incident: How America’s First Polio Vaccine Led to Today’s Growing Vaccine Crisis” (Yale University Press, 2005).

    Some of the polio vaccine administered from 1955–1963 was contaminated with a virus, called simian virus 40 (SV40). The virus came from the monkey kidney cell cultures used to produce the vaccine. Most, but not all, of the contamination was in the inactivated polio vaccine (IPV). SV40 has biological properties consistent with a cancer-causing virus, however there was no increase in cancers when this age group was studied that received the IPV between 1955-63.

    The Virus
    Poliovirus, a human enterovirus that belongs to the family Picornaviridae in the genus Enterovirus, is the causative agent of poliomyelitis. It is a single stranded RNA virus. Humans are the only natural hosts of poliovirus. The virus, however, can be transferred to monkeys when it is directly inoculated into the central nervous system (CNS). Polio is usually contracted via the fecal-oral route.

    Signs and Symptoms
    90% of individuals who contract the poliovirus are entirely asymptomatic. In fewer than 1% of cases, however, the virus enters the central nervous system, where it preferentially infects and destroys motor neurons, leading to muscle weakness and acute flaccid paralysis

    Transmission can occur through direct person-to-person contact – either through the fecal-oral route or via respiratory droplet. Polio has an R naught of 5 to 7, meaning that 80-86% of the population would need to be vaccinated before viral spread would stop, according to Infection Control today.

    The Vaccine
    Inactivated polio vaccine (IPV) is the only polio vaccine that has been given in the United States since 2000. It is given by injection in the arm or leg, d

    epending on the person’s age. Children get four doses of IPV, with one dose at 2, 4, 6-18 months, and 4-6 years

    A single-antigen vaccine called IPOL is licensed in the U.S. for active immunization of infants (as young as 6 weeks of age), children, and adults for the prevention of poliomyelitis caused by poliovirus types 1, 2, and 3.

    In unvaccinated adults, two doses of IPV should be administered at intervals of four to eight weeks and the third dose should be administered within six to 12 months of the second dose.

    Cases due to wild poliovirus have decreased by over 99% since 1988, from an estimated 350,000 cases then, to just 6 reported cases in 2021 (World Health Organization).

    Recent Outbreaks
    An unvaccinated adult suffered paralysis from polio in June of 2022, the first case in New York since 1990. Wastewater surveillance later found the virus had been spreading silently in the New York City area for months. The origin of the virus is still under investigation, but samples in New York are genetically linked to polioviruses found in London and Jerusalem wastewater. Poliovirus was first detected in Rockland County, then in neighboring Orange County, New York City, Sullivan County, and later in Nassau County on Long Island. In some areas of Rockland, only 37% of kids in this age group are up to date on their vaccine.

    London Outbreak
    In London, children ages 1-9 were made eligible for booster doses of a polio vaccine after British health authorities reported finding evidence of the virus spreading in multiple areas but found no cases in people.

    Britain’s Health Security Agency said it detected viruses derived from the oral polio vaccine in the sewage water of eight London boroughs. The agency’s analysis of the virus samples suggested “transmission has gone beyond a close network of a few individuals.” 116 isolates have been identified in 19 sewage samples in London between Feb 8 and July 5, 2022.

    Franklin D. Roosevelt
    We are all aware of the most famous polio victim, Franklin Delano Roosevelt. He began having symptoms of paralytic illness in 1921 at the age of 39. He was president of the United States from 1933 to 1945. In 1938, he founded the National Foundation for Infantile Paralysis, to push for the development of a polio vaccine. This organization later became known as the March of Dimes.

    The big question is… Did Franklin Delano Roosevelt really have polio, or was it Guillain-Barré Syndrome? Most evidence points to GBS, rather than poliomyelitis. Read the entire article here: https://pubmed.ncbi.nlm.nih.gov/26508622/. The author of this article also published a book called “Prisoners of Time”. This book is a case study of how doctors can only diagnose what they know, how millions of people can accept myth as fact, and how new research can correct the historical record.

    Interesting Points about FDR’s Diagnosis
    • The diagnosis of FDR's neurological disease still depends upon documented clinical abnormalities.
    • His age, prolonged symmetric ascending paralysis, transient numbness, protracted dysesthesia (pain on slight touch), facial paralysis, bladder and bowel dysfunction, and absence of meningismus are typical of Guillain-Barré syndrome and are inconsistent with paralytic poliomyelitis.
    • FDR's prolonged fever was atypical for both diseases.
    • Finally, permanent paralysis, though more common in paralytic poliomyelitis, is also frequent in Guillain-Barré syndrome. Thus, the clinical findings indicate the most likely diagnosis in FDR's case remains Guillain-Barré syndrome.
    • Other evidence shows FDR never had a lumbar puncture.
    • GBS was only mentioned in European literature and physicians at the time considered he might have either a blood clot, a “heavy cold”, or polio.
    For a 9 page dissertation about FDR’s diagnosis, check out HERE

    Polio Trivia
    • The first disposable syringes were a result of Salk’s polio vaccine. Becton, Dickinson, and Company (BD) developed the HYPAK syringe originally made of glass to administer the polio vaccine. The following year, Roehr Products introduced a plastic disposable hypodermic syringe called the Monoject. Because of their low cost, plastic became the standard for disposable syringes.
    • Mary Poppins’ “…just a spoonful of sugar helps the medicine go down!” was a reference to the administration of Sabin’s OPV.
    • March of Dimes was founded by President Franklin D. Roosevelt in 1938, as the National Foundation for Infantile Paralysis, to combat polio.
    • In 1946, the dime was changed to have Roosevelt’s image as his connection to the “March of Dimes.”

    I wonder what will be written about COVID, vaccines, and masking in the next 50 to 100 years! All of us students of history remember learning that Franklin Delano Roosevelt was a polio victim. His efforts with the March of Dimes provided much needed research dollars to fund Dr. Salk’s work in developing a polio vaccine.

    Have a Great Day on the Bench!!

    February 2023

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    Overview of Mumps & Rubella

    Causative agent: Mumps is a caused by a paramyxovirus, a member of the rubulavirus family. It has a single-stranded viral genome. The average incubation period for mumps is 16 to 18 days. The peak incidence for mumps is late winter to early spring but can occur any time of the year.

    It was first described by Hippocrates in the fifth century BC. 95% of adults had tested positive to prior exposure to mumps, indicating that nearly all people are eventually infected in unvaccinated populations. The R naught value for mumps is between 10-12, which is 10 times greater than influenza.

    Symptoms: Mumps typically starts with generalized symptoms such as fever, headache, muscle aches, tiredness, and loss of appetite for a few days. Patients progress to parotitis (inflammation of the parotid glands) which are salivary glands located in the front, below the ears. This lasts for about 5 days and resolves by day 10.

    Complications: Usually occur in the adult population
    • Meningitis or encephalitis: Before the vaccine was available 10% of viral meningitis cases were caused by mumps
    • Orchitis (inflammation of one or both testicles)
      • Happens in about 10% of post pubertal males
    • Mastitis (inflammation of breast tissue)
    • Parotitis (inflammation of one or both parotid glands)
      • Parotitis occurs only in 31% to 65% of individuals infected with mumps. From 15% to 27% of people with mumps have no signs or symptoms of illness.
    • Oophoritis (inflammation of one or both ovaries)
    • Pancreatitis (inflammation of the pancreas)
    • Deafness
      • occurs in 1:20,000 cases, and once was a major cause of deafness in children.
    Prevalence: United States Mumps cases: As of October 28, 2022, a total of 215 mumps cases were reported in the USA. Texas had the highest number of mumps cases with 21. In the past 20 years, there's years that had over 6000 cases:
    • 2006: 6584 cases
    • 2016: 6369 cases
    • 2017: 6109 cases
    During World War I, only influenza and gonorrhea were more common than mumps as causes of hospitalization among soldiers.


    In 2004 Rubella, more commonly known as German measles, was eliminated from the United States. Despite our success in the United States, the World Health Organization (WHO) reports that over 100,000 children worldwide have congenital rubella syndrome (CRS).

    Rubella which translated means “little red” was first lumped in with scarlet fever or measles. It first appeared in German literature as its separate disease and was given the vernacular name “German measles.” Rubella virus is the only member of the genus rubivirus, in the family matonaviridae. It is an enveloped virus with a single-stranded RNA and having a single antigenic type. There are no animal reservoirs, and humans serve as the only host for rubella.


    The average incubation period is about two weeks. Symptoms are usually mild with up to 50% of the patients being asymptomatic. In small children the rash is usually the first sign of infection. In older children and adults, there may be a 1- to 5-day period with low-grade fever, malaise, lymphadenopathy, and upper respiratory symptoms preceding the rash. Lymphadenopathy may occur a week before the rash and last several weeks.

    RASH: Rubella rash typically begins on the face and spreads downward to involve the trunk and extremities over the next 24 hours; it typically vanishes by the end of day three. Rubella can be differentiated from measles as the rash is fainter than a measles rash, does not coalesce, and is often more visible after a hot shower or bath. Diagnosis of rubella can be confirmed by polymerase chain reaction (PCR) testing or measuring specific rubella IgM antibodies.

    This virus, like so many other common childhood diseases, is spread through respiratory droplets and direct contact. The R naught value of rubella is believed to be 6-7, compared with mumps (10-12) and measles (18). Rubella does its damage to humans by infecting babies through placental transfer. In pregnant women the infected mother gets viremia, and placental transfer occurs. Cell division is interrupted, and cells can be destroyed. This disruption manifests itself in the child with impaired hearing, vision abnormalities and cardiovascular complications. Intellectual disabilities are also a manifestation of CRS.

    Of all the recently reported cases of CRS, the mother of the child was born outside the United States. Although titers to rubella wane in the years after vaccination, there is no evidence that this leads to significant susceptibility to clinical rubella or CRS. Clinical rubella and CRS-affected pregnancies are extremely rare in vaccinated persons the United States.


    MMR (Mumps, Measles and Rubella)

    MMR®-II (mumps, measles and rubella) is given to immunize against three different diseases. They contain live, attenuated viruses. Single antigen rubella vaccine is not available in the US. The first rubella vaccination was available in 1969; since then, cases have plummeted by 99%. In 1971, rubella vaccine was licensed in the United States as a combined measles, mumps, and rubella (MMR) vaccine.

    Proquad® a combination measles, mumps, rubella, and varicella (MMRV) vaccine was licensed in 2005. Like MMR-II, this product is manufactured by Merck.

    PRIORIX® is a combination measles, mumps, and rubella (MMR) vaccine manufactured by GlaxoSmithKline Biologicals (GSK).

    At least 95% of vaccinated persons age 12 months or older develop serologic evidence of rubella immunity after a single dose, and more than 90% have protection against clinical rubella for at least 15 years

    Routine vaccination:
    • 2-dose series at age 12–15 months, age 4–6 years
    • Third dose may be considered if in a high-risk population. Pregnancy should be avoided for 4 weeks after vaccination.
    • MMR or MMRV may be administered. Do not administer MMRV if over age 13.
    (consult CDC website for special cases such as travelling.)

    • MMR and MMRV vaccines both contain minute amounts of neomycin and gelatin. Persons with alpha-gal allergy may wish to consult their physician before receiving a vaccine that contains gelatin.
    • MMR or MMRV should not be administered for at least 1 month after cessation of systemic high-dose corticosteroid therapy
    Travelling: As with measles, the CDC recommends adults and teens with no evidence of immunity — such as written documentation of receiving the vaccine or having been born before 1957 — receive the MMR vaccine at least two weeks before traveling. The first dose occurs as soon as possible, with the second dose following 28 days after.

    Interestingly enough, rubella is a disease where vaccination is done not for the protection of the individual getting the vaccine. Symptoms in the patient are usually self -limited, and the patient recovers without incident. Rubella does its damage in the unborn child. Everyone (boys and girls alike) is vaccinated for the protection of unborn children, to eliminate congenital rubella syndrome (CRS). CRS is manifested by deafness, eye abnormalities (cataracts, glaucoma, retinopathy, microphthalmia), and congenital heart disease, and possibly intellectual disabilities.d

    Mumps and rubella are diseases that have been virtually eliminated by vaccines. All of the vaccines we pharmacists administer provide direct benefit to the patient who receives them.

    Rubella vaccine shows direct benefit to the unborn child. All of society gets vaccinated against rubella, but the benefit is for the unborn. An estimated 212,000 cases of mumps occurred in 1964, and I would have been one of them, as a kid in kindergarten. I remember the swollen glands, but best of all I remember being out of school for a couple of weeks! It was amazing how mumps, measles, chickenpox and colds spread through our families.

    Have a Great Day on the Bench!!

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    Childhood Vaccines: An Overview of Chicken Pox & Measles

    Chicken Pox Background: Chicken pox is a highly contagious disease caused by the varicella-zoster virus (VZV). This virus is a double stranded linear DNA virus and a member of the herpesvirus group. It is one of eight known herpes viruses. It can cause an itchy, blister-like rash. The rash appears first on the chest, back, and face, and then spreads over the entire body. Chickenpox can lead to severe disease and cause life threatening illness such as encephalitis and Reyes syndrome. The R-naught (R0) value is believed to be between 10-12.

    Varicella (Chicken Pox)
    • Is the primary infection for herpes zoster
    • Onset within 14-21 days of exposure
    • Spreads by respiratory droplet infection and direct contact with lesions
    • Fever & malaise just before eruption
    • Starts as a rash, pruritic and centrifugal then changing to papular and pustular then finally crusting.
    Varivax® (chickenpox vaccination)
    • Live attenuated virus vaccine
    • Recommended for all children 12-15 months old who have not had chickenpox.
      • Do not give to impaired immune patients as it is a live vaccine
    • Up to 90% of people who receive the vaccine will not get chickenpox.
    • People who get chickenpox after having the vaccine have a milder form of the disease.
    • Children (12 months to 12 years of age):
      • The first dose is administered between 12 and 15 months of age.
      • The second dose is administered between 4 to 6 years of age.
      • There should be a minimum interval of 3 months between doses.
    • Adolescents (age 13 and over) and Adults:
      • Two doses are administered with a minimum interval of 4 weeks between doses.
    Chickenpox treatment:
    • Treatment is usually not needed; antihistamines might be of benefit to relieve itching.
    • Clip fingernails to prevent scabbing when itching occurs.
    • Acetaminophen (Tylenol®) is recommended to relieve fever. Avoid ibuprofen because of the potential for necrotizing fasciitis, a life threatening bacterial skin infection. Avoid aspirin due to potential for Reyes syndrome.
    • Keep your child at home until no new blisters appear and scabs have formed over the blisters.
    Herpes Zoster (Shingles): Roughly 1 million cases in the US each year. There is a 1 in 4 chance of developing shingles in one’s lifetime, increasing risk with age. After age 50, 20% of patients with shingles develop post-herpetic neuralgia (PHN), a form of chronic neuropathic pain.
    • This is considered to be the “recurrent” infection, where Chickenpox (varicella) is the primary infection.
    • Pain follows a sensory nerve tract followed by painful grouped vesicles
    • Involvement is unilateral (some lesions occur outside the dermatome)
    • Lesions occur on trunk and face.
    • Caused by VZV (varicella zoster virus): the same virus that causes chickenpox, which remains dormant in the sensory nerve tracts.
    • Occurs in adults.
    • With rare exceptions, patients suffer only one attack.
    Pain: occurs 48 hours or more before lesions erupt and pain will persist, and even increase after lesions have resolved. About 10 to 18% of people who get shingles will experience PHN. The risk of PHN also increases with age.

    ZOSTAVAX® (ZVL)(varicella zoster vaccine) by Merck, was first introduced back in 2006. It was the first vaccine that pharmacists were administering but, was discontinued by Merck on November 18, 2020. SHINGRIX® Zoster Vaccine Recombinant, Adjuvanted (RZV)
    • Released on October 2017
    • Delivers >90% efficacy in patients 50 years and older.
    • Recommended for the prevention of herpes zoster and related complications for immunocompetent adults aged ≥50 years.
    • HIV patients can get SHINGRIX® after age 18.
    • Recommended for the prevention of herpes zoster and related complications for immunocompetent adults who previously received zoster vaccine live (ZVL)
    • Preferred over ZVL for the prevention of herpes zoster and related complications
    • A first dose at Month 0 followed by a second dose administered anytime between 2 and 6 months later.
    • Given IM (deltoid)
    • Solicited local adverse reactions in subjects aged 50 years and older were pain (78.0%), redness (38.1%), and swelling (25.9%)
    • Solicited general adverse reactions in subjects aged 50 years and older were myalgia (44.7%), fatigue (44.5%), headache (37.7%), shivering (26.8%), fever (20.5%), and gastrointestinal symptoms (17.3%)
    Herpes Zoster (Shingles)- Antiviral treatment: Early (within 72 hours after onset) and aggressive antiviral treatment reduces the severity and duration of post herpetic neuralgia.

    Zovirax®Acyclovir800 mg 5 times daily x 7-10 days
    Famvir®Famciclovir500 mg TID x 7 days
    Valtrex®Valacyclovir1 GM TID x 7days
    Measles: According to the CDC, “Adults born in 1957 or later should receive at least 1 dose of MMR vaccine unless they have documentation of vaccination with at least 1 dose of measles, mumps, and rubella-containing vaccine or other acceptable presumptive evidence of immunity to these three diseases.” https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/meas.pdf

    I was born in May of 1958, so I am right on the edge of this recommendation! The CDC site also mentions “Except for health care personnel who should have documented immunity, birth before 1957 generally can be considered acceptable evidence of immunity to measles, mumps, and rubella.” I find it very interesting that I have never been asked about my MMR status, even though I’ve been a health care professional for 41 years!

    Don’t worry though I do remember getting the mumps in kindergarten, and remember my mom telling me about the measles when I was a very young child. Thank heavens our kids and grandkids are so well protected against these dangerous childhood diseases.

    Measles Background: Measles also known as rubeola, was a common childhood disease back in my youth until vaccines became routinely available. The measles is a paramyxovirus, of the genus Morbillivirus. In 1912, measles became a nationally notifiable disease in the United States, requiring U.S. healthcare providers and laboratories to report all diagnosed cases. In the first decade of reporting, an average of 6,000 measles-related deaths were reported each year.

    Most of the time we hear measles, is when its R-naught value is compared to other viruses. We are aware that Influenza has a R-naught value of 1 to 1.3, meaning that for each person that gets the virus they can spread it on average to 1 to 1.3 people. Measles is the most contagious disease known to spread between humans with an R-naught value of 18, meaning that one person getting the virus can spread to 18 people. If exposed, 90% of susceptible people WILL get the disease.

    Measles lives in the nose and throat mucus of an infected person. It can spread to others through coughing and sneezing. It can also be spread through contaminated air, and by touching infected surfaces. Measles virus can live for up to two hours in an airspace after an infected person leaves an area. After the surface is touched and a person touches their mucus membranes (eyes, nose, or mouth) they can become infected.

    Infected people can spread measles to others from four days before through four days after the rash appears. It can be expected that 1 in 5 children will require hospitalization if infected. Mortality is usually due to complicating bacterial infections. Case fatality is 1–3 per 1000 cases and highest in those younger than five years of age and among immunocompromised individuals. Pneumonia accounts for 6 out of 10 measles associated deaths

    Symptoms of measles:
    • high fever (may spike to more than 104° F)
    • cough
    • runny nose
    • conjunctivitis
    • Tiny white spots (Koplik spots) may appear inside the mouth two to three days after symptoms begin.
    Rash begins 14 days after virus exposure, and three to five days after symptoms begin. It usually begins as flat red spots that appear on the face at the hairline and spread downward to the neck, trunk, arms, legs, and feet.
    • Small, raised bumps may also appear on top of the flat red spots.
    • The spots may become joined together as they spread from the head to the rest of the body.
    • When the rash appears, a person’s fever may spike to more than 104° Fahrenheit.
    • The rash then turns to a brownish hue, and “blanch on pressure” meaning they become white or pale with fingertip pressure
    MMR® Vaccine: MMR® (mumps, measles and rubella) is given to immunize against three different diseases. Sometimes varicella is included for MMRV. They contain live, attenuated viruses. Single antigen measles vaccine is not available in the US.

    Vaccine Schedule:
    • 2-dose series at age 12–15 months, age 4–6 years
    • MMR or MMRV may be administered. Do not administer MMRV if over age 13.
    • (Consult CDC website for special cases such as travelling.) https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html#note-mmr
    By 1981, the number of reported measles cases was 80% less compared with the previous year. Thanks to widespread vaccine use, in the year 2000, measles was declared eliminated by the CDC. The CDC defines eliminated as absence of continuous disease transmission for greater than 12 months. To keep this level of protection, herd immunity must be kept between 85% and 95%

    There are still occasional outbreaks of measles. In 2019, we had the highest reported number of cases (1274 patients) since the early 1990’s. As of November 24, 2022, a total of 55 measles cases were reported nationwide. Most measles cases are due to international travel, or in populations where there is a high concentration of unvaccinated people.

    Vitamin-A therapy: Vitamin A deficiency is a recognized risk factor for severe measles. The World Health Organization (WHO) recommends administration of an oral dose of 200,000 IU (or 100,000 IU in infants) of vitamin A per day for two days to children with measles in areas where vitamin A deficiency may be present. Vitamin A deficiency affects the severity of measles; delays recovery; can lead to measles-related complications, including blindness; and is associated with a higher rate of death. People mostly get vitamin A from foods such as milk, eggs, cheese, fortified cereals, leafy green vegetables, orange vegetables, fish, and meat (in particular, liver). Cod liver oil is high in Vitamin-A if you can get anyone to take it! A well-balanced diet provides the nutritional intake necessary to maintain health. However low- and middle-income people might not consume enough of these Vitamin-A rich foods, which may lead to deficiency. Vitamin-A deficiency leads to poor outcomes for measles patients.?.,mn.

    We give a LOT of SHINGRIX® vaccinations in the community pharmacy. Each time I give one of these shots I think of my wife Denise and her role in pharmacy-based immunizations. Back in 2007, she took a new job with Geisinger Health Systems, and developed the Zostavax® protocol for their community pharmacists to give Zostavax®. She worked closely with the physicians and developed a very robust Zostavax® immunization program.

    About 5 years ago on a Thursday I had a stinging pain on my left hip. There were no lesions, but a sharp burning pain. I remember commenting to Denise “I hope I’m not getting shingles.” As luck would have it, on Sunday morning two small blisters appeared on that left hip. I texted my family physician, Dr Zane Gates, and he gave me a prescription for oral valacyclovir 1GM three times daily.

    Within 2 hours of the blisters breaking out, I started my Valacyclovir prescription. Unless you are a pharmacist with store keys and direct access to your family doctor, you won’t be so fortunate! I continued to break out with an itchy and painful rash for a couple of days. Resolution of the lesions took about 2 weeks, however thanks to the Valacyclovir, I never developed any post herpetic neuralgia.

    As soon as I was eligible, I got both doses of SHINGRIX®!! Your patients need to do the same!!

    Have a Great Day on the Bench!!

    January 2023

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    Overview of RSV

    Background: RSV (does it stand for REALLY SCARY VIRUS??). In our corner of the world respiratory syncytial virus RSV rears its ugly head from October through April, with the peak occurring in January and February. RSV seems to have gotten an early start this year as many of the pediatric hospitals are loaded with kids burdened with this disease. It is believed that this large resurgence is due to previous COVID precautions decreasing its spread. The number of cases in 2022 are DOUBLE of those in 2021.

    Epidemiology: RSV is a single-stranded, large enveloped negative-sense ribonucleic acid (RNA) virus and a member of the Pneumoviridae family. These viruses are seen in mammalian species and are spread by respiratory droplets (coughing, sneezing, talking). The virus can survive on hard surfaces like crib rails, doorknobs, and tables for many hours. Nearly all kids contract RSV by the time they reach the age of 5, with most kids having the disease before their second birthday. RSV is the most common cause of bronchiolitis (inflammation of the small airways in the lungs) and pneumonia (inflammation of the lungs) in kids under one in the US. RSV can also infect adults, but the cases are usually milder. According to the CDC, each year in the United States, RSV leads to approximately:
    • 2.1 million outpatient (non-hospitalization) visits among children younger than 5 years old.
    • 58,000-80,000 hospitalizations among children younger than 5 years old.
    • 58,000-80,000 hospitalizations among children younger than 5 years old.
    • 6,000-10,000 deaths among adults 65 years and older.
    • 100–300 deaths in children younger than 5 years old.
    Symptoms occur rapidly after infection occurs usually within 4-6 days of exposure. Symptoms of RSV infection may include:
    • Runny nose
    • Decrease in appetite
    • Coughing
    • Sneezing
    • Fever
    • Wheezing
    Treatment Pharmacological: Management of pain and fever with over-the-counter pain and fever reducers, such as acetaminophen or ibuprofen. Never give aspirin or naproxen to children, due to potential of developing Reyes syndrome.
    • Ibuprofen:
      • Do not use ibuprofen in children less than 6 months of age.
      • Dose is 4-10mg/kg every six hours. Some sources say use 5mg/kg for mild fever and 10mg/kg for high fever.
    • Acetaminophen
      • Acetaminophen is usually dosed at 10-15mg/kg every 4-6 hours with a maximum of 5 doses per day. Some clinicians use the shortcut of 5mg per pound.
    Hydration: Drink lots of water to prevent dehydration. Pedialyte is also a good option to replace electrolytes. Consult your doctor or pharmacist to select appropriate over the counter medications for management of symptoms.

    Vaccines: The RSV vaccine has been slow to come to market because of its history. In 1966, infants and toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (RSV) experienced an enhanced form of RSV disease characterized by high fever, bronchopneumonia, and wheezing when they became infected with wild-type virus in the community. 80% of the kids were hospitalized, and two immunized toddlers died upon infection with wild-type RSV. Now that we have a better understanding of the immune system, this tragedy should not be repeated

    CodaVax-RSV (by Codagenix)
    • CodaVax™-RSV, an intranasal, live-attenuated vaccine candidate, for the prevention of RSV.
    • On November 7, 2022, the FDA announced the beginning of Phase-1 trials for an RSV vaccine by Codagenix. The trial will begin in 2023 after the RSV season. After Phase-1 trial, the Phase 2 dose confirming study will explore efficacy during the RSV season in 2023-2024.
    • The age group to be tested is age 6 months through 5 years.
    RSVpreF® (by Pfizer)
    • Administered to a pregnant woman to protect the newborn and can synthesize antibodies and passively transfer them to the fetus via placenta. Pfizer’s RSV vaccine candidate could be the first maternal vaccine available to help prevent this common and potentially life-threatening respiratory illness in young infants.
    • Vaccine efficacy of 81.8% was observed against severe medically attended lower respiratory tract illness due to RSV in infants from birth through the first 90 days of life with high efficacy of 69.4% demonstrated through the first six months of life.
    • The RSVpreF investigational vaccine was well-tolerated with no safety concerns for both vaccinated individuals and their newborns.
    • On March 2, 2022, Pfizer announced that its vaccine candidate received Breakthrough Therapy Designation from the FDA for the prevention of RSV-associated lower respiratory tract disease in infants up to six months of age by active immunization of pregnant women.
    • Read the press release at HERE
    RSV Prevention:
    • Do not share cups or utensils (especially if they have mild cold symptoms)
    • Do not touch your face (eyes nose and mouth) after touching potentially infected surfaces.
    • Wash hands often with antibacterial soap for at least 30 seconds.
    • Frequently disinfect “high touch” surfaces like door knobs, table surfaces and toys.
    The understanding we will have, thanks to Dr. Kendsersky, is most appreciated by the readers of this column.

    Synagis for RSV prevention:
    RSV was discovered in 1956, but took until 1998 to get a monoclonal antibody to prevent the disease. Last week we discussed two vaccines that are being studied, one that will be given intranasally (Coda-VAX-RSV®) and RSVpreF® (by Pfizer) which is given to the mother while pregnant.
    Palivizumab (SYNAGIS ® ) injection:
    • Approved in 1997 and available in 50 mg and 100 mg for intramuscular injection.
    • Designed to help prevent a serious lung disease caused by respiratory syncytial virus (RSV) in children who:
      • are born prematurely (at or before 35 weeks) and who are 6 months of age or less at the beginning of RSV season.
      • have a chronic lung condition, called bronchopulmonary dysplasia (BPD), that needed medical treatment within the last 6 months, and who are 24 months of age or less at the beginning of RSV season.
      • are born with certain types of heart disease and who are 24 months of age or less at the beginning of RSV season.
    • Dose:
      • Administered 15mg/kg at first visit, and given monthly thereafter.
      • The first dose should be given prior to the commencement of RSV season and given monthly throughout.
    Non-pharmacological Prevention Strategies
    • Hand washing in all settings, particularly when high-risk infants are at risk for exposure to respiratory infections from older siblings
    • Practicing cough hygiene – cover mouth, cough into elbow, dispose of tissues immediately
    • Avoid exposure to combustible tobacco
    • If possible, avoid daycare during RSV season
    Elderly Patients: Adults who get infected with RSV may be asymptomatic or have mild symptoms. Symptoms include rhinorrhea, pharyngitis, cough, headache, fatigue, and fever. Disease usually lasts less than five days.

    Some adults, however, may have more severe symptoms consistent with a lower respiratory tract infection, such as pneumonia. High Risk elderly include:
    • Age 65 years and older
    • Adults with chronic lung or heart disease
    • Adults with weakened immune systems
    RSV in elderly may exacerbate:
    • Asthma
    • Chronic obstructive pulmonary disease (COPD)
    • Congestive heart failure
    Although these symptoms sound rather generalized, there are tests that can help with the diagnosis with RSV:
    • Reverse transcriptase-polymerase chain reaction (rRT-PCR), which is more sensitive than culture and antigen testing. This is the best option for older patients.
    • Antigen testing is 80-90% accurate in children due to sensitivity, but not is sensitive in adults.
    There is a lot of information on-line about this drug, but I am most fortunate to be able to consult a pediatric hospital pharmacist. After last week’s column on RSV, Dr. Rebecca Wytiaz Kendsersky, PharmD reached out to me and offered to help me discuss Synagis® which as a community pharmacist, I have had no experience with. “Becca” did a residency in pediatric pharmacy and currently works at Children’s Hospital of Philadelphia. Here are her comments:

    Ah yes, Synagis definitely has a special pocket in the pediatrics world :) Happy to share more info!
    • Typical RSV/palivizumab season is November to March, however the past two years have thrown us for a loop so we've started seeing RSV cases as early as August . Because palivizumab is a bit expensive (see below), we limit dispensing in the hospital to only during " palivizumab season". This year, we deemed to begin in September and will likely go through (at least) March pending on the RSV trends in the area and nation.
      • Of note, patients are eligible to receive up to 5 doses of monthly palivizumab per year as it is thought to provide coverage through the entire season. I'm curious if this recommendation will change as the season is showing to start earlier and earlier.
      • If patients contract RSV during palivizumab Synagis season", then they are no longer eligible to receive Synagis for the remainder of the season since the chance that they'll be reinfected with RSV in the same season is highly unlikely.
    • Cost: CHOP carries the 100 mg/mL vials, which is a ripe $3,947.86! While not the most expensive drug in the world, certainly not a small cost. Although the cost of treatment is definitely cheaper than a hospital admission!
    • Administration: CHOP (and the other hospitals I've worked at) administer Synagis via intramuscular route for qualifying patients within 72H of discharge - a cost-savings and risk/benefit to not administer while still admitted to the hospital. CHOP limits administration to MWF so we can batch the doses prepared and also reduce costs in that way. After patients receive their doses on their way out the door from an inpatient admission, they'll follow up with their outpatient physicians to receive subsequent IM doses during the season.
      • One last point is that Synagis is not a vaccine (a common misnomer by many of our resident physicians) but rather a prophylactic IM injection. I like to avoid the "vaccine" classification just in case qualifying patients have anti-vaccine parents who may automatically reject this therapy without knowing more about it.

    My sister Mary, is a top flight pediatric nurse with over 40 years of practice. She has staffed pediatric wards, pediatrician’s offices and served as a school nurse. Her entire career has been devoted to the care of the little ones. I spoke with her on the phone and she was telling me that she has never seen so many RSV cases so early on.

    She spent the last week helping family members deal with RSV cases. Good nursing care kept the little ones out of the hospital. She also noticed that the kids that had it all reacted differently, with the youngest having the most respiratory distress. Since not everyone has access to a private duty pediatric nurse like Mary, the hospital pediatric wards and ER’s are busting at the seams. Like me, Mary cannot wait for the RSV vaccines to become widely available.

    Have a Great Day on the Bench!!

    December 2022

    Micro-Learning CE Associated - Click Here For Details

    Overview of Ear Infections


    OTITIS EXTERNA:Characterized by erythema (redness) and edema of the external auditory ear canal. Symptoms frequently include otalgia (ear pain), pruritis (itching), purulent discharge, and impaired hearing. Recent exposure to water or mechanical trauma (Q-tips, scratching etc.) can precipitate the condition. The ear canal may become blocked by hair follicles or wax providing a protective barrier and adequate environment for bacteria and fungi to grow. Edema commonly associated with external ear infections occurs from a change in normal pH, triggering an inflammatory response. Manipulation of auricle often causes pain response. Frequently referred to as “swimmers’ ear”. Infection is usually unilateral only affecting one ear at one time. Usually caused by gram negative rods (Pseudomonas aeruginosa and Staphylococcus aureus) or fungi (Candida and Aspergillus) which grow well warm, dark, moist environment.

    Treatment of Otitis Externa:
    • Protection of ear from further moisture and/or mechanical injury are key to treatment
    • Avoid placing cotton swabs in the ear
    • Oral acetaminophen and nonsteroidal anti-inflammatories
      • Adequate for mild to moderate pain
    • Short course of oral opioids may be prescribed for severe pain associated with uncomplicated otitis externa
      • Should resolve within 48 to 72 hours of initiating antibiotic therapy
    Primary Treatment:
    • Neomycin/Polymyxin/Hydrocortisone (Cortisporin® otic) ear drops
      • Dose: 4 drops three to four times daily
      • MAX duration of 10 days
    • Ciprofloxacin 0.3%/dexamethasone 0.1% (CiproDex Otic®)
      • Dose: 4 drops into the affected ear(s) twice daily for 7 days
    • Ofloxacin otic (Floxin otic®)
      • Dose: 10 drops into affected ear(s) once daily for 7 days
    • Ciprofloxacin + hydrocortisone (Cipro-HC®)
      • Dose: 3 drops into affected ear twice daily for 7 days
      • This preparation is not sterile
      • Cannot be used when a patient has a perforated ear drum
    • Swim Ear®:
    • Contains 95% isopropyl alcohol as a drying agent for “clogged ears”
    Fungal infection for Otitis Externa:
    • Nonperforated tympanic membrane: hydrocortisone/acetic acid otic (1%/2%)
    • Perforated: Tolnaftate topical drops (1%) (usually found in the foot section)
    • Fluconazole 200mg x1 dose then 100mg daily for 3-5 days
    OTITUS MEDIA: Inflammatory process of the middle ear. Inflammation of area behind the eardrum. It is accompanied by the presence of fluid, in the middle ear and a rapid onset of signs and symptom of ear infection.

    • Fever, otalgia, otorrhea, changes in balance or hearing, irritability, lethargy, vomiting or diarrhea.
    • Patients commonly experience upper respiratory infection symptoms as well consisting of rhinorrhea, cough, congestion.
    Types of Otitis Media
    • Myringitis: inflammation of tympanic membrane
    • Otitis media with effusion
    • Acute otitis media
    • Chronic suppurative otitis media
    Microbial Pathogens: Overall Detection in Middle Ear Fluid
    • VIRAL: up to 70% of all otitis media cases are of viral etiology.
    • Bacterial and viral is 66% of cases
    • Bacteria 92%
    • No pathogen= 4%
        • Streptococcus pneumoniae:
        Contributed to 49% of bacterial otitis media. Resistance is becoming more of a problem. Up to 50% of strains are resistant to macrolides
        • Haemophilus influenzae:
        Contributed to 29% of the cases. Bacterial resistance is due to beta-lactamase production
        • Moraxella catarrhalis:
        Contributed to 28% of cases. Almost all strains are beta-lactamase producing.
    Benefits and Risks of Pharmacological Therapy: A study conducted from 1966 to 1992 concluded that the overall rate of spontaneous resolution of acute otitis media was 81%. (https://www.aafp.org)

    According to the new guidelines, watchful waiting is considered an appropriate option for:
    • Children six months to 23 months with unilateral infection and non-severe symptoms (presence of mild ear pain for less than 48 hours and a temperature less than 39°C or 102.2°F)
    • Children two years or older with unilateral or bilateral infection and non-severe symptoms (presence of mild ear pain for less than 48 hours and a temperature less than 39°C or 102.2°F)
    • Regardless of the use of an antibiotic, an analgesic should be considered within the first 24 hours to relieve (AAP guidelines 2013)
    Conversely, antibiotic therapy should be prescribed for:
    • All children less than six months
    • Children six months of age or older with severe symptoms (presence of moderate to severe ear pain for at least 48 hours or a temperature of 39°C or 102.2°F or higher)
    • Children six months to 23 months with bilateral infection and nonsevere symptoms (presence of mild ear pain for less than 48 hours and a temperature less than 39°C or 102.2°F for less than 48 hours)
    • All children with acute otitis media with otorrhea
    Treat ear pain with ibuprofen or acetaminophen. In most patients, symptoms begin improving within 24-72 hours of initiation of therapy. As a result less than 50% of the children complete the prescribed course of antibiotics. Adherence to antibiotic regimens may be improved by selecting agents that require less frequent dosing (once or twice daily) and by prescribing shorter (five days or less) treatment courses. Advise parents to bring children with suspected otitis media to the clinic for evaluation however, they should not always expect an antibiotic.


    Otitis Media:
    • Local heat can help comfort the child
    • American Academy of Otolaryngology recommends tubes being placed in patients who have had 4 episodes of AOM in past 6 months or 6 episodes in past year
    • Myringotomy and insertion of tympanostomy tubes:
      • Incision is made in tympanic membrane; middle ear effusion is aspirated
      • Biflanged tympanostomy (ventilator tube) tube is inserted
    • These tubes decrease episodes by 50%.
      • They usually last 6-12 months
      • After extrusion there is no evidence of ongoing benefit
    Risk Factors for Otitis Media:
    • Age:peaks between 6 and 12 months of age
    • Family History: especially if siblings are prone to ear infections
    • Day Care: risk ratio is 2.8 to 5 times greater
    • Tobacco Exposure: risk ratio is 1.66 times greater
    • Pacifier Use: slight risk increase, with risk ratio of 1.24

    First line (initial empiric) therapyAmoxicillin HD (high risk patients)Amoxicillin HD or Amoxicillin/Clavulanate HD or cefuroxime, or cefdinir, or cefpodoxime or cefprozil
    (Adults--moxifloxacin or levofloxacin)
    Failure after 3 days RXAmoxicillin/clavulanate HD *or*cefprozil or cefpodoxime or cefuroxime OR ceftriaxoneCeftriaxone-IM in 3 daily doses. Clindamycin, tympanocentesis
    Failure at days 10-28Same as above, choose different regimenAmoxicillin/clavulanate HD, cefuroxime, ceftriaxone-IM x3 , tympanocentesis.

    Prescribing Rules:
    • Amoxicillin HD (high dose) (80-90 mg/kg/day)
      • First line therapy for otitis media
      • Divided into 2 or 3 doses (every 8 or every 12 hours)
    • Amoxicillin/Clavulanate high dose
      • Treatment of choice for first line failure (amoxicillin high dose)
    • Amoxicillin-UD (usual dose)
      • Not recommended for first line use in otitis media
      • 40 mg/kg in 2 or 3 divided doses
    • Amoxicillin HD
      • 80-90 mg/kg/day in 2 or 3 divided doses (q8h or q12h)
    Shortcut for Amoxicillin prescribing at 80 mg/kg (HD):
    • High Dose =80-90mg/kg.
    • Using 400 mg/5 mL concentration think of it as (80 mg/mL)
      • 80mg/1 mL equals 80mg/kg therefore every 1 kg a child weighs he/she gets 1 mL of amoxicillin 400 mg/5 mL per day.
    • EXAMPLE: Child weights 44lb. 44lb divided by 2.2lb/kg= 20kg
      • The child gets 20 mL/ day may give 10 mL twice daily (1600mg/day)

    Now here is the problem when prescribing Amoxicillin/Clavulanate (Augmentin®), which is dosed based on the component.
    DrugTo get 1500mg amoxicillinYou get this much clavulanate daily
    Augmentin 125 mg/31.25 mL12 teaspoon375 mg
    Augmentin 250 mg/62.5 mL6 teaspoon375 mg
    Augmentin 400 mg/57 mL3.75 teaspoon213.75 mg
    Augmentin-ES 600 mg/42.9 mL2.5 teaspoon107.25 mg
    Augmentin 250 mg/125 mL6 tablets750 mg
    Augmentin 500 mg/125 mL3 tablets375 mg
    Augmentin 875 mg/125 mL2 tablets250 mg

    As you can see from the above chart for a child getting Amoxicillin 1500mg per day (37lb child) would get 107.25mg of clavulanate should the prescriber use Augmentin ES 600, versus 375mg of clavulanate should the prescriber use Augmentin 250/5.

    Whenever you are prescribing Augmentin therapy HD (high dose) as is recommended for otitis media, it is critical to use Augmentin ES 600mg/42.9 to minimize clavulanate exposure and decrease incidence of severe GI upset and diarrhea. Maintain daily clavulanate dose < 10 mg/kg/day. Amoxicillin/Clavulanate can cause diarrhea in 3- 34% of patients, and this percentage varies upon dose and regimen.

    Clinical Pearls:
    The younger a child is when they develop otitis media, the more likely they are to have a recurrence.
    High dose amoxicillin is first line, do not use if child has had antibiotics the previous 30 days, or receiving prophylaxis with amoxicillin.
    Standard treatment duration is 10 days, with short course being 1-7 days.
    • Use 10 days for all children under 2 years of age, and ALL children with severe disease
    • For children age 2 and older, with mild to moderate acute otitis media a 5-7 day course is appropriate
    • A Cochrane review showed that in otherwise healthy children a 5 day course is as effective as the 10 day course supported in AAP/AAFP guidelines.
    • Clinical improvement should be evident in 48-72 hours
    • Antihistamines and decongestants are of NO value in the treatment of acute otitis media
    Maximum Amoxicillin dose: The recommended dose of amoxicillin is 80 to 90 mg/kg per day for otitis or respiratory infections due to resistant S. pneumoniae. The manufacturer recommended dose (per package insert is 1.75g/day. This is exceeded when a kid weighs over 20kg. When amoxicillin was approved in 1974, pneumococcal resistance was not a problem. Today feel comfortable dispensing 3g per day and sometimes up to 4g per day if necessary.

    Prevention of otitis externa:
    • Turn head to drain water after swimming or showering
    • Utilizing earplugs may help prevent water from getting inside the ear but if water is already present it may trap water. There have been mixed results when looking at use of earplugs
    Be sure to emphasize the importance of prevention to all parents of small children
    • Pneumococcal vaccine Use of the according to the childhood immunizations schedule has been shown to be effective in reducing the incidence of acute otitis media.
    • Influenza vaccine: many cases of acute otitis media follow a viral upper respiratory tract infection. Reducing viral infections will reduce otitis media.
    • Breastfeeding: Breastfeeding for 4-6 months reduces episodes of acute otitis media. American Academy of Pediatrics recommends exclusive breastfeeding for the first 6 months of life and to continue for at least the first year or longer, based on the abilities of the mother and child.
    • Day care: Family provided day care or small group day care helps prevent otitis media.
    • Tobacco smoke: Avoid exposure of household tobacco smoke.
    • Pacifiers: Avoid giving your infant a pacifier
    • Viral infections: Viral infections like the common cold increase the likelihood of otitis media. Wash hands frequently, do not share toys etc.
    • Allergies: Inflammation and mucus caused by allergies can block the eustachian tube and make ear infections more likely
    Prophylaxis: Antibiotic therapy for Otitis Media: Use of antibiotics to prevent otitis media is a MAJOR contributor to the emergence of antibiotic resistant S. pneumoniae.
    • Antibiotic prophylaxis for otitis media is NO longer recommended
    • Pneumococcal conjugate vaccine (Prevnar-13) decreases frequency of otitis media in children

    When my wife Denise worked in State College at a clinic pharmacy, one of the pediatricians was insistent on using only the Amoxicillin/Clavulanate (Augmentin) 600 mg/5 mL concentration. She would not tolerate prescribing any Augmentin 250 mg/5 mL or Augmentin 400 mg/5 mL for her patients. If she read the emergency room reports, or listened to any other physician writing for the 250 mg/5 mL or the 400 mg/5 mL, she would instruct the parents to dump out the product dispensed, and come the pharmacy to get the 600mg/5cc product to decrease nausea, vomiting and of course, diarrhea.

    One of my former PA students did the same. She sent me an email begging me to reinforce this concept as well. For otitis media the best option is the 600 mg/ 5mL to decrease clavulanate exposure and its side effects.

    All of the amoxicillin/clavulanate products taste horrible and cannot be made palatable with any flavoring agent. I recommend the parent use an oral syringe, and have a teaspoon ready with Hershey chocolate syrup ready. Once the child swallows, stick the spoon of chocolate syrup in their mouth to clear the nasty taste.

    Have a Great Day on the Bench!!

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    Overview of Glaucoma Therapies

    Glaucoma Medications that Decrease Production of Aqueous Humor


    • Decrease production of aqueous humor by the ciliary body without producing substantial effects on aqueous humor outflow
    • Beta activity decreases during the night, so these drugs might not be effective while patients are asleep
    • NO EFFECT on pupil size or accommodation
    Indications for Use:
    • Open angle glaucoma
    • May be used alone, or in combination with mitotics
    Warnings/Precautions/Adverse Effects:
    • Stinging upon application
    • Dry eyes
    • Only betaxolol is beta selective: Caution if using other beta blockers in cardio & pulmonary (specifically asthma) patients
      • May cause increased risk for bronchospasm, or bradycardia
    • Caution in patients with decreased cardiac function
    • Other side effects: depression, lethargy, dizziness, vertigo headaches etc.
    • If combining therapy with epinephrine: administer epinephrine 4 hours after using beta blocker
    Drug Interactions:
    • Oral beta blockers: may potentiate systemic effect of decreased heart rate
    • Digoxin and non-dihydro calcium channel blockers: may prolong atrioventricular conduction time and increase risk of hypotension or bradycardia
    Patient Education:
    • Bradycardia and bronchospasm are common signs of overdose
    • Do not touch dropper directly to the eye
    Representative products:
    • Betaxolol (Betoptic®-S) 0.25% suspension
      • Dose: 1 drop twice daily
      • Beta-1 selective: affects cardiovascular parameters
    • Timolol (Timoptic®-XE) 0.25% and 0.5% gel forming solution
      • Dose: 1 drop once daily
    • Timolol (Timoptic®) 0.25% and 0.5% solution
      • Dose: 1 drop twice daily
      • Timolol is non-selective: affects cardio and pulmonary parameters
    • Levobunolol (Betagan®) 0.25% and 0.5% solution
      • Dose: 1 to 2 drops once daily; may increase to 1 drop twice daily
      • Levobunolol is non-selective: affects cardio and pulmonary parameters
    • Carteolol (Ocupress®) 1% solution
      • 1 drop twice daily
      • Carteolol is non-selective: affects cardio & pulmonary parameters


    • The alpha agonists: Brimonidine, dipivefrin, & epinephrine decrease formation of aqueous humor AND increase outflow of aqueous humor
    • Apraclonidine (Iopidine): decreases aqueous production with NO effect on outflow
    Indications for Use:
    • Apraclonidine, brimonidine, dipivefrin and epinephrine
    • Open-angle glaucoma
    Warnings/Precautions/Adverse Effects:
    • Minimal effects on blood pressure
    • Caution with severe cardiovascular disease
    • Caution in depression & Raynaud’s phenomenon
    • May cause fatigue/drowsiness in some patients
    Patient Education: May cause fatigue or drowsiness

    Representative products:
    • Brimonidine 0.15% (Alphagan-P®) solution
      • CAUTION: new additional strength 0.1% (brand only)
      • Dosage: 1 drop three times daily (preferably Q8H)
      • Brimonidine 0.025% (Lumify®) is OTC for correction of red eyes not glaucoma


    Mechanism: Inhibits carbonic anhydrase (CA) in the ciliary process of the eye reducing the production of bicarbonate ions leading to a decrease in aqueous humor production

    Indications for Use: Reduction of intraocular pressure in patients with open-angle glaucoma

    Warnings/Precautions/Adverse Effects:
    • Sulfonamide derivatives that are absorbed systemically may cause allergic reaction: caution for hypersensitivity reactions or Stevens-Johnson syndrome (SJS) like reactions
    • Temporary blurring of vision: use caution while driving
    Patient Education:
    • These are sulfa drugs. Watch for signs of allergy!
    • Horrible taste can be mediated by using punctal occlusion (blockage of tear duct)
      • Pinch bridge of nose for 30 seconds after administration
    Representative products:
    • Dorzolamide (Trusopt®) 2% solution
      • Dosage: 1 drop three times daily
    • Brinzolamide (Azopt®) 1% suspension
      • Dosage: 1 drop three times daily
    • Acetazolamide (Diamox®) oral
      • Dose: 250 to 1000 mg daily
        • Available as 250 mg tablets or 500 mg SR capsules
      • Very useful as adjunct therapy
      • Watch for hypokalemia: consider supplementation with K+

    Although we rarely dispense pilocarpine, it reminds me of my grandfather. As a little kid growing up, my Grandpa lived only one block away, and I spent a lot of time at his house. He was a blacksmith, tall and thin and had the most gorgeous blue eyes, none of these characteristics he shared with me!

    As he got older, he struggled more with his eyesight. He used pilocarpine eye drops several times a day to manage his glaucoma. Grandpa would sit on the front porch to read his large edition of the Reader’s Digest or the newspaper. He always said the hardest part of growing was twofold, the loss of his friends and his eyesight. At age 77 he gave up his driver’s license and sold his 1952 Chevy truck.

    One day he was telling me he was sitting by the window watching the birds at his bird feeder. He described a bright red cardinal, taking a sunflower seed in his beak and breaking it open and eating the kernel inside. What amazed me is how this guy who complained of failing eyesight could see such detail with such clarity.

    As a pharmacist it all makes sense. Grandpa had pinpoint pupils from the pilocarpine drops that made him struggle to see if there was not sufficient light. As long it was a bright and sunny day Grandpa could see such minor details as the birds eating at his feeder.

    Glaucoma Medications that Facilitate Drainage of Aqueous Humor MIOTICS [GREEN CAPS]

    • Parasympathomimetic drug which duplicates the muscarinic effects of acetylcholine
    • Produces pupillary constriction, stimulates ciliary muscles, increases aqueous humor outflow
    • It causes increased tension on the scleral spur and opening of the trabecular meshwork spaces to facilitate outflow of aqueous humor
    Indications for Use:
    • Decrease intraocular pressure due to glaucoma
      • May be combined with beta blockers, carbonic anhydrase inhibitors, sympathomimetics, or hyperosmotic agents
      • May be acceptable alternative for patients that cannot tolerate cardiovascular side effects of beta blockers
    Warnings/Precautions/Adverse Effects:
    • Miotics can induce vision changes or myopia (near-sightedness) in younger patients
    • Miotics causes pupillary constriction that compromises vision in patients especially with cataracts
    • Stinging and burning on application
    • Decreased visual acuity
    • Headache
    • Decreased night vision
    Patient Education: Caution driving at night; vision may be affected

    Representative products:
    • Pilocarpine (Vuity®) 0.25%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 8%, 10%
      • Dosage: 1 drop up to four times daily; initiate on 1% and increase strength and dose based on intraocular pressure
    • Pilocarpine hydrochloride(Pilopine HS®) 4% ophthalmic gel
      • Apply ½ inch ribbon in conjunctival sac once daily at bedtime (HS)
    • Pilocarpine (Ocusert Pilo) intraocular system
      • Ocular system placed in eye
      • Changed weekly
      • Releases 20 mcg/hr for 1 week

    (considered first line by most ophthalmologists)

    Mechanism: Reduces intraocular pressure by increasing outflow of aqueous humor

    Indications for Use: Open angle glaucoma

    Warnings/Precautions/Adverse Effects:
    • May discolor iris blue eyes to brown. Color change may be permanent
    • Increases length, thickness and pigmentation of eyelashes
    • Eyelid skin darkening
    Patient Education:
    • Color changes to iris
    • Eyelash and eye lid changes
    Representative products:
    • Latanoprost (Xalatan®) 0.005%
      • Dosage: 1 drop once daily in the evening
    • Travoprost (Travatan-Z®) 0.004% solution
      • Dosage: 1 drop once daily in the evening
      • Keep at room temperature for up to 6 weeks; keep refrigerated in the pharmacy before dispensing
    • Bimatroprost (Lumigan®) 0.01% solution
      • Dosage: 1 drop once daily in the evening
    • Tafluprost (Zioptan ®) solution
      • Dosage: 1 drop once daily in the evening
      • Preservative free
      • Available in single use containers
    • Bimatoprost (Latisse®) solution
      • The first drug approved for increasing eyelash growth
      • Patients using these prostaglandin eye drops noticed thicker and longer eyelashes
      • Takes about 8 weeks to work
      • Eyelashes return to "normal" a few weeks or months after stopping treatment
      • Darkens the iris and skin around the eyes
      • The skin darkening may be reversible while the iris darkening usually is not
      • Wait 15 minutes before re-inserting contact lens
    • Latanoprostene bunod (Vyzulta®) 0.024% solution
      • Metabolized into latanoprost and nitric oxide increasing fluid outflow by two pathways
      • Not much more effective than latanoprost
      • Cost is $180 for 2.5ml vs $12 for latanoprost 2.5ml.


    • Rho kinase inhibitors increase fluid outflow through the trabecular meshwork
    • Considered to be an add on to therapy, as it modestly decreases IOP
    Indications for Use: Reduction of elevated intraocular pressure in patients with open-angle glaucoma

    Warnings/Precautions/Adverse Effects: The most common side effects are conjunctival (eye) redness, golden brown deposits in the cornea (covering of the colored portion of the eye), pain with drug application, conjunctival (eye) bleeding, blurred or decreased vision, increased tearing and redness of the eyelid.

    Patient Education: Remove contacts before administration and wait 15 minutes before reinserting

    Representative products:
    • Netarsudil (Rhophressa®) 0.02% solution
      • Dose: 1 drop once daily in the evening
      • Rhopressa modestly lowers intraocular pressure
      • Expensive product at $230.00 per 2.5ml bottle
      • Refrigerate until opening then may be stored at room temperature up to 6 weeks
    • Netarsudil 0.2% combined with latanoprost 0.005% (Rocklatan®) solution
      • Dose: 1 drop once daily in the evening
      • MAX dose: 1 drop daily

    Color Codes for Topical Ocular Medications
    Anti-infectivesTanMoxifloxacin, ofloxacin
    Mydriatics and cycloplegicsRedAtropine, tropicamide
    Nonsteroidal anti-inflammatoriesGrayBromfenac, ketorlac
    MioticsDark GreenPilocarpine
    Beta-blocker combinationsDark BlueBrimonidine and timolol
    Adrenergic agonistsPurpleBrimonidine
    Carbonic anhydrase inhibitorsOrangeDorzolamide, brinzolamide
    Prostaglandin analoguesTurquoiseLatanoprost, travoprost

    When I am explaining glaucoma drugs to my student pharmacists or student PA’s I use the analogy of a bathtub filling up with water, and a washcloth plugging the drain. As the tub is about to overflow, what corrective action would you take?

    Step one is to shut the water off; step two is to unplug the drain. These two simple steps sum up how we treat glaucoma. We can shut the water off (decrease formation of the aqueous humor) or we can unclog the drain (facilitate drainage through the canal of Schlemm.

    Have a Great Day on the Bench!!

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    Overview of Glaucoma

    IOP: intra ocular pressure : - Is physiologically determined by the relative production and elimination of the aqueous humor, the clear liquid fills the anterior and posterior chambers of the eye. The relatively constant flow (2 to 3 microlitres/minute) maintains the physiological IOP.

    Aqueous humor in the anterior chamber leaves the eye by two routes.
    • filtration through the trabecular network to Schlemm’s canal (80-85%)
    • traversal to the anterior face of the iris and absorption the iris blood vessel
    Increased IOP may result from obstruction of resistance to outflow at the angle of the anterior chamber, but it may also result from pupillary block as a result of lens dislocation or drugs (beta adrenergic agents).

    The normal range of IOP is 10-21 mmHg. Except for acute cases the diagnosis of glaucoma is not made on the basis of a single tonometric measurement. IOP over 40 is an emergency referral.

    Glaucoma presents as first loss of peripheral vision followed by progress of loss of central vision.

    Risk factors for Glaucoma:
    • Hypertension: observational studies show an association between elevated blood pressure and elevated IOP
    • Diabetes: observational studies also showed a risk for glaucoma in patients with diabetes. The risk increased 5 percent each year after the diagnosis of diabetes.
    • Age: prevalence of open-angle glaucoma is less than 1% in individuals under 55 years of age, approaches 2% at age 65, and reaches 4% by the 80th birthday.
    • Race: White and black population is more affected by open angle population, while the Asian population is more at risk for closed angle glaucoma.
    • Family history: relative risk of open-angle glaucoma increased 3.7- fold if a sibling is affected and 2.2-fold for a parent
    Closed Angle Glaucoma: primary closed angle glaucoma accounts for 5 % or less of primary glaucomas. In chronic closed angle glaucoma flow of aqueous into the anterior chamber angle is obstructed. When CAG occurs, it MUST be treated as an ophthalmologic emergency to avoid visual loss.

    Symptoms include:
    • Rapid onset in older age groups, particularly hyperopes and Asians.
    • Severe pain and profound visual loss with “halos around lights”.
    • Hazy edematous cornea. Red eye and dilated pupil.
    • May see nausea, vomiting, abdominal pain and diaphoresis.
    • In prolonged attacks vision loss may occur if IOP is high enough. Tonometry reveals IOP as high as 40-70 mmHg.
    Treatment: goal is rapid reduction of IOP to preserve vision loss.
    A single dose of Acetazolamide 500mg IV followed by 250mg by mouth four times daily.
    Treatments consists of mannitol, urea or glycerol.
    Once the IOP has started to fall administer topical Pilocarpine 4% one drop every 15 minutes for 1 hour, then four times daily.
    Definitive treatment is laser peripheral iridotomy. This procedure should be prophylactically on the other eye.


    Mechanism: are hyperosmotic drugs that are administered systemically in the pre-operative management of primary acute angle closure glaucoma.

    Indications: closed angle glaucoma

    Warnings/precautions/ adverse effects: All 3 will cause headache, nausea, diarrhea, excessive thirst and electrolyte imbalance

    Representative products:
    • Mannitol: is administered IV in adults in a 20% solution rapidly in 20 minutes. Its effect is produced in 1 hour and lasts approximately 6 hours. Since mannitol enters the eye more slowly, it produces a greater osmotic gradient, which is beneficial when inflammatory processes are active.
    • Urea: is administered IV in a 30% solution effects are produced within 45 minutes. Since it enters the eye easier than mannitol, its effects are usually not as good.
    • Glycerol: is administered ORALLY in a 50 to 75% solution. Ocular penetration is poor, which results in substantial osmotic gradient between plasma and aqueous humor. This method appears to be as effective as IV routes. (can use chronically)

    Open Angle Glaucoma: Chronic disease primarily treated with topical drugs. Primary defect is reduced drainage of the aqueous humor into the canal of Schlemm. Cause is not clearly understood, although genetic mutations have been identified in a small number of the cases.

    Benefits: decrease of IOP, will preserve vision in patients. Glaucoma is often called the silent thief of sight, because of an insidious onset and vague symptoms of discomfort. Will also preserve field of vision. Untreated glaucoma can lead to damage to the optic nerve and blindness.

    Pharmacological management consists of:
    • Decreasing the production of Aqueous Humor
    • Facilitating the drainage of the aqueous humor from the chamber.
    • Therapy is started as a single agent in one eye, to evaluate drug efficacy and tolerance. Monitoring of therapy is individualized. IOP should be measured, and the optic disc visualized initially every 2-4 weeks. Then every 1-6 months when stabilized. The visual field should be measured every 3-12 months, more frequently after any change in drug therapy.
    Drugs that Decrease production of Aqueous Humor:
    • Beta blockers (topical) (timolol, betaxolol, carteolol, levobunolol)
    • Alpha agonists (topical) Epinephrine, dipivefrin, apraclonidine, brimonidine
    • Carbonic anhydrase inhibitors: acetazolomide (po), dichlorphenamide, dorzolamide, brinzolamide
    Drugs that Increase the drainage of Aqueous humor.
    • Miotics: carbachol, pilocarpine
    • Prostaglandins: Latanoprost, Travoprost, Bimatoprost
    • Some sympathomimetics: Epinephrine, dipivefrin, brimonidine
    • Rho Kinase inhibitors: netarsudil
    Risk factors for Glaucoma: Prevention: All persons over age 40 should have tonometric and ophthalmoscopic exams every 2 years. In diabetics and individuals with a family history of glaucoma, annual exam is indicated.

    Drugs that may induce or potentiate increased IOP:

    Open Angle Glaucoma
    • Ophthalmic corticosteroids (highest risk) affect the drainage through trabecular network)
    • Systemic corticosteroids and topical steroids
    • Nasal or inhaled corticosteroids
    Closed angle glaucoma
    • Topical anticholinergics
    • Topical sympathomimetics
    • Oral sympathomimetics
    • Systemic anticholinergics
    • Low potency phenothiazines
    • Antihistamines
    • Ipratropium
    • Low risk: benzodiazepines, Theophylline, CNS stimulants, tetracyclines, MAOI, topical anti cholinergics.

    Lasers in Glaucoma YAG (yttrium –aluminum-garnet) laser is used to form a hole in the iris (iridectomy) to increase the flow of aqueous humor. Used for closed angle glaucoma.
    ALT/ SLT: (argon laser trabeculoplasty is an adjunct to topical therapy, helps clear paths in the trabecula to facilitate drainage. Helps decrease IOP in open angle glaucoma patients, where drug has not produced optimal results. It can be used as a primary measure in Open angle glaucoma
    Diode: Used as an adjuvant to control IOP

    I have only seen only one patient in my career with closed angle glaucoma, and he was suffering! He had a massive headache and had bloodshot eyes and tears streamed down his cheeks.

    Dr. Mark Dsousa enlightened me about the use of lasers in his practice. I recommend that you "google" iridotomy and see how the holes are lasered into the iris. I was also educated on the fact that brown irises are harder to treat because of the pigment, and the "power" has to be turned up. Of course, in India where Dr. Mark practiced, everyone had dark brown eyes!

    People of Chinese ancestry are also more at risk for closed angle glaucoma. We are a product of our genetics!

    Have a Great Day on the Bench!!

    November 2022

    Micro-Learning CE Associated - Click Here For Details

    Overview of NSAID Eye Drops

    Non-Steroidal anti inflammatory Eye drops:
    May cause “cornea melting” should not be used for more than one month.

    Acular® (ketorolac) 0.5% eye drops: Rx only
    • Indication: Relief of ocular itching caused by seasonal allergic conjunctivitis. Also treatment of post-op inflammation following cataract extraction.
    • Dosage: one drop four times daily (allergic conjunctivitis)
    Acular LS® (ketorolac) 0.4%: for ocular pain/stinging/burning after corneal refractive

    Voltaren® ophth soln (diclofenac) 0.1% Rx only
    • Indication: post op inflammation after corneal extraction. Photophobia and pain after corneal refractive surgery. (Worst for corneal melting may occur in 2 days)
    • Adult dose: 1 drop QID beginning 24 hours post op., for 2 weeks.
    Nevanac® ophth soln (Nepafenac 0.1%) Rx Only
    • Indication: Post op pain and inflammation following cataract surgery
    • Adults : 1 drop TID 1 day before surgery and for 2 weeks post-op
    Bromday® (bromfenac ophthalmic solution) 0.09% Rx only
    • Indiation: indicated for the treatment of postoperative inflammation and reduction of ocular pain in patients who have undergone cataract extraction
    • Adults: Instill one drop once daily beginning 1 day prior to surgery, 14 days post-op
    ILEVRO® Suspension (nepafenac 0.3%) is dosed once daily post-op compared with 3x daily for NEVANAC® (nepafenac ophthalmic suspension) 0.1%- has increased viscosity, smaller particle size and more concentrated. (Use beyond 14 days is increased risk for corneal melting)
    • Indication: treatment of pain and inflammation associated with cataract surgery.


    Indications for use: to decrease inflammation and pain. For acne rosacea in the eye. Allergic conjunctivitis. Ocular surgery. Corneal injury due to radiation or chemical burns. Endogenous anterior uveitis

    Warnings/precautions/ adverse effects
    • Contraindicated in fungal and caution with viral infections
    • May elevate IOP
    • Watch for sulfite or benzalkonium allergy.
    • Caution with contact lens.
    Patient Education: If there is no improvement of condition within 2 days, report to clinician.

    Representative products:
    • Prednisolone acetate 1% (Pred forte®) : depending on severity may begin with drop every 1 hour during day & every 2 hours during night. When favorable response is observed use 1 drop 3-4 times daily.
    • Fluorometholone (FML® 0.1%) or (FML forte 0.25%)
      • During first 1-2 days: 2 drops every 2 hours. Then 1 drop 2-4 times daily
    • Difluprednate (Durezol®) dosed QID for 2 weeks then taper
    • Loteprednol (Lotemax®) 0.5% : Initally may use 1 drop every hours then when satisfactory response: 1 drop QID Less effect on IOP
    • Loteprednol + tobramycin (Zylet®) 1-2 drops every 4-6 hours.
      • (Best to avoid steroids +antibiotic combo—Dr Mark)

    Prevalence of dry eye: 17.9 percent in women and 10.5 percent in men

    Mechanism: serve as lubricants and emollients

    Indications: for dry eyes or irritation

    Warnings/precautions/ adverse effects: Benzalkonium (preservative) may cause hypersensitivity reactions in select patients.

    Patient Education: Differences are between preservative systems.

    Can be divided into two causes:
    1. Decrease in tear production
    2. Decrease in lipid production: oil (meibum) secreted from Meibomian glands should be oily in appearance and composition. If it thickens then it cannot exit glands appropriately. Glands become clogged and no oil is released into tears.
    Associated systemic conditions causing dry eyes
    • Connective tissue and autoimmune diseases
    • Sjogren syndrome
    • Rheumatoid Arthritis
    • Wegener granulomatosis,
    • Systemic lupus erythematosus
    • Vitamin A deficiency
    Medications causing Dry Eyes
    • Medications
    • Oral contraceptives
    • Anti’s: Anticholinergics, Antihistamines, Antiarrhythmics, Antipsychotics, Antispasmotics
    • Tricyclic antidepressants, SSRIs
    • Beta blockers
    • Diuretics
    • Chemotherapy
    Lubricating eye drops- Over the Counter
    Recommend four times daily dosing to start then taper as needed
    Side effects: Slight blur and burn upon instillation
    Different formulations to treat different categories of dry eye

    Artificial Tears for aqueous deficiency:
    • Refresh®
    • Blink®
    Lipid based Artificial Tears
    Replenishes the complete tear film and provides a protective lipid barrier:
    • Systane® Balance
    • Refresh Optive® Advance
    • Soothe® XP
    • Retaine®MGD

    CYCLOSPORINE EYE DROPS (Rx only) Mechanism: immunomodulator. Decreases inflammation in patients with keratoconjunctivitis , which causes a decrease in tear production.

    Indications for use: to increase tear production.

    Warnings/precautions/ adverse effects: Caution with herpes keratitis.

    Patient Education:
    • Single dose vials. Discard immediately after each use.
    • Contact lens may be inserted 15 minutes after eye drops (patients with dry eyes are not ideal candidates for contact lens)
    Restasis® (cyclosporin) available in boxes of 30 and 60 vials.
    • Dosage: 1 drop in each eye twice daily. May take 3 months for some patients to begin noticing an increase in tear production, with significant increase in tear production at 6 months.
    • Very expensive about $660/month (60 vials)
    • 2022: generic available around $300/month (60 vials)

    XIIDRA™ (lifitegrast ophthalmic solution) 5% 2016

    Dose: Instill (1) drop twice a day in each eye, using one sterile container. Remove contact lens, instill drops and wait 15 minutes before re-insertion.

    Mechanism: dual leukocyte function-associated antigen-1 (LFA-1)/intracellular adhesion molecule-1(ICAM-1) inhibitor. LFA-1 antagonists mediate both migration and adhesion of the white blood cells to sites of inflammation. ICAM-1 may be overexpressed in corneal and conjunctival tissues in dry eye disease. LFA-1/ICAM-1 interaction can contribute to the formation of an immunological synapse resulting in T-cell activation and migration to target tissues. Also, lifitegrast may inhibit mononuclear cells from secreting inflammatory cytokines

    Adverse effects: instillation site irritation, dysgeusia (nasty taste), decreased visual acuity.

    Cost: $660.00/month

    We pharmacists are quite undertrained in the area of eye care. Back 10 or 12 years ago I got a prescription for Lotemax® (loteprednol) for a patient. The copay was $45.00. I did a test claim for Prednisolone 1% eye drops and the copay was $5.00. I called the optometrist and explained the situation.

    He said in a friendly voice “Pete, if we do that the patient has to come to my office every 2 hours to have his intra-ocular pressure measured.” He went on to say “Lotemax® does not raise the IOP like prednisolone does, so let the patient pay the $45.00."

    Whether it is Dr. Mark Dsousa, Dr. Rachel Fritz or that optometrist that educated me on loteprednol I’m always open to learning. And your commitment to continuing education shows that you are too!

    Have a Great Day on the Bench!!

    Micro-Learning CE Associated - Click Here For Details

    Overview of Eye Infections


    The membranes covering the sclera (the white part of the eye) and the inside lining of the eyelid, may be sensitive to chemical irritants, allergens, bacteria, and viruses. Conjunctivitis, also known as “pink eye”, may be a sign of systemic disease or infection, or may occur after an upper respiratory infection.

    Clinical presentation: one or both eyes may be itchy and feel as if they are burning. A clear, white, or yellow-greenish discharge may occur.

    Infectious conjunctivitis: bacterial conjunctivitis may start in one eye and spread to the other. Signs are redness, swelling, itchy painful eye, with thick discharge often yellow or green. Discharge is crusty and dried upon wakening in the morning, causing eye to stick shut. Although this condition is self-limiting, it should be treated by a clinician to decrease length of disease, decrease spread to others, and decrease possible complications. Pathogens most frequently responsible for bacterial conjunctivitis are Streptococcus pneumoniae, Haemophilus influenza, and Staphylococcus aureus Contact lens wearers should wear glasses until all signs of infection are gone.

    Treatment: consists of antibiotic eye drops or ointment given several times per day. Warm wet compresses are soothing for patients and helps to soften up the morning crust around the eye.

    Is a potent sensitizer. Many allergic reactions are confused with therapeutic failures. Not an ideal choice for conjunctivitis.

    Representative products:

    Bleph-10® or Sulamyd 10%®: Sodium sulfacetamide comes in 15cc dropper bottle.
    Dose: 1 drop in the affected eye every 2-3 hours for initial dose.

    ERYTHROMYCIN ophthalmic ointment:
    Indications: may be used for prophylaxis of aophthalmia neonatorum due to N. gonorrhoeae or Chlamydia. Excellent coverage of GM positive organisms
    Erythromycin ophthalmic ointment: dosed ½ inch four times daily for 5-7 days

    Indications: coverage for both Gram negative & gram-positive organisms. Most strep are resistant. Are not ideal choices since they are toxic to the corneal epithelium and can cause a reactive keratoconjunctivitis after long term use.

    Typical dose (drops): (it varies from clinician to clinician)
    Conjunctivitis: 1-2 drops every 2 hours while awake for 2 days, then 1-2 drops every 4 hours while awake for five days.
    • Gentamycin (Garamycin®) ophthalmic solution
    • Tobramycin (Tobrex®) ophthalmic soln
    • Tobramycin plus dexamethasone (Tobradex®) suspension
      • (Clinicians should avoid this combo, due to chance of herpes infection)
      • Ophthalmic corticosteroids can cause sight-threatening complications such as corneal scarring, melting, and perforation when used inappropriately. Chronic ophthalmic corticosteroid treatments may lead to cataracts and glaucoma
    Typical dose (ointment)
    Conjunctivitis: ½" of ointment every 3-4 hours, two to four times daily.
    • Gentamycin (Gentak®) ophthalmic ointment
    • Tobramycin (Tobrex ®) ophthalmic ointment
    • Tobramycin/dexamethasone (TobraDex®) ophthalmic ointment
      • (Clinicians should avoid this combo, due to chance of herpes infection)
    BACITRACIN Good Gram-positive coverage
    Minimal gram-negative coverage.
    Representative products
    Bacitracin® ophthalmic ointment –1/2 inch every 3-4 hours for 7-10 days.

    FLUOROQUINOLONES Indications for use: Good coverage for Gram positive and Gram negative. Good for most bacteria associated with conjunctivitis. Fluoroquinolones are the best choice to treat bacterial conjunctivitis in contact lens wearers due to the high incidence of Pseudomonas infection

    Dosage is similar: 1 drop every 2 hours while awake the first 2 days. Then 1 drop four times daily while awake.

    Representative products:
    Ciloxan® drops & ointCiprofloxacin (generic available)1st gen
    Ocuflox® dropsOfloxacin (generic available)2nd gen
    Quixin® dropsLevofloxacin3rd gen
    Vigamox® drops
    Moxeza ®
    Moxifloxacin (may dose TID)
    Moxifloxacin (dosed BID)
    4th generation
    Zymar® dropsGatifloxacin 0.3%4th generation
    Zymaxid®Gatifloxacin 0.5%4th generation
    Besivance®dropsBesifloxacin (may dose TID)4th generation

    Azithromycin (Azasite®) cost about 240.00/bottle
    Think of it as Z-pack for the eyes. Great for mid-day dosing problems (schools, etc). effective for gram (+) microbes and also against H. influenzae

    Dosage: 1 drop every 12 hours for two days; then just once daily for the next 5 days.

    Storage: refrigerate before dispensing, can be left at room temp for 14 days after it is opened.

    Flip, whip, and drip method for administering: The solution is viscous and hard to get out of the bottle. Tell patients to flip the bottle upside down before opening it; give it a whip or shake to force the solution down into the tip; then remove the cap and drip it into the eye. Is thicker when removed from pharmacy refrigerator. Keep at room temp to decrease viscosity.

    Trimethoprim has broad spectrum activity often including methicillin resistant staph. Polymyxin B has only gram (-) spectrum, and is relatively ineffective.

    Etiology: usually adenoviruses, herpes simplex or herpes zoster (shingles). Herpes simplex virus is a major cause of worldwide blindness. The herpes virus lies dormant in the trigeminal ganglia, where it remains for the life of the patient. When activated infectious viral particles travel to the ends of the neurons, where the virus is shed.

    Trifluridine (Viroptic®) available as 1% solution ($225/bottle)
    Dosage: 1 drop every 2 hours while awake. Maximum dosage of 9 drops/day. Use until corneal ulcer is healed. Following healing treat for an additional 7 days, one drop every 4 hours while awake (Minimum daily dose of 5 drops). Avoid use for more than 21 days.

    Patient information:
    • Drops MUST be refrigerated
    • Wash hands thoroughly after each use.
    • Transient stinging may occur.
    (ZIRGAN®) ophthalmic gel) 0.15% ($400/tube) is a topical ophthalmic antiviral that is indicated for the treatment of acute herpetic keratitis (dendritic ulcers).

    Dose: 1 drop in the affected eye 5 times per day (approximately every 3 hours while awake) until the corneal ulcer heals, and then 1 drop 3 times per day for 7 days
    *Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during therapy with ZIRGAN.

    Epithelial Keratitis dosing for oral antiviral agents
    • Acyclovir (Zovirax®): 400mg 3-5 times daily for 7-10 days OR
    • Valacyclovir (Valtrex®): 500mg twice daily for 7-10 days OR
    • Famcyclovir (Famvir®) 250mg BID for 7-10 days
    CAUTION: most common dispensing error for route of administration in a pharmacy is ofloxacin ear drops for the eye. BE SURE to specify route.
    1. Remember: Antibiotics usually are not needed to clear up conjunctivitis. Most cases are viral, and even bacterial infections often resolve without antibiotics.
    2. Recommend symptomatic treatment such as cold or warm compresses, ocular lubricants, and decongestants. Emphasize hand washing to prevent spreading the infection. Use paper towels in “community bathrooms”
    3. Save antibiotics for patients who don't improve in 5 to 7 days, or earlier if daycare requires treatment before a child can return.
    4. Bacterial infections are contagious until antibiotics have been on board for 24 to 48 hours.
    5. Viral infections are usually contagious until the eye clears.
    6. Bacterial conjunctivitis is less common than viral conjunctivitis. In adults, infective conjunctivitis is viral about 85% of the time and bacterial in about 15% of cases.
    7. For children, the incidence is about evenly split between viral and bacterial.
    Differentiation between bacterial and viral conjunctivitis:
    • Bacterial conjunctivitis will usually present with a purulent discharge.
      • The most common causative organisms for acute bacterial conjunctivitis are Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae.
      • Conjunctival cultures are not routinely recommended for patients with acute conjunctivitis
    • Viral conjunctivitis will present with a watery, mucous, discharge.

    Differentiating Bacterial, Viral, and Allergic Conjunctivitis
    Type of conjunctivitisBacterialViralAllergic
    Clear, watery discharge+
    Stringy, white mucus discharge+
    Purulent discharge+
    Lash matting++

    Treatment of corneal edema, or swelling of the cornea, is based on the underlying cause of the condition. Most commonly, the endothelial cells responsible for pumping fluid out of the cornea are damaged. In glaucoma, the intraocular pressure needs to be reduced. In inflammatory conditions, the inflammation needs to be treated. Hypertonic saline drops or ointment can temporarily help reduce swelling of the cornea
    • Muro-128 2% and 5% solution for daytime
    • Muro-128 5% ointment for overnight use
    • Corneal swelling causes the lens to stretch, causing loss of visual acuity
    • May be caused by:
      • ocular surgery, trauma, infection, inflammation, and secondary causes like glaucoma.
      • over-wear of certain types of contact lenses
    • Is OTC but use only if recommended by an eye care professional

    Have a Great Day on the Bench!!

    October 2022

    Micro-Learning CE Associated - Click Here For Details

    Overview of Eye Care Considerations in the Pharmacy

    General principals of eye care:

    Drugs must cross the cornea to act within the eye.

    • Must be lipophilic or uncharged
    • Adjust pH so weak bases or acids can produce larger portion of uncharged molecules.
    • Most eye drops are sterile products.
    Action of some drugs is related to eye color. Black & brown irises contain more pigment than green, gray or blue. The more pigment, the more drug that can bind to it resulting in a slower onset and longer duration of action.

    Eye drops basics

    There no FDA approved anti-infective products available OTC. Avoid “homemade” products – boric acid solution, chamomile tea compresses, etc.

    Patients must wash hands before application of ophthalmic agents.
    Remind patient to throw out any unused eye drops at end of treatment course.
    Best not to write refills for antibiotic eye drops

    Administration techniques for Eye drops:
    • If suspension, shake well.
    • Do not touch tip to the eye
    • Pull down on lower eyelid to expose conjunctival sac
    • Multiple drops: the eye can only handle 1 drop at a time. Wait 5 minutes between drops. No script should read 2 drops TID (1 drop will wash out the other)
    • Replace cap immediately and tighten.
    • Preferable to drop in the middle of the conjunctival sac and not inner canthus.
    • May be beneficial to hold lower lid for a minute after instillation and then press finger against inner corner of eye for 1 minute to prevent rapid drainage into tear duct
    • Use tissue only to remove excess liquid form the eyelid.


    Appropriate use of eye ointments:
    • Use a mirror or have someone else apply the ointment.
    • Tilt head back
    • Hold the ointment tube between the thumb & forefinger of your other hand and brace the remaining fingers of this hand against cheek or nose.
    • Place about ½ inch ribbon of ointment in the pouch formed.
    • Do NOT touch the eye or eyelid with the tip of the ointment tube.
    • Blink eye gently. Vision may be blurred for a few minutes.
    • Replace cap tightly
    • Use a tissue to remove excess ointment from the eyelid.
    General clinical pearls for eye products
    • Worsening symptoms during topical treatment with any antibiotic (particularly Polysporin® or a Sulfonamide (Sulamyd, Bleph-10®) may represent a contact allergic reaction.
    • Some locally applied drugs can cause systemic adverse effects. (a single drop of timolol for glaucoma may affect asthma, COPD, Bradycardia, Heart block, Heart failure).
    • If the patient is concerned that they won't be able to tell if the drops make it inside their eye, keep the bottle in the fridge so the medicine is cold, giving a better sensation when the drop lands.
    • If the patient concerned that the medicine will bounce out of the eye or roll down the cheek, know that each drop contains about 10 times more medicine than can fit in the tear film. What a patient feels is excess that runs down the cheek.


    Treatment of Hordeolum (Styes):
    One of the more common questions I get is for a recommendation for treatment of a stye. Styes can be internal, appearing underneath the eyelid, infecting the meibomian glands. These glands, found along the edge of the eyelids produce the oil that makes the surface of the eye “slick” and keep the tears from drying. Styes can also be external, infecting the follicle of eyelashes.

    Staphylococcus aureus is the bacteria usually implicated in styes. When we think of a walled-off staph infection we think of MRSA. MRSA is not treated with glucocorticoids, fluoroquinolones (ciprofloxacin/ofloxacin), or aminoglycosides, so treatment of styes with these products does not make sense either.

    Styes usually resolve on their own within two weeks if untreated. Most eye practitioners agree that warm compresses 5-6 times a day is the most effective treatment for styes.

    Patients with rosacea and seborrheic dermatitis near the eyes are prone to having frequent episodes of hordeolum. Doxycycline oral tablets are frequently prescribed for treatment in these patients with frequent styes.

    Eye makeup that is contaminated by bacteria, can cause styes (hordeola) by clogging and inflaming gland pores. Women should avoid using any eye makeup if they are prone to styes.

    What about the Stye® medication in our eye care section? This product only contains white petrolatum (think Vaseline®) and is of no use treating a staph infection.

    Medications that May Cause Ocular Concerns:

    Drugs causing Intraoperative Floppy Iris Syndrome:
    Alpha-1 Blockers: tamsulosin (Flomax®), doxazosin (Cardura®), (alfuzosin (Urozatral®); any of the alpha-1 blockers, that are generally used for BPH (benign prostatic hyperplasia) and hypertension.
    • The iris becomes flaccid and billows in response to intraoperative irrigation currents, causing the potential prolapse of the iris toward phacoemulsification incisions.
    • Ophthalmologists can modify their surgical techniques including using iris hooks, iris dilation rings, viscoelastic devices.
    • Ophthalmologists MUST know before surgery that patient has been on alpha blocker therapy. Usual protocol is to stop the medication 7-10 days pre-op
    Drugs causing corneal and conjunctival disturbances:
    • Chlorpromazine
    • Thioridazine
    • Chloroquine
    • Hydroxychloroquine
    • Lovastatin (progression of cataracts)
    Drugs causing retinopathy
    • Disease state: diabetes mellitus
    • Methanol (moonshine)
    • Chloroquine
    • Indomethacin
    • Amiodarone
    • Tamoxifen
    • Phenothiazines
    • Ibuprofen, naproxen, indomethacin at high doses.
    Drugs causing optic neuropathy
    • Ethambutol
    • Chloroquine
    • Quinine
    • Quinidine
    • Ethylene glycol methanol
    • Tobacco
    Drugs causing color visual disturbances
    • Digoxin
    • Oral contraceptives
    • Viagra® (sildenafil) and other 5-PDE
    • Ethambutol
    • Metronidazole


    Exclusions to self-care: If someone comes to the pharmacy and has one of the following complaints, seek professional help from an eye care specialist:
    • Blunt trauma
    • Foreign particles trapped or embedded in the eye
    • Ocular abrasions
    • Infections of the eyelid/eye surface
    • Eye exposure to chemical splash, solid chemical, or chemical fumes. “Super glue” damage
    • Thermal injury to eye
    • Bacterial conjunctivitis
    • Chlamydial conjunctivitis
    Blepharitis: Can be detected by redness of the lids, burning, itching, and scaly skin. The underlying problem such as seborrheic dermatitis, or staph aureus should be treated. Staph infection often requires antibiotic therapy. Bacitracin ophthalmic ointment may be beneficial. For seborrheic blepharitis washing with baby shampoo, applying warm compresses, and using artificial tears if the eyes are dry. Pharmacies also have disposable eye scrub kits, with disposable pads.

    Conjunctivitis (“Pink Eye”): The membranes covering the sclera (the white part of the eye) and the inside lining of the eyelid, may be sensitive to chemical irritants, allergens, bacteria and viruses. Conjunctivitis also known as “pink eye” may be a sign of systemic disease or infection or may occur after an upper respiratory infection.

    Clinical presentation: one or both eyes may be itchy and feel as if they are burning. A clear, white, or yellow-greenish discharge may occur.

    Allergic conjunctivitis: Conjunctivitis may also be caused by allergic reaction. It is often seasonal and appears in both eyes at the same time. Itchy watery eyes and swelling of the eyelids accompany this condition. May see other allergy symptoms: runny nose, sneezing or scratchy throat.

    Treatment: if using antihistamine/decongestant eye drops do not use for more than 2 weeks. May also use oral antihistamines. May also use non-steroidal anti-inflammatory eye drops. Cold wet compresses will help decrease the itchy feeling.

    Treatment Goals: Remove or avoid allergen
    • Provide symptomatic relief-limit allergy reaction
    • Protect the ocular surface

    OVER THE COUNTER Pharmacologic Therapy:
    1st line: Artificial tears
    If symptoms persist: Ophthalmic antihistamine/mast cell stabilizer. If no resolution in 72 hours. Contact eye care practitioner.

    Nonpharmacologic Therapy
    • Do not wear contact lenses until resolved
    • Apply cold compresses 3-4 times a day
    • Causes: Pollen, Animal dander, topical eye preps
    Symptoms: Red eye with watery discharge, itching

    Ophthalmic Decongestants: Constrict conjunctival vessels reducing redness-Works on alpha-adrenergic receptors of ophthalmic vasculature
    • Phenylephrine
    • Oxymetazoline
    • Naphazoline
    • Tetrahydrozoline
    Ocular decongestant side effects:
    • Generally, do not have ocular or systemic side effects
    • Long-term use leads to potential for:
      • Rebound conjunctival hyperemia
      • Allergic blepharitis
      • Abnormal dryness
    Ophthalmic Antihistamines

    Mechanism: histamine1- receptor antagonists
    • Pheniramine maleate
    • Antazoline Phosphate
    • Available in combination with decongestants
      • Pheniramine/naphazoline
      • Pheniramine/naphazoline
    • More effective than using either agent alone
    Ophthalmic Antihistamines/mast cell stabilizers

    Ketotifen fumarate (Zaditor®) OTC
    • Potent H1-receptor antagonist
    • Mast cell degranulation inhibited; release of inflammatory mediators inhibited
    • Relief in minutes, lasting for 12 hours
    • Can use in children 3 years of age and older
    Olopatadine (Pataday®) (OTC) available in 2020. Previously Rx only

    Stabilizes the mast cells, blocking histamine release. Also blocks histamines that have already been released from attaching to the histamine (H1) receptors in the eye, breaking the chain of allergic reaction.
    • Olopatadine (Pataday®) Once Daily Relief 0.2% soln
      • Dosage: 1 drop in each eye every 24 hours.
    • Olopatadine (Pataday®) Twice Daily Relief 0.1% soln
      • Dosage: 1 drop in each eye every 12 hours.

    OTC alpha agonist Brimonidine: (Lumify 0.025%®) (Alphagan is Rx)
    • the first over-the-counter low-dose brimonidine tartrate ophthalmic solution for the treatment of ocular redness.
    • Adults and children 5 years of age and over: instill 1 drop in the affected eye(s) every 6-8 hours. do not use more than 4 times daily. Remove contact lenses before use.

    Eye care is one facet of pharmacy I really push with my student pharmacists, as most of us get minimal education on eye care. When I think how many pharmacy schools are attached to a top flight hospital offering ophthalmology residencies, I find it unfathomable that more focus is not spent on eye care. We had no lectures on eye care when I graduated 40 years, and many schools of pharmacy still do no extensive teaching of eye care.

    Have a Great Day on the Bench!!

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    verview of Dual Orexin Receptor Antagonists (DORAs): A New Agent Comes to Market!

    I have always been a good sleeper and early in my pharmacy career found the complaint of insomnia personally unrelatable, but I recognized that people who experienced it really seemed to suffer a terrible degree of unhappiness and great health consequences as they continued a never-ending search for the holy grail of restful sleep. Fast forward to now when I have joined the unfortunate membership of intermittent, but extreme, insomniacs. I can fall asleep just fine, but a random wake up around 1:00 am without escape back to sleep seems to be my new normal and I am not a happy camper! Some may blame disrupted sleep patterns with the shared altered human experience as a COVID consequence, but many factors play into insomnia and restoring sleep. There is a ton of information on non-pharmacologic interventions which can help without the need for further drug therapy, but many people in need of sleep relief seek what they consider to be the fastest solution in obtaining a magic pill to cure the downstream sleepless cycling stop.

    Sleep guidelines recommendations are intended to guide prescribers in choosing a specific pharmacological agent for treatment of insomnia in adults, when treatment is indicated. Insomnia disorder is as a complaint of either trouble initiating (delayed sleep onset) or maintaining sleep (or both) when given the opportunity to sleep, which is not otherwise attributable to environmental conditions and is associated with daytime consequences. When the symptoms have persisted for less than three months, it is considered short-term insomnia but is identified as chronic when it has persisted for at least three months at a frequency of at least three times per week1.

    Short-term insomnia is more common and affects 30% to 50% of the population compared to chronic insomnia disorder, which is estimated to be at least 5% to 10% but can occur more often in patients with co-occurring medical and psychiatric diagnoses. Insomnia is associated with numerous adverse effects on function, health, and quality of life, often with significant impairment in functional status as evidenced by increased rates of work absenteeism, occupational and motor vehicle accidents, development of psychiatric disorders, increased risk of relapse for depression and alcoholism, and increased risk for cardiovascular disease and development of hypertension (1). Insomnia is not a one size fits all diagnosis. It has a high degree of variability and consequences of which some people are more resilient and others more susceptible. Medications approved for sleep onset only are not appropriate or effective for enhancing sleep maintenance and thus must be clarified prior to making an appropriate recommendation for pharmacologic intervention. For example, if someone is only experiencing trouble falling asleep but can stay asleep, taking a medication for both deficits are unnecessary and in some cases, may result in a spillover effect with feelings of next day grogginess. One example of this is zolpidem immediate release versus controlled release. Only the controlled release is approved for both onset and maintenance whereas the immediate release is just to get you to fall asleep faster. Tis the story for the DORAs then…. these agents are approved for both, which likely meets most of the insomnia needs in our current population.

    Recommendations intended as a guideline for clinicians in choosing a specific pharmacological agent for treatment of chronic insomnia in adults are presented below (Table 1.). The authors of the guidelines report that although there were weak “grades” of evidence supporting them, guidelines disclosing a weak “grade” of evidence should not be construed as an indication of ineffectiveness. It is also important to consider age specific cautions when referring to guidelines, as the Beers list may add additional information when considering benefits versus risks to older adults who may be prescribed medications for insomnia2.

    Table 1. American Academy of Sleep Medicine Clinical Practice Guidelines1

    InterventionAASM (2017)
    1ST lineCognitive Behavioral Therapy (CBT)
    2ND lineFor sleep onset:
    ramelteon, triazolam, zaleplon
    For sleep maintenance:
    doxepin, suvorexant
    For both sleep onset and maintenance:
    eszopiclone, temazepam, zolpidem
    Other considerationsNot recommended for use:
    Diphenhydramine, L-tryptophan, melatonin, tiagabine, trazodone, valerian

    One of the newest agents arriving on scene are the dual orexin receptor antagonists (DORAs). The mechanism of action is considered novel in that it uses the orexin pathway to induce their sleep promoting effects by competitively binding with both orexin receptors in the lateral hypothalamus and reversibly blocking the action of orexin. Remember that orexin is a wake-promoting neurotransmitter so antagonism at that site makes a lot of sense, pharmacologically speaking of course. DORAs have been around a while now, with suvorexant (Belsomra®) being the first in class approved by the FDA in 2014 and now, the US Food and Drug Administration (FDA) has approved the DORA daridorexant (Quviviq®) for the treatment of insomnia in adults(3). Although daridorexant is too new to have made it specifically on the recommendation list, suvorexant represents the DORAs as a treatment only for sleep maintenance insomnia (versus no treatment) in adults, despite its FDA indication that includes sleep onset as well. The phase 3 trial for daridorexant measured daytime functioning using a new patient-reported outcome instrument called the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). And because previous trials of other DORAs did not use the IDSIQ as an outcome, it is not possible to compare daridorexant with the other agents within the class on that same specific outcome (3,4).

    What if you are recommending a DORA? Remember the most common side effects include drowsiness and headache, there are also more serious, less common concerns3,4:

    Worsening depression and suicidal thoughts. Patients should be advised to contact their healthcare provider immediately if they experience thoughts of suicide or dying or if there is a worsening of depression.

    Patients should be also advised to stop taking their DORA and contact their healthcare provider right away if they experience a complex sleep behavior.

    Complex sleep behaviors such as sleep-walking, sleep-driving, preparing, and eating food, making phone calls, having sex, or doing other activities while not fully awake that you may not remember the next morning.

    Sleep paralysis which is described as temporary inability to move or talk for up to several minutes and may include hallucinations when falling asleep or when waking up.

    So, let’s look at our case for consideration

    Sherry is a 45-year-old who was seen by primary care today for a routine annual physical exam. She reported that she has been feeling exhausted during the day, not exercising like she used to and is gaining weight. She works remotely from home since the pandemic started, but she finds she falls asleep while working on the computer. When she can stay awake, she has trouble concentrating on her work. She also reports that she has been trying to overcome this sleep problem by having a few glasses of wine in her hot tub at night daily during the workweek.

    So, what about Sherry?

    1. What should we consider before making a sleep recommendation for her?
      • a.What type of sleep complaint she is experiencing?
      • b.Whether beer provides the same relief as wine does
      • c.What type of computer she is using for her remote work at home?
      • d.If she has completed the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ)
    2. If Sherry asks for a DORA, what side effects would you warn her about?
      • a.She may develop hypertension
      • b.She should report any thoughts of suicide
      • c.She may experience caffeine-like wakefulness
      • d.She will likely have significant memory loss

    By understanding the options available and knowing the appropriate questions to ask, we are better poised to help the patient!

    (1) Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307–349.
    (2) 2019 American Geriatrics Society Beers Criteria® Update Expert Panel, Fick, D. M., Semla, T. P., Steinman, M., Beizer, J., Brandt, N., ... & Sandhu, S. (2019). American Geriatrics Society 2019 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. Journal of the American Geriatrics Society, 67(4), 674-694.
    (3) https://www.drugs.com/history/belsomra.html
    (4) https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf

    Welcome to my micro-CE mini-blog based on TLD’s BEST in the classroom series! If you haven’t already participated in these, please refer to my earlier submission if you want to catch up on what you may have missed!

    Tammy Lee Demler

    September 2022

    Micro-Learning CE Associated - Click Here For Details

    Drugs used to treat CENTRAL ACTING SPASTICITY:

    TIZANIDINE [Zanaflex® 2mg and? 4mg tablets; 2mg.4mg 6mg extended release capsules]????????? approved:1996

    Dosage: start with 4mg, increase gradually in 2 to?4mg steps.? May repeat every 6-8 hours. Maximum of 36mg per day. The effect peaks at 1-2 hours and dissipates in 3 to 6 hours

    Mechanism of action: Tizanidine is an alpha-2 receptor agonist. It reduces spasticity by increasing presynaptic inhibition of motor neurons and inhibiting pre-synaptic release of nor-epinephrine. It has no direct effect on skeletal muscle fibers. Reduces facilitation of spinal motor neurons. Tizanidine is a structural analog of clonidine.

    Indications for use: short term drug indicated for the management of spasticity. Because of the short duration of effect, treatment should be reserved for those daily activities when relief of spasticity is most important.

    Warnings/precautions/adverse effects:
    • Pregnancy category: C
    • Use with caution if renally impaired. Avoid if hepatic impaired.
    • Drug interactions: interacts with oral contraceptives, because tizanidine clearance is reduced by 50%.? Avoid use with other CYP1A2 inhibitors (e.g., cimetidine, oral contraceptives)
    • Hypotension (20% decrease in blood pressure)
    • Hepatotoxicity (usually reversible, rarely fatal)
    • Ciprofloxacin and fluvoxamine (Luvox®) contraindicated due to increased tizanidine levels.? This is a major drug interaction that should not be recklessly overridden.? Ciprofloxacin can increase tizanidine levels from 7-10 fold.
    • Withdrawal syndrome: hypertension, tachycardia, hypertonia
    Drug monitoring: Taper slowly for patients on high doses for long periods. May cause withdrawal and rebound hypertension, tachycardia, and hypertonia.

    • Effect is short-lived (3 to 6 hours); reserve for time relief most important
    • Food affects absorption, and affects tablets and capsules differently
    • Monitor liver function at baseline, 3 months, and 6 months, then periodically or as clinically indicated
    • Avoid in hepatic disease
    • Dose cautiously if creatinine clearance?<25 mL/min

    BACLOFEN [Lioresal®] 10mg and 20 mg tablets??? approved 1981

    Indications for use:
    • for signs and symptoms of spasticity resulting from multiple sclerosis 
    • for spasticity of cerebral origin and spinal cord origin
    Mechanism of action: Inhibits spinal reflexes; structural analog of gamma-aminobutyric acid (GABA)

    Dosage: 10mg three times daily, may be titrated upward until desired response. Dose range 40-80mg per day.? Some patients may require over 80mg/day. Drug is also given intrathecally.

    Adverse effects: do not discontinue abruptly to reduce risk of seizures
    • Drowsiness, dizziness and fatigue, hypotension.
    • Drowsiness, dizziness and fatigue, hypotension.
    Pregnancy category: C

    • Use caution in patients with epilepsy
    • May cause constipation, nausea and headache
    • Frequent urge to urinate or painful urination
    Patient Educations: discontinue very slowly. Avoid alcohol. Watch for drowsiness

    DANTROLENE (Dantrium®)? available as 25mg, 50mg and 100mg caps (1974)

    Indications for use:
    • Spasticity due to upper motor neuron disorders (spinal cord injury, cerebral palsy, multiple sclerosis)
    • Malignant hyperthermia prevention or management (from general anesthesia)
    Mechanism: ?Blocks ryanodine channel, which inhibits calcium release, thus reducing muscle contraction. Does NOT interfere with calcium entry at the cell surface as with Calcium Channel Blockers.

    Dose: titrate slowly from 25mg daily for 1 week, to a maximum of 100mg four times a day

    Adverse effects: hepatotoxicity- most common in women over 35 years of age. Dose dependent diarrhe


    Mechanism of action: potentiates the effects of GABA and other inhibitory transmitters

    Indications for use: useful adjunct for the relief of skeletal muscle pain due to reflex spasm due to local pathology; spasticity due to upper neuron disorders: (cerebral palsy, and paraplegia)

    NET EFFECT on the GABA receptor
    • Barbiturates increase the duration of chloride ion channel opening at the GABA receptor, to increase the efficacy of GABA.
    • Benzodiazepines increase the frequency of the chloride ion channel opening at the GABA receptor to increases the potency of GABA.
    Adverse Reactions: (General adverse reactions of Benzodiazepines)

    Central Nervous System: sedation and sleepiness, depression, lethargy, apathy, fatigue, hypoactivity, lightheadedness, memory impairment, disorientation, amnesia, restlessness, confusion, delirium, headache, slurred speech, stupor, coma, syncope, euphoria, irritability, difficulty in concentration, agitation, incoordination, vivid dreams, psychomotor retardation
    Dermatological: urticaria, hair loss, ankle, and facial edema
    GI:constipation, dry mouth, coated tongue, sore gums, change in appetite
    GUchange in libido, urinary retention? EYESnystagmus, diplopia
    PSYCHbehavioral problems, hysteria, suicidal tendencies
    MISCdiaphoresis, gynecomastia, may elevate liver enzymes, hepatic dysfunction, blood dyscrasias

    METABOLISM by P450: Lorazepam, Temazepam and Oxazepam are not metabolized by P450.? They are conjugated only.? Diazepam is metabolized by the CYP 450-3A4 enzyme system.? The metabolism of diazepam is intricate. Diazepam is first demethylated by CYP3A4 and CYP2C19 in the liver to nordiazepam, and hydroxylated by CYP3A4 to form the active metabolite temazepam. Increased benzodiazepine serum concentrations due to inhibition of Cytochrome P450 3A enzymes is a major problem with azole antifungals (may be a better choice for elderly)

    Patient information:
    • May cause drowsiness: avoid driving or other tasks requiring alertness
    • Avoid alcohol or other CNS depressants
    • May take with food or water if stomach upset occurs.
    Withdrawal concerns:
    • Relapse or rebound of condition being treated
    • Withdrawal symptoms: sweating, tachycardia, tremor, insomnia, anxiety, agitation, nausea, vomiting, hallucinations, and seizures.

    We community pharmacists dispense a lot of baclofen and tizanidine frequently with opioids, prescribed by pain clinics.? As we will discuss, central muscle relaxants, although not as problematic as the opioids, are not innocuous. The tizanidine and ciprofloxacin interaction scares me.? To have a ten-fold increase in the blood levels of tizanidine could cause a lot of serious adverse effects, especially dizziness and drowsiness.? When I think of tizanidine, I think of its big brother, clonidine.?The drowsiness, hypotension, and withdrawal hypertension are a concern with both drugs.? Also, in the tizanidine/clonidine family is (lofexedine (Lucemyra®) which is used for symptomatic management of opioid withdrawal.

    Have a Great Day on the Bench!!

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    Overview of Peripheral Muscle Relaxers

    DEFINITIONabnormal increase in muscle tone caused by the increased excitability of the muscle stretch reflex. Interferes with movement or causes pain.Involuntary muscle contractions
    ETIOLOGYCentral disorder of upper motor neuronsPeripheral muscle sprain or nerve compression
    CAUSESMS, Cerebral Palsy, Spinal Cord or Brain Injury, Motor Neuron Disease, or Post-Stroke SyndromeMusculoskeletal, Fibromyalgia, Herniated Disk, Mechanical Lower Back Pain, Spinal Stenosis, Sciatica, or Myofascial Pain
    FDA APPROVED MEDSbotulinum toxin baclofen (Lioresal®) dantrolene (Dantrium®) diazepam (Valium®) tizanidine (Zanaflex®) Carisoprodol (Soma®) Chlorzoxazone (Parafon®) Cyclobenzaprine (Flexeril®) Metaxalone (Skelaxin®) Methocarbamol (Robaxin®) Orphenadrine (Norflex®)

    CHLORZOXAZONE [Parafon Forte DSC® 500mg] (approved 1958)

    Dosage: 500mg three or four times daily

    Mechanism of action: acts at the level of the spinal cord and subcortical areas of the brain, where it inhibits multisynaptic reflex arcs involved in producing and maintaining skeletal muscle spasm of varied etiology.

    Indications for use: as an adjunct to rest, physical therapy and other measures.

    Warnings/precautions/adverse effects:
    • May cause drowsiness
    • Pregnancy Category-C
    Patient education:
    • Caution driving
    • Avoid alcohol
    • May cause reddish- purple urine!

    CYCLOBENZAPRINE (Flexeril®) (approved 1977)
    Dosage: 5mg to 10 mg three times daily. Use longer than 2 to 3 weeks is NOT recommended.

    Elderly: initiate dose of 5mg TID

    Mechanism of action: relieves skeletal muscle spasm of local origin without interfering with muscle function. Does not work with muscle spasm due to CNS disease. Acts principally in the CNS at the brainstem, and in the spinal cord.

    Indications for use: adjunct to rest and PT, for relief of muscle spasms with acute painful musculoskeletal conditions

    Warnings/precautions/adverse effects:
    • Pregnancy Category: B
    • Caution if patient has urinary retention or closed angle glaucoma (atropine like effects)
    Drug interactions:
    • life threatening with MAOI
    • Enhanced effects with alcohol, barbiturates and CNS depressants
    • Anticholinergic side effects: Use may be limited by anticholinergic side effects.
    Patient education: may cause drowsiness, dry mouth and dizziness.

    • Long half-life—caution in elderly.
    • Structurally related to amitriptyline
    • Has the most evidence for efficacy
    • Dose of 5 mg three times daily seems as effective as higher doses, with less side effects
    • Is approved for use in Canada for treatment of fibromyalgia

    ORPHENADRINE (Norflex® 100mg) (approved 1959

    Dosage: Norflex 100mg: 1 tablet twice daily every 12 hours

    Mechanism of action: has anticholinergic properties. Therapeutic benefits are due to analgesic properties. Is a structural analog of diphenhydramine (Benadryl), a first-generation antihistamine.

    Indications for use: adjunct to rest and physical therapy, for relief of muscle spasms with acute painful musculoskeletal conditions. Does not directly relax tense muscles.

    Warnings/precautions/adverse effects:
    • Pregnancy Category: C
    • Dizziness & lightheadedness
    • Anticholinergic effects
    Patient education: watch for drowsiness. Avoid alcohol. It is over the counter in Canada under the trade name Orfenace®

    CARISOPRODOL (Soma®) approved 1959
    250mg and 350mg tablets (Controlled Substance, Schedule-4)

    Dosage: 350mg four times daily. There is also a 250mg strength available, seldom used due to expense.

    Mechanism of action: produces muscle relaxation by blocking intraneuronal activity in the descending reticular formation and spinal cord. Onset of action is rapid and lasts 4 to 6 hours

    Indications for use: djunct to rest and PT, for relief of muscle spasms with acute painful musculoskeletal conditions. Mode of action may be due to sedative properties. Does not directly relax tense muscles.

    Warnings/precautions/adverse effects:
    • Additive effects with alcohol
    • Careful in hepatic or renal impairment
    • Tachycardia
    • Facial flushing
    • Can cause hiccoughs or hiccups
    Patient education: Watch for drowsiness, Caution driving. Take with food or meals.

    • Avoid alcohol.
    • Use drug with caution in addiction prone individuals. Metabolized to meprobamate. May see withdrawal symptoms on discontinuation.
    • Used to enhance opiate or tramadol effects, or lessen cocaine's stimulant effects
    • Dose cautiously in renal or liver impairment
    • European Medicines Agency withdrew from market, also withdrawn from market in Canada and Indonesia.

    METAXALONE [Skelaxin®] 800mg tablets approved 1962

    Dosage: 400mg to 800mg three to four times daily

    Mechanism of action: unknown, may be due to general CNS depression. No direct action on the muscle

    Indications for use: adjunct to rest and PT, for relief of muscle spasms with acute painful musculoskeletal conditions

    Warnings/precautions/adverse effects:
    • Caution if hepatic impairment
    • Alcohol enhances CNS depressant effects
    • Pregnancy Category-C
    Patient education: Watch for drowsiness. Caution Driving. Avoid alcohol

    • May cause less drowsiness than cyclobenzaprine.
    • Requires four times daily dosing and costs twenty times more.

    METHOCARBAMOL [Robaxin® 500mg and 750mg] (approved 1957)

    Dosage: initial dosage 1500mg four times daily—then 1000mg four times daily or 750 every 4 hours

    Mechanism of action: unknown, may be due to general CNS depression. No direct action on the muscle

    Indications for use: adjunct to rest and PT, for relief of muscle spasms with acute painful musculoskeletal conditions

    Warnings/precautions/adverse effects:
    • Avoid alcohol CNS depressants
    • Pregnancy Category: C have been reports of fetal abnormalities
    Patient education:
    • Watch for drowsiness, avoid alcohol, caution driving
    • May discolor urine brown- to dark green

    Most of the drugs in this class have been around as long as me…not since I started my professional career, but since I started breathing!! Many of these drugs are over 60 years old, and they have yet to elucidate the mechanism of action!

    For the most part, these drugs cause significant drowsiness, and should be administered with caution, especially if given with alcohol or opioids. All of these drugs, because of their anticholinergic effects, sedation, cognitive impairment, weakness, urine retention, and questionable efficacy at lower doses are on the Beers list, and should be avoided in the elderly.

    Have a Great Day on the Bench!!

    August 2022

    Micro-Learning CE Associated - Click Here For Details

    Rheumatoid Arthritis: Benefits and Risks of Pharmacological Therapy

    Objectives of Pharmacological Therapy:
    • To prevent or control joint damage
    • To prevent loss of function
    • To decrease pain
    • To control synovitis
    • To maintain patients’ quality of life
    • Avoid or minimize adverse effects of treatment

    Traditional Prescribing Sequence of Medications:

    Current treatment philosophy is an “inverted pyramid”, which refers to using aggressive therapy with DMARDS (disease modifying anti rheumatic drugs). Some patients immediately start out with DMARDS with or without NSAIDS (non-steroidal anti-inflammatory drugs). Others start out with NSAIDS, then starting DMARDS 3 months later. NSAIDS basically control symptoms until DMARDs take effect.

    DMARDS fall into two classes:
    • csDMARDS: “conventional synthetic” DMARDS (hydroxychloroquine, sulfasalazine, methotrexate)
    • bDMARDS: “biologic” DMARDS (adalimumab (Humira®), etanercept (Enbrel®), baricitnib (Olumiant®)
    Treatment in a Stepwise Fashion:
    • Step-1: Establish diagnosis of RA early. Document baseline disease activity. Estimate prognosis.
    • Step-2: Initiate therapy. Start DMARDS OR NSAIDS for 3 months then DMARDS. Consider local or low-dose steroids. Start PT and OT
    • Step-3: Reassess therapy and disease activity. Refer to rheumatologist if needed.
    • Step-4: Change DMARD if needed.
    • Step-5: Methotrexate consideration (1st if Rheumatologist)
    • Step-6: Add biologics (i.e., adalimumab, etanercept)
    • Treatment failure: Patients who fail to achieve remission within three to six months of initiating therapy or who require more than 5 mg/day of prednisone to maintain a state of remission should generally escalate to a more potent disease-modifying antirheumatic drug (possibly a biologic) or combination of DMARDs.
    BRIDGE THERAPY: Bridge therapy refers to the use of NSAIDS and corticosteroids while a patient is starting on DMARD. The onset of action for the DMARDS is prolonged thus anti-inflammatory drugs are given concurrently as a bridge until the therapeutic effect occurs. Includes corticosteroids, salicylates, Cox-2, and NSAIDS INDICATIONS FOR USE OF DISEASE MODIFYING ANTI-RHEUMATIC DRUGS (DMARDS)
    DMARDS or Biologic agents should be used in all patients EXCEPT:
    • Those with limited disease
    • -class IV disease where little reversibility of the disease is expected
    • DMARD Toxicity:
      • Acute hepatitis B or C is a contraindication to all DMARDs except hydroxychloroquine and sulfasalazine. American College of Rheumatology guidelines recommend testing for hepatitis B and C before starting leflunomide or methotrexate in patients at risk
      • Recommend checking for HIV in at-risk patients prior to methotrexate or biologic initiation.
      • Patients being considered for biologics, methotrexate, or leflunomide should be screened and treated for tuberculosis.
      • DMARDs should be held in the case of a serious bacterial or fungal infection, or herpes zoster infection.
      • Watch for endemic fungal infections such as histoplasmosis in patients receiving biologics.
      • • NSAIDS do not prevent joint erosions in RA perhaps due to limited role of prostaglandins play in the inflammatory cascade. This approach should be used only in patients with milder disease for no more than 3 months as monotherapy. May stay on NSAIDS if demonstrated satisfactory response.
      • Analgesic (opioids and others) do manage the pain, but do not modify disease progression. They are not to be used as monotherapy.
      • Occupational Therapy
      • Rest (relieves stress on inflamed joints. Prevents destruction.)
      • Physical Therapy
      • Assistive devices
      • Weight reduction
      • Surgery
      • (Azathioprine (Imuran®): used for refractory RA. Very toxic bone marrow suppression, stomatitis, alopecia, diarrhea, liver failure. Azathioprine causes bone marrow suppression and lowering of blood cell counts (white blood cells, red blood cells, and platelets) particularly in patients with renal insufficiency or when used concomitantly with allopurinol or ACE inhibitors. Azathioprine:allopurinol is a level-1 drug interaction and can cause fatal blood dyscrasias. Allopurinol blocks xanthine oxidase, one of the three enzymes that metabolizes azathioprine.
      • (Cyclosporine (Neoral®): blocks T-cell activation, powerful immunosuppressive effects. Cyclosporine also inhibits Interleuken-2 and therefore has some DMARD activity. Cyclosporine is typically used to prevent kidney and liver transplant rejection. Nephrotoxicity, glucose intolerance, hepatotoxicity and hypertension that might need to be treated.
      • Tofacitinib (Xeljanz®) cost $5071.63/60 tablets
        • Dose: 5mg tablet twice daily or ER-11mg once daily
      • Upadacitinib (Rinvoq®) cost $5529.78/ for 15 & 30mg tablets
        • Dose: 15mg once a day
      • Baricitinib (Olumiant®) cost=specialty pharmacy drug
      Mechanism: Janus kinases are enzymes linked to inflammation in joints and other tissues.

      Clinkcal use:JAK inhibitors are not a first line agent. Tried and failed on methotrexate. May ADD to methotrexate Works as well as TNF inhibitors but can NOT be used along with TNF inhibitors.

      Warnings/Precautions for JAK inhibitors:
      • MUST screen for tuberculosis.
      • Increases cholesterol, and liver enzymes. Check CBC, LFT, and lipids 1-2 months after initiating therapy
      • Sept 1,2021: FDA warning- There is an increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots, and death with JAK inhibitors.
      Efficiency: : patient response is variable. Monitor therapy accordingly. Some patients who don’t respond to one JAK inhibitor might get adequate response from another. Most JAK inhibitor patients have “been through the mill” having tried bio-DMARDS and other DMARDs.

      • Costs of these medications can be a real compliance issue.
      • Because these therapies can cost over $30,000 per year, insurance companies require prior authorization to ensure that the correct diagnosis is made, and the patient has failed on methotrexate.
      • The TNF require refrigeration and special storage. Proper injection technique is a must.
      ORAL GLUCOCORTICOIDS: Low dose corticosteroids (less than 10mg/day of prednisone –or equivalent) and local injections of glucocorticoids are highly effective in maintenance therapy for rheumatoid arthritis. Due to their inability to alter the course of RA, these agents are generally considered last line therapy. They may be useful for acute flare ups and in patients with significant systemic manifestations of RA. RA is associated with an increased risk of osteoporosis; INDEPENDENT of corticosteroid therapy and the addition of corticosteroids dramatically increase the risk.
      • Patients on glucocorticoids should receive 1500mg elemental Calcium per day, and 400-800iu Vitamin D per day.
      • Many of these patients are taking acid suppressing drugs like histamine-2 blockers or proton pump inhibitors, calcium citrate is a better option as it does not require acid for absorption.
      INTRA-ARTICULAR CORTICOSTEROIDS Depending on joint size, typical doses are 5 to 40mg of triamcinolone acetonide (or equivalent). Are effective in controlling local joint inflammation without changing the treatment regimen.
      • Minimize the frequency of local steroid injections whenever possible. Repeated injections may cause a painless joint destruction.
      • It is recommended that intraarticular joint injections be performed with intervals of at least 3 months to minimize these complications.
      • Rheumatologists recommend joint rest for 24 hours after injection, to decrease leakage, and systemic absorption.
      • Based on clinical signs and symptoms of improvement
      • Reduced joint swelling
      • Decreased warmth over actively involved joints
      • Decreased tenderness to joint palpitation
      • Decrease in perceived joint pain and morning stiffness
      • Longer time to onset of afternoon fatigue
      • Improvement of ability to perform ADL’s
      • Joint radiographs to assess progression of disease.
      • Show little or no evidence of progression if treatment is effective.
      • Lab monitoring is necessary to show the drugs are SAFE but are of little value to show response to therapy

      Several of my former physician assistant students have settled into practice in rheumatology. Rheumatology is a perfect discipline for a physician’s assistant. PA’s are skilled with following patients with slow progressive diseases, such as neurology and rheumatology

      One of the biggest challenges for a community pharmacist is that so many of the biologic DMARDS are available only after prior authorizations. More times than not, the insurance companies contract with, or have their own specialty pharmacies.

      Have a Great Day on the Bench!!

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    Overview of Treatment and Preventative Options for Osteoporosis

    Treatment and prevention with SERMs and PTH analogs
    The World Health Organization (WHO) defines osteoporosis as being present when BMD (bone mineral density) is 2.5 SD or more below the average value for young healthy women (a T-score of 2.5 SD). A second, higher threshold describes “low bone mass” or osteopenia as a T-score that lies between −1 and −2.5 SD. “Severe” or “established” osteoporosis denotes osteoporosis that has been defined in the presence of one or more documented fragility fractures. “Normal” is defined as being within 1 SD of the mean level for a young adult reference population, or a T-score of -1 or above.

    All osteoporosis drugs referred to as antiresorptive agents increase bone mass, but only alendronate, risedronate, zoledronic acid, estrogen + progesterone, denosumab (Prolia®) and romosozumab (Evenity®) are shown to decrease both vertebral and hip fractures. However, the efficacy of the remaining is only for vertebral fractures. Hip fractures cause increased morbidity, mortality, and healthcare costs as compared to vertebral fractures.

    By far and away, we dispense alendronate for the most used osteoporosis drug.? There are times when other osteoporosis drugs may be a better choice.? There are at least 6 different mechanisms of action for osteoporosis treatment/prevention.

    Raloxifene (Evista®)
    Available as tablets: 60mg??? available as a generic

    Dosage: 60mg once daily

    Mechanism: binds to estrogen receptors.? Binding results in activating some and blocking other pathways. Effects on bone similar to estrogen therapy.? However, it acts as an antagonist on receptors in the breast and endometrium. I refer to this drug as “estrogen light” as it mimics estrogen's beneficial effects on bone density in postmenopausal women, without some of the risks associated with estrogen.

    Indications for use: Postmenopausal osteoporosis (prevention & treatment). A 36-month study showed that 30% reduction in vertebral fractures.? However, there was not a significant difference in reduction of non-vertebral fractures versus placebo. Bisphosphonates are a better choice if hip fracture reduction is paramount.

    • Pregnancy: Category X
    • Contraindicated in history of venous thromboembolic events
    Adverse effects:
    • Venous thromboembolic potential (PE and DVT & stroke)
    • May cause hot flashes, leg cramps, joint/muscle pain
    Drug interactions?? (raloxifene): May decrease prothrombin time

    Patient education:
    • Discontinue raloxifene 72 hours prior to prolonged immobilization (including travel)
    • Not effective in reducing hot flashes.
    • Take with calcium and Vitamin D
    The STAR Trial: (Study of tamoxifen and raloxifene)
    • Raloxifene has been shown to be as effective as tamoxifen (Nolvadex®) in preventing invasive breast cancer, with fewer side effects.?
    • Both raloxifene and tamoxifen were equivalent in reducing the incidence of invasive breast cancer in post-menopausal women at increased risk for the disease by about 50% compared with expected incidence.? (There was no control arm in the STAR trial)
    • These drugs are given for a 5-year period, there the side effect profile becomes very important
    • Tamoxifen side effects include endometrial & uterine cancers, blood clots, strokes and cataracts.
    • Tamoxifen also increases menopausal symptoms (hot flashes) and minor gynecologic problems (vaginal dryness)
    Raloxifene was not as effective as tamoxifen in controlling the incidence of non-invasive breast cancers.? Tamoxifen is approved in both POST and PRE menopausal women.

    Teriparatide (Forteo®)? (PTH-134)
    ($4,200.00/month Aug-2017)???? approved 1987

    Subcutaneous injection once daily given in periumbilical region.

    Mechanism: while the usual role of PTH in calcium homeostasis is bone resorption, when given in daily subcutaneous injections, it actually exerts an anabolic effect, stimulating the activity of osteoblasts.

    Indications for use: Women with a history of osteoporotic fracture, multiple risk factors for fracture, have failed or intolerant of osteoporotic therapy. Reduces risk of vertebral and non-vertebral fractures in postmenopausal women. Increases vertebral and femoral neck BMD.? Does?not?prevent hip fractures.

    Warnings/Precautions: Osteosarcoma: don’t use in high-risk patients: Paget’s, skeletal radiation, unexplained elevations of alkaline phosphatase, and open epiphyses. Do not use in patients with bone metastases Watch renal function

    Adverse effects:
    • Metallic taste
    • Nausea, diarrhea, abdominal cramping
    • Paresthesias
    • Muscle pain
    • Drug interactions: using in combination with bisphosphonates impairs the ability of teriparatide to stimulate new bone formation.? Don’t use together.
    Patient education:
    • Must be?refrigerated?at all times.? Return to refrigerator promptly after each use.
      • If left out, you must contact Eli Lilly: 1-800-545-5979.? On a case-by-case basis they will help you determine if product left out of refrigeration can be used.? Must be clear, colorless and no particulates.
    • Subcutaneous injection once daily give in periumbilical region.
    • Contact provider if symptoms of hypercalcemia arise: Nausea, Vomiting, Constipation.
    • Use calcium, Vitamin-D and weight bearing exercise.
    • Be sure to prescribe pen-needles for administration
    • No risk for osteonecrosis of the jaw.

    Abaloparatide (Tymlos®)?80mcg once daily.? (2017)
    Mechanism, warnings, precautions are the same as teriparatide:
    Avoid in patients with pre-existing hypercalcemia or an underlying hypercalcemic disorder, (e.g., primary hyperparathyroidism)
    Warn patients that abaloparatide may cause orthostatic hypotension.
    • monitor urine calcium in patients with previous hypercalciuria or if kidney stones are suspected
    • Use for a maximum of 2 years due to dose-dependent risk of osteosarcoma in rats
    • 2-yr treatment course may be followed by bisphosphonate to maintain BMD.
    Patient education:
    • Must be refrigerated until first use, then may be kept at room temperature.
    • Subcutaneous injection once daily, given in the periumbilical region.
    • Contact provider if symptoms of hypercalcemia: Nausea, Vomiting, Constipation
    • Use calcium, Vitamin-D and weight bearing exercise.
    • Be sure to prescribe pen-needles for administration
    • No risk for osteonecrosis of the jaw.

    • Calcitonin salmon (Miacalcin®? nasal spray)??????????? (approved 1978)?
    • Fortical® nasal spray (recombinant) doesn’t have benzalkonium chloride?
    • One spray daily in alternating nostrils.???
    Mechanism: inhibits bone resorption by binding to osteoclasts.?

    Indications for use:?
    • Postmenopausal osteoporosis: (nasal spray and injection)?
    • Paget’s disease of the bone: injection only?
    • Hypercalcemia: injection only.?
    • Most feel this drug should be used in patients who cannot use a bisphosphonate, raloxifene, estrogen, denosumab, abaloparatide, or teriparatide.?
    • *Provides pain relief from compression fractures.?
    PROOF study? (Prevent Reoccurrence Of Osteoporotic Fracture)
    A significant reduction (33%) in vertebral fractures was observed, however there was no significant reduction in hip fractures.??
    Calcitonin may provide pain relief in acute fractures.? Because it is less effective than other osteoporotic medications it is used most often in patients with fracture pain, or for whom other therapy is unsuitable.? Calcitonin shows significant increases in BMD when combined with Vitamin-D

    Warnings/Precautions: Pregnancy Category-C?

    Adverse effects:
    • Rhinitis, epistaxis, nasal irritation & sinusitis
    • Salty taste?
    • Facial & hand flushing
    Drug interactions: Non-significant (may affect lithium levels)? Drug monitoring: Normal osteoporosis follow up? Patient education:
    • Store unit in refrigerator until needed.? Do not freeze.?
    • Assemble and prime, once at room temperature.?
    • After opening the bottle store at room temperature for 30 days. (Each bottle holds 30 doses)?
    New FDA Safety Evaluation: A meta-analysis of 21 random controlled trials with calcitonin-salmon (nasal spray and investigational oral forms) suggests an increased risk of malignancies in calcitonin-salmon treated patients compared to placebo-treated patients (4.1% vs 2.9%). The FDA found this non-significant and believes there is no conclusive evidence of a causal relationship between the use of these products and cancer and has chosen to keep calcitonin-salmon products on the market to provide options for those patients who cannot or do not want to use other treatments for osteoporosis. Health care professionals are urged to weigh the risks and benefits of all available treatments.???

    RANKL inhibitor:?

    Denosumab (Prolia®)????? ($1420.00/6months)?????????? approved 2010
    Injectable monoclonal antibody osteoporosis treatment?

    Mechanism: slows bone loss by inhibiting?rank ligand?which is a protein in the tumor necrosis factor family that's involved in bone breakdown.?Is as effective as bisphosphonates.?

    Adverse effects: higher risk of serious infections such as cellulitis, diverticulitis, and UTIs. May exacerbate pre-existing hypocalcemia.? Watch for increased infection.

    Dosage: 60 mg administered subcutaneously by a healthcare professional once every 6 months.

    Storage: REFRIGERATE.? Remove from refrigerator and let stand in room temperature for 15 to 30 minutes. Should be at room temperature (up to 25°C or 77°F) prior to injection.?

    Omosozumab-aqqg (Evenity; Amgen)?????? approved 2019
    Sclerostin inhibitor:?

    Indication: injection for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapies.?

    Mechanism: inhibits the action of sclerostin, a regulatory factor in bone metabolism. This allows the drug to rapidly increase?bone formation?and, to a lesser extent, decrease bone resorption.?

    Dose: once a month. As the anabolic effect wanes after 12 monthly doses of therapy, duration of therapy should be limited to 12 monthly doses; treatment with an antiresorptive drug (bisphosphonate) should be considered if continued osteoporosis therapy is needed.?

    • Do NOT use if patient has had myocardial infarction or stroke.?
    • Avoid in patients susceptible to osteonecrosis of the jaw.?

    Suggested daily doses for Osteoporosis:?
    • Conjugated Estrogens (Premarin®) 0.625?
    • Ethinyl Estradiol? 0.02mg?
    • Estropipate: 0.625mg?
    • Micronized Estradiol: 1mg?
    • Transdermal estradiol: 0.05mg/day?
    Remember, estrogen therapy should be used ONLY for relief of vasomotor symptoms, at the LOWEST possible dose for the SHORTEST period of time!

    Vitamin D is required for absorption of Calcium from gut.?
    Normal dosage 400-800iu per day. Experts are recommending 1000iu-2000iu, especially necessary in the nursing home environment.?

    Remember that calcium citrate is the best option for elderly with poor stomach acid secretion, or any patient on H2RA or Proton pump inhibitors.? Also, calcium citrate is the best option for gastric bypass patients.

    About 16?years ago I had two patients, a husband and wife who attended our church.? He was a bright man, read the Wall Street Journal every morning and took care of his wife.? She had COPD and was on oxygen therapy. He cooked, shopped, cleaned the house did all the family finances and was one of the most personable guys you would ever want to meet.? He was meticulous about her care, making sure her oxygen was set just right, there were no obstacles on the floor, and did everything to keep her safe.

    One morning while getting her breakfast he tripped over her oxygen hose and crashed to the ground.? He called his son to come over and help him up, stating it was a “bad bruise”.? His son called for an ambulance, and he was taken to the hospital where he was diagnosed with a fractured hip.?

    He had surgery and moved to a nursing home, where he died six months later.? His sickly wife that he so meticulously cared for outlived him by 3 years. Safety in the home is as important as drug therapy; a broken hip can lead to a nursing home stay, decreased quality of life and early death.

    Have a Great Day on the Bench!!

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    Overview of Osteoporosis
    According to the American Family Physician, one fourth of elderly persons who sustain a hip fracture will die within six months of the injury, more than 50 percent of older adults who survive a hip fracture are discharged to nursing homes, and nearly half of that population will still reside in a nursing home a year later. Deaths can be due to pulmonary embolism, infection and heart failure.

    Prevention is key in keeping our baby boomers out of the hospital. Strengthening and fall prevention must be stressed.?

    Environmental adjustments to reduce fall risk:
    • Floor coverings
    • Grab bars in bathroom
    • Showers are safer than tubs
    • Increased lighting
    • Handrails on steps—both sides.
    • Use of a cane/ walker rollator for stability
    Exercise:? in 2 studies, one hour of walking and running 2 or 3 times a week significantly increased the lumbar spine bone mass.

    Weight-bearing, aerobic, and strength training all help to strengthen bone and increase bone mineral density (BMD). Remember, Wolff’s Law!!

    • Osteoporosis: a disorder of compromised bone strength causing an increased risk of fragility fractures
    • Osteopenia: reduced bone mass due to a decrease in the rate of osteoid synthesis to a level insufficient to compensate normal bone lysis
    • Osteomalacia: a condition marked by softening of the bones due to impaired mineralization, usually resulting from deficiency of Vitamin-D and calcium
    • Osteoblast:?a cell which arises from a fibroblast, and as it matures is associated with the production of bone. Osteoblasts?build bones.
    • Osteoclasts: a large multinuclear cell associated with the absorption and removal of bone. Osteoclasts?chip bones.
    Pharmacological Prevention of Osteoporosis- BISPHOSPHONATES Mechanism: inhibits osteoclast activity.? Must be continuously administered to suppress the osteoclasts on newly formed resorption surfaces.? It reduces bone turnover, causing bone formation to exceed bone resorption at the remodeling sites. Thus, there is progressive gain in bone mass. Indications for use:
    • Osteoporosis in post-menopausal women
    • Increase bone mass in men
    • Glucocorticoid induced osteoporosis
    • Paget’s disease of the bone
    • Severe erosive esophagitis Pregnancy Category-C
    • AVOID: Renal insufficiency—do not use if CrCl is less than 35mL/minute
    • Inability for patient to sit erect for 30 minutes
    Drug interactions for oral bisphosphonates: NSAIDS and Aspirin may increase potential for GI bleeding
    Patient education (bisphosphonates)
    • Take with at least 8oz of water, 30 minutes prior to the first meal of the day.
    • Remain upright for at least 30 minutes after ingestion; 60 minutes for ibandronate.
    • Calcium supplementation: is required for maximal benefit.
    Alendronate (Fosamax®)?approved Sept 1995 Available as:? ????
    • 5mg, 10mg, and 40mg tablets?? ? (daily dosing)
    • 35mg & 70mg in a 4-tablet pack (weekly dosing)
    • available with Vitamin D (Fosamax + D)
    **Male or Female Osteoporosis: ?70mg weekly?? (rarely: 10 mg/day)

    **Osteoporosis-Post menopausal women:? 35mg/week (rarely: 5 mg/day) Paget’s disease of the bone: 40mg/day for 6 months Glucocorticoid induced osteoporosis: 5mg/day?? (10mg/day post-menopausal women without estrogen)

    Risedronate (Actonel®)??????(approved March 1998)??generically available
    Available as: (most common dosing)
    • 35mg in a 4-tablet blister pack for weekly dosing.
    • Actonel 150mg one tablet once a month

    How long to use bisphosphonates?
    FLEX study: Many women when therapy of alendronate for was stopped for up to?five years?does not appear to significantly increase nonvertebral fracture risk. Women at very high risk of clinical vertebral fractures may benefit from continuing alendronate beyond five years.

    Osteonecrois of the jaw (ONJ) due to bisphosphonates: 94% of cases are in cancer patients getting prolonged therapy with IV zoledronic acid (Zometa®) or pamidronic acid (Aredia®)
    (IV bisphosphonates used for hypercalcemia of malignancy)
    • Most cases occur after dental work that traumatizes the jaw (extractions, etc.)
    • Incidence is less than 1/100,000 if taking oral bisphosphonates
    Prevention: recommend dental exam and any necessary procedures 3 months before beginning bisphosphonate therapy
    • Good dental hygiene
    • Inform dentist you are taking bisphosphonates
    • Avoiding any elective jaw procedure
    • Baseline and routine dental exams including panoramic jaw radiography
    • Delaying bisphosphonate therapy, if risk factors allow, to complete dental procedures for teeth or dental structures with poor prognosis
    • Educating patients about the importance of good oral hygiene, symptom reporting, and regularly scheduled dental assessments1
    Patients already receiving bisphosphonates should:
    • Maintain excellent oral hygiene and have routine dental examinations
    • Obtain routine dental cleanings (require careful attention to avoid soft-tissue injury)
    • Have aggressive nonsurgical management of any dental infection
    • Have root canal treatment if needed rather than dental extraction when possible

    I remember all of the fanfare when alendronate (Fosamax®) hit the market in the 1990’s.? Alendronate has been a game changer indeed, keeping bones strong and patients out of the nursing home. ?Physical therapists are extremely valuable in getting patients to exercise within their abilities.

    I always talk about Wolff’s Law, when discussing osteoporosis. In the late 19th century, German surgeon Julius Wolff described bone remodeling and how it relates to the stress placed on bones. According to Wolff, bones will adapt according to the demands placed on them.? Bones will grow in the direction to oppose the force put on them.? Exercise accelerates bone healing and strengthening. As our Baby Boomers continue to age, we will be seeing an increased need to offer preventative strategies to prevent nursing home admissions.?

    Have a Great Day on the Bench!!

    July 2022

    Micro-Learning CE Associated - Click Here For Details

    Overview of Prolactin and Adrenal Hormones

    The Hypothalamus
    The hypothalamus is the “governor” of the pituitary gland. It precisely releases stimulating hormones that cause hormone release from the pituitary. These hormones influence the endocrine glands in our body.
    • Feedback Mechanism – end product inhibition tightly controls hypothalamic and pituitary gland hormone release
    • Negative feedback – in homeostasis where the first hormone in a pathway is shut off by the last hormone or product in a pathway
    • The usual normal range for serum prolactin is approximately 5 to 20 ng/mL
    • Release of prolactin is caused by serotonin, acetylcholine, opiates, and estrogens
    • Inhibition of prolactin release is caused by dopamine. Any drugs that block dopamine are expected to cause hyperprolactinemia.

    Drugs that block dopamine:
    • Metoclopramide (Reglan®)
    • First generation antipsychotics
    • Risperidone (Risperdal) and Paliperidone (Invega®): can elevate prolactin levels up to 300 or even 400 ng/mL
    • Remember too, that these dopamine blockers may cause/exacerbate Parkinson’s symptoms
    Drugs that stimulate prolactin:
    • SSRIs (selective serotonin reuptake inhibitors): fluoxetine, sertraline, fluvoxamine, citalopram (slight)
    • Estrogens (increasing levels of estrogen in late pregnancy appears to be responsible for elevated prolactin levels that prepare the mammary gland for lactation at end of gestation)
    • Cimetidine (Tagamet®) – antiulcer medication
    • Opioids (narcotics – codeine, hydrocodone, etc.)

    In men, elevated prolactin levels are associated with decreased libido, infertility, erectile dysfunction, gynecomastia, and, rarely, galactorrhea.

    In post-menopausal women, because they are already hypogonadal, a prolactinproducing adenoma needs to become large enough to cause headaches or impair vision for most to be detected. In premenopausal women, excess prolactin can lead to menstrual cycle irregularities and infertility. Hyperprolactinemia accounts for 10-20% of the cases of amenorrhea.

    Prolactinomas: Prolactinomas account for 40% of all pituitary adenomas but, with an incidence of only 60-100 cases per million, they are considered a rare disease. Treatment is usually essential when the tumor is large enough to cause neurologic symptoms, such as visual impairment or headache. Dopamine agonists decrease the size of the prolactinoma, as well as decreasing prolactin secretion.

    Prolactin function:
    • During pregnancy, prolactin levels rise to above normal levels
    • Prolactin induces lobuloalveolar growth of the mammary gland
    • Prolactin stimulates lactogenesis after giving birth
    • All other conditions where prolactin levels are in excess (hyperprolactinemia), are considered to be pathologic
    Prolactin as a Diagnostic Test: elevated serum prolactin may be helpful in differentiating generalized tonic-clonic and focal seizures from psychogenic nonepileptic seizures in adults and older children. A low serum prolactin does not exclude epileptic seizure, although it lowers the likelihood of an epileptic seizure if the event appeared to be a generalized tonic-clonic seizure.

    Pharmacotherapy with dopamine agonists is VERY effective in normalizing serum prolactin levels, in restoring menstruation and reducing tumor size in 70-100% of the affected patients within 3-6 months of therapy.
    • Bromocriptine (Parlodel®) – ergot alkaloid
      • Dosed twice a day (2.5mg and 5mg twice daily)
      • First drug used for the treatment of hyperprolactinemia
      • Causes more nausea and is usually considered second-line
      • Because it is an ergot alkaloid, cardiac valvular disease can occur and should be monitored
    • Cabergoline (Dostinex®) – ergot derived
      • Dosed once a week
      • Less nausea
      • Long acting and has become the agent of choice for hyperprolactinemia
      • Cardiovascular evaluation should be performed, and echocardiography should be considered to assess for valvular disease, especially if over 2mg per week. (May be attributed to cabergoline’s affinity for serotonin receptors on cardiac valves.)
    • Ropinirole (Requip®) and pramipexole (Mirapex®) – non-ergot dopamine agonists
      • Commonly used for the treatment of restless legs syndrome and Parkinson’s disease

    The Adrenal Gland
    The adrenal cortex can be divided into 3 distinct layers of tissue based on their organization:
    NameLayerPrimary Product
    Zona glomerulosaMost superficial cortical layerMineralocorticoids (aldosterone)
    Zona fasiculataMiddle cortical layerGlucocorticoids (cortisol)
    Zona reticularisDeepest cortical layerWeak androgens

    Conditions treated with systemic glucocorticosteroids:
    • Allergic diseases
    • Collagen diseases
    • Dermatologic diseases
    • Edematous states
    • Endocrine disorders: primary or secondary adrenal cortical insufficiency
    • GI diseases
    • Hematologic disorders
    • Neoplastic diseases
    • Nervous system
    • Ophthalmic
    • Respiratory
    • Rheumatic disorders
    Action: Natural occurring adrenocortical steroids have both anti-inflammatory (glucocorticoid) and salt retaining (mineralocorticoid) activities. They modify the body’s response to diverse stimuli.

    • Hydrocortisone (cortisol) and cortisone used for replacement therapy
    • Prednisone, primarily used for glucocorticoid effect (has mineral effect too)
    • Fludrocortisone (Florinef®) primarily used for mineralocorticoid effect
    • Triamcinolone, dexamethasone, methylprednisolone, betamethasone: marked glucocorticoid activity. Potent anti-inflammatory drugs.
  • Prolonged therapy of pharmacologic doses may lead to hypothalamicpituitary- adrenal suppression
    • Abrupt discontinuation may lead to a withdrawal syndrome without evidence of adrenal insufficiency. To minimize morbidity associated with adrenal insufficiency, gradually taper dose.
    Symptoms of adrenal insufficiency:
    • Nausea, fatigue, anorexia, dyspnea, HYPOtension, hypoglycemia, myalgia, fever, malaise, arthralgia dizziness, desquamation of the skin, fainting

    Trivia fact: Oral prednisolone is usually used in horses and cats since they can't convert the prednisone as easily as dogs can. Prednisone gets activated to prednisolone in the liver in humans.

    Most Common Adverse Effects of Corticosteroids
    Side effects:
    • Infection: mask signs of infections
    • Ocular effects
    • Osteoporosis (inhibits calcium absorption)
    • Weight increase
    • Edema
    • Elevates blood sugars (monitor diabetics)
    • Thin fragile skin, impaired healing, hirsutism
    • Suppression of growth in children (long term)
    • Sodium and fluid retention
    • GI upset, increased appetite, weight gain
    • Muscle weakness (steroid mypoathy)
    • Eyes: increase IOP (intra ocular pressure), cataracts
    • Stomach ulcers
    • Hypokalemia
    • Emotional labiality
    • Systemic fungal infection
    • Live virus vaccines
    • Caution with immunosuppressed patients
    • Active TB cases can reactivate disease

    Preventing and Decreasing Adverse Effects of Glucocorticosteroids
    • Take with food or snack
    • Watch for signs of adrenal insufficiency.
    • Taper dose
      • Adults who get up to 60 mg/day of prednisone for 10 days or less don't need tapering
      • Adrenal suppression usually doesn't occur until patients take prednisone 40 mg/day for more than 2 weeks. Taper patients taking more than 20 mg/day of prednisone for longer than 3 weeks to prevent adrenal problems.
      • Tapering is necessary for patients who have been on chronic oral corticosteroids
    • Use glucocorticoids for shortest amount of time. Use intermediate acting glucocorticoids to minimize the risk of adrenal suppression. Prednisone every OTHER day if long term.
    • Use only if absolutely necessary.
    • Nasal and inhaled corticosteroids cause minimal adrenal suppression. (Betamethasone is worst)
    Glucocorticoid Equivalencies
    Short ActingEquivalent potencyAnti-inflammatory potencySodium retaining
    Cortisone (Cortone®)25mg0.82
    Hydrocortisone or Cortisol (Cortef®)20mg12
    Intermediate acting
    Prednisone (Deltasone®)5mg41
    Prednisolone (Prelone®)5mg41
    Triamcinolone (Aristocort® or Kenalog®)4mg50
    Methylprednisolone (Medrol®)4mg50
    Long acting
    Dexamethasone (Decadron®).75mg20-300
    Betamethasone (Celestone®).6mg20-30o

    Key points about mineralocorticoid activity:
    • When given at regular doses, triamcinolone, dexamethasone, and betamethasone have no clinically important mineralocorticoid activity. They would never be used for Addison’s Disease.
    • 20mg hydrocortisone and 25mg of cortisone acetate each provide a mineralocorticoid effect that is approximately equivalent to 0.1 mg fludrocortisone. Hydrocortisone (Cortef®) is most commonly used for Addison’s Disease.
    • Prednisone or prednisolone given at anti-inflammatory doses ≥50 mg per day provides a mineralocorticoid effect that is approximately equivalent to 0.1 mg of fludrocortisone
    Pharmacological Treatment of Poison Ivy with Oral Corticosteroids:
    • Oral prednisone: 0.5 to 2mg/kg/day tapered over 14- to 21-day period
    • Medrol dosepak (6-day therapy) is not long enough of duration
      • “rebound dermatitis”
    • Sterapred DS® – 10mg begins with a 60mg dose and is tapered over 12 days is acceptable

    There are other pituitary hormones, such as oxytocin, thyroid stimulating, luteinizing hormone, follicle stimulating hormones, etc. Not many medications in the community pharmacy arena apply to these hormones. Prolactin, however, warrants closer examination, because so many drugs we dispense on a daily basis affect prolactin.

    I once had a lactation nurse at the hospital call in a prescription for metoclopramide for a nursing mother, to assist with her milk “letdown.” I also remember a while ago when bromocriptine was used to help “dry up” mothers who would be formula feeding their newborn. Once we understand the mechanisms of action of these drugs, it makes sense how we can use them for other than their common indications.

    Have a Great Day on the Bench!!

    June 2022

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    Seasonal Allergies are coming At-Choo Soon

    Key Terms
    • Anticholinergics: act locally on nasal mucosa to inhibit serous and seromucous gland secretions
    • Antihistamines: selectively block peripheral histamine-1 receptors, to minimize response to triggers
    • IgE: immunoglobulin E, antibodies produced by the immune system as part of the body’s defense against specific triggers
    • Leukotriene receptor antagonists: inhibits activation of receptors that are correlated with pathophysiology of asthma, airway edema, smooth muscle contraction, and inflammatory responses
    • Mast cell stabilizers:act locally to reduce histamine degranulation from mast cells
    • Rhinitis medicamentosa: chronic nasal congestion associated with overuse of vasoconstrictor nasal medications, sometimes referred to as “rebound” nasal congestion
    Shifting Trends
    Springtime brings with it warmer weather, baseball games, and budding trees. In the Fall, we enjoy Friday night football games and pumpkin-flavored everything. For many, these seasonal changes also bring unrelenting watery eyes, runny noses, and scratchy throats. And it is only getting worse.

    In 2010, the Asthma and Allergy Foundation of America (jointly with the National Wildlife Federation) released a report on the effect of a warming climate on allergies and asthma.1 Ragweed is the chief Fall trigger for many patients’ allergies. According to the report, it grows faster and produces more pollen in an environment with more carbon dioxide. Longer growing seasons as a result of warmer weather allow ragweed plants to grow larger, releasing more pollen. In the Spring, budding trees and flowers are the primary pollen producers. A warmer climate means their habitat will expand to previously inhospitable areas. Fungal allergens, too, could be more problematic as the planet warms.

    Review of Allergic Pathophysiology
    Allergic rhinitis is characterized by sneezing, runny nose, nasal obstruction, and often accompanied by itchy, watery eyes. The physiological response to seasonal allergens is an IgE antibody-mediated inflammatory response.2 The severity of this response can be mild to severe and varies with trigger type, the extent of exposure, and patient-specific factors.

    The Pharmacist’s Role in Treating Seasonal Allergies
    Allergic rhinitis is likely a condition that affects many of your patients. Indeed, surveys indicate physician-diagnosed allergic rhinitis affects upwards of 20% of adults and 13% of children in the United States. The functional and economic toll of seasonal allergies is immense. Impaired physical and social functioning and daytime somnolence can lead to lost days of work and lower quality of life.

    As patients reach for over-the-counter allergy medications, the incidence of potentially harmful drug interactions increases as well. It is in this capacity that pharmacists can play a key role in alleviating patients’ symptoms while helping them minimize the effects of medications.

    Cornerstones of Treatment for Seasonal Allergies
    The most common medications used to treat allergic conditions are antihistamines, decongestants, and glucocorticoids. Leukotriene inhibitors, mast cell stabilizers, and anticholinergics can be useful in some cases, too. In recommending a medication to a patient, we should maximize symptom reduction and improve patient productivity while minimizing adverse effects and drug-drug interactions. The latest treatment guidelines were published in 2020 by the American Academy of Allergy, Asthma, and Immunology (AAAAI).3

    Oral antihistamines have long been the standard for seasonal allergies. They can be used proactively to minimize symptoms prior to trigger exposure, or reactively post-exposure. First-generation agents tend to be more sedating and require multiple daily doses. Second-generation agents, conversely, tend to cause less sedation and are taken once daily. These second-generation agents are sometimes called “non-sedating” antihistamines, but a more accurate label is “less-sedating.” Medications in both generations are available without a prescription.

    Oral AntihistaminesGenerationRecommended Adult Dose
    (≥12 years)
    Recommended Pediatric Dose
    (6≥11 years)
    Chlorpheniramine14mg every 4-6 hours2mg every 4-6 hours
    Clemastine fumarate11.34mg BID, or 2.68mg daily0.67mg BID, or 1.34mg daily
    Diphenhydramine125mg every 4-6 hoursNot recommended3
    Hydroxyzine110-25mg at bedtime12.5-25mg at bedtime
    Triprolidine12.5mg every 4-6 hours1.25mg every 4-6 hours
    Cetirizine (Zyrtec®)210mg daily5-10mg daily
    Desloratadine (Clarinex®)25mg daily2.5mg daily
    Fexofenadine (Allegra®)260mg BID, or 180mg daily30mg BID, or 60mg daily
    Levocetirizine (Xyzal®)25mg daily2.5mg daily
    Loratadine (Claritin®)25mg BID, or 10mg daily5-10mg daily

    Many of the agents listed above (and several other medications) are also available in ophthalmic and nasal dosage forms. The topical formulations generally cause little to no sedation. With all antihistamines, it is important that the patient use caution when drug-induced sedation would interfere with activities.

    Nasal steroids are now the gold standard for allergic rhinitis. They are the single most effective maintenance therapy and cause very few adverse effects. They can successfully treat both nasal and ophthalmic symptoms of seasonal allergies. Antihistamines often do little to relieve allergic nasal congestion; nasal steroids are particularly effective in these cases. Many of nasal steroids are available over the counter. The choice of agent is generally patient preference. Dose and frequency of these agents is product specific. Generally, though, the recommended dose for most products is 1 or 2 inhalations in both nostrils once or twice daily.

    It is important that patients be counseled on correct dosing technique with nasal steroids. Proper positioning of the head will ensure the medication is distributed to the nasal tissues rather than draining down the throat. The patient should tilt the head slightly downward, while pointing the spray upward, away from the septum.

    Older, first-generation agents are associated with higher systemic bioavailability. Second-generation agents are typically undetectable at the systemic level, which is preferable especially for children and when using year-round. The maximum effect of nasal steroids usually arrives after one to two weeks of daily use. In the interim, oral antihistamines can be used concurrently to treat allergy symptoms.

    Nasal SteroidGenerationOTC/Rx
    Beclomethasone (Beconase®, Qnasl®)1Rx
    Budesonide (Rhinocort®)1OTC
    Flunisolide (Nasarel®)1Rx
    Triamcinolone (Nasacort®)1Rx and OTC
    Ciclesonide (Omnaris®, Zetonna®)2Rx
    Fluticasone furoate (Flonase Sensimist®)2OTC
    Fluticasone propionate (Flonase®)2Rx and OTC
    Mometasone (Nasonex®)2Rx

    Two of the above products – beclomethasone and ciclesonide – are delivered via dry aerosol. This delivery form may be preferable for patients put off by the scent or taste effects of the other aqueous solutions.

    Anticholinergics and Mast Cell Stabilizers
    The anticholinergic ipratropium bromide, in nasal spray form, can be useful for treating rhinorrhea (runny nose), but it is still less effective than the nasal glucocorticoids for sneezing, itching, and nasal obstruction.4 If runny nose is still not well controlled on nasal steroids, it can be used concurrently. Ipratropium requires frequent dosing. Because of its inferiority to nasal steroids, ipratropium is not considered first-line treatment for seasonal allergies.

    Cromolyn sodium, a mast cell stabilizer, is particularly useful for people who have episodic symptoms that can be anticipated. For example, a patient who is allergic to cats can use cromolyn nasal spray about 30 minutes prior to visiting a friend who has a cat to minimize nasal allergen triggering. In the same way, cromolyn can be initiated 1-2 weeks prior to environmental pollen peaks as a prophylactic measure. This agent does require frequent daily dosing when used for seasonal allergies. Cromolyn is also considered second-line treatment to nasal steroids but can be useful when other agents are not- well tolerated.5

    Second-Line AgentsOTC/RxTypical Dose and Frequency
    Ipratropium (Atrovent Nasal®)Rx2 sprays in each nostril 2-3 times daily
    Cromolyn (NasalCrom®)OTC1 spray in each nostril 3-4 times daily

    Nasal Decongestants
    Nasal decongestants work by causing local vasoconstriction. Phenylephrine, oxymetazoline, xylometazoline, and naphazoline are the agents in this class. While they are very effective for nasal congestion, they are not recommended for allergic rhinitis monotherapy. Chronic use of nasal decongestants can give rise to rhinitis medicamentosa or “rebound” congestion. Downregulation of alpha-adrenergic receptors in the nasal tissues can occur in as little as 3 days of use. Patients who use nasal decongestants frequently often find themselves in a cycle of nasal congestion both caused by and relieved by the medication. Therefore, patients should be warned against using any of these singly agents for more than 72 hours.

    Patients with congestion-dominant seasonal nasal symptoms may find benefit from a combination of once-daily nasal steroid plus the long-acting nasal decongestant agent oxymetazoline. A study that evaluated this combination found that nasal symptoms were less than in the placebo group, and even less in the group using a steroid alone.6 Moreover, the study found that the once-daily dosing with the steroid did not bring on rhinitis medicamentosa. Still, it is still advisable to discontinue use of a nasal decongestant once symptoms are well-controlled.

    Leukotriene Receptor Antagonists
    One medication in this class, montelukast (Singulair®), was used for patients who could not tolerate nasal sprays. However, recent trials revealed troubling neuropsychiatric changes associated with the drug. As a result, the FDA issued a boxed warning for montelukast, citing its link to insomnia, anxiety, depression, and suicidal ideation.7, 8 With this new information, the risk/benefit ratio of montelukast increased significantly. Given the number of other safer alternatives for treating seasonal allergies, montelukast (and other agents in its class) should be avoided.

    When to Refer at Patient to a Specialist
    If a patient fails multiple courses of the recommended agents, an evaluation for non-allergic etiologies is advisable. A specialist should rule out other conditions before initiating allergen immunotherapy. Adult and pediatric patients who have prolonged, severe symptoms, co-existing asthma or nasal polyps should also be referred for further evaluation.

    Seasonal allergy symptoms and allergic rhinitis are very common conditions, affecting 10-30 percent of adults and children in industrialized countries. Prevalence is increasing. Medications to treat allergic nasal symptoms are numerous, many available without a prescription. As such, pharmacists play a key role in advising patients on safe use of these medications.

    The treatment of choice for most patients is a nasal glucocorticoid. These agents offer safety, minimal systemic absorption, convenient once-daily dosing, and over-the-counter availability. Nasal steroids can also be combined with oral antihistamines when symptoms are most severe. For some patients, targeted therapy with ipratropium or cromolyn may be beneficial. Nasal decongestants offer some short-term relief but should be used very cautiously – and briefly – to avoid “rebound” vasoconstriction. Recent warnings about serious neuropsychiatric adverse effects of leukotriene receptor antagonists have taken montelukast off the recommended list of allergy treatments. If patients have other pulmonary conditions, or fail multiple trials of the standard agents, an immunologist or otolaryngologist consult is warranted.

    • National Wildlife Federation. Extreme Allergies and Global Warming.; 2010. Accessed March 22, 2022. https://www.aafa.org/media/1634/extreme-allergies-global-warming-report-2010.pdf
    • Dykewicz MS, Wallace DV, Baroody F, et al. Treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2017;119(6):489-511.e41. doi:10.1016/j.anai.2017.08.012
    • Dykewicz MS, Wallace DV, Amrol DJ, et al. Rhinitis 2020: A practice parameter update. J Allergy Clin Immunol. 2020;146(4):721-767. doi:10.1016/j.jaci.2020.07.007
    • Milgrom H, Biondi R, Georgitis JW, et al. Comparison of ipratropium bromide 0.03% with beclomethasone dipropionate in the treatment of perennial rhinitis in children. Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol. 1999;83(2):105-111. doi:10.1016/S1081- 1206(10)62620-8
    • Pitsios C, Papadopoulos D, Kompoti E, et al. Efficacy and safety of mometasone furoate vs nedocromil sodium as prophylactic treatment for moderate/severe seasonal allergic rhinitis. Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol. 2006;96(5):673-678. doi:10.1016/S1081-1206(10)61064-2
    • Baroody FM, Brown D, Gavanescu L, DeTineo M, Naclerio RM. Oxymetazoline adds to the effectiveness of fluticasone furoate in the treatment of perennial allergic rhinitis. J Allergy Clin Immunol. 2011;127(4):927-934. doi:10.1016/j.jaci.2011.01.037
    • Druss B, Pincus H. Suicidal ideation and suicide attempts in general medical illnesses. Arch Intern Med. 2000;160(10):1522-1526. doi:10.1001/archinte.160.10.1522
    • Federal Drug Administration. FDA requires Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis. Drug Safety and Availability. Published March 4, 2020. Accessed April 10, 2022. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-boxed-warning-about-serious- mental-health-side-effects-asthma-and-allergy-drug

    May 2022

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    New Updates to Asthma Treatment

    Key Terms
    DPI: dry powder inhaler
    ICS: inhaled corticosteroid
    LABA: long-acting beta-2 adrenergic agonist
    MART: maintenance and reliever therapy
    MDI: metered-dose inhaler
    OCS: oral corticosteroids
    SABA: short-acting beta-2 adrenergic agonist

    Have you met GINA?
    The Global Initiative for Asthma (GINA) guidelines were established in 1993 and are now considered the gold standard for best practices in treating patients with asthma. The GINA report is updated every year, with cumulative reviews of new evidence twice yearly. The newest update was issued in 2021. It expounds on a significant change in the standard of care for most patients that was first suggested in 2019. The 2021 update also addresses many aspects of asthma treatment relative to COVID-19 risk and management. A free download of the GINA reports is available for personal use at http://ginasthma.org.

    Review of Asthma Step Treatment The standard of care for treating adults and adolescents with asthma follows a stepwise approach, based on symptom severity.
    • Step 1: symptoms less than twice per month
    • Step 2: symptoms twice a month or more
    • Step 3: symptoms most days, or waking at night once or more per week
    • Step 4: daily symptoms, waking at night once or more per week, and low lung function
    • Step 5: persistent exacerbations and worsening symptoms despite aggressive treatment
    In the 2021 GINA report, treatment recommendations for each step were updated to reflect the most recent studies. Of all patients with asthma, almost one-quarter will require high-intensity treatment (high-dose ICS-LABA or medium-dose ICS-LABA plus OCS). Of those, about 17% have multiple treatment failures on high-intensity regimens. And, furthermore, about 4% of patients with difficult-to-treat asthma will be classified as having severe-refractory disease, with poor symptom control despite good inhaler technique and medication adherence.1 These patients fall in Step 5, and should always be managed by a pulmonologist and/or immunologist.

    A Sea-Change in Asthma Treatment
    In 2019, the GINA guidelines changed the recommendation for medication therapy in Step 1 asthma patients.2 Until then, patients who had infrequent symptoms (less than two exacerbations per month) and no risk factors for exacerbations were given a single medication – a SABA (e.g., albuterol or levalbuterol) for as-needed use. At that time, the GINA report recommended treatment with either symptom-driven (as needed) or daily low-dose ICS inhaler regimens. Monotherapy with a SABA had been first-line for fifty years. However, the GINA report clearly stated a SABA-only regimen was no longer recommended for adults and adolescents.

    In making this fundamental change, the report cited safety evidence that SABA-only treatment increased the risk of severe exacerbations, and that adding any ICS significantly reduced that risk. A study in 2007 found of patients with infrequent asthma symptoms (less than weekly), up to 20% of those were at risk of dying during an acute exacerbation.3 More recent studies demonstrated higher uses of SABA inhalers were associated with adverse clinical outcomes like severe exacerbations and death.4, 5

    At that time, GINA did not alter its recommendations for more severe asthma (Step 2 and above). Patients with more frequent asthma symptoms, or who have more risk factors for exacerbations, were to continue the standard combination LABA-ICS inhaler on a scheduled-dose basis, along with a SABA as a “rescue” inhaler.

    The GINA 2021 update built upon the 2019 guidelines.6 This report states the new preferred mild asthma treatment strategy is a low-dose ICS, specifically combined with inhaled formoterol. Formoterol is classified as a LABA, but it has a similar onset of action to SABAs (5-15 minutes).

    GINA 2021 also established two “tracks,” based on evidence gleaned since the 2019 change. Track 1 (the preferred approach) is a low-dose ICS-formoterol combination inhaler, either as-needed or scheduled based on the patient’s disease severity. Track 2 is the use of a single-drug SABA plus a separate ICS inhaler used immediately after SABA. This sequential inhaler use can be as-needed for symptom control for milder-severity asthma patients. Patients with more severe and frequent symptoms should use the ICS on a schedule and the SABA as needed. Track 1 is preferred because using low-dose ICS as a symptom reliever has been shown to reduce the risk of severe exacerbations compared to the use of a SABA as the reliever. The latest GINA report named this type of therapy “maintenance and rescue therapy” (MART).

    For patients requiring high-intensity treatment (Steps 3-5), GINA acknowledged that MART would require modification. A medium dose ICS, oral corticosteroids, or biologic therapy should be considered to reduce the risk of exacerbations.

    Classification of Medication Intensity
    The following tables classify the recommended total daily dose ranges into low, medium, and high-intensity treatment options. These tables do not represent drug-dose equivalence.

    Adults and Adolescents
    ICSDaily ICS Dose in Micrograms
    Beclomethasone diprop. DPI100-200>200-400>400
    Budesonide MDI or DPI200-400>400-800>800
    Ciclesonide MDI80-160>160-320>320
    Fluticasone fur. DPI100100200
    Fluticasone prop. MDI or DPI100-250>250-500>500
    Mometasone fur. MDI200-400200-400>400
    **Adapted from GINA 2021, Box 3-6A6

    Children Ages 6-11 Years
    ICSDaily ICS Dose in Micrograms
    Beclomethasone diprop. DPI50-100>100-200>200
    Budesonide MDI or DPI100-200>200-400>400
    Budesonide nebules250-500>500-1000>1000
    Ciclesonide MDI80>80-160>160
    Fluticasone fur. DPI5050n/a
    Fluticasone prop. MDI or DPI40-100>100-200>200
    Mometasone fur. MDI100100200
    *Adapted from GINA 2021, Box 6-66

    GINA Recommendations for Children
    The 2021 GINA update saw similar treatment recommendations for children under age 12. As always, adherence and inhaler technique should be closely assessed in children before increasing asthma medication doses. For young patients in Steps 1-2, the use of an ICS whenever the SABA is used is the standard. Step 3 patients should follow MART using a very low-dose ICS-formoterol combination inhaler. Those in Steps 4-5 should use a medium-dose or high-dose ICS-LABA (or low-dose ICS-formoterol MART) and be referred to a pediatric pulmonologist.6

    COVID-19 Implications on Asthma Treatment
    We now have two years of data on the risk and complications of coronavirus infection on asthma sufferers. First, people with asthma are not at higher risk for acquiring COVID-19, nor are those with well-controlled asthma more likely to die if infected.7 However, studies have shown asthma patients who recently required oral glucocorticoids8 or hospitalization9 to treat an exacerbation were more likely to die after acquiring COVID-19. For these reasons, it is critical to select asthma medications that maximize symptom control to prevent fatal COVID-19 complications. There is one caveat to this recommendation: nebulized medications should be avoided to minimize COVID virus transmission.

    Vaccination Recommendations
    The COVID-19 vaccines available in the U.S. have been successfully tested on patients with asthma. Generally, adverse events related to the various COVID-19 vaccine products are very rare. With current data in this population, GINA recommends COVID-19 vaccination for all patients with asthma who do not have contraindications.6 The vaccines should be given in a healthcare setting where severe reactions can be addressed quickly if they occur. Any patient who has a history of a severe allergy to polyethylene glycol, or any other vaccine ingredient, should not receive a product with these ingredients. The other standard vaccine precautions apply to patients with asthma.

    The CDC’s Advisory Committee on Immunization Practices (ACIP) also recommends patients with asthma receive an annual influenza vaccine, along with appropriately-timed Tdap, pneumococcal, and zoster immunizations.10

    • Asthma guidelines for adults, adolescents, and children were updated in 2021 based on safety data that showed adding an ICS for even mild asthma reduced the risk of death, hospitalization, and exacerbations.
    • Low-dose ICS treatment provides the most clinical benefit for most patients with asthma.
    • Two treatment “tracks” were established by GINA in 2021. Track 1 involves the use of a low-dose ICS-formoterol combination inhaler, either as-needed or scheduled. Track 2 is comprised of a single-drug SABA plus a separate ICS inhaler used immediately after the SABA. This new recommendation is called “maintenance and reliever therapy,” or MART.
    • A scheduled ICS-formoterol regimen is preferred for patients with more frequent symptoms, or risk factors for exacerbations. The ICS strength should be titrated to adequate symptom control.
    • Regimens that offer optimal symptom control are crucial to reducing the complications of and hospitalizations for COVID-19.
    • Asthma patients should receive COVID-19, influenza, Tdap, and pneumococcal vaccinations on schedule unless they have contraindications to these products
    1. Hekking PPW, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015;135(4):896-902. doi:10.1016/j.jaci.2014.08.042
    2. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2019. Published online 2019. http://www.ginasthma.org
    3. Dusser D, Montani D, Chanez P, et. al. Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations. Eur J Allergy Clin Immunol. 2007;62(6):591-604.
    4. Nwaru B, Ekström M, Hasvold P, et. al. Overuse of short-acting β2-agonists in asthma is associated with increased risk of exacerbation and mortality: a nationwide cohort study of the global SABINA programme. Eur Respir J. 2020;55(5):1901872. doi:10.1183/13993003.01872-2019
    5. Stanford RH, Shah MB, D’Souza AO, Dhamane AD, Schatz M. Short-acting β-agonist use and its ability to predict future asthma-related outcomes. Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol. 2012;109(6):403-407. doi:10.1016/j.anai.2012.08.014
    6. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2021. Published online 2021. http://www.ginasthma.org
    7. Wu T, Yu P, Li Y, et al. Asthma does not influence the severity of COVID-19: a meta-analysis. J Asthma. Published online April 23, 2021:1-7. doi:10.1080/02770903.2021.1917603
    8. Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020;584(7821):430-436. doi:10.1038/s41586-020-2521-4
    9. Bloom CI, Drake TM, Docherty AB, et al. Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK. Lancet Respir Med. 2021;9(7):699-711. doi:10.1016/S2213-2600(21)00013-8
    10. Centers for Disease Control and Prevention. Lung Disease Including Asthma and Adult Vaccination. Accessed March 21, 2022. https://www.cdc.gov/vaccines/adults/rec-vac/health-conditions/lung-disease.html

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    Overview of Lithium: What to know when you didn’t remember what you needed to know!

    The use of lithium in psychiatry goes back to the mid 1800s, however more scientific rigor in examining its role in mania began in the mid 20th century.1 Fast forward ahead to today where lithium is FDA approved for the treatment of bipolar disorder (i.e., Bipolar I Disorder), including acute mania and maintenance therapy.

    Although the FDA has approved lithium for this condition, different guidelines recommend the use of lithium in different ways. Therefore, pharmacists should not expect a rigid “cookie cutter approach” to its use. For example CANMAT (Canadian Network for Mood and Anxiety Treatments) and BAP (British Association for Psychopharmacology) recommend lithium as a 1st line intervention for acute mania and mixed episodes whereas NICE (National Institute for Health and Care Excellence) and WFSBP (World Federation of Societies of Biological Psychiatry) suggest the use of other agents such as second generation antipsychotics (SGA) with what might be perceived as less adverse effects when compared to lithium, first.

    Our case for consideration
    TS is a 32-year-old patient who returns monthly to your community pharmacy for refills on lithium along with a few other medications. According to his most recent lab report, his lithium levels are appropriate and no other monitoring parameter are out of range. Here is TS’s complete medication list:
    • Lithium 600mg twice daily for bipolar disorder x 10 years
    • Metformin 1000mg twice daily for T2DM x 2 years
    • Lisinopril 20mg daily for hypertension x 5 years
    • Melatonin 3mg daily at bedtime for sleep
    • Multivitamin daily for nutritional supplementation
    TS expresses concern over a recent emergence of acne that has caused distress and embarrassment.

    What is Bipolar Disorder (BP)? Although there is a specific criteria list of symptoms and duration of illness for formal diagnosis, typical symptoms include a rotation and range of extreme moods including elevated (mania) and depression. Both the duration and severity of the mood episodes are different based on the type of BP the individual is diagnosed with, however the presence of mania and whether or not hospitalization is required generally leads clinician’s towards making the more severe BP I diagnosis. Typical symptoms of mania include hyperactivity, decreased need for sleep, poor judgement, flight of ideas, grandiosity (exuding unrealistic pompous superiority) and possible aggression. Sometimes individuals can experience a “mixed state” and have both depression and mania occurring at the same time.

    Clinical pearls for safe and effective Lithium use

    Dosing is just one part of the program! Lithium is generally dosed to a target serum concentration range somewhere between 0.6mEQ/L to 1.2mEQ/L. In some severe cases, targets can be as high as 1.5mEq/L but anything over this threshold is considered potentially toxic and should be avoided. Because there is a very narrow range between therapeutic and toxic, lithium is a narrow therapeutic range medication and is often considered a “high alert” medication in medication safety organizations and communities. Also, it should be noted that some prescribers may opt for lower dosing thresholds purposefully. Routine ongoing therapeutic drug concentration monitoring, in addition to other regular tests to prevent adverse outcomes, is a necessary part of lithium therapy.

    A good starting dose for most healthy adults is 300 mg by mouth 3 times per day with serum lithium concentrations measured after 3 days with labs drawn 12 hours after the last oral dose and regularly until the patient is stabilized which takes about 5 days after given a steady scheduled dose. Dose changes are best if implemented by 300 mg doses every 3 days until the desired outcome is achieved. There has also been a liquid formulation available with 8mEq lithium citrate = 300mg lithium carbonate, however the recent supply chain disruption has been associated with raw ingredient shortage and lack of availability and uncertain future access of the lithium liquid.

    Basic pharmacokinetics:
    • No hepatic metabolism and no CYP450 drug interactions
    • Renal excretion; avoid using in patients with pre-existing renal compromise as evidenced with CrCl less than 30ml/min but cautious dosing is permitted for patients with CrCl above 30mL/min
    • Susceptible to drug interactions that result from impact on kidney function
    • Linear and predictable. Double the oral dose and expect that serum concentration to double too. Pregnant women may require higher doses during pregnancy but dose decreases prior to delivery to accommodate for normalization of volume of distribution that occurs late in 3rd term.
    Drug interactions
    Let’s review an illustrative summary to refresh your memory. Refer to the package label for a complete list of drug interactions! There are times when drug interactions may be present, but when combined use is medically necessary, can be managed with appropriate monitoring and vigilance.

    Blood pressure:
    • Ace inhibitors/ARBs: decreased sodium reabsorption, sodium loss and reduced GFR leading to a compensatory reabsorption of lithium and increased lithium concentrations
    • Diuretics: thiazide diuretics are the main problem-can result in 50% increase in lithium concentration and thus should be avoided; loop diuretics when used judiciously, generally result in less clinically significant consequences if over-diuresis can be avoided. Other diuretics should be considered on a case-by case basis.
    • Non-dihydropyridine Calcium channel blockers (such as diltiazem, and verapamil): increased risk of neurotoxicity when combined with lithium
    NSAIDS: thought to be result of inhibited prostaglandin synthesis, decreased renal blood flow and increased lithium concentrations

    Other: although rare, reported increased risk of neuroleptic malignant syndrome when combined with antipsychotics. Reports of serotonin syndrome are even more rare.

    What about the adverse effects we should expect with lithium treatment?
    Let’s review an illustrative summary to refresh your memory but always remember to refer to the package label for a complete list of adverse effects reported and recommendations to mitigate these risks!

    Genitourinary-can occur in up to 33% of patients but mitigated with once daily dosing and targeting the lowest effective serum concentration.
    • Polyuria
    • Acute more common versus chronic kidney disease
    Endocrine/metabolic- monitor thyroid panels-exogenous thyroid supplementation generally preferred over lithium discontinuation when clinically appropriate. Monitor bone density based on prescribers’ clinical judgement and patient specific clinical risks
    • Hypothyroidism
    • Hyperparathyroidism
    • Weight gain
    • QT prolongation, ECG changes and arrhythmias-avoid in patients with underlying cardiac conditions (avoid entirely in patients with 3rd degree block and if family history of sudden death in young adults).
    Gastrointestinal- tends to be transient early in treatment; emergence of later episodes could be suggestive of lithium toxicity (evaluation needed)
    • Nausea
    • Thirst/dry mouth
    • Muscle weakness and lethargy, tremor
    • Leukocytosis reported (generally benign)
    Acne, psoriasis and alopecia-both newly emergent or exacerbated preexisting condition (may resolve with lower doses; addressing the dermatologic side effect is the preferred mitigation versus discontinuing lithium whenever clinically appropriate and possible). These seemingly “cosmetic” problems can be personally distressing and may result in non-adherence therefore addressing these adverse effects with appropriate concern and subsequent pharmacologic recommendations is essential.

    Patients are best positioned to “see something and to say something” when it comes to adverse effects. Please give lithium a fair shake and keep my tip sheet for future use when you encounter new prescriptions and opportunities to educate prescribers and patients on safe, effective and appropriate use of this oldie but goodie medication!

    So what about TS?
    1. What pharmacologic intervention should be recommended when a patient reports a new emergence or worsening of a dermatologic condition such as acne?
      1. Acne usually occurs due to a drug interaction with lithium so discontinue other drugs that can interact with lithium
      2. Acne is usually a sign of a bigger problem and lithium should be discontinued immediately
      3. Acne can be personally distressing and should not be ignored; initiate a topical acne product as a first line intervention
      4. Acne is not a big deal; explain that the patient should be more worried about the mental health condition and just continue lithium
    2. You are concerned that TS is on an ACE inhibitor for blood pressure along with lithium since this can represent a significant drug interaction. Looking in TS’s history, he has had intolerable adverse reactions to almost all other blood pressure medications and his lisinopril is resulting in improved blood pressure control without complaints of side effects. What action do you take when advising pharmacotherapeutic recommendations?
      1. TS should not be on lisinopril; it is contraindicated with lithium therapy
      2. TS can remain on lisinopril provided TS’s renal function remains acceptable and lithium levels are appropriate
      3. TS can only remain on lisinopril at half dose to prevent complications resulting from hepatic metabolism
      4. TS should not be on lithium if he needs lisinopril

    I have had the privilege of developing and presenting programs that have covered a wide range of mental health topics. And, while I love this part of the CE experience, it is really the Q & A with you that I treasure the most. After each Q & A session I reflect back on the questions asked and felt compelled to circle back to these and use them in future updates._Viola! Perfect for the new launch of the micro CE mini-blog based on Tammie Lee Demler’s BEST in the classroom series..

    During my psychiatric updates, I am often asked how lithium fits in. I have become an increasing fan of lithium and I observe that many prescribers are hesitant to use this very effective medication because of fear of side effects. Here I share some basics and clinical pearls to refresh you in your advocacy for the safe use of lithium!

    Have a Great Day on the Bench!!

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    Overview of Drugs Requiring Renal Monitoring

    Drugs contraindicated in renal failure: Mnemonic

    Students often find the following amusing and memorable mnemonic helpful in recalling the major drugs that fall into this category:
    • Many (Metformin)
    • People (Potassium sparing diuretics)
    • Like (Lithium)
    • Napping (Nitrofurantoin)
    • Naked (N-SAIDS)
    In no particular order, then, let’s tackle some of the ‘big ones’:

    NSAID/COX-2 Inhibitors

    No difference in the safety profile of these two classes for drugs in renal insufficiency. Both can lead to edema, hypertension, acute and chronic renal failure.

    Acetaminophen is by far the safest analgesic in patients in renal failure. Use colchicine, renal adjusted dose joint injection or brief course of corticosteroids for episodic gout in renal failure.


    Withdrawal of lithium therapy can be associated with disastrous consequences and should only be done under the supervision of a physician experienced in the management of bipolar affective disorder. Because lithium is almost entirely renally excreted, monitor BUN, creatinine and TSH before and while a patient is on therapy. Use caution if the patient is sodium depleted or taking diuretic therapy. Maintenance lithium level is 0.6-1mEq/liter to minimize side effects.
    • Draw blood levels 12 hours after last dose.
    • Check blood levels: 5-7 days after initiation & any change in dosage.
    • Maintenance: every 1-2 months. In stable patients, every 6-12 months.
    • Monitor more frequently if volume depletion, or diuretic use, diarrhea or vomiting.
    • Check thyroid and renal function before starting lithium and every 6-12 months.
    • Hypothyroidism can occur and contribute to bipolar exacerbations
    IV contrast dye

    At least 5 percent of patients who undergo cardiac catheterization experience a transient rise in the plasma creatinine concentration of more than 1.0 mg/dL due to contrast-induced renal dysfunction. This risk is greater in patients who have diabetes. The plasma creatinine concentration usually returns to baseline within seven days, and less than 1 percent of patients, usually patients who have diabetes with underlying severe chronic kidney disease, go on to require chronic hemodialysis.

    High molecular weight/ ionic contrast dye can cause severe vasospasm in the afferent arteriole and acute renal failure. Risk factors include: diabetes, myeloma, chronic renal failure, dehydration, diuretic therapy and CHF. Less common with newer lower molecular weight/ nonionic contrast dyes. Best to avoid all together by utilizing MRI, ultrasound, CT scans.

    Acetylcysteine (Mucomyst®) can also be given orally to prevent nephrotoxicity caused by radio contrast dye. Usually administered orally the day before and the day of the procedure.

    Statin have also been shown to be protective of kidneys during cath procedures. At some institutions, it is now standard of care to put acute coronary syndrome (ACS) patients who are a candidate for percutaneous coronary intervention (PCI) on statins to prevent contrasted-induced acute kidney injury. High-dose rosuvastatin given on admission to statin-naïve patients with ACS who are scheduled for an early invasive procedure can prevent CI-AKI (contrast induced acute kidney injury) and improve short-term clinical outcome. (Statin Contrast Induced Nephropathy Prevention [PRATO-ACS]. Rosuvastatin (Crestor®) was given to statin naïve patients at a dose of 40mg for the first dose, then 20mg daily. https://www.jacc.org/doi/abs/10.1016/j.jacc.2013.04.105

    Antibiotics that do NOT require Dosage adjustment in Renal impaired:
    • Azithromycin (Zithromax®)
    • Cephtriaxone (Rocephin®)
    • Ciprofloxacin XL (Cipro-XL)
    • Clindamycin (Cleocin®)
    • Doxycycline Vibramycin®)
    • Linezolid (Zyvox®)
    • Minocycline (Minocin®)
    • Moxifloxin (Avelox®)
    For an excellent reference, consult the latest edition of the Sanford Guide. It features 23 pages of renally adjusted antibiotic/antiviral medications.

    Factor Xa inhibitors
    Pay attention to CrCl when dosing these anticoagulants. Even though they don’t require INR monitoring, renal function needs to be checked before prescribing.

    Rivaroxaban (Xarelto®): Nonvalvular Atrial Fibrillation (NVAF):
    • For patients with CrCl >50 mL/min: 20 mg orally, once daily with the evening meal
    • For patients with CrCl 15 - 50 mL/min: 15 mg orally, once daily with the evening meal
    Apixaban (Eliquis®)
    • Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation:
      • The recommended dose is 5 mg orally twice daily.
      • In patients with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily.
    Edoxaban (Savaysa®)
    Treatment of NVAF: Assess CrCL before initiating therapy. The recommended dose is 60 mg once daily in patients with CrCL >50 to ≤ 95 mL/min.
    • Do not use edoxaban in patients with CrCL > 95 mL/min (sorry, your kidneys are “too” good for this drug!)
    • Reduce dose to 30 mg once daily in patients with creatinine clearance 15 to 50 mL/min
    Metformin (Glucophage®)
    • Metformin medications should be stopped at the time of or prior to CT studies with IV Contrast and withheld for 48 hours after the procedure.
    • Most experts prefer using creatinine clearance because it's adjusted for the patient's age, weight, and gender. (Cockcroft-Gault equation). When using creatinine clearance, avoid in patients with clearance less than 30 mL/minute.
    Allopurinol (Zyloprim®):
    Requires renal dosage adjustments: Titrate to dosage to lower uric acid to 6mg/dL. Decrease dose if renal impaired for maintenance.
    • If Creatinine clearance: 20mL/min= 200mg daily.
    • If Creatinine clearance: 10mL/min = 100mg daily
    STATINS: All statins require renal dosing adjustments except for Atorvastatin (Lipitor®)

    • The lipophilic beta blockers labetalol (Normodyne®), metoprolol (Toprol-XL®, Lopressor®) and Carvedilol (Coreg®) are the best options.
    • Most references recommend Carvedilol as the best choice due to its renal protective effect. Carvedilol with its alpha blocking ability blocks the unopposed alpha vasoconstriction.
    BISPHOSPHONATES: Should be avoided in CKD. AVOID: Renal insufficiency—do not use if CrCl is less than 35ml/minute

    When we look at the laundry list of medications in this piece, these drugs are most frequently used in patients at risk for renal impairment. Patients with metabolic syndrome, Type-2 diabetes, heart failure and hypertension are most likely to take these medications.

    Lithium is not a favorite among most family practitioners for bipolar disorder. Most family practice clinicians leave monitoring of this drug to the psychiatrists. At the clinic I helped staff two days a week we had a 20-year-old patient come in with his caregiver.

    It was in the summer and as I do with all of my lithium patients, reminded them of the need for adequate hydration. His caregiver alerted me that the kid was drinking a 2-liter bottle of water about every half hour. My ears perked up. When I see any lithium patient, I think thyroid and kidneys. I alerted our very astute PA, and the patient was diagnosed with lithium induced nephrogenic diabetes insipidus.

    This condition is rather common, occurring between 20-40% of all lithium patients. Especially during summer months, it is important for all pharmacists to caution lithium patients. While you are at it, remind your topiramate and zonisamide patients to drink up as well!

    Have a Great Day on the Bench!!

    April 2022

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    Overview of ACEs and ARBs


    ACE inhibitors are not nephrotoxic per se, or at least not in the manner that cyclosporine or aminoglycosides are. By inhibition of ACE (angiotensin converting enzyme) they alter the hemodynamics within the glomerulus. ACEI prevents the conversion of Angiotensin-I to Angiotensin II thus releasing the vasoconstriction of the efferent glomerular arterioles, with a subsequent decrease in the glomerular hydrostatic pressure. With less glomerular hydrostatic pressure, there is less glomerular filtration.

    How ACEI has beneficial renal effects: they decrease proteinuria possibly by selectively decreasing the permeability of the glomerular membrane to protein by stabilization of basement membrane of glomerulus. There is a risk of renal impairment in patients taking an ACE inhibitor (or ARB), diuretic, and NSAID. Combining any two of these drugs can lead to acute renal failure (Acute Kidney Injury) in susceptible patients. Combining all three is a "triple whammy."

    Mechanism: In the normal kidney, glomerular filtration is related to glomerular blood flow. In school we learned that the glomerulus is like a coffee filter. However, I would propose that the glomerulus is more like an espresso machine. An espresso machine is dependent on PRESSURE. If we INCREASE the flow into the vessel, and INHIBIT the outflow, pressure builds and filtration occurs.

    Endogenous prostaglandins are responsible for vasodilatation of the afferent arterioles, which allows increased blood flow to the glomerulus. When these prostaglandins are blocked, perfusion is reduced and filtration is inhibited.

    Angiotensin II is responsible for the vasoconstriction in the efferent arterioles, which is necessary to drive up pressure. We think of Angiotensin-II as a “bad guy” since it is responsible for elevating blood pressure. HOWEVER, this vasoconstriction in the efferent arterioles facilitates filtration, by essentially blocking the outflow.
    • NSAIDS: block prostaglandin mediated afferent arteriolar VASODILATION. (Allows blood to perfuse into the glomerulus)
    • ACE/ARB: blocks Angiotensin-2 mediated efferent arteriolar VASOCONSTRICTION (increases pressure for filtration)
    • DIURETICS: decrease plasma volume

    WHO’s AT RISK?
    Is a problem in patients who already have impaired renal function or at risk due to:
    • older age
    • heart failure
    • dehydration
    It is best to avoid chronic NSAIDs or aspirin for pain, including COX-2 inhibitors like celecoxib (Celebrex®).

    DON'T stop low-dose aspirin (doses of 325 mg/day or less aren't likely to cause renal problems)

    What to do:
    Monitor susceptible patients for worsening renal function:
    • increased blood pressure
    • elevated potassium (hyperkalemia)
    • edema
      • Don't reduce the dose or stop an ACE /ARB unless serum creatinine increases more than 30% within 2 months of starting the drug.
      • Stop (or reduce) ACE/ARB if serum potassium exceeds 5.5 mEq/L.
    ACE’s /ARB ‘s for diabetes
    Treatment with ACE inhibitors (or Angiotensin Receptor Blockers) results in kidney protection due to reduction of systemic blood pressure, intraglomerular pressure, an antiproliferative effect, reduction of proteinuria and a lipid-lowering effect in proteinuric patients (secondary due to reduction of protein excretion). Elderly patients with diabetes mellitus, coronary heart disease or peripheral vascular occlusion are at risk for deterioration of kidney function due to a high frequency of renal artery stenosis in these patients.
    Source: https://pubmed.ncbi.nlm.nih.gov/9036682/#:~:text=Treatment%20with%20ACE%20inhibitors%20results,to%20reduction%20of%20protein%20excretion

    Between 33% and 50% of patients with renal artery stenosis will usually have a mild decline in GFR, occurring within a few days after the administration of an ACE/ARB. A large decline in kidney function occurs in less than 5 to 10 percent of cases. The ACE inhibitor-induced reduction in GFR in renovascular disease almost always resolves after cessation of therapy. For renal protection in diabetics, it is always best to “start low and go slow.” If a patient has an elevated serum creatinine of more than 30% within one week of initiation of ACE/ARB therapy, bilateral renovascular disease should be strongly suspected.

    One of the toughest questions I answer from students is this: “Why do we give a drug like an ACE inhibitor or ARB to diabetics for renal protection when, in fact, they can be nephrotoxic?” My students love the analogy of the espresso machine, which is dependent on PRESSURE. If we INCREASE the flow into the vessel, and INHIBIT the outflow, pressure builds, and filtration occurs.

    Except for one student. One of my students was a family practice physician who just came to the United States. All throughout this segment he would shake his head. At the end of class he said, I understand everything you said, I just don’t believe it!

    Some find it hard to believe, since ACE inhibitors are revered for their effects on the kidneys and STAR ratings for Medicare. STAR ratings are based on patients with diabetes taking “RAS” drugs, including ACE inhibitors or ARBs. Physicians and pharmacists get “dinged” if their patients are not taking an ACEi or an ARB… regardless of the reason.

    That is unfortunate too, because we always need to be looking at the entire patient. Medicare plans look at numbers, while we look at patients!!!

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    Overview of Nephrotoxicity


    Acute kidney injury (formerly known as acute renal failure) occurs in the hospital setting at a rate of 22% worldwide. Half of all the acute kidney injury cases occur in critically ill patients.

    Drugs Causing Tubular Epithelial Cell Damage:
    • Aminoglycoside antibiotics
    • Radiographic contrast media
    • Cisplatin & Carboplatin
    • Amphotericin-B: both tubular injury and renal vasoconstriction contribute to this drug’s nephrotoxicity
    • Tacrolimus and cyclosporine
    Hemodynamically mediated Renal Failure:
    • ACE inhibitors & ARBS
    • NSAIDS
    Obstructive Nephropathy: Drugs can cause renal stone formation either by raising excretion rates of naturally occurring stone components or by directly precipitating within the urinary tract. Seen in patients with volume depletion and renal insufficiency.
    • Acyclovir
    • Sulfadiazine
    • Indinavir & Foscarnet
    • Tricyclic Antidepressants
    • Triamterene (Potassium sparing diuretic)
    • Ciprofloxacin
    Glomerular disease:
    • NSAIDS
    • Hydralazine
    • Avoid potassium sparing diuretics if CrCl is less than 30
    Tubulointerstitial disease:
    • Methicillin
    • NSAIDS
    • Cyclosporine
    • Lithium
    • Methotrexate
    Pseudo-renal failure:
    • Corticosteroids
    • Trimethoprim
    • Cimetidine

    Selected antimicrobial agents causing nephrotoxicity:

    Aminoglycosides - examples:
    • neomycin –most nephrotoxic
    • Tobramycin and Gentamycin are about the same nephrotoxicity
    • Streptomycin is the least nephrotoxic.
    • Tetracyclines are nephrotoxic—(Doxycycline is safe, as it is fecally excreted)
    Mechanism: they accumulate in the proximal tubule, causing acute tubular necrosis.

    Cephalosporins: Keflex ® (cephalexin) may be nephrotoxic, use with caution in patients with CrCl less than 50mL/min.

    Selected antineoplastic agents causing nephrotoxicity:

    Cisplatin & Carboplatin: Proximal tubular damage occurs acutely after administration as a result of impairment of cell energy and production, possibly by binding to proximal tubular cellular proteins and sulfhydryl groups. Nephrotoxicity was 50-100% in the 1980’s but has been decreased to 6-13% by limiting total drug dose, and reducing the rate of administration. Contributes to acute renal failure if used with other nephrotoxins.

    Selected immunosuppressant drugs causing nephrotoxicity

    Cyclosporine (Neoral®) and Tacrolimus (Prograf®): Toxicity is usually dose dependent. It causes distal tubular dysfunction from severe vasoconstriction. Causes reversible vasoconstriction and injury to glomerular afferent arterioles, possibly because of increased activity of vasoconstrictors. Regular blood monitoring is necessary to prevent nephrotoxicity. Kidney biopsy is necessary in transplant patients to distinguish rejection from toxicity. Calcium channel blockers are useful, blocking the vasoconstrictive effects of cyclosporine.

    Tacrolimus and cyclosporine: calcineurin inhibitors with a high risk of developing kidney injury either as acute kidney injury, which is largely reversible after reducing the dose, or as chronic progressive kidney disease, which is usually irreversible.

    Managed with dose reduction and/or discontinuing interacting drugs.

    Renal failure is insidious, and frequently slips by prescribers. Many drugs that are in our fast-moving section require a lot of respect. Drugs like ibuprofen, lisinopril, hydrochlorothiazide, metformin, cephalexin, and allopurinol are purchased in bottles of 500 or 1000, and we dispense them frequently. All of them can cause problems with kidney function.

    A “triple whammy” is sometimes observed, featuring ACE’s/ ARBS when given with a diuretic and an NSAID. Numerous drugs we frequently dispense require renal dosing from antibiotics to gabapentin and the Factor Xa inhibitors for anticoagulation.

    These fast movers deserve our respect.

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    Overview of Beta-3 Receptor Agonists for Overactive Bladder & Agents for Female Sexual Function Disorder

    Mechanism of Action: By stimulating beta-3 receptors, these drugs relax the detrusor muscle during the storage phase of the urinary bladder fill-void cycle thereby increasing bladder capacity.

    Mirabegron (Myrbetriq®) $420/month (FDA approved:2013)
    • Available as extended-release tablets: 25mg or 50mg
    • Available as extended release suspension 8mg/mL 100mL bottles (28 day expiration)
    Advantages: does NOT cause anticholinergic side effects. Less likely to cause prolongation of QT on EKG. Disadvantages:
    • Moderate blocker of CYP2D6 pathway (increases metoprolol and digoxin levels)
    • May cause increases in blood pressure (8-10% incidence).
    • Allow 8 weeks to see full benefit.
    • Don’t exceed 25mg/day if patient has renal impairment
    Vibegron (Gemtesa®) $480/month April-2021
    • Available as 75mg tablets
    • Being a Beta-3 agonist, it does not cause anticholinergic side effects.
    • Less increases in blood pressure than seen with mirabegron
    • Does not block CYP-2D6
    • Less discontinuation- significantly less side effects
    Female Sexual Dysfunction:

    Women have very limited treatment options in the realm of sexual dysfunction, with the available options (flibanserin (Addyi®) and bremelanotide (Vyleesi®) being grossly cost prohibitive. A year’s worth of flibanserin would be $6,600 for six sexual encounters per year, while the same $6,600 would buy approximately a months’ worth of bremelanotide.

    The Diagnostic and Statistical Manual of Mental Disorder, Fifth Edition (DSM-V) defines Female Sexual Disorders (FSD) as disturbances in the female sexual response cycle, resulting in marked distress and interpersonal difficulties. In particular, female sexual arousal disorder (FSAD) belongs to the subcategory “female sexual interest/arousal disorder” and is one of the most prevalent subcategories of FSDs.

    - Includes lack of sexual desire, impaired arousal, inability to achieve orgasm, anxiety about sexual performance, not finding sex pleasurable or pain with sexual activity - Approximately 40% of women in the U.S. have sexual concerns - Sexual response cycle: Desire (libido) → Arousal (excitement) → Orgasm → Resolution

    Risk Factors: depression, anxiety, psychotic disorders, benzodiazepines, SSRIs

    Treatment: treat underlying cause, lifestyle modifications (weight loss, diet, sleep), lubrication, therapy

    Female Hypoactive Sexual Desire Disorder (HSDD):
    • Estrogen - (alone or in combination with progestin) for peri/postmenopausal atrophic vaginitis
      • May improve vaginal environment - less dryness, improved mucosa, reduced pH
    • Testosterone - NOT FDA approved, often prescribed off label w/ or w/o estrogen
      • May be effective for short-term treatment but limited evidence for treatment >6 months
      • Increases # sexually satisfying events by around 1.2 events/month
      • Formulations: tablet, transdermal spray, patch
      • Contraindications: presence/high risk of breast/endometrial cancer, VTE, CV disease
      • Adverse events: hirsutism/virilization, acne, CV complications, breast cancer
    • Bupropion - norepinephrine-dopamine reuptake inhibitor
      • May increase sexual arousal and orgasm (may or may not improve desire) in HSDD
    Flibanserin (Addyi®)- serotonin receptor 1A agonist/serotonin receptor 2A antagonist, 2015
    • Cost for 30 tablets is ~$550.00
    • 100 mg tablet, once daily at bedtime (NOT PRN) in premenopausal women
    • Increases number of sexually satisfying events by approximately 0.5 events/month
    • Can cause dizziness, somnolence, nausea, fatigue, insomnia, dry mouth
    • Interacts with CYP3A4 inhibitors, alcohol CONTRAINDICATED with use (can cause severe hypotension/syncope), must enroll in REMS program to prescribe
    • Not for those with HSDD due to medical/psych conditions, medications or other drug substance, or relationship problems
    Female Orgasmic Disorder: mainstay of treatment is psychotherapy

    Sexual Pain Disorder: conduct pelvic exam, consider hormonal treatments (estrogen, ospemifene)

    Bremelanotide (Vyleesi®) (approved June 21,2019)

    Cost: ~$6,667.00 per month (9 autoinjectors)

    Mechanism: Activates melanocortin receptors, but the mechanism by which it improves sexual desire and related distress is unknown.
    • The First FDA-Approved As-Needed Treatment for premenopausal women experiencing distress or interpersonal difficulty due to low sexual desire
    • 1 in 10 Premenopausal Women in the U.S. (Approximately 6 Million Women) suffer From HSDD
    EFFICACY: There was no difference between treatment groups in the change from the start of the study to end of the study in the number of satisfying sexual events. Bremelanotide does not enhance sexual performance. (source: FDA)
    • 25% of patients treated with bremelanotide had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2 to 6.0, with higher scores indicating greater sexual desire) compared to about 17% of those who took placebo
    DOSING: Inject SQ at least 45 minutes prior to sex
    • Only one dose per 24 hours
    • Maximum of 8 doses per month
    • Only for use in pre-menopausal women
    • Available as an auto-injector 1.75mg dose (per 0.3mL)
    • STOP: treatment after eight weeks if they do not report an improvement in sexual desire and associated distress.
    • nausea (40%) and vomiting, (13% needed meds to control nausea and vomiting)
    • flushing
    • injection site reactions
    • headache
    • hypertension- usually resolves in 12 hours, not recommended for uncontrolled hypertension or cardiac patients
    MAJOR DRUG INTERACTION: Naltrexone (Revia®) if taken by mouth, bremelanotide may significantly decrease the levels of naltrexone in the blood. Patients who take a naltrexone-containing medication by mouth to treat alcohol or opioid dependence should not use bremelanotide because it could lead to naltrexone treatment failure.

    Watch for female sexual dysfunction caused by meds - review medication list for SSRIs/benzodiazepines
    • Highest risk antidepressants (>30%): fluoxetine, fluvoxamine, paroxetine, sertraline
    • Medium risk (10-30%): citalopram, duloxetine, escitalopram, venlafaxine
    • Lowest risk: bupropion, mirtazapine, desvenlafaxine, vilazodone, vortioxetine
    NOTE: In one study, the incidence of individuals who spontaneously reported sexual side effects was 14% compared with 58% of individuals who reported sexual side effects when asked directly by their physicians. It is fair to say, it is an issue worth bringing up. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007725/

    Management strategies for SSRI-induced sexual dysfunction:
    1. Consider decreasing dose of offending medication.
    2. Switching to another SSRI or antidepressant, augmenting therapy with bupropion.
    Remember to taper, cross-taper, or leave wash-out periods when switching between SSRIs/antidepressants as appropriate!

    The distinct side effect profiles of anticholinergics and beta-3 receptor agonists, is a “no-brainer.” All of the peripheral side effects of the anticholinergics, along with the increase chance for dementia, make them no competition for the beta-3 agonists. Beta-3 agonists are as efficacious, albeit more expensive.

    Beta-3 receptor agonists appear to be at least effective as the anticholinergic medications, without the side effects of dry mouth, constipation, cardiac issues and possibly dementia. Reduced discontinuance rates may favor these products, however due to their expense, might require prior authorizations from insurance companies.

    Have a Great Day on the Bench!!

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    Overview of Anticholinergics for the Pharmacological Management of Overactive Bladder

    Mechanism: Drugs with anticholinergic activity are often the first drug used for Urge Urinary Incontinence (UUI). Drugs with anticholinergic activity act by antagonizing muscarinic cholinergic receptors, through which efferent parasympathetic nerve impulses evoke detrusor contraction. The detrusor muscle is responsible for urine flow. The net effect of cholinergic blockade is increased bladder capacity and decreased urgency. In addition, women with mixed Urinary Incontinence (UI) or UUI plus urethritis or vaginitis may benefit from topical or systemic estrogen (alone or in combination with an anticholinergic.)

    General Distribution of Muscarinic Receptor Subtypes

    M1Brain (cortex, hippocampus), glands, sympathetic ganglia
    M2Heart, smooth muscle (including detrusor), hindbrain
    M3Smooth muscle (detrusor), salivary and excretory glands
    M4Brain (cerebral cortex, striatum), lung
    M5Brain (substantia nigra) eye

    Brand NameGenericM3 selectivityDosage
    Ditropan 5mgOxybutynin+(5mg) 2 to 4 times daily
    Ditropan XL 5mg, 10mg , 15mg tabsOxybutynin+(5 to 30mg) once daily
    Detrol 1mg,2mgTolterodine+(1mg –2mg) BID
    Detrol LA 2mg, 4mgTolterodine+(2mg-4mg) once daily
    Sanctura 20mgTrospiumleast(20-40mg) BID
    Sanctura XR 60mg capsTrospiumleast60mg once daily in am
    Enabelex 7.5 & 15mgDarifenicin+++(30mg) daily
    Vesicare 5mg & 10mgSolifenacin++(5mg-10mg) once daily
    Toviaz® 4mg & 8mgFesoterodine++4-8mg daily (use 4mg if on CYP450 blocker)

    Differences in the available products:

    Sanctura ® (trospium), although is the least M3 selective is most commonly used in Europe. It is a quaternary amine/anticholinergic. Not as lipid soluble and minimal blood brain barrier penetration, and less sedation. Improves OAB symptoms in 3 days. Negligible amount metabolized by P450, therefore minimal drug interactions. Give on empty stomach.

    Detrol (oxybutnin) and Detrol LA (oxybutynin ER) are the most commonly used anticholinergics at this time.

    Toviaz ® (fesoterodine) is a prodrug, with the same active metabolite as tolterodine (Detrol). Cost is over $400/month. Topical anticholinergic for bladder control. Avoids first metabolism and less anticholinergic side effects.

    Oxytrol® Oxybutynin patch (3.9 mg/24 hr patch) dose 3.9mg twice a WEEK Available Rx cost approximately $740.00 per box of 8 patches. Over the Counter (retail $29.99) per box of 8 patches.

    Gelnique® available in one gram foil packets. Apply 1 gel-packet once daily. Cost is around $450.00/month

    Oral oxybutynin is available as a generic, and is dosed 3 times daily. This is often the first choice of the insurance companies due to costs. Sanctura® (trospium) is also generically available. Many insurance companies require a patient to “try and fail” on generic oxybutynin before approving the more expensive ($120-$430/month) brand name products.

    Anticholinergics: Even a single anticholinergic medication can increase the risk of cognitive impairment by up to 50%...even more in patients who've had a stroke or have a family history of dementia. Anticholinergics are also linked to higher hospitalization rates. Anticholinergics are sometimes added for incontinence that's caused or exacerbated by a cholinesterase inhibitor, used for Alzheimer’s. These cholinesterase inhibitors increase cholinergic activity and may lead to OAB symptoms.

    The more potent the anticholinergic, the more likely it will cause memory loss. The potent anticholinergics were most often associated with poorer memory and executive function, brain hypometabolism, brain atrophy, and increased risk of clinical conversion to cognitive impairment. Source: JAMA Neurol. 2016;73(6):721-732. doi:10.1001/jamaneurol.2016.0580

    Other anticholinergics: Drugs with significant anticholinergic adverse effects decrease urinary bladder detrusor muscle contractility, resulting in urinary retention (examples: antihistamines, tricyclic antidepressants, phenothiazines).

    Drugs like Detrol® (tolterodine) poses little risk of urinary retention, IF there is good flow. Antimuscarinics work during storage, rather than voiding.

    This category of drugs is frustrating as a community pharmacist. Third party payers sometimes demand that patients try and fail anticholinergics, potentially causing a whole boatload of problems. We give drugs for Alzheimer’s that increase cholinergic activity (donepezil) and others. Then, a prescriber must prescribe an ANTI-cholinergic if the patient has overactive bladder. These payers sometimes insist that prescribers give cholinergics and ANTI-cholinergics to the same patient!

    I was also amazed to see that our warehouse (McKesson) still has oxybutynin (Oxytrol®) over the counter. The cost difference is nearly $700!

    Have a Great Day on the Bench!!

    March 2022

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    Overactive Bladder (OAB) is characterized by the presence of involuntary bladder contractions that occur during bladder filling, despite the patients attempt to suppress them. An individual presenting with OAB is likely to present with several of the following symptoms:
    • Increased daytime frequency: individual believes that he or she voids too often during the day.
    • Urgency: the sudden compelling desire to pass urine, which is difficult to defer.
    • Urinary incontinence: any involuntary leakage of urine. Should be described further by specifying other relevant factors, such as type, frequency and severity.
    Additional symptoms of OAB may include:
    • Urge Urinary Incontinence (UUI): involuntary leakage accompanied by or immediately preceded by urgency. Can present in different symptomatic forms, for example small losses between micturition or complete bladder emptying. UUI is most commonly found in older women and believed to be from detrusor muscle overactivity.
    • Stress Urinary Incontinence (SUI): involuntary leakage on effort or exertion or sneezing or coughing or anything that builds up abdominal pressure. Believed to be due to the lack of mechanical support of the urethra which leads to insufficient resistance to outflow of urine during increased abdominal pressures. Seen most commonly in women ages 45 to 49 years.
    • Mixed Urinary Incontinence (MUI): involuntary leakage associated with urgency, and also with exertion, effort sneezing or coughing.
    • Overflow Urinary Incontinence: can be due to detrusor muscle underactivity and is characterized by a loss of urine with no warning or triggers. The volume leaked may be small or large and can occur with a change of position or activity.
    • Nocturia: waking to void at night 2 or more times.
    Drugs that can affect bladder contractility:
    • Anticholinergics
      • Tricyclic antidepressants such as amitriptyline (Elavil®)
      • First generation antihistamines such as diphenhydramine (Benadryl®), chlorpheniramine (Chlor-trimeton®)
      • GI spasmolytics: dicyclomine (Bentyl®), hyoscyamine (Levsin®), glycopyrrolate (Robinul®)
      • Anticholinergics for Parkinson’s: trihexyphenidyl (Artane®) and benztropine (Cogentin®)
    • ACE inhibitors: (lisinopril etc.) decreases contractility, as well as potentially causing an increased frequency of cough.
    • Benzodiazepines: (diazepam, lorazepam etc) their muscle relaxation effect may impair bladder emptying.
    • Alpha blockers like Tamsulosin (Flomax®) terazosin (Hytrin®) and all members in this class decrease urethral sphincter tone.
    • Any antipsychotic, antidepressant or muscle relaxants with anticholinergic effects will decrease bladder contractility
    • Alcohol: decreases contractility
    • Caffeine: increases contractility and rate of emptying. Diuretic effect increases urine volume.

    Non-Pharmacological Management: There is no cure for OAB, so management techniques are essential. Keep a bladder diary. Keep a record of ins & outs.
    • Education about lifestyle interventions
    • Regulate fluid intake
    • Eliminate bladder irritants (alcohol & caffeine, carbonated beverages, artificial sweeteners, citrus juices, tomato-based products, chocolate)
    • Maintain bowel regularity
    • Kegel exercises- Pelvic muscle rehab. Strengthens muscles in pelvic floor which support the bladder neck & urethra. Method:
      • Find the right muscles: imagine you are trying to stop yourself from passing gas. Squeeze the muscles you would use, if you sense a “pulling feeling” those are the right muscles.
      • It is important not to squeeze other muscles, at the same time, and NOT to hold your breath. Be careful not to tighten your stomach, leg, or buttock muscles. Squeezing the wrong muscles can put undue pressure on bladder control muscles.
      • Pull in muscles, hold for count of 3. Relax for a count of 3. Work up to 3 sets of 10 repeats.
      • Start doing these exercises lying down, this is easiest because muscles do not need to work against gravity. When muscles get stronger, do them sitting or standing. Working against gravity is like adding more weight.
      • Repeat but don’t overdo it
    • Bladder training-void regularly every hour on the hour. Then increase duration between voids by 15 minutes each week, until comfortable with urinary frequency. This helps with control by suppressing involuntary detrusor contractions. Check out: https://medlineplus.gov/ency/patientinstructions/000141.htm

    According to the Agency for Healthcare Research and Quality, approximately 15.1 % of US women report overactive bladder (OAB) and 11.0 % report OAB with urge urinary incontinence.

    When we see the selection of incontinence products in our over-the-counter space and the number of OAB meds on our shelves, we can make a definite difference in this population.

    Most of the treatment options for OAB, with the exception of two, are taking advantage of the “side effects” caused by anticholinergic therapy. This represents a huge market where patient consultation is a must.

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    Overview of Treatment Options for Interstitial Cystitis (Bladder Pain Syndrome)

    Pentosan polysulfate sodium (Elmiron®) 100mg caps
    Recommended dose: 300 mg/day taken as one 100 mg capsule orally three times daily. The capsules should be taken with water at least 1 hour before meals or 2 hours after meals.
    Patients should be reassessed after 3 months. May take 3-6 months for improvement.

    Weak anticoagulant effect: This drug is a heparin-like compound, with approximately 1/15th the effect of heparin. It is in the low-molecular weight heparin family. Mechanism of action for IC is unknown. Pregnancy Category-B (inform clinician if pregnant) FDA WARNING 2020: Retinal pigmentary changes
    • A detailed ophthalmologic history before starting therapy.
    • For patients with preexisting ophthalmologic conditions, get a baseline before starting therapy for future comparison.
    • A retinal examination is suggested for all patients within six months of initiating treatment and periodically while continuing treatment. If pigmentary changes in the retina develop, access risk versus benefits.
    • May be a cumulative effect.
    The most common side effects are hair loss (almost always limited to a single area of the scalp), diarrhea, nausea, blood in the stool, headache, rash, upset stomach, abnormal liver function tests, dizziness, and bruising.

    Some foods are well known for causing interstitial cystitis (IC): Start by eliminating the top offenders: citrus (Vitamin-C), spicy hot foods, Mono Sodium Glutamate (MSG), soy, caffeine, coffee, tea, sodas, alcohol, tomatoes, cranberry juice, and chocolate.

    There are lists of: “Most bothersome”, “IC friendly” and “Foods worth trying”. Each individual should maintain a food diary. A useful website that I recommend is:

    • Bladder training with “urge suppression" may be helpful.
    • Patients might also get relief from OTC therapy such as ibuprofen, acetaminophen, or naproxen.
    • Tricyclic Antidepressants, such as amitriptyline might be helpful to relieve the neurogenic pain component as well as help manage the depressant symptoms of the disease state.

    Phenazopyridine (Pyridium®) 100mg & 200mg tablets
    available OTC: Azo-standard® 95mg and 97.5mg
    • Mechanism: Phenazopyridine is an “azo” excreted in the urine, where it exerts a direct topical analgesic effect, on urinary tract mucosa. 65% remains unchanged in the urine.
    • Phenazopyridine has been marketed since 1925 and since 1951 has had a dual status of prescription and over-the-counter
    • status of prescription and over-the-counter Indication: symptomatic relief of discomfort and pain
    OTC Dosage:
    • 97.5mg (maximum strength) three times daily with meals.
    • 95mg (regular strength) three times daily with meals
    • Do not administer for more than 2 days with antibacterial agents (no benefit if longer). May mask symptoms of inappropriate antibiotic choice.
    Indication: symptomatic relief of discomfort and pain, before antibacterial therapy becomes effective.

    Prescription dosage: Phenazopyridine (Pyridium®) 100-200mg three times daily with meals. Do not administer for more than 2 days with antibacterial agents. (no benefit if longer). May mask symptoms of inappropriate antibiotic choice.

    Warnings, precautions, adverse effects:
    • Headache/ rash /pruritis
    • Staining of contact lens
    • Discoloration of urine – reddish-orange in color
    • Patient information
    • Avoid if glucose-6-phosphate dehydrogenase deficient
    • Avoid if kidney function is less than 50mL/minute.
    Patient education:
    • This medicine will change the color of your urine to red or orange. This is temporary and harmless, but it can stain clothing and towels. Other body fluids may be discolored as well. Recommend mini-pads to minimize staining.
    • Don't wear soft contact lenses while taking this medicine. It can permanently stain your lenses.
    • Take with food
    • May mask symptoms of active infections

    I met a patient a few years back, a 30-year-old female with interstitial cystitis (IC), or what is commonly known as ‘bladder pain syndrome’. She kept track of her IC triggers, which included smoked foods, soda, especially “citrus based soda”, iced tea, and sports drinks.

    It is also advisable that the patient maintain a bladder diary, as patients truly suffer with this disease state. Many patients seem to get the most benefit from dietary restriction. This incurable inflammatory bladder condition affects up to half a million people, primarily women (10:1 females:males) . It causes severe pain and urinary frequency, similar to the symptoms caused by a severe bladder infection. Unlike infections, however, bacteria are not usually found.

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    Prophylaxis of Urinary Tract Infections

    Prophylaxis is indicated for:
    Women with 3 or more episodes per year (or 2 or more in 6 months). Be sure to exclude abnormalities: stones, reflux, fistula etc.
    Agents must eliminate pathogenic bacteria from the fecal or introital reservoirs, and not cause bacterial resistance. Prophylaxis is appropriate if recurrent cystitis episodes have no association to coitus.

    ANTIBIOTIC PROPHYLAXIS: Once daily dosing-usually at bedtime
    • Trimeth/Sulfa SS (400/80): ½ tablet daily at bedtime
    • Trimethoprim 100mg daily
    • Cephalexin (Keflex®)? 250mg daily
    • Nitrofurantoin (Macrodantin®)? 50mg or 100mg daily
    Note : this product is?NOT?MacroBID®.? It is an immediate release product. Take with food or milk to prevent GI upset.

    Post coital dosing for prophylaxis:
    • Trimeth/Sulfa SS (400/80) one tablet once
    • Trimethoprim 100mg one tablet once
    • Cephalexin 250mg one capsule once
    • Nitrofurantoin: 50mg or 100mg one capsule once
    Self-administered antibiotic therapy:
    • Self-administered single dose of Trimeth/Sulfa DS two tablets at onset of symptoms
    UTI prevention tips that actually work:
    • Urinate immediately after having sexual intercourse. Urinating flushes out bacteria that may have entered the urethra during intercourse.
    • Use proper hygiene. Wipe front to back.?
    • Rinse the vulva after sex.
    • Keep well hydrated with water and avoid “holding it” throughout the day
    • Wear regular cotton underwear. Thong underwear can lead to UTI’s by tracking bacteria from the rectal area into the urethra via the vagina.
    • Don’t smoke; it lowers immunity.
    • Avoid condoms coated with nonoxynol-9
    • In post-menopausal women, topically administer estrogen cream.? It decreases the colonization of the E.coli.
      • Nitrofurantoin is more effective; however, clinicians worry about pulmonary fibrosis with long term nitrofurantoin use.
    • Methenamine Hippurate (Hiprex®) FDA approved 1967: 1,000 mg twice daily
    • Methenamine Mandelate (Mandelamine®): 1,000 mg 4 times daily
    Urinary tract infection, prophylaxis/suppression. Prophylaxis or suppression of recurrent urinary tract infections when long-term therapy is indicated, and infection has been eradicated by appropriate antimicrobial treatment.? Needs acidic urine for maximum efficacy. Restrict alkalinizing foods and medications to maintain urine pH ≤5.5.

    Mechanism: methenamine component is hydrolyzed to formaldehyde in acidic urine. Hippuric or mandelic acid, has some antibacterial activity and also acts to keep the urine acidic.

    Note: should only be used?after?eradication of the infection by other appropriate antimicrobial agents.

    Cranberry appears to work by inhibiting the adhesion of type I and P-fimbriated uropathogens (e.g. uropathogenic E. coli) to the uroepithelium, thus impairing colonization and subsequent infection.? It seems to work in the lab, but there is no compelling data to “push” these products.

    Because of clinical study designs and the lack of consensus regarding the dosage regimen and formulation to use, cranberry products cannot be recommended for the prophylaxis of recurrent UTIs at this time.

    Cranberry tablets- (AZO Cranberry®) no data to support its use, and causes significant GI upset and heartburn.

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    Overview of Treatment Options for Urinary Tract Infections in Pregnancy

    Tetracyclines, Sulfonamides (1st and late 3rd trimester), fluoroquinolones.


    Cephalosporins: Cephalexin (Keflex®) 250-500mg every 6 hours for 7 days.
    Cefpodoxime (Vantin®) 100mg BID for 5-7 days (third-generation cephalosporin)
    Penicillins: Amox/clav (Augmentin®) 500mg every 8 hours OR Amox/clav 875/125 twice daily for 7 days.
    Nitrofurantoin: MacroBID® 100mg twice daily for 7-10 days (avoid if G-6-PD & at term).
    • Historically marked as ‘Pregnancy Category B’. Recommended that nitrofurantoin be AVOIDED during the first trimester and late last trimester of pregnancy due to potential for hemolytic anemia in newborns.
    Trimeth/Sulfa (Bactrim DS®): 1 tablet BID x 7days.
    • Avoid Trimeth/Sulfa during 1st trimester and 3rd trimester near term. Avoid if G-6-PD.
    • Remember, trimethoprim is a folic acid antagonist, and should be avoided during the first trimester.
    • Avoid all sulfonamides in the last days before delivery because they can displace bilirubin from plasma binding sites in the newborn, which may possibly increase risk for kernicterus.
    Fosfomycin (Monurol®) only indicated for UTI

    Mechanism: broad spectrum bactericidal antibiotic, that interrupts cell wall synthesis. It also reduces bacterial adherence to the uroepithelial cells.

    Dosage: 1 packet (3gm of granules) mixed with 3-4 oz. cool water and dissolve. Drink at once.
    May see diarrhea (9%) and Headache (4%) and nausea (4%)
    Pregnancy category-B

    Patient information:
    • May take with or without food.
    • Symptoms should improve in 2 or 3 days. If not, call clinician. Do not repeat dose.
    • Always mix with water. Do not ingest in dry form.
    • Clinician note: this drug is seldom used, so call the pharmacy to see if it is in stock.
    • Good choice if the patient is pregnant.
    • Good choice if the patient is sulfa allergic, or if local E.coli are over 20% resistant.
    • Approximate cost: $75.00 for 1 packet (1 dose)
    Fluconazole: For yeast infections, high dose fluconazole (400mg-800mg/day) is teratogenic. However, the 150mg dose for vaginal yeast infections has data that is not so clear. Best to avoid since topical azole antifungals such as clotrimazole and miconazole are so safe and effective.

    I would have to think that the toughest job for any OB/GYN would be prescribing any medication in pregnancy. I remember when Bendectin® was pulled from the market in 1983, due to lawsuits. Bendectin® was a combination of doxylamine and pyridoxine, both which were Pregnancy Category A drugs at the time. Today, we have Diclegis® and Bonjesta®, which contain the same ingredients for nausea of pregnancy.

    One day when my wife Denise was working the bench, the OB/Gyn department called with a question. They had a patient with a UTI and were not sure what to give. The patient was pregnant (so, no fluoroquinolones/tetracyclines). The culture showed resistance to penicillins (so, no cephalexin/penicillins), and the patient was from the Middle East and had Glucose-6 Phosphate deficiency (so, no nitrofurantoin or Trimeth/sulfa)! Of course, my wife knew the only answer...Fosfomycin (Monurol®), which the practitioners had never heard of!

    Denise ordered in the drug for the patient, who recovered without incident. As I always tell my student pharmacists, yes those patients are REAL and many times come to our pharmacies. We have to be the drug experts!

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    February 2022

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    Treatment of Uncomplicated Cystitis


    UTI’s are the most common bacterial infection in women. The most common bacteria found in acute uncomplicated cystitis is E.coli, which is responsible for 75% to 95% of all cases. The remainder of the cases are caused by Proteus mirabilis, Klebsiella pneumoniae, and Staphylococcus saprophyticus. Most cases can be treated with short course therapy.

    I highly recommend that pharmacists call the inpatient pharmacies at their local hospitals, as resistance rates may vary significantly by region. Hospital pharmacists are the keepers of the antibiograms.


    Sanford Guide recommends use only if local E.coli resistance is less than 20%, and patient has no allergy.
    Watch for drug interactions, especially with warfarin.
    Pregnancy Category D
    Complicated: Trimeth/Sulfa DS: Give BID for 7-10 days

    Sanford Guide recommends use of fluoroquinolones if local resistance patterns for E. coli are 10% or less and patients can’t take SMX/TMP.

    Watch for drug interactions.
    Absorption can be blocked with di and trivalent cations such as calcium, iron, magnesium etc.
    May cause fluctuations in blood sugars.
    Is an alternative choice for patients with sulfa allergy or contraindications (G6P-dehydrogenase).
    (Note: moxifloxacin does not achieve high enough levels in the kidney/bladder for treatment of UTI’s)

    Complicated: Ciprofloxacin 250-500mg BID for 7 to 10 days.
    • LEVOFLOXACIN (Levaquin 250mg) (1) TABLET DAILY FOR 3 DAYS
    Complicated: Levofloxacin 250mg daily for 7 to 10 days


    Recommended writing for “MacroBID” do not confuse for “Macrodantin”.
    Avoid if G6P-dehydrogenase. Pregnancy Category B
    Prescribing tips:
    • AVOID nitrofurantoin in patients with creatinine clearance less than 60mL/minute. However, there is a bit of a controversy, with some references saying 30-40mL per minute. The newest Beers list allows for nitrofurantoin use down to 30mL/minute.
    • AVOID nitrofurantoin if early pyelonephritis is suspected, because serum concentrations don’t get high enough to treat systemic infections.
    • AVOID last week of pregnancy due to potential for hemolytic anemia in newborns.
    • WATCH for: increased risk for pulmonary toxicity, neuropathy, hepatotoxicity.
    • AVOID in complicated UTI

    Fosfomycin (Monurol®) only indicated for UTI

    Mechanism: broad spectrum bactericidal antibiotic, that interrupts cell wall synthesis. It also reduces bacterial adherence to the uroepithelial cells.

    Dosage: 1 packet (3gm of granules) mixed with 3-4 oz. cool water and dissolved. Drink at once.

    May see diarrhea (9%) and Headache (4%) and nausea (4%) Pregnancy category-B

    Patient information:
    • May take with or without food
    • Symptoms should improve in 2 or 3 days. If not, call the clinician. Do not repeat dose
    • Always mix with water. Do not ingest in dry form.
    • Clinician note: this drug is rarely used, so call the pharmacy to see if it is in stock
    • May be a good choice if patient is pregnant
    • May be a good choice if the patient is sulfa allergic, or if local E.coli resistance rates are over 20%.
    • Approximate cost: $75.00 for 1 packet (1 dose)

    I am always impressed with the bacterial resistance rates in the areas that I practice. It makes sense to me that nitrofurantoin resistance rates are always less than 10% for E.coli.

    Given the fact that trimethoprim/sulfamethoxazole and the fluoroquinolones can be used for a variety of infections, there is more potential for overuse of these medications. Nitrofurantoin has limited use, and therefore, is much less likely to be “overprescribed.”

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    Overview of Acute Pyelonephritis


    Is an infectious inflammatory disease involving the kidney parenchyma and renal pelvis. Gram negative bacteria (most likely: E.coli) are most common. Infection usually ascends from the lower urinary tract, with the exception of Staph aureus, which is spread hematogenously. Usually occurs in women 18-40 years of age.

    Clinical presentation:
    • Temperature over 102F
    • Definite costovertebral tenderness (flank pain)
    • Voiding symptoms
    • Positive urine culture.
    Mild cases can be treated with oral medication. Severe cases should be hospitalized.
    • ALWAYS perform culture and sensitivity!
    • Monitor for drug interactions if using SMZ-TMP or fluoroquinolones.
    Antibiotics should be dosed for at least 2 weeks. Highly active agents such as fluoroquinolones can be given for 7 days.

    Sanford guide recommends:
    Ceftriaxone 1gm IV, then may transition to:
    fluroquinolones for 5-7 days.
    • Ciprofloxacin (Cipro®) 500mg BID x 7 days OR
    • Levofloxacin (Levaquin®) 750mg Daily for 7 days
    Other Options:
    • SMZ/TMP (Bactrim-DS®) should not be used for initial empiric therapy because of high rates of resistance, SMZ/TMP 160/800 mg (one DS tablet) PO twice daily x 14 days is appropriate treatment of uncomplicated cystitis for pathogens known to be sensitive.
      • Watch for warfarin interactions and hyperkalemia
    • Oral Cephalosporins for 14 days. (Oral beta-lactams are less effective for acute pyelonephritis and frequently relapse.)
    • Amoxicillin/Clavulanic acid (Augmentin®) for 14 days. (Oral beta-lactams are less effective for acute pyelonephritis and frequently relapse.)
    • Nitrofurantoins (MacroBid®) are not recommended for acute pyelonephritis as it does not attain therapeutic levels in renal parenchyma.
    Hopkins Antibiotic Guide recommends: consider an initial dose of a parenteral agent, particularly if fluoroquinolone resistance is >10%. Then complete treatment as guided by antimicrobial sensitivity results.
    • Ceftriaxone 1 gm IM or IV x 1
    • Gentamicin 5 mg/kg IM or IV x 1
    • Ciprofloxacin 400 mg IV x 1
    If hospitalized: treat until patient is afebrile for 24-48 hours, then complete a 2-week course with oral drugs. Follow up with urine culture 2 weeks after course of antibiotic therapy is completed, to ensure response and to prevent relapse.

    Chronic pyelonephritis: recommended treatment is 3 to 6 months of therapy.

    Pharmacists occasionally see patients coming into our practice sites seeking something for bladder burning and head to the phenazopyridine section.

    I make it a point to ask about having any back pain (flank pain) and if they have a fever. Acute pyelonephritis is a condition that phenazopyridine has no role in its treatment.

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    Urinary Tract Infections: The Basics 

    Causative Agents

    Pathogens most likely to cause urinary tract infections include primarily Escherichia coli, but also other Enterobacteriaceae (Klebsiella). Other gram-negative bacilli such as Pseudomonas aeruginosa may be involved. Staphylococci, enterococci, Proteus, and Candida species can also be implicated in urinary tract infections.

    Female Anatomy and the Risk of UTI
    • Short urethra facilitates ascent of organisms from the introitus into the bladder
    • Frequency of UTI increases after puberty due to sexual activity
      • Approximately 50% of women will develop at least one UTI within their lifetime, with 1 in 3 women having a UTI by the age of 24
    • Women with recurrent UTI may have more adhesive receptors on GU mucosa—allowing more binding sites for pathogens
    • Women whose mucosal secretions lack fucosyltransferase activity are more prone to recurrent UTI, as this enzyme keeps bacteria from adhering to the urethra
    • The female urethra is usually colonized with bacteria believed to originate from the fecal flora
      • Bacteria reach the bladder by a “massaging action” during sexual intercourse
    • Use of spermicides and diaphragms increase the risk of UTI
    • Risk factors include pregnancy, mechanical instrumentation, catheterization
    • Lactobacilli which produce lactic acid & decrease E. coli colonization in the vaginal flora help to prevent UTI, as well as circulating estrogen levels. Use of beta-lactam antibiotics (penicillins and cephalosporins) will destroy Lactobacillus, which is protective for UTI
    • In elderly females, poor bladder emptying due to prolapse may increase risk

    Male UTIs
    • Higher incidence in uncircumcised men has been observed
      • Over their lifetime, uncircumcised men are four times more likely to experience a UTI than circumcised men
    • The prostate secretes zinc, a potent antibacterial that stops the ascent of infection
    • Lower zinc levels in prostatic secretions of men with bacterial prostatitis
    • In elderly males, prostatic hypertrophy causes obstruction
    • Therapy is more difficult than in females. Treatment should last 10 to 14 days.
    • Uncomplicated infections are rare. Most infections are complicated, because of structural or functional abnormality which disrupts normal defense mechanisms.

    • Elderly population (over 65) equal ratio between male and female UTI
    • Most age-related UTI are asymptomatic
    • In patients with dementia, fecal incontinence causes increased incidence if UTI
    • Neuromuscular disease, such as strokes, may cause increased incidence
    • Catheterization is more common in elderly
    • Residual urine volume due to anticholinergic use, prostatic hypertrophy, urethral stricture, calculi, tumors, and bladder diverticula

    Treatment of Elderly Patients
    • Make sure there are symptoms, and that urine is abnormal, not just a positive culture
      • Treatment of asymptomatic UTI in the elderly is not advised. It is said to be a benign disease and treatment is not warranted.
    • Asymptomatic Bacteriuria is dependent on age. Check for obstruction if there are recurrent symptoms. Don’t treat chronic bacteriuria in elderly females; this is often due to diverticuli in the bladder.
    • Males: most common cause of infection is due to bladder outlet obstruction, because of prostatic hypertrophy
      • Obtain culture before treatment... because cause of infection is NOT as predictable in men as they are in women

    Treatment of Pediatric Patients

    If the child is under 5 with a positive urine culture, he/she should be treated even if asymptomatic with conventional courses of therapy used for symptomatic infections. In children, there is a greater risk of developing renal scarring and long-standing renal damage during the first five years of life.

    Urinary tract infections are common depending on the age group. We see most UTIs in young, sexually active females. Back in the day, the condition was referred to “honeymooner’s cystitis.” Urinary tract infections can also be common on the other end of the spectrum, affecting older women who have issues with incomplete bladder emptying.

    When I see my patients reaching for those urinary tract medications, such as phenazopyridine, I make sure they understand this is for symptomatic relief. Appropriate treatment for the UTI is still needed.

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    Overview of Testosterone Replacement Options

    Warnings/Precautions and/ Adverse effects: Traditional oral tablets: may cause GI upset and are of little value because of extensive first pass metabolism. May also cause hepatotoxicity. However, there is a newer formulation which bypasses these traditional issues caused by oral testosterone.
    • Edema, weight gain
    • Hypertension, CHF
    • LABS to be checked: hematocrit (red blood cell levels) (D/C if over 55%), serum testosterone, lipid profile every 6-12 months. PSA yearly and digital rectal exam twice yearly.
    • CANCER: men over 50 years who begin testosterone treatment should be reevaluated for prostate cancer three months and one year after beginning treatment
    • Acne can be exacerbated
    • Exacerbate benign prostatic hyperplasia, or enhanced growth of prostate cancer
    • Avoid testosterone in males with breast cancer, as testosterone can be converted to estradiol by aromatase.
    • Caution in patients with sleep apnea
    Drug Interactions:
    • May increase insulin requirements.
    • Increased clearance of propranolol.
    Chronic drugs that LOWER testosterone levels:
    • Prednisone 5mg/day and greater, or
    • Morphine 100mg/day or greater AND their equivalents.

    Representative Products and Dosages (Testosterone replacement):
    • • Delatestryl® (testosterone enanthate) 200mg/mL & Depo-Testosterone (Testosterone cypionate) 100 & 200mg/mL. Administered intramuscularly (IM) (generics are very inexpensive)
    Dosage: 200mg every 2-4 weeks. Generally, doses of over 400mg/month are not necessary.
    • Androderm® 2.5mg and 5mg patches. Apply to arm, back, abdomen or thighs. Change every 24 hours. Do NOT apply to the scrotum. Cost approx. $600/month
    TESTOSTERONE topical gels:

    Advantages: Provides therapeutic testosterone levels without large fluctuations, easier to use and less skin irritation than patches.

    Disadvantages: Transfer of gel or solution from one person to another --avoid this by washing hands after application and wearing clothing over application site.

    Comments: Do not apply to genitals.

    Testosterone Monitoring: Check testosterone level at least 7 to 14 days after initiation of therapy.
    • Androgel® testosterone gel 1.62% packets and pump ($650/month) generic available Apply once daily to upper arm, shoulders or abdomen. One study showed a 30 percent lower bioavailability when it was applied to the abdomen as opposed to the arms and shoulders.
    • Fortesta®: testosterone gel 2% 10mg per pump ($490/month) generic is available Dosage: Start with 40 mg (4 pump actuations) once daily in the morning applied to thighs to minimize product transfer. Max dose is 70 mg per day.
    • Testim® gel (1%) ($710.00/month) generic is available Start with 5 g (50 mg of testosterone) once daily applied to shoulders or upper arms. Increase to 10 g if needed. Do not apply to abdomen.

    Oral Testosterone: Testosterone undecanoate (Jatenzo®) : 158mg, 198mg and 237mg

    Mechanism: Jatenzo® is lipophilic, absorbed through the intestinal lymphatic system, which then eliminates first pass metabolism. Previous oral testosterone therapies (methyltestosterone) saw first pass metabolism and associated liver issues.

    Dose: 1-2 capsules twice daily with food.

    Dose range: minimum of 158 mg twice daily and a maximum of 396 mg twice daily based on serum testostxerone drawn 6 hours after the morning dose at least 7 days after starting treatment or following dose adjustment and periodically thereafter

    • No liver function issues
    • No topical transfer
    • Ease of use

    Warnings: May cause hypertension and cardiovascular events such as myocardial infarction and stroke

    Cost: for the two lower strengths around $950/month. Highest strength is $1900/month. Bottles of 120 capsules

    • Check a morning TOTAL testosterone...and repeat to confirm. FREE testosterone: check if the total is borderline especially if the patient has factors that can alter levels, such as: obesity, diabetes, cirrhosis, hypo- or hyperthyroidism, etc
    • Check serum testosterone 4 to 12 weeks after starting therapy. In older men, aim for the low end of normal, such as 400 to 500 ng/dL.
    • Measure midway between injections for testosterone enanthate and cypionate
    • Also monitor for increased hematocrit and PSA and do a digital rectal exam at baseline, 3 to 6 months, and then yearly.

    Direct to consumer advertising is a real thing when it comes to testosterone replacement. One of the physician assistants I had the privilege to work with directly said he seldom complies with an older male’s request to do testosterone levels. For the most part, they are low! And when the guy finds out they are low he wants a supplement.

    Direct to consumer advertising for testosterone replacement in males really works.

    Between 2009 and 2013 among US men residing in 75 United States direct marketing areas, regional exposure to televised direct to consumer advertising was associated with greater testosterone testing, new initiation, and initiation without recent testing. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471355/

    Testosterone levels are rarely identified as a cause of erectile dysfunction. Must do an endocrine workup, must also exclude prostate cancer by PSA and digital rectal exam. Testosterone should only ever be administered to hypogonadal men, with documented low testosterone levels.

    Testosterone requires conversion to dihydrotestosterone (DHT) for its action on the external genitalia, sexual hair, and of course the prostate gland. Testosterone requires conversion to estradiol to have its effects on bone strength. If a male has aromatase deficiency, osteoporosis occurs.

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    January 2022

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    Treatment of Premature Ejaculation (PE)

    IELT: Intravaginal Ejaculatory Latency Time (time from intromission until ejaculation)
    Prevalence is consistently around 30% in men age 18-59 in the U.S.
    In the Diagnostic and Statistical Manual of Mental Disorders V (DSM-V), PE is defined as a sexual disorder with:
    • consistent ejaculation within 1 minute or less of vaginal penetration
    • duration over a period of at least 6 months
    • experienced 75–100% of the time
    • the condition results in clinically significant distress, sexual frustration, dissatisfaction, or tension between partners
    • this condition is not better accounted for by another non-sexual mental disorder, medication or illicit substance use, or medical condition
    Topical anesthetics
    Mechanism: contain benzocaine or lidocaine, a local anesthetic, causing a decreased sensation. Promoted to decrease premature ejaculation.

    There are desensitizing gels with 7.5% lidocaine, as well as condoms with benzocaine (4-5%) to cause desensitization

    Warnings/Precautions and/ Adverse effects:
    • Sensitivity to this product/ or benzocaine or lidocaine
    • Apply 10-15 minutes before intercourse
    • Use a condom to prevent transfer to partner.
    Is a SSRI and meets many of the ideal treatment criteria, including oral administration, pharmacokinetic profile suitable for PRN administration, and a good side effects profile.'

    Can be taken with a PDE5 inhibitor or alcohol without any significant interactions. Compared to placebo, the 60mg to 100mg produced statistically significant improvement in the men’s IELT generating an approximately 3 fold increase in average IELTs from just under 1 minute at baseline, to 2.91 minutes (60mg) and 3.1 minutes (100mg).

    Nausea is the most common side effect at approximately 9%

    In October of 2005, the FDA sent a non-approvable letter to Johnson & Johnson. The drug “Priligy” by Jaansen Pharmaceuticals is available in Europe.

    Paroxetine is far superior to fluoxetine and other SSRIs within this realm, with one study showing an increase of IELT of 9 minutes. For improvement of IELT, it requires chronic daily dosing which patients find inconvenient and laden with unpleasant side effects. SSRIs have a slow onset of action and adverse effects including nausea, drowsiness, cognitive impairment, and sexual side effects. With any SSRI, start with a low dose and gradually increase at monthly intervals. Will take at least 2-3 weeks of therapy to see desired effect.

    In one study, off label use of clomipramine was shown to be more effective in prolonging IELT than sertraline and fluoxetine. Side effects were more common than other agents.

    Dose: clomipramine 25mg taken 4 to 6 hours before intercourse.

    Substantially prolonged ejaculation time in about half of the men, although was of little benefit with short initial IELT’s.

    Considered a third line agent, due to its effects with serotonin and norepinephrine. Because of the potential for opioid abuse, this therapy is not recommended.

    Ejaculatory dysfunction
    Frequently seen with tamsulosin, switching to alfuzosin provides relief from ejaculatory dysfunction from other alpha blockers.

    Getting your patients comfortable to discuss sexual dysfunction does require a lot of trust. When I notice that a guy is not being adherent to his tamsulosin, I will inquire if he is having sexual dysfunction. I have had four male patients admit to me that they were having painful ejaculation while taking tamsulosin. I recommended to their physician to switch to alfuzosin, which the physician made the change. All four patients were quite pleased with the results of the switch.

    On another occasion, a young couple come to the pharmacy and wanted to talk with me. She was complaining that he was "taking too long” and was it the clonazepam or sertraline causing this problem. Of course, it was the sertraline, and I explained to them that any of the SSRI's can cause this problem. He was changed to bupropion for his depression, and the issue resolved.

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    Overview of Nontraditional Options for Erectile Dysfunction

    Alprostadil Intracavernosal injection (FDA approved 1995)

    Mechanism: direct injection of vasoactive prostaglandins onto the corpora cavernosum.

    Warnings/Precautions and/ Adverse effects: First injection should be done in a clinician’s office with trained personnel. Must stay in office until complete detumescence occurs. If there is no response, the next higher dose may be given in 1
    • Generally reserved for patients who have failed other regimens.
    • May be used only twice a week.
    • May cause: Penile fibrosis, priapism, penile pain. hematoma, ecchymosis
    Contraindications: sickle cell anemia, leukemia, (any condition predisposing patient to priapism), penile angulation, Peyronies disease , cavernosal fibrosis & penile implants.

    Representative Products and Dosages:
    • Alprostadil (Caverject®) 5mcg/ml , 10mcg/ml, 20mcg/ml, 40mcg/ml injection
    • Alprostadil (Edex®) 10mcg/ml, 20mcg/ml
    For purely neurogenic dysfunction, start with 1.25mcg. If other etiologies, start with 2.5mcg. Final dose should not exceed 60mcg, should produce an erection adequate for intercourse within 5 to 20 minutes ideally to last no longer than 1 hour. (Mean dose at end of 6 months- 20mcg) (cost about $90.00 per injection)

    Alprostadil urethral suppository (FDA approved 1996)

    Mechanism: alprostadil inserted via suppository into the urethra. Apply post urination, residual urine disperses the medicated pellet permitting alprostadil to be absorbed by the urethral mucosa. Then transported through the erectile bodies by communicating vessels between corpus spongiosum and corpora cavernosa. Induces vasodilatation in the vascular beds.

    Erection occurs in 5 to 10 minutes and lasts 30-60 minutes. Can be used up to twice daily.

    Warnings/Precautions and/ Adverse effects:
    • May cause transient penile pain, and hypotension
    • NOT priapism
    • Headache and dizziness, testicular pain
    • Possible urethral abrasions and bleeding
    • Do NOT use if partner is pregnant, unless using a condom

    Representative Products and Dosages:

    Alprostadil (Muse®): 125mcg, 250mcg, 500mcg, and 1000mcg urethral suppositories. Are small pellets one time use applicator/injector containing the alprostadil dose, about 30mm into the urethra. (cost= about $75/dose)

    Papaverine penile injection
    Mechanism: Smooth muscle relaxer
    Relaxes blood vessels and allows increased blood flow to the penis.
    Possibly inhibits phosphodiesterases and it may have direct actions on calcium channels.
    A natural opiate from the poppy plant.
    • Onset: 10 minutes. Intercourse should be attempted within 2 hours. Maximum 3 times per week.
    • Dose: 30 to 60mg: slowly inject over one or two minutes to completely inject the dose. This minimizes serious adverse effects such as arrhythmias.
    Mechanism: blocks presynaptic alpha-2 adrenergic receptors. Increases parasympathetic and decreases sympathetic activity. Erection is linked to cholinergic activity, and alpha-2 blockade, which theoretically results in increased penile blood inflow, decreased outflow or both.

    Widely used as an aphrodisiac to improve sexual drive. Frequently seen in herbal or “natural” remedies for erectile dysfunction.

    Warnings/Precautions and/ Adverse effects/Drug Interactions
    May cause: anxiety, insomnia, tachycardia and hypertension.
    • American Urological Society has cautioned against the use of yohimbine.
    • HAS NO FDA sanctioned indications
    • Contraindicated with antidepressants
    Alprostadil (Prostaglandin E1, PGE1) is used in the management and treatment of erectile dysfunction in males and for temporary patency of ductus arteriosus in newborns with congenital heart diseases before surgical intervention. PGE1 causes smooth muscle relaxation, leading to vasodilation, increasing peripheral blood flow and helping with erectile dysfunction.

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    Overview of 5-PDE Inhibitors for Erectile Dysfunction

    Phosphodiesterase type-5 inhibitors:

    sildenafil (Viagra®)-approved 1998
    vardenafil (Levitra®) approved 2003
    tadalafil (Cialis®) approved 2003

    Mechanism: Works by enhancing the effect of nitric oxide by inhibiting phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by Phosphodiesterase-5 inhibitors produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, which in turn produces an erection.

    Warnings/Precautions and/ Adverse effects:
    • Color disturbances: (blue/green) important for pilots (PDE-6 found in retina) can be affected at higher doses.
    • Headache (16%), facial flushing, dyspepsia
    • Hypotension: 8-10mm decrease in systolic & 5-6 mm in diastolic.
    • Hearing loss: ISMP-2016: reports a strong association between PDE5 drugs and hearing loss. PDE5 caused hearing loss 21.5 times higher than similar comparators.
    • In 1998, there were 123 sildenafil related deaths, 67% were MI and 36% developed CV symptoms within 5 hours of administration. Interestingly, less than 20% of these patients took nitrates.
    Drug Interactions (5-PDE inhibitors)
    • CONTRAINDICATED with nitrate use.
    • CONTRAINDICATED with alpha blockers due to hypotension.
    • Caution with all blood pressure medications.
    • Metabolized by Cytochrome P450 3A4. Cimetidine increases sildenafil levels by 56%. Also increased with ketoconazole and erythromycin (180% increase)
    • Give lower doses to men who take potent CYP3A4 inhibitors such as erythromycin, ketoconazole, itraconazole, ritonavir, or indinavir.
    Representative Products and Dosages

    BrandGenericDose mgOnset min.Duration
    Viagra®sildenafil25,50,10030 min4 hours
    Levitra ®vardenafil2.5,5,10,2020 min4 to 5 hours
    Cialis®tadalafil5, 10, 2030 min36 hours (weekend)
    Cialis®tadalafil2.5mg or 5mgTaken once daily
    Stendra®avanafil50,100,200mg15 min4 hours

    Dosage: On demand dosing - Taken on an as needed basis, usually ½ to 1 hour before sexual activity

    Cialis® tadalafil continuous dosing The low-dose daily dosing provides an option for men with ED who want a medication that can be taken without regard to timing of sexual activity and who anticipate sexual activity at least twice weekly. Men will take 2.5 or 5 mg tadalafil daily instead of 5 to 20 mg as needed. The long half-life of tadalafil allows for continuous daily dosing, so men do not need to plan ahead.

    Revatio® (sildenafil) 20mg: treatment of pulmonary arterial hypertension. Retails for $.50- 2.00/tablet…
    • Dose: 20mg 3 times daily, spaced 6 hours apart.
    • May improve exercise tolerance
    • May slow down worsening changes in physical condition
    • NOTE: all strengths of sildenafil (25,50 and 100mg) are available as GENERICS. Prices are less than 10% of the cost of the brand name Viagra®


    ALZHEIMER's PREVENTION: Cleveland Clinic’s Genomic Medicine Institute examined a database of more than seven million patients, finding that the ED medication performed significantly better at Alzheimer’s prevention than high blood pressure and diabetes drugs like losartan and metformin. Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate. Based on retrospective case–control pharmacoepidemiologic analyses of insurance claims data for 7.23 million individuals, it was found that sildenafil usage was significantly associated with a 69% reduced risk of AD.

    High Altitude Pulmonary Edema (HAPE) is the abnormal accumulation of plasma and some red blood cells in the lung air sacs due to a breakdown in the pulmonary blood-gas barrier, triggered by “thin oxygen” seen at higher altitudes. PDE-5 inhibitors sildenafil and tadalafil prevented hypoxic pulmonary hypertension and the development of HAPE.
    • • Sildenafil: single dose of 50 or 100 mg just prior to exposure for acute ascent, or give 50 mg every eight hours if staying 2-6 days.
    • • Tadalafil: 10 mg every 12 hours
    I am amazed with the numerous uses for the 5-PDE inhibitors. Their side effects of hypotension can be so bothersome, that pilots cannot fly, according to FAA regulations, for 8 hours after using sildenafil and vardenafil. For tadalafil on ‘as needed’ basis, pilots have to wait 24 hours!

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    Broad Overview of Erectile Dysfunction

    Erectile dysfunction: (DSM IV- American Psychiatric Association)
    • The consistent inability to achieve and/or maintain an erection adequate for satisfactory sexual intercourse
    • Cause is marked by distress or interpersonal difficulty
    • Cause is not better accounted for by a drug of abuse or medication or direct physical effects of a substance
    It’s complicated---both physical and psychological components are at play. Most men experience spontaneous erections during rapid eye movement sleep and often wake up with an erection during the night. Complete loss of nocturnal erections is present in men with neurologic or vascular disease and may help rule out a psychogenic component. Parasympathetic nerves mediate an erection, while sympathetic nerves are responsible for ejaculation and penile stiffening. Nitrous oxide and other chemicals cause vasodilation, which leads to venous occlusion, rigidity and erection.

    • Cerebrovascular disease 70%
    • Coronary artery disease 60%
    • Coronary artery bypass graft 60%
    • Diabetes mellitus 50%
    • Peripheral vascular disease 70%
    • Untreated hypertension 10%
    Complete erectile dysfunction: About 5 percent of men (1/20) that are 40 years old have complete erectile dysfunction. About 15 percent of men at age 70 have complete ED.

    Mild and moderate erectile dysfunction affects approximately 10 percent of men per decade of life:
    • 50 percent of men in their 50’s
    • 60 percent of men in their 60’s.
    • 70 percent of men in their 70’s
    Classes of Drugs implicated with ED
    • Major antipsychotics (typical)
    • Tricyclic antidepressants
    • SSRI antidepressants
    • Anxiolytics (benzodiazepines)
    • Anticholinergics (as antispasmodics & anti-Parkinson’s drugs)
    • Antihistamines (especially sedating)
    • Muscle relaxants
    • Antiarrhythmic (disopyramide) (amiodarone) (mexiletine)
    • Diuretics: thiazides and spironolactone
    • Central sympatholytics: methyldopa and clonidine
    • Beta-Blockers (propranolol & metoprolol)
    • Cimetidine
    • Digoxin
    • Indomethacin
    • Lithium
    • Metoclopramide
    • Phenytoin
    • Ketoconazole
    • Anti-androgenic agents (bicalutamide, flutamide, leuprolide)
    • Amphetamines
    • Barbiturates
    • Cocaine
    • Marijuana
    • Narcotics/Opiates (especially if over 100 MME per day)
    • Nicotine

    MECHANISMS for medications causing ERECTILE DYSFUNCTION

    Medication:Mechanism Proposed:Modified Libido/Sexual Response:
    Antihypertensives, anxiolytics, ethanol, muscle relaxants, narcotics, neuroleptics sedativesSEDATIONDecreased libido
    Cimetidine, Marijuana, Digoxin, excess Ethanol, Ketoconazole, SpironolactoneTestosterone antagonismLibido
    Metoclopramide, Narcotics, AntipsychoticsProlactin elevationLibido
    Anticholinergic Agents, TCAs, antihistamines (1st generation)Parasympathetic dysfunctionPenile tumescence
    Diuretics, methyldopa, beta-blockersDecreased arteriolar flow to corporaPenile tumescence

    DRUG causing sexual dysfunction:Possible alternative:
    AnticonvulsantsValproic acid
    AntihypertensivesACE inhibitors & Calcium Channel Blockers, ARBS, alpha-blockers
    Anti-ulcer drugsFamotidine
    Nonsteroidal anti-inflammatoryDiclofenac
    Antihistamines (1st generation)Second generation antihistamines

    I remember as a teenager watching an episode of M*A*S*H where “Hawkeye” was out with a nurse and was having “difficulties”. He was talking with BJ, his tentmate and told him the “couldn’t”. BJ responded, “couldn’t what?”. Hawkeye said, “you know, the big couldn’t.” That was the only reference that I ever remember seeing on TV until sildenafil (Viagra®) came out in 1998.

    Now, guys walk into the pharmacy and say, “Hey doc, I need a refill on my Viagra”. Wow how times have changed. Before the three PDE-5 inhibitors became generic, the Super Bowl was overrun with ads for ED drugs. Remember Bears Coach Mike Ditka (Pitt alumnus) promoting ED products? Now that these generics are cheap, more and more men are buying them on a regular basis.

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    December 2021

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    Benign Prostatic Hyperplasia (BPH): Complicating Medications & Related Conditions

    Benign Prostatic Hypertrophy
    • Most common benign neoplasm of American men.
    • Nearly ubiquitous condition among all elderly men. Nearly 80% of men who live to be 80 have BPH. 50% will be symptomatic. 50% of the symptomatic patients require treatment.
    Irritative symptoms:
    • Dysuria (discomfort when urinating)
    • Nocturia (frequent urination at night)
    • Urgency
    • Frequency
    • Burning
    • Hesitancy
    • Straining
    • Dribbling
    • Weak stream
    • Incomplete emptying
    MEDICATIONS to Avoid with BHP
    • Testosterone: causes prostate enlargement and growth. Although the television is chocked full of commercials for men with “low T”, care must be exercised in the older population so as not to exacerbate prostate issues
    • Sympathomimetic agents may cause or worsen urinary difficulty in patients with prostate enlargement due to smooth muscle contraction in the bladder neck via stimulation of alpha-1 adrenergic receptors. Therapy with sympathomimetic agents should be administered cautiously in patients with hypertrophy or neoplasm of the prostate. Avoid all amphetamine products as well as pseudoephedrine (Sudafed®) in the older population.
    • Drugs with significant anticholinergic adverse effects: decrease urinary bladder detrusor muscle contractility, resulting in urinary retention.Avoid first generation antihistamines, tricyclic antidepressants, phenothiazines. However, drugs like tolterodine (Detrol®) poses little risk of urinary retention, if there is good flow. Antimuscarinics work during storage, rather than voiding.
    • Anticholinergics: Avoid anticholinergics such as benztropine, hyoscyamine and trihexyphenidyl.
    • Diuretics: polyuria secondary to high dose therapy may present as urinary frequency.

    Be sure to rule out Bacterial Prostatitis:
    Inflammation of prostate gland and surround tissue as a result of infection. Pathogenic bacteria, usually gram-negative organisms, must be present in prostatic secretions and in urine. A urine gram stain is indicated in any patient with suspected bacterial prostatitis.

    Clinical appearance:
    • Sudden onset of fever, chills, myalgia, malaise, cloudy urine
    • Localized pain: perineal and or suprapubic regions.
    • Digital palpitation of the prostate via the rectum may reveal a swollen, tender, warm, tense or indurated gland.

    Prostatitis Usual etiologyTreatment
    Less than age 35 years oldN. gonorrhoeae, C.trachomatisceftriaxone 250mg IM + doxycycline 100 BID x10 days
    Over 35 years of ageEnterobacteriacae (coliforms)Fluoroquinolones OR Trimeth/Sulfa DS BID for 10-14 days
    Chronic bacterialEnterobacteriaceae (80%)
    Pseudomonas aeruginosa
    Ciproflox 500 BID x 4 weeks or Levoflox 750mg daily x 4 weeks. Trimeth/Sulfa DS BID for 1-3 months.

    Patients frequently inquire about getting something for their cold symptoms that is safe for hypertensive patients. Although pseudoephedrine is safe for most patients with controlled blood pressure (it raises blood pressure by about 3mm Hg), we need to be cautious in patients with prostate issues.

    I always ask any patients with as much gray hair as I have if they have any issues with their prostate. Most of us are aware that first generation antihistamines (such as diphenhydramine) should be avoided, but we also need to avoid pseudoephedrine. Although phenylephrine may be safer, it’s practicality as a decongestant is limited.

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    Overview of 5-Alpha Reductase Inhibitors for Benign Prostatic Hyperplasia (BPH)

    Getting to know the prostate:
    • At birth, it is pea-sized and weighs 1gm. The prostate stays pea sized until puberty, reaching “adult size” by age 25 to 30.
    • The prostate typically remains that size until patient is 40. At that time, a second growth spurt begins and continues until the man is 70 or 80. During this time, the prostate can double or triple in size.
    5-Alpha Reductase Inhibitors

    Mechanism: Inhibits the production of dihydrotestosterone. Most useful in male patients whose prostates are very large. Minimal benefit in patients with normal or moderately enlarged prostate gland, and whose BPH symptoms are caused primarily by muscle cell overgrowth.

    Indications: Patients with large prostates (50-60 gm), who are not good surgical candidates, those who wish to avoid surgery, and those who cannot tolerate the side effects of alpha-adrenergic antagonists.

    Warnings/Precautions/Adverse effects:
    • Pregnancy Category-X
    • Women who are of childbearing age should not handle tablets, crushed or broken.
    • Erectile dysfunction in about 4%
    • Decreased libido, decreased ejaculate volume.
    • Breast tenderness and enlargement
    • Testicular pain
    • Dutasteride (Avodart®) : 0.5mg capsules : one capsule daily
    • Finasteride (Proscar®) : 5mg tablets : 1 tablet daily.
    • Finasteride (Propecia®): 1mg tablets-------for alopecia, not for BPH
    Prescriber notes: Finasteride and Dutasteride are available generically and decrease the need for surgery by 50% compared to alpha blockers. Dutasteride is three times more potent of an inhibitor of 5-alpha-reductase type 2 and 100 times more potent of an inhibitor of 5-alpha-reductase type 1, when compared to finasteride. Dutasteride 0.5mg reduces serum DHT by 94% compared to Finasteride 5mg at around 70%.

    Drug interactions: Dutasteride is metabolized by CYP450-3A4. According to in vitro data, blood concentrations of dutasteride might increase in the presence of CYP3A4 inhibitors such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, and ciprofloxacin. These are considered to be moderate drug-drug interactions.

    Natural remedies—Saw palmetto

    Many previous studies suggest that saw palmetto leads to mild to moderate improvement of urinary symptoms of BPH. Some studies suggest that it's comparable to finasteride, but probably less effective than alpha-blockers. A well-designed NIH trial shows no significant improvement in men with moderate to severe BPH who took saw palmetto for a year.

    The difference might be: patient study group had more severe symptoms, or different formulation of saw palmetto. Typical dose 160mg twice daily. Always expect different results from different formulations. More rigorous studies suggest that saw palmetto isn't better than placebo for BPH symptoms.

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    Overview of Alpha Blockers for Benign Prostatic Hyperplasia (BPH)


    Mechanism: Relaxes smooth muscles, especially in the urinary tract and prostate. By relaxing muscles around the prostate, they increase urinary flow. Minimal effect on sex drive.

    Alpha blockers are classified according to selectivity and half-life. Alpha-1a receptors are localized to the prostate and bladder neck, and selective blockade results in fewer systemic side effects (orthostatic hypertension, dizziness, tiredness, headache & rhinitis). These agents work quickly and may exhibit symptomatic relief when appropriately dosed, within 2 weeks. Approximately 70% of patients will respond.

    Nonselective alpha blockers: Terazosin (Hytrin®), Doxazosin (Cardura®), Prazosin (Minipress®). Prazosin is not approved for BPH.

    Selective alpha-1a blockers: Tamsulosin (Flomax®) and Alfuzosin (Uroxatral®) Silodosin (Rapaflo®)

    Warnings/precautions (alpha blockers): Orthostatic hypotension may occur with the first few doses. Minimize by slow titration. Watch for syncope. Best to have patient take at bedtime to minimize dizziness.

    Significantly less side effects with the selective alpha-1a blockers. Titration not required for Alfuzosin (Uroxatrol®)

    Adverse effects: (alpha blockers):
    • Orthostatic hypotension
    • Dry mouth
    • Urinary urgency
    • Constipation
    • Priapism, ejaculatory problems
    Intraoperative Floppy Iris Syndrome: ALL Alpha-1 Blockers cause intraoperative floppy iris syndrome (IFIS). The iris becomes flaccid and billows in response to intraoperative irrigation currents, causing the potential prolapse of the iris toward phacoemulsification incisions. Ophthalmologists can modify their surgical techniques including using iris hooks, iris dilation rings, viscoelastic devices. Ophthalmologists MUST know before surgery that patient has been on alpha blocker therapy.

    Drug interactions:
    NSAIDs decrease antihypertensive effects
    Beta Blockers and Diuretics increase the antihypertensive effects of these agents

    Patient Education:
    • Watch for postural hypotension
    • Watch for drowsiness
    • If priapism occurs, seek medical treatment immediately.
    DOXAZOSINCARDURA®BPH1mg at bedtime1-16mg/day16mg=HTN
    PRAZOSINMINIPRESS®1mg at bedtime2-20mg (in 2-3 doses)40mg
    TERAZOSINHYTRIN®BPH1mg at bedtime1-20mg20mg/day

    TAMSULOSINFLOMAX®BPH0.4 mg at bedtime0.4- 0.8mg0.8mg
    SILODOSINRAPAFLO®BPH8mg with food8mg with food (4mg if CrCl=30-50)

    Prescriber notes:
    • Alfuzosin (Uroxatral®) is least likely of alpha blockers to cause ejaculatory problems. Does not require dosage titration.
    • Silodosin (Rapaflo®) : Contraindicated with potent CYP3A4 inhibitors
    • Tamsulosin (Flomax®) is least likely of alpha blockers to cause orthostatic hypotension, and MOST likely to cause ejaculatory problems

    One of my favorite stories I share with students occurred in the family practice office I worked at two days a week. A patient was not being adherent to his terazosin (Flomax®) and, when I questioned him, he was experiencing sexual side effects. We changed his medication to alfuzosin (Uroxatrol®). Three months later when I saw him at a Christmas party, I got the biggest hug! He was so pleased with the change in therapy. The truth is we had at least 4 other gentlemen at the clinic with the same issues and changed with good results.

    At the same office, we had a patient in for a simple physical for cataract surgery. The patient did not understand the ophthalmologist’s instructions and continued to take his tamsulosin and was scheduled for surgery in just two days. I called the eye doctor’s office and informed them, and the nurse said they would inform the surgeon doing the surgery. He simply used iris hooks to stabilize the iris, and the surgery was uneventful. When we get prescriptions for eye drops for a patient preparing for cataract surgery, if it is a male, I always check for alpha blockers on their chart.

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    Prescriptions That May Contribute to Hair Loss

    DRUG CLASSExamplesComments
    ACE inhibitorsCaptopril, Lisinopril, RamiprilUp to 5% of Ramipril patients may experience hair loss
    AndrogensTestosteroneMay cause androgenic alopecia
    Blood ThinnersWarfarin especially high doses HeparinOver 5% of warfarin patients see hair loss; up to 50% if on high doses
    AntifungalsFluconazole, Terbinafine, KetoconazoleUp to 20% with fluconazole / Over 5% for terbinafine
    Anti-ThyroidMethimazole & PropylthiouracilAlso, check thyroid levels for any hair loss
    Aromatase inhibitorsExemestane, Anastrozole, LetrozoleThey block estrogen formation / Frequency: Exemestane-15% ; Anastrozole-5%
    BuspironeBuspar®May cause hair loss 5%
    Calcium Channel BlockersNifedipine (Procardia)May cause hair loss up to 5%
    Chemotherapeutic agentsDepends on drug. Antimitotic agents are the worstCauses anagen effluvium. (Active follicles)
    AntidepressantsbupropionBupropion had highest risk; paroxetine had lowest
    Estrogen blockerTamoxifenCauses androgenic alopecia
    ImmunosuppressantsLeflunomide mycophenolate tacrolimus Leflunomide- 15% ; mycophenolate=15% tacrolimus =28%
    InterferonsFor MS and HepatitisMay cause hair loss 50% of the time
    Mood StabilizersLithium; Divalproex & Carbamazepine can be used for seizuresLithium up to 20% / Divalproex up to 28%- may treat with zinc and selenium / Carbamazepine up to 6%
    Oral ContraceptivesThe more androgenic progestins are most likely to cause TE. Desogestrel, norgestimate, drospirenone are LEAST androgenic progestins
    Vitamin-A analogsAcitretin and isotretinoinIsotretinoin for acne -5% / Acitretin for psoriasis up to 75%
    StatinsAtorvastatin and SimvastatinRosuvastatin does not cause hair loss

    Treatment of Hair Loss

    Finasteride: Although we are accustomed to dispensing Finasteride (Proscar®) at a dose of 5mg per day for treatment of benign prostatic hypertrophy, the dose for treatment of male patterned is finasteride 1mg (Propecia 1mg). 1mg per day inhibits the production of dihydrotestosterone in the scalp by more than 60%. Finasteride does not have any affinity for androgen receptors. Long term treatment is necessary; hair count showed a 9% increase after 1 year and showed a 24% increase after 4 years. Hair regrowth will be lost 9-12 months after drug discontinuation.

    Minoxidil (topical) 2% and 5%: Product works directly on the hair follicles by promoting hair growth by increasing the duration of anagen, shortening telogen, and enlarging miniaturized follicles. The 5% strength shows greater efficacy. Initially, hair shedding may occur at the initiation of treatment possibly due to stimulation of telogen follicles to reenter the anagen phase. Apply to the scalp twice daily, not to the hair. Combination therapy with finasteride plus minoxidil produces better results than either agent alone. These hair loss treatments seem to work best in patients that have shorter duration of baldness and more limited areas of baldness seem to do better with finasteride or minoxidil treatment.

    Biotin: Biotin deficiency is very rare and occurs from drinking raw egg whites. Supplementation for the purposes of hair loss is not beneficial for most patients.

    Last week we discussed the three phases that our hair cycles through. The telogen phase is when the hair is “at rest”. Telogen effluvium (TE) results from changes in follicular cycling that leads to the excessive shedding of telogen hairs. A wide variety of endogenous and exogenous factors have been linked to induction of telogen effluvium. Serious illness, major surgery, childbirth, rapid weight loss, nutritional deficiency, profound emotional stress, and drug exposure have been implicated in causing TE. Always recommend checking the thyroid!

    Telogen hair loss develops within two to three months after the inciting factor, and reverses once the inciting factor is eliminated. The cause of telogen effluvium may be multifactorial in patients who have multiple medical problems or who are taking multiple drugs. In some cases, an inciting factor cannot be identified. But, let’s look at medications implicated in causing hair loss. I’ve included the most common culprits (causing hair loss more than 5% of the time)

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    Hair Loss---The basics

    Our hair growth undergoes three distinct cycles. 90% of our hair follicles are in the “anagen” hair growth phase. In this cycle our hair grows about 0.3mm per day, which translated would be 9mm (1/3 inch) per month. Activation of the androgen receptor in the hair follicles shortens the anagen or growth phase in the normal hair growth cycle.

    The other 10% are in the “transformation” and “resting” phases. We lose about 50-150 hairs per day on average. Infrequent shampooing will show increased losses on days that the patient shampoos, due to manual dislodging, but the average is the same. A common cause of hair breakage is prolonged tension of hair by tight braids & ponytails. Ask the patient when they look at the lost hairs, do they see the follicular “bulb” at the bottom, to rule out hair breakage. If they are seeing the distinct white bulb, this indicates hair loss of the shaft in the resting or “telogen” phase.

    Thanks Mom: It's not ALL Mom’s fault! Baldness is strongly associated with the AR gene found on the “X” chromosome, but other chromosomes are at play too. A large study looking at 12,806 men of European ancestry found that people with the gene had more than twice the risk of developing male patterned baldness than people without it. However, factors from the father’s side, as well as other external factors can be implicated in male pattern baldness. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364959/)

    Patterned baldness- where genetics and aging meet:

    Male pattern hair loss or androgenetic alopecia in men is characterized by the slow, progressive loss of hair in a characteristic distribution. The condition is mediated by the action of androgens on androgen-sensitive hair follicles in genetically susceptible males. Drugs like low dose finasteride (Propecia®/Proscar®) are used to block the testosterone, which affects the androgen sensitive follicles. Finasteride and dutasteride, commonly used for enlarged prostate, are 5-alpha reductase inhibitors that block the conversion of testosterone to the more potent dihydrotestosterone. Interestingly, no one can find a link between baldness and prostatic hypertrophy.

    Female pattern hair loss most frequently presents as hair thinning on the frontal and vertex areas of the scalp. The frequency of this condition increases with age and is most commonly seen in women that are post-menopausal. It will affect as high as 19% of Caucasian women. Again, testosterone is the villain in our female patients, although most ladies have normal levels. Topical minoxidil (Rogaine®) is the first line treatment. If they poorly respond to minoxidil or have elevated testosterone levels, the anti-androgens like spironolactone (Aldactone®) or finasteride (Proscar®/Propecia®) can be tried. Allow at least a 4–6-month trial of minoxidil, finasteride or spironolactone to see benefits.

    Polycystic ovary syndrome is a common cause of excessive androgen production in women. Common dermatologic manifestations of elevated testosterone include excessive hair growth (hirsutism), acne, brown patches on the neck (acanthosis nigricans), and male patterned baldness (androgenic alopecia). Hirsute women often have increased activity of 5 alpha-reductase. Androgens affect the formation of acne by increasing sebum production from sebaceous glands in the skin. The diagnosis of polycystic ovary syndrome includes a complete history, physical examination with emphasis on evidence of androgen excess, and appropriate laboratory investigation to exclude other causes of hyperandrogenism. Treatments for the dermatologic conditions of hyperandrogenism include: diet and exercise, oral contraceptives, antiandrogens, and insulin-sensitizing medications, such as metformin.

    Vitamins?? Excess vitamin A from supplements (retinoids, isotretinoin, etc.) may cause hair to fall out. Deficiencies of zinc, iron, biotin, or vitamin D can also cause hair to thin. Supplementing these vitamins is only beneficial if there is a deficiency of that vitamin.

    Foods? Green tea, onions, pumpkin seeds, and edamame, among other foods and beverages, contain nutrients that may lower DHT levels and prevent hair loss. Obviously, this needs more study, but these foods are healthy additions to anyone’s diet regardless of their effect on hair loss.

    As this seasoned pharmacist gets older a lot of changes in the hairline have occurred. When my barber cuts my hair, the trimmings are a lot whiter and the pile seems to be smaller. We get questions about hair loss: could some of the drugs we dispense cause hair loss? could biotin or “Hair/Skin/Nails” formula help? Biotin deficiency, after all, is implicated in hair loss. Biotin deficiency, though, is very rare, and supplementation does little to restore hair growth.

    Have a Great Day on the Bench!!

    November 2021

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    Running out of Options: Now What? A Review of Rarely Used Epilepsy Drugs

    Felbamate (Felbatol®) ??(approved 1993)
    Rarely used due to extreme side effect profile. Parent or legal guardian should sign a legal consent form before administration.

    Mechanism: Blockade of NMDA ( n-methyl-d-aspartate)

    Dosage: 1200-3600mg in 3 divided doses. Days to steady state: 4 to 5 days

    Adverse effects: aplastic anemia, hepatotoxicity, blurred vision, diplopia, photosensitivity anorexia

    Contraindications: last resort therapy

    Drug Monitoring:? ?Aplastic anemia: rates of 20 to 30% may be as high as 70%. Liver failure is common; administer liver function tests every 1 – 2 weeks.

    Patient education: Report signs of infection, easy bruising, weakness, or fatigue

    Tiagabine (Gabitril®)?????(approved 1997)
    Available as tablets= 2, 4, 12 & 16mg

    Mechanism: selective GABA reuptake inhibitor (SGRI

    Use: adjunctive treatment for focal seizures in patients 12 years of age and older

    Dosage: Adults: (over 18yrs)= 4mg daily. May increase by 4mg per day at weekly intervals. Take in divided doses 2-4 times per day. Time to steady state is 2 days. Usual adult maintenance: 32-56mg in 2 to 4 divided doses. (max=80mg)

    Adverse effects: dizziness (27%), asthenia, somnolence, nervousness & nausea.

    Patient education: Take with food to minimize GI upset. Exercise caution when driving or operating dangerous machinery.

    Rufinamide (Banzel®)?(approved 2008)
    Available as 200 mg, 400 mg tablets

    Mechanism: modulates activity of sodium channels

    Use: Adjunctive treatment of Lennox-Gastaut syndrome in adults and children 4 years and older

    Adults Dose: Initial: 400-800 mg/day, divided twice daily (Max/day: 3200 mg--divided twice daily)

    Adverse effects: QT interval shortening, multiorgan hypersensitivity reaction, including rash
    • Drug interactions: CYP2E1 inhibitor (weak) andCYP3A4 inducer (weak). Watch for drug interactions with inducers and inhibitors of CYP450.
    • Take with food
    • Serum level monitoring not needed

    Perampanel (Fycompa®)? ??????????(approved 2012)
    Available as: 2mg,4mg,6mg,8mg,10mg,12mg tablets

    Mechanism: first?glutamate?receptor antagonist. Remember that glutamate is the most prevalent?excitatory?neurotransmitter. (GABA is an inhibitory transmitter).

    Use: Approved for the treatment of focal-onset seizures (four years of age and older), and as adjunctive treatment of primary generalized tonic-clonic seizures in patients with epilepsy 12 years of age and older. Maximum dose is 12mg/day.

    Schedule III controlled substance: possible euphoria and abuse.? Watch for mood changes such as anger, hostility.

    Drug interactions:
    • CYP450-3A4;? perampanel? 12 mg/day reduces the efficacy of levonorgestrel contraceptives. Select an additional or alternate contraceptive
    • Perampanel undergoes extensive liver metabolism.? Its effect will be decreased by CYP inducers like phenobarbital, carbamazepine and phenytoin.

    Cannabidiol (Epidiolex®) oral solution? 100mg/mL ?(Schedule-V)? (June-2018)
    Available as: 12.5mg, 25mg, 50mg, 100mg, 150mg and 200mg tablets
    • CBD is a chemical constituent of the cannabis plant
    • CBD does not cause intoxication or the euphoria that comes from tetrahydrocannabinol (THC), the primary psychoactive component of marijuana
    Inication: For the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older.

    Dose: Administered orally.
    • The starting dosage is 2.5 mg/kg twice daily (5 mg/kg/day).
    • After one week, the dosage can be increased to a maintenance dosage of 5 mg/kg twice daily.

    Pushing the dose to 20 mg/kg/day dosage resulted in somewhat greater reductions in seizure rates than the recommended maintenance dosage of 10 mg/kg/day, but with an increase in adverse reactions.

    Precautions: be sure to order liver function tests (ALT and AST) before starting therapy.
    • 32% of treated patients experienced drowsiness and sedation.
    • can cause decreases in hemoglobin and hematocrit
    • metabolized by CYP3A4 and CYP2C19
      • Inducers will lower blood levels.
      • Blockers will raise blood levels.

    Cenobamate (Xcopri®)?(approved 2019)
    Available as: 12.5mg, 25mg, 50mg, 100mg, 150mg and 200mg tablets

    Mechanism: inhibits voltage-dependent sodium channels and enhancing gamma-aminobutyric acid (GABA) inhibition through the GABA-A receptor.

    Use: focal (partial-onset) seizures in adults. Should be used in adults with treatment-resistant focal seizures.

    Dosing: Long titration schedule, starting with 12.5mg per day, escalating the dose every 2 weeks until the maintenance dose of 200mg per day is reached.? Maximum daily dose is 400mg.

    Drug interactions: expect lots, due to metabolism by CYP2E1, CYP2A6, CYP2B6, and to a lesser extent by CYP2C19 and CYP3A4/5, and glucuronide conjugation. May increase concentration of clobazam, phenobarbital and phenytoin.?

    Avoid in patients with hepatic or renal impairment.

    Our discussions on seizure medications shows us that our understanding of epilepsy is still in its infancy. Although we don’t see a lot of phenytoin and phenobarbital dispensed, we see even less of the drugs in today’s discussion dispensed. Newer agents are equally effective, and in most cases, better tolerated than older agents.

    Some of the newer drugs are only approved for adjunct therapy, while others may be appropriate for monotherapy. Many older drugs (carbamazepine, phenobarbital, phenytoin, primidone, valproic acid) have significant side effects, requiring serum monitoring, as well as tolerance developing. Also, some are enzyme blockers and inducers, having lots of drug interactions.

    I had a patient on felbamate 30 years ago, when the patient’s doctor ran out of options for seizure treatment. Just recently I dispensed a prescription of cerobamate.? One of the readers of Clinicians Corner has a family member who has benefited immensely with CBD for seizure control.

    We have a long way to go in neurology, as the neurons have yet to be completely understood!

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    Overview of Gabapentinoids

    Gabapentin (Neurontin®) FDA approved in 1993
    capsules 100mg, 300mg, 400mg; tablets 600mg & 800mg (available generically) Mechanism: A GABA analog, with no GABA receptor interaction, or GABA effects. Binds to the voltage-gated calcium channels at the alpha 2-delta subunit in the central nervous system. Seems to block excitatory neurotransmitters, as well as modulating the release of several neurotransmitters including glutamate, noradrenaline, and substance P.

    • Postherpetic neuralgia in adults
    • Adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy
    • ‘Off Label’ Uses: restless leg syndrome, hot flashes, diabetic peripheral neuropathy, back pain, paresthesia, anxiety in bipolar disease, alcohol withdrawal etc.
      • These are NOT FDA approved indications.
    • ADULT: initial: 300mg at bedtime, increase to 900mg over 3 days.
    • Maintenance 1,800 to 2,400mg/day in divided doses.
    • Most clinicians are using 2,400 to 4,800mg/day for epilepsy
    • For neuropathic pain don’t exceed 3,600mg per day.
    • CHILD: start 10 to 15mg/kg/day in 3 divided doses. Maintenance dose of up to 50mg/kg /day
    Renally impaired patients require dosage adjustment: GABAPENTIN
    Renal clearance CrCl in mL/minTotal Daily dosage range (mg/day)
    Over 60900-3,600mg
    15 and less100-300mg (reduce proportionally)

    Adverse effects: Fatigue, dizziness, headache drowsiness, ataxia, nystagmus, aggressive behavior in children.

    Contraindications: None

    Drug Monitoring: No optimal level given. Titrate to therapeutic effect, takes about one day to reach steady state.

    Drug interactions:
    • Antacids reduce bioavailability by 20%
    • Cimetidine reduces renal excretion of Gabapentin, causing increase in Gabapentin effect.
      • Separate by 2 or 3 hours.
    • Gabapentin does NOT induce or inhibit liver enzymes.
    • Elimination half-life is 5-7 hours; takes 2 days to completely clear the body
    • Takes at least 7 days to taper a patient off of gabapentin
    Patient education:
    • Watch for drowsiness-caution driving.
    • Avoid cimetidine & antacids by 2 hours.
    Abuse potential: especially with alcohol and high doses. Be on the lookout for frequent requests for early refills. Some states now have Gabapentin in Schedule-V
    • States where gabapentin is classified as a controlled substance: Alabama, Kentucky, Michigan, North Dakota, Tennessee, Virginia, and West Virginia.
    • Not controlled but mandated reporting: Connecticut, Washington DC, Indiana, Kansas, Massachusetts, Minnesota, Nebraska, New Jersey, Ohio, Oregon, Utah, and Wyoming.
    • States thinking about mandatory reporting: Delaware, New York, and Wisconsin.

    Pregabalin (Lyrica®) FDA Approved 2004
    available as capsules: 25, 50, 75, 100,150, 200, 225, 300mg
    Lyrica CR® : Extended-release tablets: 82.5 mg, 165 mg, and 330 mg

    Schedule-V controlled substance

    Mechanism: Not well understood. Looks like GABA but has no effect on GABA or BZ receptors. Pregabalin binds to the voltage-gated calcium channels at the alpha 2-delta subunit in the central nervous system, resulting modulation in the release of several neurotransmitters including glutamate, noradrenaline, and substance P.

    Dosage and Administration: May give with or without food. Immediate release is FDA Approved for:
    • Epilepsy: for adjunctive treatment of partial onset seizures.
    • Diabetic peripheral neuropathy
    • Post herpetic neuralgia
    • Fibromyalgia
    • Neuropathic pain associated with spinal cord injury
    • Once-daily dosing (CR) for diabetic peripheral neuropathy and post-herpetic neuralgia, but not for fibromyalgia.
    • When converting from IR twice daily to CR once daily, take the daily dose in the morning. Add 10% to total IR dose to get CR dose. (75mg IR= 82.5CR; 150mgIR=165mgCR; 600mgIR=660mg ER, etc.)
    Warnings/ Precautions/Adverse Effects:
    • Weight gain and edema (especially if given with thiazolidinediones)
    • Visual disturbances (notify clinician if occurs)
    • Report any muscle pain, tenderness, or weakness & fever
    • May see additive effects with CNS depressants (opioids & benzodiazepines).
    • Avoid alcohol
    • Pregnancy Category-C
    • May cause male mediated teratogenicity. (inform clinician if planning to father a child)
    • Dizziness and somnolence
    • MUST taper drug over a 1-week period. Do NOT stop abruptly.
    • In clinical practice, this drug is used for post herpetic neuralgia, and diabetic neuropathy.
    The U.S. Food and Drug Administration (FDA) is warning that serious breathing difficulties may occur in patients using gabapentin (Neurontin®) or pregabalin (Lyrica®, Lyrica CR®) who have respiratory risk factors. These include the use of opioid pain medicines and other drugs that suppress the central nervous system, and conditions such as chronic obstructive pulmonary disease (COPD) that reduce lung function. The elderly are also at higher risk.

    Gabapentinoids are often being combined with CNS depressants, which increases the risk of respiratory depression. CNS depressants include opioids, anti-anxiety medicines, antidepressants, and antihistamines. There is less evidence supporting the risk of serious breathing difficulties in healthy individuals taking gabapentinoids alone.

    Be aware of the potential additive effects of all these CNS depressants and plan accordingly, by starting with low doses, titrating carefully, and informing patients of the potential for CNS and respiratory depression and their symptoms. The gabapentinoid prescribing information already includes guidance for health care professionals to caution patients about dizziness, somnolence, and the potential for impaired ability to operate a car or complex machinery. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-serious-breathing-problems-seizure-and-nerve-pain-medicines-gabapentin-neurontin

    Is there a drug in the pharmacy that we dispense more inappropriately than gabapentin? It seems to be part of most pain management doctors regimen, also including tizanidine or cyclobenzaprine, and an opioid.

    I have yet to ask a student pharmacist what the FDA approved indications are for gabapentin and received a correct answer. I most often get “neuropathic pain” or “diabetic peripheral neuropathy” as the answer. The truth is gabapentin is only FDA approved for post herpetic neuralgia and seizure management.

    Many physicians see gabapentin as “not as bad as” opioids, but we as pharmacists still need to warn our patients about the dangers of this drug, especially given the fact it is frequently prescribed in conjunction with opioids, and other CNS suppressants such as tizanidine, tricyclic antidepressants and cyclobenzaprine.

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    Overview of Topiramate and Lacosamide Use in Seizure Disorders

    Topiramate (Topamax®) FDA approved:1996
    tablets: 25mg, 50mg, 100mg, 200mg.
    Sprinkle caps: 15mg,25mg (available generically)
    • Qsymia®: phentermine/ topiramate: 3.75 mg/23 mg; 7.5 mg/46 mg; 11.25 mg/69 mg; 15 mg/92 mg. Approved 2012 for weight loss (BMI over 30 or BMI over 27 with other risk factors.)
      • This drug requires a REMS program that is available on the website at https://qsymiarems.com/information-for-pharmacists.htm
    Mechanism: blocks voltage dependent sodium and calcium channels, augments the activity of the neurotransmitter GABA at some subtypes of the GABA-a receptor and antagonizes the kainate subtype of the glutamate receptor.

    Indications for use:
    • Partial onset seizures
    • Tonic-clonic seizures
    • Unlabeled use: alcohol dependence, binge eating, bulimia nervosa, cluster headache, infantile spasms, migraine prevention, weight loss in obesity.
    Dosage: Recommended dose: 200mg-400mg /day in 2 divided doses. 400mg/day as adjunct for tonic clonic seizures. Start with 25-50mg/ day; then may increase by 25mg-50mg increase per week. Pediatrics: 5-9mg/kg/ day (ages 2-16; Not approved for use under age 2.)

    Adverse effects: 28% of patients taking this drug discontinued therapy because of the following side effects: anorexia (2.7%); ataxia (2.1%); confusion (3.1%; depression (2.6%); difficulty with concentration (2.9%); fatigue, mental difficulty & somnolence (3.2%). Most of the side effects are dose dependent. Impaired cognition.

    Pregnancy Category: D (was changed March 2011 from Cat-C): causes oral clefts and low birth weight.

    Drug interactions:
    • Avoid alcohol (increases drowsiness)
    • Avoid carbonic anhydrase inhibitors (promotes stone formation by reducing urinary citrate excretion, and by increasing urinary pH. Topiramate is a weak carbonic anhydrase inhibitor. Be sure patients are adequately hydrated in summer months.
    • Mild inducer of CYP-450--- caution with oral contraceptives.
    Patient education:
    • Monitor weight, may cause weight loss
    • Maintain adequate fluid intake to minimize renal stone formation
    • Watch for drowsiness- caution driving
    • Reduces effectiveness of oral contraceptives. Decreases plasma concentrations of ethinyl estradiol by 25%. Consider alternate method or increase estrogen dose.

    Lacosamide (Vimpat®) FDA approved: 2008
    Tablets: 50mg, 100mg 150mg & 200mg tabs; solution and injection 200mg/20mL.
    Schedule-V controlled substance

    Indications for Use:
    • An adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy who are 17 years and older.
    • Injection is indicated as short-term replacement when oral administration is temporarily not feasible in these patients.
    Dosage: Initially, give 50 mg twice daily (100 mg/day). The dose may be increased, based on clinical response and tolerability, at weekly intervals by 100 mg/day given as two divided doses to a daily dose of 200 to 400 mg/day.

    Mechanism: In vitro electrophysiological studies show selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.

    Adverse effects:
    • Most common side effects: double vision, headache, nausea, dizziness
    • Suicidal ideation
    • Dizziness and ataxia
    • Schedule V controlled substance; can cause euphoria or "drunk" feeling
    • Check EKG at baseline and after dose titration in patients with cardiac conduction problems, heart disease, or heart failure.
    • Serum level monitoring not needed.
    • Minimal interactions with CYP 450 ---is a CYP2C19 substrate and inhibitor (same as omeprazole). Elimination may be decreased by coadministration of divalproex.

    One of my patients that was taken Topiramate and said he stopped taking it because he was feeling lightheaded and fuzzy, he referred to the drug a “Dope-a-max”. We use a fair amount of topiramate for migraine prevention, and I always warn my patients in the summer to be sure they are adequately hydrated because of the risk of oligohidrosis (lack of sweating).

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    Overview of Levetiracetam and Brivaracetam

    Levetiracetam (Keppra 250mg, 500mg, 750mg (available generically) FDA approved in 1999

    Mechanism: has a most unusual mechanism of action described as binding to the synaptic vesicle protein SV2A; binding at this site may modulate synaptic transmission through alteration of vesicle fusion. SV2a does not cause immediate seizures but may contribute to a state of heightened epileptogenicity. SV2A dysfunction is linked to seizure activity.

    Indications: Most neurologists will start new patients on this medication, due to efficacy and low generic cost, and lack of drug interactions. Levetiracetam has a broad spectrum of use.
    • adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy.
    • adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy.
    • adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy.
    Dosage: initial dose: 500mg twice daily. Titrate by 1000mg/day increments every 2 weeks. Maximum = 3000mg/day

    Adverse effects: drowsiness, headache & dizziness.

    Drug Monitoring: None necessary. Time to steady state: 2 days.

    Drug interactions: Not extensively metabolized. Not dependent on P450 isoenzymes.

    Patient education:
    • Swallow tablets whole. Do not chew or crush
    • May cause drowsiness. Use caution when driving or operating dangerous machinery.
    • Report any behavioral changes to practitioner, such as: hostility, irritability, hallucinations, thoughts of suicide.
    • Considered to be weight neutral. Some reports show significant weight loss.
    Oct-2021: Study results showed that individuals treated with levetiracetam showed improvement in cognitive function, and those with silent epileptic activity showed a clear benefit from the drug. There’s a subtype of Alzheimer’s disease, consider it an epileptic variant, that’s quite common, occurring in approximately 60% of patients. Patients with this form of Alzheimer's disease show symptomatic improvement with levetiracetam, by improved cognitive function.
    Among Alzheimer’s patients, an estimated 10-22% develop seizures, while an additional 22-54% exhibit silent epileptic activity.

    Brivaracetam (BRIVIACT®) FDA approved in 2016 Schedule-V
    Available as Tablets: 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg and oral solution: 10 mg/mL. cost $1,200/ month

    Indications: approved as monotherapy or adjunctive therapy for focal-onset seizures in patients one month of age and older.

    Mechanism: same as Levetiracetam, binding to SV2A protein.

    Dosage: Monotherapy or adjunctive therapy is 50 mg twice daily. Dose can be adjusted dosage may be adjusted down to 25 mg twice daily (50 mg per day) or up to 100 mg twice daily (200 mg per day), based on patient tolerability..

    Drug interactions: Brivaracetam is 60% metabolized by CYP450-2C19 (same isoenzyme that activates clopidogrel) Weak metabolizers of CYP2C19 might experience excess levels of brivaracetam, causing toxicity. Best to avoid inducers of CYP2C19, such as phenytoin, carbamazepine, and phenobarbital as they may increase metabolism of brivaracetam. Adverse effects: Sleepiness, dizziness, fatigue and nausea.

    I’m always amazed with the new information coming out with old established drugs. Such was the case this past week, when I read about levetiracetam being used in Alzheimer’s patients. I was never aware that Alzheimer’s patient exhibited increases in seizure activity.

    As we discussed in a previous column, the cholinesterase inhibitors helped 1/12 Alzheimer’s patients. It shows our very rudimentary knowledge of Alzheimer’s, seizures and function of the CNS.

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    Overview of Lamotrigine for Seizure Disorders

    Lamotrigine (Lamictal®)
    FDA approved 1994
    Available as: chew: 2mg, 5mg & 25mg, tablets: 25, 100, 150 & 200mg

    Mechanism: is unknown but may interfere with sodium channels and stabilize neuronal membranes, modulation presynaptic excitatory amino acid release (glutamate & aspartate). Also, may have a slight effect on calcium channels.

    Lamotrigine is FDA-approved for adjunct therapy for Lennox-Gastaut syndrome, primary generalized tonic-clonic seizures (adjunctive), and focal onset seizures (monotherapy or adjunctive therapy); may be used off-label for other seizure types.

    The investigators at the SANAD (Standard and New Antiepileptic Drugs) trials concluded that lamotrigine should be the first drug of choice for use in focal seizures.

    Although we think of lamotrigine as being a seizure medication, it is more commonly used for bipolar disease. Lamotrigine has better evidence of efficacy than lithium for monotherapy for bipolar depression. Lamotrigine is the best choice for prevention of recurrent depressive episodes. Lamotrigine does not have great efficacy for mania. Dosage:

    Adults: read and follow all package instructions concerning dosing.
    Because of risk for Stevens-Johnson Syndrome, slow titration is a must. The incidence of rash, which has included Stevens-Johnson syndrome, is approximately 0.3% to 0.8% in pediatric patients (2 to 17 years of age) and 0.08% to 0.3% in adults receiving lamotrigine. Rash, if it occurs, is almost always seen in the first 8 weeks of therapy.
    There are different dosage regimens to follow:
    • Adding lamotrigine to AED regimen containing Valproic acid (Depakote®)
      • 25mg every other day, for 2 weeks. Then 25mg every day for 2 weeks.
    • Adding lamotrigine to EIAED (enzyme inducing anti-epileptic drug). CBZ, DPH, PBARB without valproic acid.
      • 50mg daily for 2 weeks. Then 100mg daily in 2 divided doses for 2 weeks.
    • Start lamotrigine without any inducers/ inhibitors:
      • 25mg daily for 2 weeks. Then 50mg daily for 2 weeks.
    Adverse effects: skin rash (discontinue if it appears)-Black box warning. Titrate slowly, especially if taking Valproic acid.

    Lamotrigine Safety Alert April 2021
    The FDA has issued a drug safety communication after a review of study findings showed a potential increased risk of arrhythmias in patients with heart disease who are taking lamotrigine (Lamictal®)

    Drug interactions: many drug interactions between enzyme blockers and inducers. Although lamotrigine does not induce or inhibit other drugs, its metabolism is affected. Adding valproic acid to lamotrigine, will double lamotrigine steady state concentration.

    Half-life for lamotrigine is 6-8 hours.

    Drug Monitoring: optimal blood level: 4 to 20 mcg. Days to steady state: 4 to 5 days

    Patient care points:
    • Be sure to follow titration guidelines.
    • If rash should occur, stop the drug and immediately contact your prescriber.
    • Inhibits dihydrofolate reductase. Folic acid supplementation may be necessary.
    • May also cause nausea, dizziness, tremor, diplopia.
    • Lamotrigine may reduce the effectiveness of combined estrogen-progestin contraceptives
    • Pregnancy may cause an increase in seizures by increasing lamotrigine clearance by 65%. It quickly reverts to pre-pregnancy levels after delivery.

    Lamotrigine dosing is a textbook example of drug interactions. I included this drug as an example in my intro to Pharmacology lectures. If a patient is on a CYP3A4 blocker, you cut the dose in half. If a patient is on a CYP3A4 inducer you double the dose.

    We frequently see lamotrigine used for bipolar, especially in patients that lean to the depressive side. This drug, like carbamazepine, does require that patients be warned of the potential for rash, which could be Stevens Johnson Syndrome, “The Mother of all Rashes.” For lamotrigine, a benign rash may occur in up to 10% of patients; the rate for SJS is 1/1,000 patients.

    Unlike carbamazepine, there is no blood or genetic test to determine who is at risk for SJS. Slow titration and good counseling need to be standard processes with each patient.

    Have a Great Day on the Bench!!

    October 2021

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    Overview of Valproic Acid and Divalproex for Seizure Disorders

    Depakene® (approved 1978), Depakote® (approved 1983), Depakote ER® (approved 2000)

    • Increases levels of GABA by potentiating post synaptic GABA response by inhibiting the enzymatic response for the catabolism of GABA
    • Valproate is considered the most effective antiseizure medication for idiopathic generalized epilepsy with generalized tonic-clonic seizures
    • Affects potassium channel creating direct membrane stabilizing effect
    Depakene capsules, Depakote tablets, Depakote-ER DOSING: Adults: 1000 to 3000mg daily in divided doses. (Depakote ER as a single dose). Maximum is 60mg/kg/day.
    Child: start with 10-15mg/kg per day. Divided into 2 or 3 doses. Expect dose to escalate. Don’t exceed 60mg/kg/day.
    • Depakote® (divalproex sodium) is an enteric coated valproic acid derivative.
    • Written as “Depakote® 500mg” implies the enteric coated but multiple dosed.
    • Only Depakote ER 500mg should be given as a single dose (Multiple tablets given together)
    • Depakote is available as 125mg enteric coated tablets, 250mg tablets & 500mg tablets. Also available as 125mg sprinkle capsules.
    • Depakote ER® is available as 250mg and 500mg tablet (these are silver colored)
    • Divalproex ER (Depakote-ER) is used for epilepsy, mania, and migraine prophylaxis. Effective in preventing depressive recurrences in mania by 30
    • Divalproex DR (Depakote) is used for epilepsy. Divide doses if over 250mg.
    • Depakene® is valproic acid capsules and is available as a generic. Depakote and Depakote ER are available generically:
      • Depakote= divalproex delayed release
      • Depakote-ER= divalproex extended release
    Adverse effects: Hepatotoxicity, Teratogenicity, Pancreatitis are in the Black Box Warning.

    Stomach upset, alopecia, weight gain, tremor, easy bruising, thrombocytopenia.

    Blocker of P4503A4

    Teratogenicity: Divalproex has the highest risk for teratogenicity of all available anti-epileptic drugs.

    Contraindications: Hepatic disease and known urea cycle disorders

    May cause hyperammonemic encephalopathy which can lead to seizures, coma and death.

    Drug Monitoring:
    • Optimal blood level is 50-125mcg/mL. May take 2- 4 days for steady state blood levels.
    • Liver function tests are necessary: initial therapy: every 1 to 2 weeks, then periodically
    Patient education:
    • Take with food to minimize stomach upset.
    • Swallow tablets whole. Do not chew or crush.
    • Will cause weight gain. Monitor weight.
    • Watch for drug interactions, as this is a blocker of P450 3A4 metabolism

    Primidone (Mysoline®) 50 and 250mg tablets (approved 1954)

    Mechanism: Metabolized to Phenobarbital and PEMA (phenylethylmalonamide)
    Used for focal seizures and generalized tonic-clonic seizures.
    In some refractory patients, the PEMA potentiates the activity of phenobarbital.

    Essential tremor: Low dose primidone (start with 25mg) may also be effective when used intermittently for essential tremor that is exacerbated by situational stress or anxiety. Frequently used with propranolol.

    • Maintenance: 250mg three to four times daily. Maximum 500mg four times daily (2 grams/day)
    • Children under age 8: days 1-3= 50mg at bedtime; days 4-6 = 50mg twice daily. Days 7-9: 100mg twice daily. Maintenance: 125 to 250mg three times daily
    Adverse effects:
    • CNS: drowsiness, alteration of sleep cycles, sedation, lethargy, behavioral changes, hyperactivity, ataxia, tolerance, dependence
    • Children: hyperactivity
    Drug Monitoring: optimal blood level: 10-40mcg/mL. Days to steady state: 10 days

    Drug interactions: Inducer of CYP-3A4 (similar to phenobarbital, one of the metabolites).

    Patient education:
    • Watch for drowsiness.
    • Report multiple drug therapy to practitioner.

    Both divalproex and primidone, although effective for seizure management, are more commonly used for other conditions. Most of the divalproex I dispense is written by mental health professionals. We also see a good bit of divalproex used for migraine prophylaxis.

    Divalproex is a drug that be challenging to prescribe, given the delineation between ER and DR. It was not such a challenge when we were dispensing brand Depakote versus Depakote-ER.

    Now that it is available generically, the confusion may occur between Divalproex ER versus Divalproex DR. I advise my prescribers to write it by the brand name, and we pharmacists will dispense the generic.

    Although divalproex and primidone have lots of side effects and drug interactions, sometimes divalproex is the best choice for migraine, bipolar and epilepsy.

    Primidone seems, at low dose, to be effective for essential tremor, along with propranolol. Chances are that if you see a prescription for primidone, it probably is for essential tremor.

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    Overview of Carbamazepine

    Carbamazepine (Tegretol®, Carbatrol®)
    Tegretol: FDA approved 1968
    • Tegetol® available as : 100mg chew, 200mg tablets, & XR 100,200 ,400mg. Tegretol suspension=100mg/5mL. Generic equivalents available for susp, chew tabs and 200mg tablets
    • Carbatrol®: extended release capsules 100, 200 & 400mg
    Mechanism: thought to act by reducing polysynaptic responses and blocking post-tetanic potentiation.

    • treatment of focal and generalized seizures
    • affective illnesses such as bipolar disorder
    • chronic pain syndromes such as trigeminal neuralgia.
    • Adults: initial-200mg twice daily. May increase to 800 to 1600mg daily in divided doses.
      • May increase at weekly intervals of no more than 200mg/day.
      • Maintenance level: 800-1200 per day
    • Child: 10-20mg/kg/day in 2 or 3 divided doses. Max dose 35mg/kg/day.
      • May increase at weekly intervals of no more than 100mg/day
    USE: For newly diagnosed, new onset, and refractory epilepsy

    Adverse effects:
    • Bone marrow suppression –FDA box warning: Aplastic anemia, agranulocytosis, pregnancy category-D, hyponatremia.
    • Men may have higher rates of sexual dysfunction due to lowering of testosterone.
    • May cause aggression! Slow titration minimizes adverse effects.
    Contraindications: Drug interactions - extensively metabolized by the P450 3A4 isoenzyme. The metabolism of carbamazepine is blocked by: cimetidine, erythromycin, clarithromycin, fluoxetine & azole antifungals.

    Is a potent enzyme inducer: it will speed the metabolism of drugs metabolized by the P450 enzyme system. Will decrease the effect of: oral contraceptives (recommend another method), doxycycline, haloperidol, anticoagulants, benzodiazepines, theophylline. It . Carbamazepine induces its own metabolism!
    • Half-life after chronic therapy decreases. Autoinduction occurs 3-4 weeks after starting carbamazepine, resulting in a decrease in carbamazepine levels
    • Phenytoin and phenobarbital may lower carbamazepine levels but increase levels of its active metabolite carbamazepine 10,11-epoxide
    HYPERLIPIDEMIA: Enzyme-inducing antiseizure drugs have been associated with increased hyperlipidemia. Order lipid panels for patients who require long-term therapy with enzyme-inducing drugs.

    Drug Monitoring: target serum concentration: 4 to 12 micromol/mL. Carbamazepine 10,11-epoxide is the metabolite that is measured. Measure at 3, 6 and 9 weeks, then every 60 days until constant levels. Time to steady state: 3-4 days.
    • Perform blood counts and liver function at baseline.
    • Monitor sodium levels
    • Do CBC and LFT (liver function testing) monthly
    • Monitor blood level of drug closely every 2 weeks, for first 2 months
    • After patient titrated, do CBC and LFT every 6-12 months.
    • Check blood levels every 3-6 months and after each dosage change

    Patient education:
    • May cause drowsiness, dizziness and blurred vision.
    • Report any unusual bleeding or bruising, fever, sore throat rash or ulcers
    • Report liver reactions: anorexia, N/V, or jaundice
    -Note: minimal cognitive impairment compared with other antiepileptic drugs.

    Genetic Testing
    It is recommended to genetically test many Asians BEFORE starting carbamazepine to predict risk of a serious drug reaction. This is the first time that genetic testing is recommended before using a rather common drug.

    Carbamazepine carries a FDA box warning recommending that patients of Asian descent be screened for the HLA-B*1502 (HLA=Human Leukocyte antigen) gene before starting carbamazepine.

    HLA-B*1502 is seen almost exclusively in Asian populations (Chinese & South Asian Indian). About 5% of patients who have it will develop Stevens-Johnson syndrome or toxic epidermal necrolysis with carbamazepine.

    Symptoms of Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis:
    Both Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis can start with non-specific symptoms such as: coughing, aching, headache, fever, vomiting, diarrhea. Symptoms usually occur within the first 8 weeks to therapy.

    This is usually followed by a red rash across the face and the trunk of the body, which can continue to spread to other parts of the body. Blisters then form across the body in places such as the nose, mouth, eyes, and genital areas, and the mucous membrane becomes inflamed. With some people, the nails and hair begin to come out as well. In the case of Toxic Epidermal Necrolysis patients, the skin can start to come away in sheets leaving exposed flesh that could be likened to serious burning and is very susceptible to infection.

    Both disease variations are potentially deadly. In drug related cases, the symptoms for both diseases can take one or two weeks to manifest from the first time the patient takes the drug.

    Treatment for Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis
    If the cause is drug related, doctors can stop the drug immediately. In the case of a new infection on top of the condition or a bacterial infection, select a suitable antibiotic. In severe cases, the patient is treated in a burn unit. Patients have to be treated in meticulously hygienic environments to alleviate the risk of further infection, which could result in death. In cases where the patients have lost a lot of fluid through seeping areas where the skin has come away, intravenous fluid replacement may be required. The hospital may also use topical and oral corticosteroids to treat affected areas.
    Reference: http://www.skinassn.org/stevens-johnson-syndrome-symptoms-treatment.html

    Carbamazepine is another 50 plus year old drug. When I taught students in the neurology component of pharmacology, seizure meds seem to be the most challenging. For us older practitioners, we simply divide them into “old drugs” those that we had on the shelves when we started practicing: phenobarbital, phenytoin, primidone, valproic acid, and carbamazepine were the go-to drugs for seizure management until the early 1990’s. Then came a landslide of seizure medications in the 1990’s with more introduced every couple of years.

    These drugs are a hodge-podge of drug interactions and needs for frequent lab monitoring. Neurologists seldom use these five drugs, but psychiatrists frequently use divalproex and carbamazepine for mood stabilization.

    Carbamazepine with its drug interactions and potential drug interactions deserves special attention. Be sure to look at the “entire patient” and if the patient is of Asian descent, genetic testing for HLA-B*1502 antigen is a must. Stevens-Johnson syndrome is frequently referred to as “the Mother of all Skin Rashes.”

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    Overview of Phenobarbital and Phenytoin


    Phenobarbital tablets 15mg,30mg,60mg,90mg, 100mg

    20mg/5cc elixir
    Phenobarbital was first marketed in 1912 by Bayer under the brand name Luminal®.

    Mechanism: binds to GABA receptors and intensifies the effects of GABA.
    INCREASES the duration of the GABA mediated chloride channel opening. Chloride is the major inhibitory ion in the central nervous system.

    Use: partial and generalized seizure

    Child: 3-6mg/kg/ day in divided doses.
    Adult: 60-100mg/day

    Neonates: is drug of choice for seizures. May cause delayed intellectual development. Adverse effects: drowsiness, depression, and confusion

    Contraindications: drug abusers, alcohol abusers, depressed patients

    Drug interactions: Phenobarbital is a potent p450 enzyme inducer.
    Decreased serum levels of: Warfarin, OC’s, propranolol, lamotrigine, and theophylline (speeds up metabolism)

    HYPERLIPIDEMIA: Enzyme-inducing antiseizure drugs have been associated with an increased incidence of hyperlipidemia. Order lipid panels for patients who require long-term therapy with enzyme-inducing drugs.

    Drug Monitoring: therapeutic blood level 10 to 40mcg/mL, Time to steady state: 14 to 21 days

    Patient education:
    • withdraw slowly from drug, under a practitioner’s advice
    • Schedule IV drug

    • NET EFFECT on the GABA receptor
    • Barbiturates increase the duration of chloride ion channel opening at the GABA receptor, to increase the efficacy of GABA.
    • Benzodiazepines increase the frequency of the chloride ion channel opening at the GABA receptor to increase the potency of GABA.
    Other Uses:
    • To prevent seizures in newborns, who are born to mothers with a history of heroin use during pregnancy
    • To increase breakdown of bilirubin in neonates to prevent jaundice. (Gilberts syndrome)

    Phenytoin, “Diphenylhydantoin, DPH (Dilantin®)

    History: In 1908, phenytoin was first synthesized as a barbiturate derivative in Germany by professor Heinrich Biltz (1865-1943) and subsequently resynthesized by an American chemist of the pharmaceutical company Parke-Davis in 1923 in Detroit. In 1938, it was discovered to be an effective anti-seizure medication.

    Available as capsules: 100mg, chew tabs 50mg, suspension 125mg/5cc and Phenytek® 200mg & 300mg

    Mechanism: stabilizes neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of sodium ions.

    Use: simple/complex partial, generalized tonic-clonic.

    Dosage: Adult: 300mg-700mg/day

    Adverse effects: nystagmus, ataxia, sedation, confusion, gingival hyperplasia, hirsutism, blood dyscrasia, vitamin K deficiency, osteomalacia, & folate deficiency. Can cause megaloblastic anemia.

    Contrandications: do not use in sinus bradycardia, or cardiomyopathies

    Drug Interactions
    • Drugs increasing the effect of phenytoin - inhibit metabolism: Allopurinol, benzodiazepines, cimetidine, alcohol, fluconazole, metronidazole, omeprazole, sulfonamides, valproic acid, and trimethoprim. Alcohol-acute ingestion
    • Drugs decreasing effect of phenytoin - increase metabolism: Barbiturates, carbamazepine, alcohol- (chronic), theophylline
    • Phenytoin is also an enzyme inducer- it will decrease the effectiveness of oral contraceptives. It also decreases the effectiveness of: Acetaminophen, amiodarone, carbamazepine, quinidine, theophylline & valproic acid.
    Hyperlipidemia: Enzyme-inducing antiseizure drugs have been associated with an increased incidence of hyperlipidemia. Order lipid panels for patients who require long-term therapy with enzyme-inducing drugs.

    Drug Monitoring: optimal blood level 10-20mcg/mL. Time to steady state: 5-10 days

    Patient Education (Phenytoin):
    • Practice good oral hygiene to decrease gingival hyperplasia/li>
    • Take with food to decrease GI upset.
    • Avoid alcohol
    • Watch for drowsiness, dizziness, blurred vision. Exercise caution when driving.
    • Encourage use of another method of birth control

    Both phenytoin and phenobarbital have been available for over 100 years. From the folks who brought us aspirin and heroin, Bayer Pharmaceuticals also brought phenobarbital to market in the early 1900’s, under the brand name Luminal®. Luminal® was used as a sedative and also as an anti-seizure medication.

    Phenobarbital also has a very dark side. In the 1940’s Adolph Hitler used Luminal® as part of his child euthanasia plan to kill mentally and physically handicapped children. Over 5,000 children were killed as part of Nazi Germany’s Kinder-Euthanasie program which led to the extermination of even more children in the concentration camps. It all started with Luminal® being administered to 50 intellectually disabled children in 1940 at a clinic in Ansbach Germany.

    Phenytoin also has a story line, albeit not as tragic as phenobarbital. It was described that Richard Nixon was given phenytoin to stabilize his mood swings when he was in the White House. Jack Dreyfus of the Dreyfus Fund fame, was reported to give Richard Nixon large doses of phenytoin after he was elected in 1968, as Dreyfus felt it helped with mood swings and depression.

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    Overview of Seizure Disorders

    Seizure Basics:: What type of seizure the patient experiences is important to the selection of pharmacotherapy. The purpose of this piece is not to make us amateur neurologists, but to cover the basics:

    Seizures can be divided into two classes: focal or generalized
    • Focal (partial) seizures involve only a portion of the brain and are broken down to their impairment of awareness.
    • Generalized seizures are broken down into motor and non-motor seizures. The most obvious generalized seizure is the tonic-clonic variety.
    Seizures by the numbers: (source: International League Against Epilepsy (ILAE)
    • 90% of people with epilepsy are aware of their diagnosis as a treatable brain disorder
    • 80% of people with epilepsy have available to them safe, effective and affordable medications
    • 70% of patients with epilepsy experience adequate seizure management
    • 10% of the world’s population will experience a seizure in their lifetime
    What meds to choose: Treatment for the first seizure is not immediately recommended if what provoked the seizure can be resolved. Usually, 50% of patients with a new diagnosis of epilepsy will become seizure free with the first antiseizure medication prescribed. Treatment for the first seizure depends on the following:
    • Seizure type
    • Patient preference
    • Risk benefit ratio: side effect profile
    • Patient’s age
    • Potential for pregnancy
    FDA Requires Warnings about Risk of Suicidal Thoughts and Behavior for Antiepileptic Medications. (2008)
    The U.S. Food and Drug Administration announced it will require the manufacturers of antiepileptic drugs to add to these products' prescribing information, or labeling, a warning that their use increases risk of suicidal thoughts and behaviors (suicidality). The action includes all antiepileptic drugs including those used to treat psychiatric disorders, migraine headaches and other conditions, as well as epilepsy.

    The FDA is also requiring the manufacturers to submit for each of these products a Risk Evaluation and Mitigation Strategy, including a Medication Guide for patients. Medication Guides are manufacturer-developed handouts that are given to patients, their families and caregivers when a medicine is dispensed. The guides contain FDA-approved information about the risks of suicidal thoughts and behaviors associated with the class of antiepileptic medications.

    OK, so what about the newer anti-epileptic drugs approved since 2008?
    The August 2, 2021 edition of JAMA Neurology states that “suicidality was evaluated prospectively in trials of 5 antiseizure medications eslicarbazepine (Aptiom®), perampanel (Fycompa®), brivaracetam (Briviact®), cannabidiol (Epidiolex), and cenobamate (Xcopri®), including 17 trials involving 5996 patients, including 4000 patients treated with antiseizure medications and 1996 treated with placebo. There was no evidence of increased risk of suicidality (ideation or behavior) overall or for any individual drug.”

    Basically the study shows: “There is no current evidence that newer antiseizure medications increase suicidality in epilepsy; therefore, a suicidality class warning is not warranted.”
    JAMA Neurol. Published online August 2, 2021. doi:10.1001/jamaneurol.2021.2480


    Older agents: Before 1990, we only had 6 drugs to treat all forms of epilepsy: These agents included carbamazepine (Tegretol®), ethosuximide (Zarontin®), phenobarbital, phenytoin (Dilantin®), primidone (Primidone®), and valproic acid (Depakote®/Depakene®). These drugs were used as monotherapy and in combined regimens in newly diagnosed and refractory cases, yet 20% to 30% of epileptic patients are refractory to these drugs.

    All six had in common:
    • Drug interactions (very complex pharmacokinetic parameters)
    • Need for blood level monitoring
    • Teratogenic potential

    I have witnessed four seizures and all four times I was scared to death. I have seen a middle-aged woman have a seizure in church, a 20 something year old female who was waiting for her levetiracetam prescription to be filled, and a 24-year-old who had a seizure as a result of hypoglycemia.

    The lady in the store handed me her empty bottle of levetiracetam and asked “How long is this going to take? I have been out of this for a couple of days.” Within minutes, she was on the floor with a clonic tonic seizure.

    Every time, after every seizure I called 911 to summon help, especially when it happens in the store. Sometimes your most important job is keeping the spectators away from “gawking”, by moving them to the next aisle and allowing the patient some level of dignity.

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    Overview of NMDA Receptor Antagonists in the Management of Alzheimer’s Disease

    NMDA receptor antagonists

    Memantine (Namenda®): tablets 5mg & 10mg (approved 2003) generic available Namenda-XR®: once daily available as 7mg,14mg, 21mg, 28mg XR capsules (approved 2010) generic available

    Mechanism: Persistent activation of CNS n-methyl-d-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been postulated to contribute to symptoms of Alzheimer’s. The drug memantine (Namenda®) has low to moderate affinity for the NMDA receptor. In the presence of memantine, an open channel antagonist, excessive calcium is prevented from entering, effectively lowering background noise. Memantine binds deep inside the channel, not at the glutamate receptor. This helps memantine discriminately block abnormal glutamate activity.

    Memantine remotely modulates the receptor, preventing excessive flow, BUT allowing normal function. The abnormal glutamate activity that leads to neuronal loss is prevented, but physiological activation that produces learning and memory is preserved. Memantine (Namenda®) blocks neuronal toxicity and has a neuro-protective effect on the glutaminergic and cholinergic neurons.

    Dosage: start 5mg daily, increase to 5mg BID, then 5mg in am and 10mg in PM, then 10mg BID. Wait 1 week between dosage interval increases. For XR capsules, start with 7mg/day titrating to 28mg max. Separate dosage increases by 7 days.

    NOTE: this drug is often used in combination with the cholinesterase inhibitors. Is used for moderate to severe Alzheimer’s disease. This drug is said to improve behavior.

    Adverse Effects: generally, well tolerated.

    Contraindication: drugs that make urine alkaline- sodium bicarbonate, carbonic anhydrase inhibitors or severe UTI’s

    Drug Interactions: Clearance of memantine is reduced by 80% in alkaline urine conditions pH=8. May also interact with drugs secreted by tubular secretion (HCTZ, ranitidine, cimetidine, triamterene, quinidine)

    Memantine and Donepezil Extended Release (Namzaric®) 28/10 and 14/10
    (cost= $507.00/month)
    Treatment of moderate to severe dementia of the Alzheimer's type in patients stabilized on:
    • Memantine (10 mg twice a day or 28 mg ER once a day) and donepezil 10 mg once a day, or
    • Memantine (5 mg twice a day or 14 mg ER once a day) and donepezil 10 mg once a day in patients with severe renal impairment
    Lecithin Lecithin is a major dietary source of choline, so extra consumption may reduce the progression of dementia. After multiple studies it showed no more effect than placebo in the treatment of Alzheimer’s disease. Has no therapeutic effect in early onset Alzheimer’s.

    CROSSWORD PUZZLES — possibly the most efficacious prevention for Alzheimer's https://www.alzinfo.org/articles/crossword-puzzles-alzheimers/
    “We report a direct association between cognitive activity and Pittsburgh compound B uptake, suggesting that lifestyle factors found in individuals with high cognitive engagement may prevent or slow deposition of beta-amyloid, perhaps influencing the onset and progression of Alzheimer’s disease,” the researchers write.”

    Pittsburgh compound B binds to beta-amyloid, a toxic protein that builds up in the brains of those with Alzheimer’s and is the main component of the brain plaques that characterize the disease.

    The researchers found that the more often someone engaged in mentally stimulating activities, the less buildup of beta-amyloid they were likely to have in the brain. Other tips to reduce the risk of cognitive decline or dementia, some evidence (not high-level) supports the following:
    • For adults who smoke, offer interventions to facilitate smoking cessation.
    • Reduce or stop excessive alcohol consumption
    • Mediterranean-like diet may be beneficial
    • Offer cognitive training for mild to moderate impairment.
    • Hypertension, diabetes, dyslipidemia (at mid-life), and weight (at mid-life) management may be offered.

    Alzheimer’s disease affects 1 in 9 older Americans, with 2/3 of them being women. Currently there are 6 million people living with Alzheimer’s disease, and that number is expected to double by the year 2050. Currently, this disease costs the nation $355 billion dollars. Between 2000 and 2019, deaths from heart disease have decreased 7.3% while deaths from Alzheimer’s have increased 145%.

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    An Overview of Cholinesterase Inhibitors in Alzheimer’s Disease

    Cholinesterase Inhibitors

    Donepezil (Aricept®) 5mg and 10 mg tablets; 23mg tablets (approved 1996) Dosage: initial: 5mg at bedtime. May increase to 10mg 4 to 6 weeks later. Take in the evening, just prior to retiring.
    • 5mg: mild to moderate AD
    • 10mg: mild, moderate, severe AD
    • 23mg: moderate and severe AD (only increased score 2 points out of 100)
    Donepezil® (Aricept) 23mg tablet: For moderate to severe dementia. Must be stabilized on 10mg dose for 3 months before instituting the 23mg dose. Causes significant GI distress. Adverse effects: insomnia, dizziness, nausea, diarrhea, headache. (all less than 10%). Much higher incidence of GI upset and weight loss with 23mg dose.

    Contraindications: increases gastric secretions. Watch for GI bleeding especially if on NSAIDS

    Drug interactions: P450 inhibitors could increase blood levels. Anticholinergics (such as those of IBS and Overactive bladder) will decrease effectiveness.

    Patient education: Take right before bedtime. May take with food. Generally, well tolerated.

    Rivastigmine (Exelon®) caps: 1.5, 3,4.5 & 6mg (approved 2000)
    Dosage: initial: 1.5mg BID. May increase to 3.0mg BID after 2 weeks.
    • May increase to 4.5mg BID after two weeks, and to 6mg BID in 2 weeks.
    • Usual maintenance dose is 3 to 6 mg BID.
    • Take with food in divided doses in the morning & evening.
    Adverse effects: nausea (47%), vomiting (31%), diarrhea (31%), headache (17%), dizziness (21%) anorexia (17%)

    Contraindications: cholinergics increase gastric secretions. Watch for GI bleeding especially if on NSAID

    Drug interactions: not metabolized by P450. Anticholinergic drugs will decrease effectiveness.
    Patient education: High incidence of nausea, vomiting and diarrhea
    NOTE: Rivastigmine is the only cholinesterase inhibitor approved for dementia in Parkinson’s Disease

    Rivastigmine (Exelon®) patch:
    Dosage available: 4.6mg and 9.5mg/day patch
    • For patients who have trouble swallowing
    • Once daily dosing instead of the BID oral formulations increases compliance.
    • Less nausea and vomiting because drug levels are lower and steadier than with caps
    • New start: 4.6 mg patch, then increase to 9.5 mg after 4 weeks if tolerated.
    Switching from oral: prescribe the 4.6 mg patch for those taking less than 6 mg/day of oral or the 9.5 mg patch for patients on higher doses.

    Galantamine (Razadyne®) 4, 8, 12mg tabs. ER caps available. (approved 2001)
    {name was originally Reminyl, but was changed due to confusion with Amaryl®}
    An anticholinesterase, but also has activity as a nicotinic receptor agonist

    Dosage: start: 4mg twice daily for 4 weeks. Then 8mg twice for 4 weeks. Then increase to 12mg twice daily for 4 weeks, then 16mg twice daily.

    Maintenance dose: 8 to 16mg BID

    Adverse effects: Pregnancy Category B

    Contraindications: Cholinesterase inhibitors increase gastric secretions. Watch for GI bleeding if on NSAID

    Drug interactions: Anticholinergics will reduce its effect.

    Drug monitoring: dosage adjustments are necessary in hepatic impairment and renal impairment.

    Patient education: if therapy is interrupted for several days, the patient must be re-titrated. Starting on the lowest dose and escalated to maintenance dose.

    Class side effects: donepezil, rivastigmine, galantamine)
    • There is an increased risk of bradycardia and fainting in patients taking cholinesterase inhibitors
    • Remember: cholinergic stimulation can slow heart rate which can to a higher risk of fainting, falls, hip fractures, and pacemaker insertion.
    • Cholinesterase inhibitors increase gastric secretions. Watch for GI bleeding if on NSAID
    Bottom Line: One in 12 patients will experience side effects (mostly GI) with cholinesterase inhibitors. Conversely, only 1 in 12 patients show any improvement. No good evidence that drugs delay nursing home placement. Rate of functional and cognitive decline do not improve with drug therapy.

    Alzheimer's drugs have always been expensive. Back in 2010 the chief financial officer called me for some advice. He was curious as to how the Long-Term Care unit of the business had drastically decreased their monthly wholesaler bill.

    He said, “I know they are good, but they cut over $240,000 off last month’s bill.” I explained that donepezil (Aricept®) went from being $240.00 for thirty tablets per patient per month to the generic being around $6.00 per patient per month.

    Most of us seasoned pharmacists remember the first Alzheimer’s drug tacrine (Cognex®) by Parke Davis. It was dosed four times daily. When I first dispensed it and explained the dosing to the patient’s husband he quipped “If she can remember to take this medicine four times a day, does she really have Alzheimers?!!”

    Efficacy of these drugs is questionable, at best. We indeed are treating the caregiver and not so much the patient.

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    Overview of Alzheimer’s Disease

    Signs and symptoms of Alzheimer’s Disease (AD):

    ForgetfulnessDisorientationAgnosia* (more pronounced)
    Word-finding difficultyIncreased memory lossApraxia*
    Poor attentionInsomniaAgitation
    Difficulty with complex tasksWanderingIncontinence
    DepressionSpeech difficultyPoor Basic ADL
    Work TroubleRestlessGait disturbance
    Difficulty with IADL

    • Apraxia: inability to carry out purposeful movements in the absence of paralysis or other motor/sensory impairment
    • Agnosia: loss of the power to recognize the import of sensory stimuli
    • ADL: activities of daily living
    • IADL: instrumental activities of daily living
    • Vitamin B12 deficiency
    • Depression, which is a treatable comorbid condition.
    • The incidence and prevalence of Alzheimer’s disease increases with age, essentially doubling in prevalence every 5 years after the age of 65 years.
    • Onset of AD before age 60 has been associated with a genetic disposition (less than 1% of patients.)
    • Patients with Down Syndrome can develop signs of AD 10-20 years earlier than their counterparts.

    Cholinesterase inhibitors
    The cholinergic system is the system MOST often associated with the early degeneration of Alzheimer’s Disease (AD). Large numbers of cholinergic neurons in the basal forebrain innervate the cortex and hippocampus and are intricately involved in normal learning and memory. In addition to loss of these neurons, cholinergic impairments observed in patients with AD also include:
    • Decline in choline acetyltransferase activity
    • Depletion of acetylcholine (Ach)
    • Acetylcholine in CNS: COGNITION
    • Acetylcholine in PNS: MUSCLES and AUTONOMIC nervous system
    • Decline in acetylcholinesterase activity
    Site of dysfunction is also important:
    • Cortex: loss of cholinergic output contributes to attention deficits
    • Amygdala: cholinergic loss is associated with emotional changes.
    Cholinesterase inhibitors function by blocking ACh destruction and increasing the lifespan of the neurotransmitter in the synaptic cleft, therefore compensating for the loss of ACh containing neurons. While they may enhance cognitive function, they do not slow the degenerative process that underlies the disease.

    Mechanism: enhances cholinergic function by reversible inhibition of acetycholinesterase.

    Aducanumab (Aduhelm®)
    Since aducanumab has been in the news and has caused a lot of controversy, lets discuss it first. Mechanism: Aducanumab is an amyloid beta-directed antibody indicated for the treatment of Alzheimer’s disease. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease. Treatment with aducanumab should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials

    Dose: given as a one-hour infusion, given every 4 weeks. Must be titrated, starting with 1mg/kg ending at 10mg/kg. MRI’s need to be obtained before the 7th and 12th infusion.

    Cost and controversy: $56,000 per year. If all 6 million Alzheimer’s Disease patients were treated with aducanumab, we could significantly strain Medicare funds, to the tune of $336 BILLION. For comparison, Medicare Part B, the hospital insurance plan for seniors, spent $37 billion total on ALL drugs in 2019! This amounts to a 10-fold increase for just ONE drug. (Don’t forget the cost of infusion, as well as those MRI’s required by the package insert)

    Efficacy: Efficacy: Biogen states it slows the progression of AD, but only showed a reduction in the number of amyloid plaques, but there is not a direct correlation to the severity of Alzheimer’s.

    Alzheimer’s is indeed a devastating disease. The drug therapy we have isn’t very robust at all. The cholinesterase inhibitors seem to cause lots of side effects and have issues with efficacy. The NMDA antagonist memantine does not show much efficacy either. In short, our toolbox is limited.

    I always use the analogy with my patients of jumping out of an airplane when discussing AD drug therapy. If they jump out of an airplane with a parachute, and I jump out without one, what happens? We both will hit the ground, me a lot faster. Even with the parachute you will eventually hit the ground, just a lot longer time. At their very best, therapies we have for AD are parachutes, not cures.

    I truly feel with the lack of efficacy of the AD drugs, we are treating the caregiver… just by showing we do care about their loved one with AD.

    Have a Great Day on the Bench!!

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    Overview of Treatment Considerations for Patients with Parkinson’s Disease

    Parkinson's Disease

    Parkinson’s Disease has more surgical and pharmacological treatments than any other disease of the central nervous system. The effect on activities of daily living (ADL) are the primary determining factor for selection of pharmacological treatment options. The current belief is that the choice and timing of initial therapy for PD, regardless of mechanism of action, has little impact on the long-term outcome of PD in terms of motor fluctuations.

    Holding off treatment unnecessarily deprives patients of therapeutic benefit early in the disease, when the potential for sustained improvement is greatest. This needs to be a shared clinical decision with the patient and their family.

    Hoehn & Yahr Scale (used to describe severity of Parkinson’s)
    • Stage 1 : unilateral involvement
    • Stage:2 bilateral involvement, no postural abnormalities
    • Stage 3: Bilateral involvement , mild postural imbalance, patient is independent
    • Stage 4: Bilateral involvement postural instability, patient requires much help
    • Stage 5: Severe, fully developed disease, patient restricted to bed or chair
    Wehn to start levodopa treatment...
    • Delay treatment: evidence suggests long term L-dopa therapy can cause response fluctuations, dementia, and loss of L-dopa efficacy.
    • Dyskinesias are more likely the longer patients are on levodopa. (window keeps getting smaller)
    • Start ASAP: counter-argument that response fluctuations is due to disease progression and not L-dopa therapy. In a 3-year multicenter study, mortality doubled if L-dopa therapy is delayed.
    • Current thinking is to initiate treatment when disease interferes with person’s occupation or activities of daily living. The former belief of holding off levodopa therapy (think rationing levodopa therapy) has been unfounded.

    For end-of dose deterioration (“wearing off”) consider:
    • Increase frequency of carbidopa-levodopa doses.
    • Use controlled release carbidopa-levodopa
    • Add dopamine agonists, selegiline, tolcapone or amantadine.
    • Add apomorphine
    For delayed onset of response consider:
    • Giving on an empty stomach before meals
    • Crushing or chewing with a full glass of water
    • Reducing protein intake and antacids
    • Adding dopamine agonists
    • Using morning standard release carbidopa-levodopa instead of sustained release
    For drug-resistant “off periods” consider:
    • Increasing dose and/or frequency of carbidopa-levodopa
    • Crushing or chewing and take with a full glass of water
    • Adding dopamine agonists, and or apomorphine
    For treatment of random oscillations (“on-off”), consider:
    • Adding dopamine agonists, selegiline, or tolcapone
    • Using ‘drug holidays’
    For treatment of start hesitation (“freezing”), consider:
    • Increasing dose of carbidopa-levodopa
    • Adding dopamine agonists
    Treatment of Parkinson’s Disease Dementia
    • Parkinson's disease dementia: dementia that occurs more than a year after onset of Parkinson's
    • Hallucinations or delusions can occur in as many as 50 percent of patients with Parkinson’s disease at some time during the course of their illness.
    • Lewy body dementia
      • cause: abnormal protein deposits in brain
      • deficient in BOTH acetylcholine (like Alzheimer’s) and dopamine (like Parkinson’s).
      • challenge: Treating one symptom worsens the other. (cholinesterase inhibitors help dementia but makes Parkinson’s worse). L-dopa helps motor movements but makes dementia worse.
    • L-dopa and dopamine agonists may cause psychiatric symptoms including delirium, agitation, paranoia, delusions, or hallucinations.
    Treatment choices for dementia:
    • Pimavancerin (Nuplazid®): first and only medication indicated for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.
      • What makes it different: doesn’t block dopamine receptors; it is an “inverse agonist” at the 5-HT2a receptor.
      • Dose=34mg/day
      • Reduce dose by ½ if strong CYP450-3A4 inhibitor. Dose= 17mg/day
      • Potential for QT prolongation. Caution with other drugs
    • Clozapine (Clozaril®) at low doses is effective but requires monitoring for neutropenia. (only available at specialized pharmacies)
    • Quetiapine (Seroquel® started at 12.5mg / week and titrated upward by 12.5mg/week is also safe and effective and doesn’t require the monitoring for neutropenia that Clozaril® requires.
    • Rivastigamine (Exelon®) the only cholinesterase inhibitor approved

    Stepwise Approach to Drug-Induced Psychosis in Parkinson’s Disease:
    1. Simplify regimen. Stop medications with highest risk to benefit first.
      1. Stop anticholinergics and antidepressants with anticholinergic activity
      2. Stop Selegiline
      3. Taper and stop dopamine agonists
      4. Taper and stop amantadine (watch for amantadine withdrawal)
      5. Stop COMT inhibitors.
    2. Start quetiapine (Seroquel®) or pimavancerin (Nuplazid®) or rivastigamine (Exelon®) therapy.
    Dextromethorphan=20mg + quinidine=10mg (Nuedexta®):
    Used for treatment of pseudobulbar effect, which is emotional lability manifested by laughter or crying outbursts in neurological conditions such as MS, ALS, neurological conditions. Pseudobulbar effect has been treated by TCA’s, and SSRI. Quinidine (antiarrhythmic) blocks the first pass metabolism of DM and causes an increase of 25 fold in the AUC of DM.

    Drug interactions: stop SSRI, SNRI or TCA or MAOI.

    Parkinson’s Disease is arguably the worst of the neurological diseases. Patients experience their own decline every single week; they are worse this week than they were last week, and next work will be even worse. If the physical manifestations of Parkinson’s Disease are challenging enough, the psychological manifestations of the disease can be equally disabling.

    Have a Great Day on the Bench!!

    August 2021

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    An Overview of Carbidopa/Levodopa Therapy for the Management of Parkinson’s Disease

    Levodopa therapy

    Mechanism: Dopamine does not cross the blood brain barrier (BBB), however Levodopa the metabolic precursor, does cross the BBB. It is decarboxylated into dopamine in the basal ganglia and in the periphery by dopa-decarboxylase. Hence the blood dopamine is increased.
    • Sinemet® (carbidopa/levodopa):10/100, 25/100, 25/250 immediate release.
    Controlled release: 25/100 and CR 50/200
    • Rytary® (carbidopa/levodopa): Extended-release capsules: Carbidopa and levodopa 23.75 mg / 95 mg, 36.25 mg / 145 mg, 48.75 mg / 195 mg, 61.25 mg / 245 mg. Immediate release beads, coupled with extended-release beads. Released at different intervals in the gastrointestinal tract.
    • Stalevo®: (carbidopa/levodopa and entacapone)
      • Stalevo® 50: 12.5mg carbidopa/ 50mg levodopa/ 200mg entacapone
      • Stalevo® 100: 25mg carbidopa/ 100mg levodopa/ 200mg entacapone
      • Stalevo® 150: 37.5 carbidopa/ 150mg levodopa/ 200mg entacapone
    • Inbrija®: Levodopa for inhalation: Is a dry powder for inhalation containing 84mg per dose (2 capsules at 42mg each), for breakthrough freezing episodes. Can be used up to 5 times a day for a maximum of 420mg/day. Works within 10 minutes of inhalation.
    I watched the video, and can’t imagine how a Parkinson’s patient could load this device. It is similar to the Spiriva Handihaler®, where a capsule gets punctured, and the dry powder gets inhaled. Check out the video: https://www.inbrija.com/how-to-use

    Effects of carbidopa:
    • decreases peripheral conversion of levodopa to dopamine by blocking dopa-decarboxylase
    • increases amount of levodopa to cross blood brain barrier
    • carbidopa does NOT cross blood brain barrier.
    • carbidopa has a levodopa sparing effect, decreasing the amount of Levodopa necessary to obtain a clinical response by 75%
    Dosage: must be individualized.
    Start with Sinemet 25/100 three times daily, or 10/100 three or four times daily
    Ideal carbidopa range =70 to 100mg. (over 125mg has no more effect)
    • Adjust carbidopa dose based on side effects. When more carbidopa is required, move up to 25/100.
    • Adjust levodopa dose based on desired effects. If more levodopa is required move up to 25/250. Maximum daily dose of levodopa is 3g.
    May increase by one tablet daily or every other day.
    NOTE: sustained release formulations may cause more erratic absorption.

    Adverse effects: When used alone, L-Dopa effects are common: nausea & vomiting (80%), cardiac arrhythmias (10%) postural hypotension (25%). These all occur secondary to the peripheral conversion of levodopa to dopamine. Therefore, carbidopa is added, based on side effects.

    Challenges with Levodopa therapy
    • Medication dosages taking too long to “kick in” and start working
    • Medication wearing off before the next scheduled medication dose
    • Severe on-off medication fluctuation periods (e.g. rapid cycling during the day ranging from feeling completely on medication to completely off medication)
    • Dyskinesia (too much movement, usually resulting from too high of a blood level of dopamine)
    • Too many pills
    • Too many medication dosage intervals; such as taking medications every 1-2 hours throughout the waking day
    Wearing off: 2/3 of patients will experience loss of efficacy after 5 years.

    ON/OFF: wide fluctuations between hyperkinetic to hypokinetic state, potentially occurring several times a day.

    “ On” period: : is characterized by dyskinesias of face, neck & limbs, augmented by stress or movement at a time of maximal levodopa benefit. They appear as abnormal, choreiform movements, usually involving the neck, trunk and upper extremities.

    Dyskinesias can be thought of as too much movement secondary to the extension of the pharmacologic effect or too much striatal dopamine stimulation. Dyskinesias are more likely to occur with L dopa therapy (D1 and D2 agonism) suggesting that the D1 receptor is involved in producing dyskinesia. Most patients however will tolerate these mild dyskinesias as a trade-off for good mobility.

    “Off” period: characterized by akinesia & dystonia. Can be painful and immobilizing generalized to limb, face & trunk. This can be very debilitating as it can cause a freezing of gait. Rock hard spasms of abdominal musculature may occur.
    Can address this concern of on/off by using Sinemet SR®. May also add COMT or MAO-b inhibitors.

    Other Adverse effects: akathisia, delirium, depression, hallucinations, paranoia & dementia.

    Contraindications: levodopa may activate malignant melanoma. Rule out any suspicious skin lesions before therapy.

    Food interactions: Competes with protein for absorption. Lower protein meals during the day and main protein at dinner.

    Drug interactions: MAOI (antidepressants). Stop for 2 weeks before initiating therapy. Pyridoxine (B-6) decreases Levodopa effect; however, this is seen less often with carbidopa/levodopa combinations. Chelation (Iron, Calcium, multivitamins) can affect absorption.

    Drug Monitoring: Clinical response drives the therapy and dosing. Notify practitioner if uncontrollable movements of face, tongue, limbs, mood or mental changes, irregular heartbeat, difficult urination, or persistent nausea and vomiting.

    Patient Education Levodopa therapy:
    • May take a few weeks for optimal results.
    • Avoid vitamins with B-6 (pyridoxine)
    • Exercise caution when driving.
    • Watch for orthostatic hypotension.
    • Take medication with food.
    • Do not crush SR tablets
    Other Drugs:
    • Levodopa (Larodopa®): is available as 100mg & 500mg tablets
    • Carbidopa (Lodosyn®): is available as 25mg tablets.

    There seems to be a shortage of neurologists in most areas, so primary care physicians, nurse practitioners and physician assistants will become more engaged in the management of Parkinson’s disease and drug therapy. One of my favorite neurologists several years ago was resistant to hiring physician assistants and CRNP’s because neurology patients are such a challenge. After he finally broke down and had to hire two physician assistants, he said it was one of the best decisions he ever made. He said, “I finally get to be a doctor again, and my PA’s help keep the loose ends tied together.” The pharmacist, as the drug expert, will be called upon to guide family practice physicians and their mid-level prescribers to provide advice for their Parkinson's patients.

    Most neurologists at one time held off on Levodopa therapy until after all of the other treatment options were exhausted. Today’s recommendations are to start when the patient needs it. Shared clinical decision making is the best approach for starting any Parkinson’s therapy.

    Have a great day on the bench!!

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    An Overview of Adjunctive Therapies for Parkinson’s Disease

    Adjunctive therapies for Parkinson’s Disease

    COMT inhibitors: (catecholamine-o-methyl-transferase)
    • Entacapone (Comtan®) 200mg tablets (approved 1999)
    • Tolcapone (Tasmar®) 100mg & 200mg tablets (approved 1998)
    • Opicapone (Ongentys®) – 2020 available as 25mg and 50mg capsules (approved 2020)
    Mechanism: no effect on Parkinson’s disease as monotherapy. They are used with carbidopa/levodopa to prevent peripheral conversion. Inhibits COMT, increasing dopamine levels. When carbidopa blocks dopa decarboxylase as with carbidopa/levodopa (Sinemet®), COMT is the main metabolizing enzyme for levodopa.

    Significantly decreases off times and decreases levodopa requirements. Prolongs and potentiates the levodopa effect and thereby reduce "off" time when used as add-on therapy with levodopa.

    Increases blood levels (AUC), but does not increase Cmax or Tmax.

    May theoretically be better than CR products because they don’t delay time to maximal effect. Overall help simplify carbidopa/levodopa (Sinemet®) dosing, may reduce Levadopa requirements and decrease time in “off” period.

    Dosage: decrease the dose of levodopa 10 to 30 percent to avoid exacerbating peak-dose dyskinesia and other dopaminergic side effect
    • Entacapone (Comtan®): 200mg with each dose of carbidopa/levodopa max=1600mg/day
    • Opicapone (Ongentys®): The recommended dosage is 50 mg once daily at bedtime
    • Tolcapone (Tasmar®): 100mg three times daily. (May cause severe liver failure, making it a last line choice)
    Adverse effects: dizziness, drowsiness, diarrhea, orange discolored urine (tolcapone, entacapone). Because of increased dopaminergic stimulation, patients might see dyskinesia, psychiatric effects (such as visual hallucinations), nausea, orthostatic hypotension, and somnolence.

    Contraindications: tolcapone (Tasmar®): liver disease

    Drug interactions: COMT also breaks down sympathomimetics. May increase BP & HR, possible arrhythmias

    Drug Monitoring: tolcapone (Tasmar®): liver enzymes. D/C at once if ALT or AST is above ULN.

    Carbidopa/ Levodopa/ Entacapone:
    • Stalevo® 50: 12.5mg carbidopa/ 50mg levodopa/ 200mg entacapone
    • Stalevo® 100: 25mg carbidopa/ 100mg levodopa/ 200mg entacapone
    • Stalevo® 150: 37.5 carbidopa/ 150mg levodopa/ 200mg entacapon
    Istradefylline (Nourianz®) approved 2019

    Mechanism: Istradefylline is an adenosine receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing “off” episodes

    Dosage: 20mg daily, up to a maximum of 40mg daily.
    Note: Patients who smoke 20 or more cigarettes per day (or the equivalent of another tobacco product), recommended dosage is 40 mg once daily

    Adverse effects: The most common adverse reactions were dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia. Patient Education: avoid OTC sympathomimetics. Watch for postural hypotension. Exercise caution when driving.

    I love the brand name for entacapone (Comtan®); it’s nice to have a brand name that describes the mechanism of action, like Namenda®, which is an NMDA receptor antagonist for Alzheimer’s.

    Istradefylline intrigues me. It is a methylxanthine like caffeine, theobromine, theophylline and pentoxifylline.

    So, this class of drugs contains a stimulant (caffeine), an ingredient in chocolate (theobromine), an asthma/COPD medication (theophylline), a drug to improve blood flow for intermittent claudication (pentoxifylline) and a Parkinson's drug (istradefylline). Now that is diversity in a family!!

    Lots of mechanisms of action for Parkinson’s treatment, all based on providing sufficient dopamine to the brain. I tell my students to remember the three big enzymes for dopamine metabolism: catecholamine-o-methyl-transferase (COMT), monoamine oxidase (MAO) and dopa-decarboxylase (DDC).

    Have a great day on the bench!!

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    An Overview of Monoamine-B Oxidase Inhibitors

    Monamine Oxidase Inhibitors (MAO-b)

    Monoamine oxidase-B (MAO-b) is an enzyme responsible for the chemical breakdown of dopamine in the brain. MAO-B inhibitors act by inhibiting the activity of this enzyme and therefore slowing the breakdown of dopamine, which allows for increased levels of dopamine in the brain.

    MAO-b inhibitors can be given either as a monotherapy or they can be combined with carbidopa-levodopa therapy. They are considered to be modestly effective as early symptomatic treatment for Parkinson’s disease. Although MAO-b inhibitors have been shown to bring about only a modest decrease in the severity of Parkinson’s symptoms, initiation for MAO-b therapy can delay the reliance on levodopa.

    Selegiline (L-deprenyl) brand: Eldepryl® (1989) or Carbex®/ Zelapar(ODT) 5mg caps (now generic)

    Mechanism: irreversible inhibitor of MAO-b

    Dosage for Selegiline: Parkinsonian patients receiving levodopa/carbidopa therapy who demonstrate a deteriorating response to this treatment:
    Dose: 5mg at breakfast and at lunch (gets metabolized to an “amphetamine like” metabolite). Don’t exceed max daily dose of 10mg, because of non-selective inhibition of MAO over that dose.

    Adverse effects: Dosing over 10mg per day puts patients at risk for dietary reactions with tyramine containing foods, referred to as “cheese reaction”.

    Contraindications: No dietary restrictions are required due to selective MAO-b inhibition

    Drug interactions: Although no interactions with fluoxetine & meperidine have been reported with this medication, it is prudent not to administer these drugs.
    • Selective Serotonin Reuptake Inhibitors (SSRI) and Serotonin Norepinephrine Reuptake Inhibitors (SNRI) , Buspirone, and mirtazapine may cause Serotonin Syndrome (excessive levels of serotonin): Confusion, agitation, tremor, seizures & death.
    Drug Monitoring: clinical presentation

    Patient Education: Don’t exceed 10mg. Take at breakfast & lunch. Report severe headache or elevated blood pressure

    Selegiline oral disintegrating tablets (Zelapar®) 1.25mg
    • Designed to minimize first pass metabolism, increase bioavailability, and reduce amphetamine-like metabolites.
    • Start with 1.25mg dissolved in mouth. After 6 weeks, may increase to maximum dose of 2.5mg.
    Rasagiline (Azilect®) Teva Neuroscience ,2006 0.5mg, 1mg (now generic)
    • Approved for initial monotherapy, as well as adjunct therapy in moderate to advanced disease.
    • Is a MAO-B inhibitor that blocks the breakdown of dopamine, primarily in the brain.
    • Adverse effects: hallucinations, headache arthralgia, dyspepsia, depression, falls and flu-like symptoms
    • Dosage:
      • Monotherapy: 1mg daily
      • Combination therapy: initial dose 0.5mg daily. May increase to 1mg if inadequate response. May potentiate adverse effects of L-dopa (hallucinations and dyskinesias)
    Safinamide (Xadago®) 50mg & 100mg ($800/month) new-2017
    • A reversible (new class of drugs) MAO-B inhibitor as an adjunct to carbidopa/levodopa therapy in patients that experience on/off motor fluctuations.
    • Currently not approved as monotherapy.
    • Used in mid-late-stage Parkinson’s and increases ON time without causing dyskinesias.
    • Not known if there are any advantages over the older irreversible MAO-B inhibitors.
    I don’t think anyone waited more anxiously for the introduction of Selegiline (L-deprenyl) than my wife’s family. My mother-in-law as I described in the first unit of this Neurology section, was a robust and brilliant reading supervisor. She had been afflicted with Parkinson’s in her early 50’s. We waited anxiously for Selegiline to become available, as we heard about its success in Europe.

    As I described at the beginning of this letter, MAO-b inhibitors are lightweights. Once the drug became available in the US, I’m sure my mother-in-law was one of the first to have it prescribed for her. Unfortunately, it provided no benefit as her condition was so advanced.

    Have a great day on the bench!!

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    An Overview of Dopamine Receptor Agonists

    Dopamine Receptor Agonists

    Mechanism: Dopamine agonists are ineffective in patients who have shown no therapeutic response to levodopa. Seems to be more efficacious in early Parkinson’s disease.
    • Direct stimulation of dopamine receptors
      • Although they do not “look” like dopamine, they stimulate the dopamine receptor.
    Class effects:
    • Associated with pathologic gambling, compulsive sexual behavior, binge eating or compulsive buying, in up to 50 percent of patients with long-term use.
      • Remember, dopamine is known as the “pleasure hormone”/li>
      • Dopamine agonist withdrawal syndrome (DAWS): If stopped suddenly, anxiety, panic attacks, depression, sweating, nausea, pain, fatigue, dizziness, and drug craving, like cocaine withdrawal may occur.
      • Class adverse effects: watch for dizziness, hallucinations can occur, may all cause drowsiness, may cause nausea, vomiting, headache, dry mouth and fatigue. Vivid dreams are common leading to sleep disturbances.
    Bromocriptine (Parlodel®) tablets: 2.5mg caps: 5mg
    Classification: Ergot Dopamine Receptor Agonist

    Start with 1.25mg BID with meals. May increase dose by 2.5mg /day every 2 to 4 weeks.
    Usual dosage range: 10 to 40mg/day. Don’t exceed 100mg/day. Seldom used for Parkinson’s disease, mostly used as second line therapy for hyperprolactinemia. Patients unresponsive to L-dopa therapy are poor candidates for bromocriptine.

    CAUTION: CAUSES stiffening of heart valves. Causes significant nausea.

    Cycloset® (Bromocriptine) is an add on treatment for Type-2 diabetes. Initial dose is one tablet (0.8 mg) daily increased weekly by one tablet until maximal tolerated daily dose of 1.6 to 4.8 mg is achieved.

    NON-Ergot dopamine receptor agonists: Pramipexole & Ropinirole

    Pramipexole (Mirapex®) (non-ergot) 0.125mg, 0.25mg, 0.5mg 1mg and 1.5mg (available generically)
    MIRAPEX ER® 0.375, 0.75, 1.5mg, 3.0mg, 4.5mg (available generically)
    • tablets are taken once daily, with or without food
    • Is approved as monotherapy
    • Usually dosed three times daily for Parkinson’s disease
    • Maintenance dose: 1.5 to 4.5mg/day
    • If used with Levodopa, may decrease L-dopa dosage. (May see average decrease of 27%)
    Ropinirole (Requip®) (non-ergot) 0.25mg, 0.5mg 1mg,2mg, 4mg (available generically)
    REQUIP XL: once daily : Tablets: 2 mg, 4 mg, 6 mg, 8 mg, and 12 mg
    Approved for monotherapy--(generics are available)
    • Take 3 times daily with or without food.
    • Starting dose is 0.25mg three times daily
    • Increase dose by 0.25mg thee times daily for each week for 4 weeks.
    • When used as an adjunct to levodopa, the levodopa dose can be decreased gradually as tolerated.
    Contraindications: may need to reduce levodopa based on clinical response

    Drug interactions: Ropinirole: CYP1A2 is the major enzyme responsible for the metabolism of ropinirole. Thus inhibitors (ciprofloxacin, fluvoxamine) or inducers (omeprazole or smoking) of CYP1A2 may alter the clearance of ropinirole.

    Drug Monitoring: clinical management of symptoms

    Patient Education:
    • Exercise caution when driving
    • Take with food or milk to reduce GI upset
    • Report mood changes and uncontrolled movements
    USE (Parkinson’s disease): :
    • may be used as monotherapy early on, so as to delay L-dopa therapy.
    • less effective for motor symptoms but do cause less dyskinesias and motor fluctuations.
    • less effective for motor symptoms but do cause less dyskinesias and motor fluctuations. May be effective as add-on treatment to L-dopa therapy induced motor fluctuations.
    USE (restless leg syndrome): :
    • • Requip® (ropinirole) is approved for restless legs syndrome. Begin therapy for RLS: Ropinirole 0.25mg daily 1 to 3 hours before bedtime, with increased doses as needed (by 0.5mg/ week), and as tolerated to a maximum of 4mg/ day. Median dose studied was 2mg.
    • • Mirapex® (pramipexole) is approved for restless legs syndrome as of December. Begin therapy for RLS: Pramipexole 0.125mg once daily 2-3 hours before bedtime. Can be titrated every 4-7 days if needed. 3 strengths available for RLS 0.125mg, 0.25mg and 0.5mg for convenient titration. 75% of patients will have relief at 0.25mg 2-3 hours before bedtime.
    Key diagnostic Criteria for Restless Legs Syndrome (RLS) :
    • Urge to move the legs (usually caused by uncomfortable leg sensations- may be described as aching, burning or painful)
    • Temporary relief with movement – partial or total relief from discomfort by walking or stretching.
    • Onset or worsening of symptoms in the evening or at night.
    • During evaluation, rule out pregnancy, renal failure, or iron deficiency.
    Apomorphine hydrochloride (Apokyn®) injection 10mg/ml (non-ergot)

    Indication: for acute intermittent hypo mobility on “off” or “end of dose wearing off” episodes through stimulation of postsynaptic dopamine D2-type receptors within the caudate-putamen in the brain. Associated with advanced Parkinson’s disease. Helpful for freezing episodes

    Kynmobi® (apomorphine hydrochloride) for the acute, intermittent treatment of off episodes in patients with Parkinson disease (PD)
    • a sublingual film formulation (doses 10mg, 15mg, 20mg, 25mg, and 30mg ) of apomorphine, a non-ergoline dopamine agonist.
    • Adverse reactions: nausea, oral/pharyngeal soft tissue swelling, oral/pharyngeal soft tissue pain and paresthesia, dizziness, and somnolence.
      • Because of the high incidence of nausea and vomiting, an antiemetic starting 3 days prior to the initial dose of Kynmobi is recommended. Avoid ondansetron (Zofran®) for nausea due to hypotension.
    Rotigotine (Neupro®) is a patch. Approved May 2007 (non-ergot).
    Available strengths: 1 mg/24 hr.; 2 mg/24 hr.; 3 mg/24 hr.; 4 mg/24 hr.; 6 mg/24 hr.; 8 mg/24 hr.
    • For early-stage idiopathic Parkinson’s disease and restless legs syndrome. Rotigotine is a dopamine agonist, mimicking the effects of dopamine.

    “Who is the most famous Parkinson’s Disease patient of all?” I would ask my class and the response was usually “Michael J. Foxx”. Wrong! The next answer invariably was “Mohammed Ali”. I would remind the students they are at St. Francis University and this guy’s image could be found anywhere! That’s right “Pope John Paul II” was the answer I would be looking for.

    Exactly 20 years ago we were in Rome Italy, on a pilgrimage with our beloved priest as our tour guide. We went to outdoor Mass at St. Peter’s Square for St Peter and Paul’s Feast Day, which is a holiday in Italy. At the beginning, Pope John Paul walked out with his Cardinals, he read his sermon while he was sitting. By the end of Mass (about 1.5 hours after the start), he was wheeled off in a wheelchair.

    How could he deteriorate so quickly? I later read that before any big event, the Pope’s physician would give him an injection of apomorphine, that would enable him to participate for a while. Unfortunately, it wore off quickly.

    Have a great day on the bench!!

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    An Overview of Drugs Used in the Management of Parkinson’s Disease

    Initial therapy for Parkinson's Disease--manage the symptoms!

    • Symmetrel® 100mg capsules, syrup 50mg/5mL
      • Dose is usually 100mg twice daily. Never exceed 400mg.
    • Gocovri® 68.5mg and 137mg ER capsules. /li>
      • The initial daily dosage is 137 mg; after 1 week, increase to the recommended daily dosage of 274 mg .
      • Dosed at bedtime
    • Osmolex ER® Extended-release tablets containing 129 mg, 193 mg, or 258 mg amantadine.
      • Start with 129mg in morning; titrate to a max of 322mg.
    History: Initially developed as an antiviral medication to treat influenza. Was approved in 1968, but later found to be useful as a treatment for Parkinson’s Disease. Because of resistance, amantadine is no longer recommended for prophylaxis or treatment of influenza A, as of 2006.

    Mechanism: Decreases pre-synaptic uptake of dopamine. And enhances dopamine synthesis and release from presynaptic storage granules

    Dosage: 100mg BID max= 300mg/day (dosage adjustment required if renal impaired)
    Response is rapid and is effective in 50% of patients.

    Adverse effects: hyper excitability, tremor, confusion, livedo reticularis (rose colored mottling of skin), slight anticholinergic effects.

    Patient educations:
    • Tolerance develops in 6 to 12 weeks of the initiation of therapy.
    • Take last dose well before bedtime to decrease insomnia.
    Use: To treat early Parkinson’s Disease or as adjunctive treatment in later stages. May be effective in treating tremor which can be resistant to dopamine treatment. Effect may last only a few weeks. Withdraw slowly so as not exacerbate symptoms.


    Mechanism: Decreases cholinergic function, thereby increasing relative activity of the remaining dopamine. Monotherapy for patients with Parkinson Disease who are less than 65 years of age and have disturbing tremor but do not have significant bradykinesia or gait disturbance. Used for management of symptoms only.

    Drugs and dosage:
    • Benztropine (Cogentin®): tablets = 0.5mg, 1mg & 2mg (generic available)
      • 1 to 2 mg at bedtime, may also divide doses. Up to 6mg/day
    • Trihexyphenidyl (Artane®) : tablets 2mg & 5mg (generic available)
      • Start 1 –2mg first day. May increase by 2mg/day every 3 to 5 days. Max= 15mg
      • Give in divided doses.
    Adverse effects:
    • Minor: you know the big 4 anticholinergic side effects! With apologies for the crudeness here, I will offer a reminder of the popular memory tool here:
      • Can’t see, can’t pee, can’t spit, can’t s**t!
    • Major: delirium, disorientation hallucinations, agitation & anxiety
    • Disease State Interactions: decreased gastric motility, may cause gastric deactivation of L-Dopa
    Patient Educations:
    • if GI upset is a problem, take with food
    • Exercise caution with drowsiness/dizziness, especially during dangerous tasks & driving
    • Hard candy may help relieve symptoms of dry mouth
    • Avoid alcohol
    Use: May be most useful in treatment of tremor and drooling. Withdraw slowly so as not to exacerbate these symptoms.

    Treatment of Parkinson’s Disease can be challenging. Most neurologists usually start with ‘symptom management drugs’ such as amantadine and the anticholinergics. I always found it interesting that benztropine (Cogentin®) was always prescribed by psychiatrists primarily to prevent the adverse effects caused by the first-generation antipsychotics like perphenazine, trifluoperazine, thiothixene etc.

    Neurologists always prescribed trihexyphenidyl (Artane®) for Parkinson’s disease. I asked a neurologist once why trihexyphenidyl was written for by neurologists, and he responded “Gee, I don’t really know; that’s just how we were trained!” Simply explained as “tradition.”

    Most neurologists hold off on treatment with dopamine agonists and levodopa until the patients see impact on their activities of daily living. This is truly when “shared decision making” is a must for treatment of Parkinson’s disease.

    Have a great day on the bench!!

    July 2021

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    An Overview of Idiopathic Parkinson’s Disease

    Idiopathic Parkinson’s Disease (IPD)
    • A progressive and irreversible degeneration of melan-containing dopaminergic neurons within the pars compacta of the substantia nigra.
    • The severity of IPD generally correlates with the degree of cell loss. Neural degeneration also correlates with a decrease in dopaminergic neurotransmission.
    • Loss of dopamine results in a deficiency of dopamine relative to other neurotransmitters, particularly acetylcholine (ACH). Typically, noticeable symptoms for diagnosis do not arise until 80% of neurons are gone.
    Incidence: Parkinson’s impacts over 1 million people in North America. Parkinson’s disease is uncommon in those under age 40, with a rapid increase at age 60. Mean age of diagnosis is 70 years, with men being diagnosed twice as frequently as women.

    Smoking: interestingly enough, smokers have a lower rate of Parkinson’s disease.

    Hoehn & Yahr Scale: (used to describe severity of Parkinson’s)

    Stage 1: unilateral involvement
    Stage 2: bilateral involvement, no postural abnormalities
    Stage 3: Bilateral involvement, mild postural imbalance, patient is independent.
    Stage 4: Bilateral involvement postural instability, patient requires much help
    Stage 5: Severe, fully developed disease, patient restricted to bed or chair.

    Parkinson symptoms
    • Micrographia (small writing)
    • Hypomimia (“Masked faces”)
      • caused by rigid movement of facial muscles, creating an expression that appears to lack emotion
    • Tremor at rest
      • begins unilaterally and are present in 70%
    • Tremors (not during sleep)
      • may worsen with stress
    • Rigidity of limbs trunk and face
    • Bradykinesia (slow movement when walking)
    • Soft or low voice
    • Some people report loss of smell many years before onset of tremor/symptoms
    • Depression is reported in up to 50% of Parkinson’s patients
    • Abulia: loss of the impulse, will, or motivation to think, speak, and act, usually due to presence of a disease

    Secondary Parkinson’s Disease: May be precipitated by trauma, neoplasms or severe ischemic vessel disease, medications. Need MRI to rule out.

    Drug induced Parkinsonism:
    • May be indistinguishable from idiopathic Parkinsonism. /li>
    • Drug-induced symptoms are often symmetrical and occur within weeks to months after starting an offending medication.
    • About 10% of Parkinson-like motor symptoms are caused by mediations.
    • Drug induced is reversible, occurs later in treatment than the preceding extrapyramidal symptoms.
    High potency neuroleptics (antipsychotics), especially first-generation antipsychotics, frequently require anti-Parkinsonism drugs.

    Treatment: decrease dose of antipsychotic. Use anti-Parkinson drugs. After 4 to 6 weeks, these anti-Parkinson drugs may be stopped.

    Common drugs causing Parkinson-like effects:
    • Metoclopramide (Reglan®) (very significant)
    • Prochlorperazine (Compazine®)
    • Haloperidol: Haldol® (block dopamine receptors)
    • Phenothiazine: Chlorpromazine, Trifluperazine etc. (block dopamine receptors)
    • Second generation antipsychotics: risperidone, paliperidone, and olanzapine
      • (quetiapine and clozapine are considered safest in this regard)
    • Cholinesterase inhibitors: donepezil, rivastigmine
    • Amitriptyline
    • Carbamazepine
    • Reserpine
    • Less common: valproate, lithium and SSRI’s
    • Other Agents: Carbon monoxide, Cyanide, Lead, Mercury, Methyl chloride, photographic dyes.
    NOTE: Drug Induced Parkinsonism is most commonly seen in elderly women, who are taking higher doses of the offending drug.

    Of the all the neurological diseases, none hit home for me like Parkinson’s disease. My beautiful mother-in-law, Dolores succumbed to this dreaded disease at age 61. She presented with symptoms in her early fifties, and we saw her gradual decline. She was a vibrant, attractive and brilliant woman who raised 6 kids. She was a reading supervisor and was loved by her students and her colleagues in the elementary schools she visited.

    I once had a nurse at a long-term care facility tell me that she thought Parkinson’s disease was the cruelest of the neurological diseases because the patients were able to see firsthand their own decline. Parkinson patients are very cognizant of the fact that they get a little worse every day.

    I remember seeing Denise’s mom deteriorate every time we saw her. My daughters in elementary school, when asked what their favorite food was didn’t respond “pizza” or “chicken nuggets”. It was chicken gravy over waffles, because we seemed to eat that once a week because it was Grandma’s favorite. It was a staple meal for quite a few years in our home, because it was something she could enjoy, as she had difficulty chewing and swallowing.

    None of Denise’s four sisters have seen any sign of this dreaded disease. I’ve combed through pages of genetic studies with regard to the PARK2 gene, and there doesn’t seem to be a strong genetic generational link. For that, our entire family is thankful

    Have a great day on the bench!!

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    An Overview of Antiarrhythmics

    CLASS I AGENTS: Sodium Channel Blockers


    Indications for Use:
    • Treatment of: Supraventricular tachycardia, ventricular tachycardia, prevent ventricular fibrillation, symptomatic ventricular premature beats.
    • Delay the recurrence of occasional atrial fibrillation
    Mechanism of Action: Sodium channel blocker- depresses phase 0 depolarization, slows conduction, prolongs repolarization. Increases QRS interval and increases QT interval.
    Examples: disopyramide (Norpace®) and quinidine (Quinaglute®)


    Indications for Use: ventricular tachycardia, prevention of v-fib, symptomatic ventricular beats.
    Mechanism of Action: Sodium channel blocker; modest depression of conduction, shortening of repolarization, decrease in QT interval.
    Examples: Lidocaine®, Mexiletine (Mexitil®), tocainide (Tonocard®)

    Indications for Use: life threatening ventricular tachycardia, or v-fib, refractory supraventricular tachycardia Mechanism of Action: Sodium channel blocker. Markedly depress phase 0 repolarization, slows conduction

    Examples: Flecainide (Tambocor®); Morcozine (Ethmozine®), Propafenone (Rythmol®)


    Indications for Use: Supraventricular tachycardia, may prevent v-fib, digitalis induced ventricular arrhythmias Mechanism of Action:
    • Beta blockers- suppress phase 4 depolarization. Slows AV conduction. Decreases heart rate.
    • Reduces sympathetic stimulation of the heart (beta-1). Slows sinus rhythm without significantly changing the QT or QRS interval. Decreases HR and myocardial oxygen demand.

    CLASS III AGENTS: Potassium channel blockers

    Amiodarone (Cordarone®, Pacerone®) 100mg, 200mg & 400mg tablets (approved 1985)

    Mechanism of Action: potassium channel blockers. Causes prolonged action potential (QT prolongation). refractory v-tach, suprav-tach, prevention of v-tach, a-fib, v-fib
    Indications for Use: For atrial and ventricular tachycardia. Has been shown to decrease patient arrhythmic deaths in patients after a myocardial infarction.
    • Should only be initiated in the hospital setting.
    • Is the most effective for prevention of a-fib and v-tach or v-fib.
    • More effective than sotalol or drugs in reducing recurrent tachycardia.
    • Most effective drug for atrial fibrillation.
    • The most effective antiarrhythmic drug for maintenance of normal sinus rhythm.
    Dosage: loading dose of 800-1600mg/day for 1 to 3 weeks. When control is achieved dose can be decreased to 600-800mg/day for 1 month. Maintenance dose is usually 400mg/day.

    Warning/Precautions & Adverse Effects
    • Life threatening pulmonary toxicity (especially if over 400mg/day)
    • Most patients develop corneal micro deposits, 1 to 4 months after therapy.
    • Monitor for hypotension and brady arrhythmias
    • Monitor for hepatic dysfunction, thyroid disorders (hypo & hyper), and photosensitivity
    • May cause blue/gray skin discoloration
    • Half-life is 65 days....drug interactions may continue after drug is discontinued (May have adverse reactions for 4 months after therapy has ended!)
    Patient Information:
    • Watch for photosensitivity
    • Take consistently with regard to meals (food affects absorption)
    • Choose amiodarone over dronedarone for patients with paroxysmal or persistent atrial fib who need rhythm control, especially if they have heart failure or severe left ventricular hypertrophy.
    Dronedarone (Multaq®) available as 400mg tabs (approved 2009)
    • Evidence suggests that patients with permanent atrial fibrillation actually have a higher risk of death and cardiovascular events, when on dronedarone.
    • Avoid dronedarone or other antiarrhythmics for permanent atrial fibrillation. None of them improve outcomes.
    Sotalol (Betapace®) approved 1992

    • Treatment of life-threatening, documented ventricular arrhythmias, such as sustained ventricular tachycardia
    • Maintenance of normal sinus rhythm (delay in time to recurrence of AFIB/AFL) in patients with symptomatic AFIB/AFL who are currently in sinus rhythm.
    Mechanism of Action: non-selective beta blocker
    • methanesulfonanilide, is a class III antiarrhythmic drug that is used for the treatment of both atrial and ventricular arrhythmias.
    Dosage: Hospitalized patients initiated or re-initiated on sotalol for at least 3 days or until steady-state drug levels are achieved, in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring.
    Typical Dose: 80mg twice daily.
    Adverse Effects:
    • Renal dosing is required. Dosing frequency is determined by renal clearance.
    • Sinus bradycardia (heart rate less than 50 bpm) occurred in 13% of patients receiving sotalol

    Dofetilide (Tikosyn®) approved 1999
    • Use: conversion or prevention of a-fib and a-flutter. Not considered first line. Use only if patient is not a candidate for amiodarone or sotalol
    • Dosage calculated by creatinine clearance and QTc interval
    • Watch patients for Torsades
    • Monitor closely for CYP4503Ar4 drug interactions
    • Patients initiated on this therapy must be placed in a facility that can provide calculations for creatinine clearance, continuous ECG monitoring, and cardiac resuscitation for a minimum of 3 days

    CLASS IV AGENTS---Calcium channel blockers

    Indications for Use:
    • treatment and prevention of supraventricular tachycardia
    • first line agent for prevention of PSVT (paroxysmal supraventricular tachycardia)
    Mechanism of Action: CCB inhibit the influx of calcium through its channels causing slower conduction through the SA and AV nodes. They slow ventricular rates, in atrial flutter, atrial fibrillation, and PSVT. Only diltiazem (Cardizem®) and verapamil (Isoptin®) are indicated for heart dysrhythmias.

    • Inform patients that complete remission is unlikely, notify if you have increase in arrhythmias
    • Patients with a-fib or a-flutter should be educated about importance of antithrombic therapy, as well as signs and symptoms of stroke:
      • Drooping of mouth, sudden onset of slurred speech, muscle weakness. FAST!!!!
    • Monitor drug interactions. Carefully change therapies.
    • Periodic ECG and lab assessments are necessary.
    • All antiarrhythmics are proarrhythmic
    • Cardiac arrhythmias may range from benign to lethal
    • Use anticoagulation to help prevent strokes...and rate control with a beta-blocker, verapamil, diltiazem, or digoxin.
    • Tell patients that it is often okay to stay in atrial fib especially if they don't have symptoms.
    • Most antiarrhythmics are hepatically eliminated, thus drug interactions are common
    • Non-Pharmacological therapies are necessary for life threatening v-tach & v-fib
    • Treatment of a-fib should include assessment of antithrombic therapy
    • Direct current cardioversion is typically treatment of choice for severe arrhythmias
    • The ICD is the most highly effective method in preventing sudden death due to recurrent ventricular tachycardia or ventricular fibrillation.
    I remember in the early 1980’s we bought procainamide (Procan SR®) and quinidine (Quinaglute Duratabs®) in bottles of 500 and moved them. We were excited when tocainide (Tonocard®) and flecainide (Tambocor®) came out in 1985, as new and improved antiarrhythmics. Then, the bottom fell out of that market. It was discovered that rhythm control was not as important as rate control.

    Today we seldom use antiarrhythmics, maybe an occasional flecainide and mostly amiodarone. Amiodarone is a great drug to discuss with student pharmacists. Most are taught that after 5 half-lives there is minimal drug in the body (actually 3.125%).

    With a half-life of 65 days, it takes amiodarone 1 year (5 x 65 days) to clear out of the patient. I would tell my PA students to make sure they have done every test necessary before initiating amiodarone therapy. I have had a couple of patients have thyroid issues (usually hypothyroid) while on amiodarone therapy. I spell it out amIODarone, and notice the presence of iodine in the compound. Remind your patients to have their physicians to do a yearly TSH.

    Have a Great Day on the Bench!!

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    An Overview of ARNIs in Heart Failure


    Sacubitril/valsartan (Entresto®):Approved 2015
    Sacubitril= neprilysin inhibitor AND
    Valsartan=angiotensin II receptor blocker (ARB)

    Indications: reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

    • Sacubitril blocks neprilysin, which degrades the beneficial compounds in the Renin-Angiotensin Aldosterone system. By increasing the levels of natriuretic peptides, bradykinin and adrenomedullin, sodium is lowered, vasoconstriction is decreased as well as decreases in maladaptive remodeling.
    • Valsartan is an Angiotensin-1 receptor blocker. By blocking the effects of Angiotensin-2, vasoconstriction is decreased, along with decreasing sodium retention.
    Entresto®: available as tablets: (sacubitril/valsartan) 24/26 mg; 49/51 mg; 97/103 mg

    Initial Therapy:
    • Allow a 36 hour “washout” period if switching from a previous ACE or ARB
    • Starting dose: 49/51 mg (sacubitril/valsartan) twice daily
    • Double the dose after 2-4 weeks, to a maintenance dose 97/103 mg (sacubitril/valsartan) twice daily, as tolerated by the patient.
    • Caution patients about the risk for angioedema, and hypotension. Avoid for severe hepatic impairment.
    • Be aware of hypotension and avoid Entresto® when systolic BP < 100 mmHg. Watch for syncope!
    Bad News for Entresto® (sacubitril/valsartan)
    • In the phase 3 Paradise-MI trial, Entresto® missed its primary endpoint to reduce the risk of cardiovascular death and heart failure after an acute myocardial infarction. Basically, Entresto® (sacubitril/valsartan) lost to an ACE inhibitor. Although Entresto® fared better than ramipril (Altace®), the outcome was not statistically significant.
    • There was a 6% rate of heart failure hospitalizations in the Entresto® arm, versus 6.9% in the ramipril cohort. And 1.4% of Entresto® patients developed outpatient heart failure compared to 2% in subjects who received ramipril.
    • Reference: https://www.acc.org/latest-in-cardiology/clinical-trials/2021/05/14/01/22/paradise-mi
    • Wholesale acquisition cost of Entresto®, is nearly $600/month.
    • Wholesale acquisition cost for Ramipril= $6.00/ month
    • Adherence: Entresto® requires twice daily dosing, while ramipril and most ACE inhibitors/ARBs are dosed once a day.


    MORTALITY REDUCING DRUGS (best options in parentheses)
    • ACEI’s: (ramipril, enalapril)
      • ARB’s (losartan, valsartan, candesartan)
    • Beta-Blockers: (metoprolol-XL, carvedilol, bisoprolol)
    • Aldosterone Antagonists:
    • ARNI’s: (sacubitril/valsartan)
    • Hydralazine/BiDil:
    • SGLT2 inhibitors: Dapagliflozin (Farxiga®) was shown to prolong survival in heart failure. Canagliflozin (Invokana®) Empagliflozin (Jardiance®), were shown to have benefits in cardiovascular disease, to varying degrees.
    • Diuretics
    • Digoxin
    • Ivabradine
    The pharmacist is critical for the following:
    • Watch for drugs that can worsen heart failure, such as nonsteroidal anti-inflammatory drugs, antiarrhythmic drugs, calcium channel blockers like diltiazem (Cardizem®) and verapamil (Isoptin®), thiazolidinediones like rosiglitazone (Avandia®), pioglitazone (Actos®).
    • Patient Education for self-management
      • Weighing daily and reporting significant weight gain
      • Limiting fluids
      • Watching salt intake and diet
      • Monitoring shortness of breath, especially at night
      • Adherence to prescribed medication
      • Monitoring pulse
      • Caution with dizziness
      • Providing pill boxes, especially for multiple dosing regimens
    ACE: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753869/

    “New and improved” ---we see it from automobiles to dishwashing soap. I have to admit for the longest time, I thought Entresto® (sacubitril/valsartan) was in a class by itself. The latest data from May, though, doesn’t seem to support that.

    As Entresto® hones in on the 5-billion-dollar annual sales mark, I have to wonder how many of those patients would have had similar outcomes with an ACE inhibitor, given the information from the latest trials. The average prescription for Entresto® approaches $600.00 per month versus $6.00 for a month supply of ramipril!

    I can easily tell the difference in my original dish soap, versus the ‘new and improved’. I am not so sure we can see significant differences between these two drugs, and certainly when the cost is 100 times more.

    Have a great day on the bench!!

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      An Overview of Heart Failure Drugs Isosorbide dinitrate/hydralazine and Ivabradine


    Isosorbide DN 20mg/Hydralazine 37.5mg (BiDIL®) FDA approved:2005
    • Hydralazine: reduces afterload + dilates arterioles
    • Nitrate: reduces preload + dilates veins
    • Dose: start with 1 tablet three times daily, with a maximum dosage of 2 tablets three times daily
    • There are no large-scale studies that support their use as monotherapy
    • Have been used in combination with nitrates
    • Reduces pulmonary congestion
    • Increases CO, by reduction of preload and afterload.
    • Adjunct to standard therapy in self-identified African American patients to improve survival, improve time to hospitalization for heart failure, and to improve patient reported functional status. This is the first “race specific” drug approved by the FDA.
    • Is added on with ACEI/ARBs , diuretics, digoxin
    • The African American Heart Failure trial was terminated early because at 12 months the BiDil® group showed a 43% reduction in overall mortality.
    • May cause lupus like symptoms
    • May cause symptomatic hypotension
    • Hydralazine may cause myocardial ischemia and anginal attacks
    • May cause headache (50%), dizziness (32%)
    • May cause GI upset
    Drug interactions
    • Caution with erectile dysfunction PDE-5 inhibitors (i.e. sildenafil, vardenafil, etc.)
    • Caution with alcohol & MAOI


    Ivabradine (Corlanor®) FDA approved 2015
    • Available as tablets 5mg, 7.5mg

    • Reduces the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤ 35%, who are in sinus rhythm with resting heart rate ≥ 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use
    • No effect on myocardial contractility or ventricular repolarization
    • Beta-blockers are STILL first line treatment in heart failure. Treat to target doses (Carvedilol 25mg twice daily, or Metoprolol succinate 200mg/day or Bisoprolol 10mg/day)
    Dosing Schedule:
    • Starting dose is 5 mg twice daily
    • After 2 weeks of treatment, adjust dose based on heart rate
    • Maximum dose is 7.5 mg twice daily
    • In patients with conduction defects or in whom bradycardia could lead to hemodynamic compromise, initiate dosing at 2.5 mg twice daily
    • Prevents 1:25 patients being hospitalized.
    • Lowers heart rate without decreasing blood pressure; elevated plasma norepinephrine concentration is a marker for poor survival in these patients. An elevated heart rate contributes to adverse outcomes in patients with HFrEF
    • Inhibits the sinoatrial modulating pacemaker If (“I sub f”) or "funny” current in the heart. This in turn lowers heart rate without decreasing blood pressure. High heart rates reflect adverse effect of heart failure.
    Warnings/Precautions: Avoid ivabradine in patients with:
    • Acute decompensated heart failure
    • Avoid in A-fib or other arrhythmias
    • Blood pressure less than 90/50 mmHg
    • Sick sinus syndrome, sinoatrial block or 3rd degree AV block, unless a functioning demand pacemaker is present
    • Resting heart rate less than 60 bpm prior to treatment
    • Severe hepatic impairment
    • Pacemaker dependence (heart rate maintained exclusively by the pacemaker)

    BiDil® (hydralazine/isosorbide) was the first race specific drug. This points to the fact that we are all different in the ways we metabolize drugs, as well as their efficacy among various populations. A lot of talk has been around for years about “precision medicine”. Hopefully the day will soon get here that we see more and more benefits of precision medicine.

    About 5 years ago Denise and I were at our alma mater, the University of Pittsburgh, where they did some genetic tests. We both found out that we are intermediate metabolizers of CYP 450-2C19. This is the enzyme system that activates clopidogrel to its active metabolite. Denise and I would not see much benefit from clopidogrel if it were prescribed, because of our inability to activate the drug.

    Asian patients should not be started on more than 5mg of rosuvastatin. Chinese patients are more susceptible to Stevens-Johnson-Syndrome caused by carbamazepine. Chinese patients also have a significantly higher incidence of closed angle glaucoma.

    We’re all different and I look forward to the day that our genomic sequence will be part of our charts. That will be precision medicine!

    Have a great day on the bench!!

    June 2021

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    An Overview of Digoxin


    ?Although digitalis glycosides have been in use for over 250 years, it was not until the 1920s were they clearly demonstrated to have a positive ionotropic effect on the heart. The efficacy of digoxin in heart failure and supraventricular tachyarrhythmias such as a-fib, is well established and widely accepted. The role in heart failure patients with normal sinus rhythm is more controversial.

    Current recommendations are:
    • Patients with LV systolic dysfunction & supraventricular tachyarrhythmias (a-fib)
      • consider early in therapy to control ventricular response rate
    • Patients with normal sinus rhythm
      • digoxin does not improve survival, but its positive ionotropic effects, symptom reduction, and quality of life improvement are evident in patients with mild to severe heart failure
      • should be used with other heart failure therapies (DIUR, ACEI, BB)
    • Inhibits the Na/K APTase pump. This results in an increase of intracellular calcium and in turn causes a positive inotropic effect.
    • Recent evidence indicates it decreases sympathetic outflow from the CNS thus blunting excessive sympathetic activation that occurs in heart failure.
    • Recent evidence suggests digoxin acts by furthering the activation of neurohormonal systems; this results in deactivation of renin-angiotensin-aldosterone compensation which promotes diuresis, decreases fluid volume, decreases renal sodium reabsorption and diminishes edema
    • Overall, it increases force of cardiac contraction
    • Heart failure: Mild to moderate heart failure
      • increases left ventricular ejection fraction, and improves heart failure symptoms, as evidenced by exercise capacity, and heart failure related hospitalizations, emergency care.
    • Atrial fibrillation: controls ventricular response rate in patients with chronic a-fib.
      • less effective than beta-blockers or calcium channel blockers
    Warnings/Precautions/Adverse Effects:
    • Cardiac: arrhythmias, bradycardia, heart block
    • GI: anorexia, abdominal pain, nausea and vomiting
    • Neurological: visual disturbances, disorientation, confusion, fatigue
    • Current target range: 0.5-1 nanogram/mL
    • Toxicity occurs over 2 nanogram/mL but may occur at lower levels if the patient has hypokalemia, hypomagnesemia, or is elderly.?
      • Be sure to monitor for blood levels of potassium and magnesium, especially if patient takes loop diuretics.
      • Digoxin has a narrow therapeutic range
        • Toxicity can be fatal in a significant percentage of patients experiencing toxicity
    Drug interactions

    INCREASES the Digoxin effect: (increased serum concentrations):
    • Quinidine, Verapamil, Amiodarone: decrease dose of digoxin by 50% if added.
    • Propafenone (Rhythmol®), Flecanide (Tambocor®)
    • Macrolide antibiotics (Erythromycin, Clarithromycin)
    • Itraconazole (Sporanox®)
    • Spironolactone (Aldactone®)
    • Cyclosporine
    DECREASES the effect of Digoxin (decreased serum concentrations):
    • Antacids
    • Cholestyramine (Questran®), Colestipol (Colestid®),
    • Metoclopramide (Reglan®)
    • Bupropion (Wellbutrin®)
    • Inducers of p-glycoprotein, such as rifampin, phenytoin (Dilantin®), carbamazepine (Tegretol®), phenobarbital, St. John’s Wort
    OTHER concerns:
    • Diuretics: increases the risk of digoxin toxicity when hypokalemia and hypomagnesemia are present. (Be sure to keep potassium levels at 4- 5.5mmol/L)
    • Renal insufficiency: Digoxin clearance is reduced, therefore monitor closely for toxicity.
    • Biotin: can interfere with the assay for digoxin by interfering with lab test.? This may appear as an artificial increase in digoxin levels
    • Lanoxin® (digoxin) tablets 0.125mg (yellow), 0.25mg (white)
    • Lanoxin® (digoxin) elixir 0.05mg/mL (pediatric)
    • Lanoxin ® (digoxin) injection 0.25mg/mL
    • Based on clinical response. There are several tables in the literature for rapid digitalizing in the hospital setting based on age, lean body weight, renal function, and concomitant disease state.? Also, there are regimens for slow and fast initiation of therapy.
    Initiation Dose:
    • 0.25mg/day in patients less than age 70 with good renal function?
    • 0.125mg in patients greater than age 70 or with impaired renal function.
    • 0.0625mg in patients with marked renal impairment.?
    Maintenance Dose:
    • 0.125 to 0.5mg daily
    • Doses may be increased every 2 weeks
    • Remember: 0.25mg= 250mcg; 0.125mg= 125mcg
    Patient Education:
    1. Know the SIGNS of Digoxin Toxicity
      • Anorexia: common and early sign
      • Fatigue, headache and malaise
      • Nausea and vomiting
      • Mental confusion, disorientation
      • Alterations in visual perceptions (halos around lights)
      • Cardiac effects: premature ventricular contractions, ventricular tachycardia, SA/AV block, atrial tachycardia with AV block.
    2. Eat small frequent meals (4-6/day) to decrease metabolic demands
    3. Moderate sodium restriction may be helpful as well.
    Treatment of Digitalis Toxicity:
    • DigiFab® (40mg per vial) or DigiBind® (38mg/vial)
    • Each vial binds approximately 0.5mg of digoxin
    • Treatment of life threatening or potentially life-threatening digoxin toxicity or overdose. Not indicated for milder cases of digitalis toxicity.
    • Known suicidal or accidental consumption of more than 10mg of Digoxin in healthy adults or 4mg in previously healthy children or ingestion causing steady state serum concentrations greater than 10 nanograms/mL
    • Binds the molecules of digoxin making them unavailable for binding at their site of action. The Fab fragment/digoxin complex accumulates in the blood and is excreted by the kidney.? It shifts the equilibrium away from binding digoxin to its receptors and reverses its effects.
    • Infused IV through a 0.22micron filter

    We seasoned pharmacists love digoxin, but don’t dispense it as much as we did in previous years.? I remember as a student pharmacist in the 1980’s working for a small independent pharmacy selling Lanoxin® (digoxin) by Burroughs Wellcome for $1.89 for 30 tablets.?

    Back then, pharmacists charged a 40% mark-up on medications, and actually made money without filling hundreds of prescriptions per day! This was before the Angiotensin Converting Enzyme Inhibitors (ACEI’s) were introduced, and quickly became first line therapy for heart failure.

    This evening, I checked our warehouse site, and the current price is $1,372.61 per 100 tablets, which would be a 400-fold increase from the price paid back in 1981.? The digitalis glycosides were first isolated from the foxglove plant (Digitalis lanata) by William Withering an English Physician in 1785.? Before the United States became a country, digitalis glycosides were being used to treat “dropsy”, so a 400-fold increase in a 40 year seems drastic at best.?

    If automobiles had increased at the same rate, the Datsun 210 that Denise and I bought in 1981, would now cost 1.6 million dollars!

    Have a great day on the bench!!

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    A Broad Overview of Medications Used in Heart Failure

    HEART FAILURE--- the Basics
    Heart Failure: a clinical syndrome resulting from a variety of cardiac disorders that impairs the ability of the ventricle to fill with or eject blood.
    • Heart failure is the only major cardiovascular disease increasing in prevalence.
    • Heart failure is the most common hospital discharge diagnosis for Medicare patients. More Medicare dollars are spent for the diagnosis and treatment of heart failure than any other disorder.
    • Symptom management and reduction of hospitalization are the primary goals of treatment

    Improvement in symptoms (improved morbidity) can be achieved with the use of diuretics, beta blockers, ACE inhibitors, ARBs, ARNI, hydralazine plus nitrate, digoxin, and aldosterone antagonists.

    Prolongation of patient survival (improved mortality) has been documented with the use of beta blockers, ACE inhibitors, ARNI, hydralazine plus nitrate, and aldosterone antagonists. More limited evidence of survival benefit is available for diuretic therapy

    The primary manifestations of heart failure are dyspnea (shortness of breath) and fatigue, which may limit exercise tolerance and fluid retention, which may lead to pulmonary edema and peripheral edema. Some patients have marked exercise intolerance and little fluid retention, whereas others have prominent edema and few symptoms of fatigue or dyspnea.

    Ejection fraction: Patients with a left ventricular ejection fraction less than 40% are considered to have systolic dysfunction. In general, there is poor correlation between ejection fraction and symptoms. Most patients will present with Heart Failure with Reduced Ejection Fraction (HFReF)

    smoking cessation
    restriction of alcohol consumption
    salt restriction
    weight reduction if obese (BMI >30.0)
    monitor weight every day to detect fluid accumulation before it becomes symptomatic.

    DRUGS that can precipitate or worsen heart failure:
    Antiarrhythmics: disopyramide, flecainide, propafenone
    Beta blockers
    Calcium Channel Blockers: Verapamil & Diltiazem (non-dihydropyridine)

    Role of Calcium Channel Blockers:
    First generation CCB (verapamil & diltiazem) may accelerate progression of CHF
    Amlodipine (Norvasc®) is safe with severe heart failure. (No better than placebo)

    Avoid CCB unless treating angina or hypertension. If needed, use amlodipine.

    Classification Based on Patient Symptoms: NYHA

    Class-1: patients with cardiac disease, but without limitations of physical activity. Ordinary physical activity does not cause undue fatigue, dyspnea, or palpitations. (no limitations)
    • Described as Ejection Fraction <40% with no signs of dyspnea
    • TREATMENT: ACEI; may consider BB
    Class-2: patients with cardiac disease, that results in slight limitations of physical activity. Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. (can climb 2 flights of stairs)
    • Described as mild dyspnea on exertion.
    • Treatment: Volume Overload: diuretic, ACEI or ARB or ARNI and digoxin. Later, consider Spironolactone.
    • Treatment: No Volume Overload: ACEI or ARB or ARNI and BB
    Class-3: patients with cardiac disease that results in marked limitations of physical activity, although patient is comfortable at rest, less than ordinary activity leads to symptoms. (climbs ½ flight of stairs)
    • Described as moderate dyspnea on exertion
    • Initiate and titrate diuretic, ACEI or ARB or ARNI; Add digoxin then initiate BB (if not already done), consider spironolactone.
    Class-4: patients with cardiac disease that results in an inability to carry on physical activity without discomfort. Symptoms of CHF are present even at rest. With any physical activity increased discomfort is experienced. (won’t even look at a flight of stairs) (Source: American Heart Association)
    • Described as severe dyspnea on exertion
    • Consider hospitalization. Initiate diuretic, ACEI or ARB or ARNI, add digoxin & titrate BB
    • Add spironolactone later. If no improvement, add IV ionotropes.

    ACE-inhibitors or ARBSDiuretics (prefer-loop)
    Beta-blockersthiazides are ok
    Aldosterone antagonistsDigoxin
    ARNI’s (Entresto®)vabradine
    Hydralazine/ISDN (BiDil) – if African American
    Dapagliflozin (Farxiga) SGLT2 inhibitor for diabetes.

    When I would teach heart failure to my class I would throw in a little history and use the British term “dropsy”. One of my students from Jamaica came up after class and was pleased that I used the term “dropsy” in class. He said as a boy in Jamaica he would see several old people sitting around with their feet elevated, and he was told that they had “dropsy.” He shared with me that he often wondered about this disease, and what the medical term was.

    Heart failure treatment has come a l-o-n-g way since I graduated in 1981. Ace inhibitors were not available yet, and the standard treatment was digoxin (Lanoxin®), furosemide (Lasix) and potassium because of the furosemide.

    Today, ACE inhibitors or Angiotensin Receptor Blockers (ARB’s) are first line treatment as they do reduce mortality. Community pharmacists have a huge role in treatment of heart failure by making sure patient adherence is optimal, to reduce hospitalizations.

    Next we will discuss drugs specific for the treatment of heart failure. Kind of interesting to see a diabetes drug , dapagaflozin (Farxiga®) being used for heart failure!

    Have a great day on the bench!!

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    Hypertension: A Glance at Special Patient Populations

    Treatment of SPECIFIC PATIENTS

    I. PREGNANCY Methyldopa (Aldomet®) during all trimesters of pregnancy is traditionally the “go to” due to remote chance of fetal harm. Use only if clearly needed.
    • Methyldopa is Category-B; watch for fatigue and dizziness.
    • Nifedipine-ER (a CCB) – is considered safe
    • Labetalol (Normodyne®): appears to be better able to prevent the appearance of fetal growth retardation.
    AVOID: ACEI, ARB, Aliskiren, Eplerenone, Spironolactone

    Drug of Choice: Calcium Channel Blockers
    AVOID: BB, especially if non-selective beta-blockers

    Drug of Choice: Angiotensin Converting Enzyme Inhibitors (ACEI’s)/ Angiotensin Receptor Blockers (ARB’s); CCB (2nd choice)
    AVOID: Beta Blockers (BB) & diuretics

    Drug of Choice: Beta Blockers (non-ISA) and CCB
    AVOID: peripheral vasodilators

    Drug of Choice: ACEI/ARB and diuretic
    Also, non-Dihydropyridine (diltiazem, verapamil) and low dose BB

    VI. AFRICAN AMERICANS Drug of Choice: Diuretic or CCB Monotherapy with BB or ACEI are often ineffective. May add ACEI—40% of blacks have good response to ACEI May add BB: BB plus diuretics are equally efficacious in blacks and whites.

    Drug of Choice:
    • Thiazide plus ACEI, (preferred if diabetic or HF)
    • BB if hypertensive with angina
    • Men with BPH: use alpha blockers
    • AVOID: central acting alpha agonist
    AVOID: central alpha agonists & beta-blockers

    Drugs of choice: ACEI, ARBs and CCB
    Avoid BB and alpha agonists, and diuretics

    Drug of Choice: ACE & ARBS; Loop Diuretics
    CAUTION: ACE if bi-renal arterial stenosis.
    AVOID: Thiazides

    1. ALWAYS check with the pharmacy to see if poor adherence is the problem before proceeding with additional hypertensive medications.
    2. Simplify regimens such as using combination products to decrease the number of pills per day, and lower number of copays. (Lisinopril/hctz) (Diovan/HCT) (Amlodipine/benazepril). Will see additive effect and decrease in side effects.
    3. Bedtime dosing may be helpful if early morning hypertension is a problem
    4. Secondary causes of resistance include: obstructive sleep apnea, renal artery stenosis, primary aldosteronism. Screen for these conditions.
    5. Check for drugs that can elevate blood pressure such as NSAIDs and COX-2 inhibitors, sympathomimetics amines (pseudoephedrine)
    6. Many experts feel a diuretic should be used. Chlorthalidone (Hygroton®) and indapamide (Lozol®) two old diuretics, seldom used today are usually more effective than HCTZ for blood pressure reduction.
    7. Use Loop diuretics if impaired renal function
    8. Most patients need an ACE/ARB plus CCB or BB.
    9. Next step is to use an aldosterone blocker (spironolactone, eplerenone), because these patients (20%) have elevated aldosterone levels.
    10. Watch potassium levels, with aldosterone blockers, especially if combined with ACE or ARBs
    COMBINATION therapy:
    Start 2 drug therapy if patients are over 20mmHg(systolic) or 10mmHg(diastolic).
    Pick combos for UNCOMPLICATED hypertension using this summary.
    Preferred Combos
    • ACEI + thiazide
    • ACEI + dihydropyridine CCB
    • ARB + thiazide
    • ARB + dihydropyridine CCB
    • CCB + thiazide
    Acceptable Combo
    • Thiazide + potassium-sparing diuretic
    • Aliskiren + thiazide or CCB
    • B-blocker + diuretic or dihydro CCB
    • B-blocker + ACEI or ARB
    • Dihydropyridine CCB + non-dihydropyridine CCB
    NOT Preferred Combos
    • ACEI + ARB
    • Aliskiren + ACE or ARB
    • B-blocker + Nondihydropyridine CCB
    • B-blocker + Central acting (clonidine, methyldopa, etc)

    Only a gray-haired pharmacist like me and my colleagues would remember SER-AP-ES® which was a combination product for treating high blood pressure (Serpasil-Apresoline-Esidrex). It contained three drugs: reserpine (an adrenergic uptake inhibitor), hydralazine (vasodilator) and hydrochlorothiazide (diuretic).

    After we graduated in 1981, the ACE inhibitors took over. Combination therapy went out the window, as clinicians were told to push the dose of monotherapy, so you knew where the side effects were coming from.

    Now the pendulum has swung in the opposite direction, using low doses of combination therapy to minimize side effects, and to maximize the additive benefit of mechanisms of action. “The more things change, the more they remain the same!”

    Have a great day on the bench!!

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    Hydralazine, Aliskiren, and Minoxidil: The Lesser Known Antihypertensives

    In this session, we cover three drugs that are not frequently used. Of the three, I have dispensed hydralazine the most. It has been years since I’ve dispensed aliskiren (Tekturna®) or minoxidil (Loniten®). I think most clinicians associate minoxidil with hair growth more often than with hypertension!

    Hydralazine remains a relevant player, as we will discuss its use when we cover heart failure. Hydralazine is part of BiDil®, along with isosorbide, for heart failure in self-described African American patients. I was amazed to discover that hydralazine (Apresoline®) was first approved in 1953.

    Tekturna (aliskiren) --approved 2007
    cost: $290 (Generic now available at around $180/month)
    Mechanism: is the first direct renin inhibitor.
    Available as 150mg or 300 mg and is dosed once a day.
    It works earlier in the renin-angiotensin-aldosterone system than ACE inhibitors or ARBs.

    Indications: is approved only for hypertension.
    • Works as well as: ARBs, ACE inhibitors, and thiazides.
    Do not add to an ACE or an ARB, provides no cardiovascular benefit, and causes an increase in adverse events, such as angioedema and hyperkalemia.

    Adverse effects
    • can cause diarrhea especially at the higher dose. Use a lower dose or a different drug if this is bothersome.
    • may also cause cough and angioedema, but probably less often than ACE inhibitors. Considered to be third- or fourth-line for hypertension, not considered monotherapy.
    Pregnancy: Categories C (first trimester) and D (second and third trimesters)

    NOTE: Avoid this class of drugs, unless necessary, to treat refractory hypertension unresponsive to all other agents. They should not be used alone, secondary to increases in plasma renin activity, cardiac output & heart rate. Use only with beta-blockers and diuretics (usually Loop diuretics). BB will block the baroreceptor reflex response, and decrease the likelihood or precipitating an angina attack.

    Mechanism: Direct relaxation of peripheral arterial smooth muscle, and therefore significantly decreases peripheral resistance, possibly by inhibition of calcium release from the sarcoplasmic reticulum and inhibition of myosin phosphorylation in arterial smooth muscle cells

    Indications: severe hypertension that has been refractory to other agents.

    • Monitor for fluid accumulation
    • Hydralazine: may cause drug induced systemic lupus
    • Caution with pulmonary hypertension
    • Caution with significant renal failure or CHF
    Adverse effects
    • Dizziness, hypotension, fatigue, malaise, joint ache
    • Minoxidil: hirsutism—(Remember Rogaine®?)
    • Peripheral neuropathy
    • Headache
    Patient Education: Notify physician immediately if: HR over 20 bpm over baseline, rapid weight gain (over 5lb) unusual swelling of extremities, face or abdomen, breathing difficulty, new or aggravated angina, severe indigestion, lightheadedness.


    Hydralazine (1953)Apresoline®25mg BID50-300mg (2-4 doses)300mg
    Minoxidil (1979)Loniten®5mg /day5mg /day 5-40mg/day40mg

    Have a great day on the bench!!

    May 2021

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    Overview of Angiotensin Receptor Blockers (ARB's)

    Mechanism: AT1 receptors are normally acted upon by Angiotensin II to produce to produce vasoconstriction & aldosterone release. When the AT1 receptor is blocked, aldosterone secretion is blocked, and vascular smooth muscle is relaxed (vasodilation)

    • Nephropathy in Type II diabetics
    • Heart failure
    • Hypertension
      • Can be used alone but are frequently combined with a diuretic
      • Less cough, and reduced incidence of angioedema than ACEI’s
    • May cause hyperkalemia
    • (ARBS) Pregnancy category D; report pregnancy ASAP
    • May be nephrotoxic if combined with HCTZ/NSAIDS
    Drug interactions
    • Watch potassium levels monitor for HYPERkalemia (excessive potassium levels)
    • Caution with drugs that elevate potassium (K+ supplements, spironolactone)
    Patient Education:
    • Report pregnancy as soon as possible. Stop drug.
    • WATCH Potassium Levels! Avoid salt substitutes, K+ sparing diuretics.
    • May be NEPHROTOXIC (especially if combined with HCTZ/NSAID)
    Prescribing information:
    Generic nameBrand nameStarting doseAverage daily doseMaximum daily doseHalf life
    25, 50, 100mg
    50mg/day25-100mg100mg2hrs. Metabolite=6-9 hrs
    80, 160, 320mg
    80mg/day80-320mg320mg6 hrs
    40, 80mg
    40mg/day20-80mg80mg24 hrs
    16mg/day monotherapy2mg-32mg80mg9hrs
    5, 20, 40mg
    Edarbi®40-80mg80mg80mg, then combo11hr

    Because ACEI’s and ARBS affect different steps in the Renin-Angiotensin-II pathway, what value would they have if used in combination?
    • Heart Failure:
    An ARB (valsartan-Diovan®) or (candesartan- Atacand®) can be added to a HF regimen containing an ACE, and a BB for further symptom relief, and possible reduction in mortality.
    • Acute MI
    Although ACEI’s are first line, if patient is intolerant, valsartan (Diovan®) is a viable alternative. However, combination therapy of ACEI and ARB are NOT recommended.
    • Renal impairment
    Combination therapy of ACEI and ARB has been shown to reduce microalbuminuria, compared with monotherapy, in patients with diabetic and nondiabetic renal disease. The reduction in proteinuria seen in patients in the combination therapy group came at a cost of increased renal impairment. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183919/

    ARBs practice points:

    Olmesartan: in 2013 the FDA announced Olmesartan (Benicar®) can produce a "sprue-like enteropathy" characterized by severe chronic diarrhea and weight loss. This may occur months to years after starting drug therapy.
    Irbesartan, Olmesartan and Telmisartan: have the longest half-lives and are available as generics.
    Losartan: has shown a decrease in serum uric acid levels by 1-2mg/dl. It is the only ARB with the ability to significantly lower uric acid levels.

    Stopping the ACEI cough:
    • ARBs have about 1/3 of the incidence of cough versus ACEI’s.
    • May occur with 1 or two weeks of therapy but may take up to 6 months.
    • Women experience the ACEI cough more than men.
    • It usually begins within one to two weeks of instituting therapy, but it can be delayed up to six months.
    • Chinese have the highest ethnic prevalence.
    • May take up to 4 weeks to resolve after discontinuation.

    When I practiced in Altoona, we used a lot of irbesartan (Avapro®) at the clinic because the Physician Assistants were former students. Losartan (Cozaar®) was the first ARB approved, and hence the first generic approved, and the insurance companies jumped on Losartan as the preferred drug.

    Most people take a once-a-day blood pressure medication in the morning. You may recall that after 5 half-lives, there is minimal drug in the body. With a 2-hour half-life, that 7am dose of Losartan is negligible after 5pm! This is concerning, because patients are most likely to have a stroke at 4:00am, when there is virtually no losartan available for the receptors. For this reason, ARBs with a longer half-life, such as irbesartan, are preferred.

    The most in-depth discussion I ever had about ARBs was last February when a local pulmonologist quizzed me about the specificity of the ARBs for the AT-2 receptor. After a bunch of research, I found that none of the ARBS covered the AT2 receptor. As you can guess he was looking to block the AT2 receptor to prevent attachment of the SARS-COV2 virus.

    Have a great day on the bench!!

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    Overview of ACE Inhibitors

    Indications: for specific populations, ACE inhibitors are first line choice for these compelling indications:
    • Diabetes, post MI, high coronary disease risk, chronic kidney disease, recurrent stroke prevention.
    • Decreases or stabilizes microalbuminuria. Are nephroprotective in diabetics and patients with renal disease.
    • Decreases incidence of new onset diabetes.
    Prescribing Notes:
    • Captopril and enalapril are considered to be the shortest acting, all of the other ACE inhibitors are long acting and should be used once a day.
    • ACE inhibitors are less effective in African American patients unless prescribed with a thiazide diuretic or calcium channel blocker
    Warnings/precautions: Pregnancy category C (1st trimester); Category-D (2nd & 3rd trimester): report pregnancy ASAP. Watch for HYPERkalemia (Excessive potassium levels)

    Adverse effects
    • Neutropenia is rare, but serious
    • Proteinuria
    • May be NEPHROTOXIC (especially if combined with hydrochlorothiazide)
    • Dry, non-productive cough. Possibly due to bradykinin formation in the lungs
    • Altered sense of taste (captopril)
    • Angioedema (rare)
    • NO adverse effect on Erectile dysfunction
    Drug interactions
    • NSAIDs may diminish their effectiveness.
    • WATCH potassium levels
    • Use caution with potassium sparing diuretics
    • Use caution potassium supplements (salt substitutes)
    • Yaz® or Yazmin® oral contraceptives have drosperidone (spironolactone relative)
    Patient Education:
    • Watch for signs of angioedema: swelling of lips, tongue, lips, difficulty in swallowing or breathing.
    • May cause rash or impaired taste perception (captopril)
    • Report pregnancy to practitioners ASAP
    Generic nameBrand nameOther indications
    (all are indicated for hypertension)
    Starting doseUsual
    hypertensive dose
    Maximum daily dose
    HF, post MI, diabetic nephropathy25mg BID50mg-two to four times daily450mg
    2.5, 5. 10.20mg
    HF, asymptomatic LV dysfunction5mg10-40mg daily (divide doses)40mg
    Prinivil® or Zestril®
    HF, post MI5-10mg /daily20-40mg daily40mg
    HF10mg/day20-80mg/d or BID80mg
    HF, post MI2.5mg/day5-20mg/d or BID20mg

    SMACK DOWN on ACE inhibitors: ACE inhibitors have a worse adverse effect profile than angiotensin receptor blockers (ARBS). We’re all aware of the dry, irritating cough that is the most common adverse effect of ACE inhibitors. I’ve seen percentages range from 5 to 20%. This ACE inhibitor cough is particularly pronounced in Asian patients. Angioedema, a more serious adverse effect that is sometimes fatal, is more common in those using ACE inhibitors than in those using angiotensin receptor blockers.

    With efficacy for cardiac outcomes being similar, the authors find no reason to prescribe ACE inhibitors. The Angiotensin Receptor Blockers (ARBs) are now as cheap as ACE inhibitors and have equal to or better outcomes for stroke, cardiac and diabetic nephropathy. The author feels that ARB's (which we will discuss in the next session) should be first line.


    I share this story with my student pharmacists, especially if they tell me they were told in class not to warn patients of the ACE inhibitor cough. Students at one university were told not to warn patients of the potential for an ACE inhibitor cough, because it “puts ideas in patient’s heads”.

    Some years ago, a patient transferred to my store. I went over to talk to her about her lisinopril prescription. She stated she has taking it for years. Regardless, I went over the side effects such as cough and angioedema. Four weeks later she came in with her husband and pointed to me and said, “He’s the guy who told me about my blood pressure pill, and the cough.”

    Turned out she had this persistent cough that was treated with an Azithromycin pack, promethazine/codeine cough syrup, and prednisone. Previously she saw her PCP and was ultimately referred to an ENT specialist.

    She was scheduled for a throat biopsy, because of the concern for esophageal cancer. She discussed my ACE inhibitor cough concern with her PCP, who changed her to valsartan, and the cough went away! I always discuss ACE inhibitor coughs, especially with any new start.

    Have a great day on the bench!!

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    Review of the Renin-Angiotensin-Aldosterone System (RAAS)

    Most of us, including me, have wondered what the purpose of the Renin-Angiotensin-Aldosterone-System (RAAS) has other than to cause hypertension and heart and kidney failure. I was fascinated to read that the activation of this system was a critical adaptation for survival of mammals that migrated from sea to land. It protected against life-threatening circumstances like salt and water deprivation, diarrhea, or hemorrhage. While we seem to no longer need this protection, activation of the system in many patients leads to disease, most commonly hypertension and heart failure. Sodium retention, coupled with hyperaldosteronism, results in vascular remodeling of the heart and disease progression. When we block this system and its effects, we can prevent or at least manage heart failure, chronic kidney disease, myocardial infarction, and hypertension. This system plays a vital role in cardiac, renal and vascular diseases, primarily causing renal failure, hypertension and heart failure.

    • Renin inhibitors block the first step. They inhibit ACTIVATION of the whole system.
    • Angiotensin Converting Enzyme (ACE) inhibitors work further down. They inhibit the PRODUCTION of angiotensin II, but some is still produced by other routes.
    • Angiotensin Receptor Blockers (ARBs) inhibit BINDING of angiotensin II at the receptors; but don't inhibit the cascade at all. Also, keep in mind ARBs block only type 1 receptors; angiotensin II can still bind to other receptors.

    Naturetic peptidesAngiotensin II (vasoconstrictor)
    bradykininAldosterone (sodium retention)
    adrenomedullin“Bad guys” cause sodium retention and vasoconstriction, driving up blood pressure.
    Positive effects of the “good guys”: lowers sodium, decreases vasoconstriction, decreases “maladaptive remodeling”“Bad guys” are made by Angiotensinogen, Renin, Antiotensin-I, Angiotensin-II. Their effects are blocked by ACE-I, ARBS, Renin Blockers.
    DEGRADED by neprilysin, which can be blocked by sacubitril. Blocking neprilysin increases the “good guys”.
    Renin: Is released by the kidneys in response to reduced renal arterial pressure, sympathetic neural stimulation, or reduced sodium delivery to the distal tubule.

    Angiotensin II: Is a potent peripheral vasoconstrictor, and also stimulates aldosterone release from the adrenal glands.
    • Elevated aldosterone causes an increase in sodium reabsorption, which leads to an increased blood volume, thereby increasing blood pressure.
    • Therefore, ACE inhibition results in decreased Angiotensin II production which leads to decreased sodium & water retention, decreased potassium excretion, and arterial vasodilation.
    • Angiotensin Converting enzyme is also responsible for the metabolism of bradykinin, a vasodilator.
    • ACE inhibitors cause bradykinin levels to increase because of decreased breakdown.
    • The vasodilation caused by increased bradykinin levels may contribute to the hypotensive effects of the ACE inhibitors.
    • It has been postulated that elevated levels of bradykinin in the lungs may be responsible for the cough that ACEI’s induce in patients.
    Adrenomedullin: Identified as a potent vasodilator considered by some to be the most potent endogenous vasodilatory peptide found in the body. It is metabolized by neprilysin.

    Bradykinin: also a vasodilator, and also affects vascular permeability. It is metabolized by neprilysin and angiotensin converting enzyme.

    Natriuretic peptides: enhances sodium output in the kidneys, and plays a role in heart remodeling in congestive heart failure. It is metabolized by neprilysin.

    Aldosterone: Aldosterone binds to the mineralocorticoid receptor in various tissues. Its main actions occur in the distal tubule of the kidney where it causes sodium and water reabsorption and potassium secretion. This potassium excretion occurs in the urine, as well as the feces, sweat, and saliva.

    There is probably not another system that points out the need for continuing education more than the Renin-Angiotensin-Aldosterone System (RAAS). I remember in pharmacology back in 1980 our professor mentioning this system and this new drug he was studying called captopril. Captopril was released just as we were graduating in 1981.

    Before we continue our conversation in subsequent sessions about three classes of drugs, the Angiotensin Converting Inhibitors (ACEi), Angiotensin Receptor Blockers (ARBs) and the seldom used Renin Inhibitor, it is important to review the basics of where they work and the enzymes and hormones they affect.

    Have a great day on the bench!!

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    Focus on Dihydropyridine Calcium Channel Blockers

    Mechanism: inhibits the influx of calcium through slow channels in vascular smooth muscle, and causes relaxation. In the vascular system, arterioles appear to be more sensitive than veins; therefore, postural hypotension seldom is an adverse effect. Generally, the dihydropyridines have a greater ratio of vascular smooth effects relative to the cardiac effects than do verapamil and diltiazem. From a patient population perspective, black and elderly patients tend to respond well to these drugs.

    • Alternative drugs in patients unable to take beta blockers such as angina patients, bronchospastic patients, and patients with Raynaud’s.
    • CCB differ in degrees of systemic and coronary arterial vasodilation, SA node and AV node depression, and decrease in myocardial contractility.
    Dihydropyridines: [Amlodipine (Norvasc®), Felodipine (Plendil®), Nifedipine (Procardia®) , Isradipine (Dynacirc®), Nisoldipine (Sular®), and Nicardipine (Cardene®)]
    • have greater affinity for vascular, versus myocardial channels (potent vasodilators)
    • watch for vasodilatory side effects: edema, headache, flushing, rarely orthostatic hypotension
    • Minimal effect on heart conduction: not useful for supraventricular tachycardias
    • Can be used with Beta Blockers or in patients with heart block
    • Minimal drug interactions. Caution with amlodipine (weak inhibitor of CYP-450-3A4) and higher doses of amlodipine may see two-fold increase in simvastatin levels.
    • Grapefruit juice may increase levels of dihydropyridines: amlodipine, felodipine and nifedipine
    Patient Education:
    • Notify physician if any of the following occur: irregular heartbeat, shortness of breath, swelling of hands and feet, constipation, dizziness, hypotension.
    • Instruct patient in postural hypotension
    • Avoid grapefruit juice in dihydropyridines
    • Most of the products in this class are sustained release. Do not open capsules, or chew or crush tablets.

    GenericBrandDate of IntroductionComments
    AmlodipineNorvasc® 2.5, 5mg 10mg (Pfizer)1992
    NifedipineNifedipine Procardia-XL® -30, 60, 90mg (Pfizer)1981 (caps)Don’t use capsules for hypertension
    FelodipinePlendil® 2.5, 5, 10mg (Merck)1991
    NisoldipineSular® 20,30, 40mg (Zeneca)1995
    NimodipineNimotop® 30mg (Bayer)1988Used for subarachnoid hemorrhage
    NicardipineCardene® 20, 30mg1988Longer half-life than amlodipine
    IsradipineDynacirc® 2.5, 5mg (SKB)1990

    Other than hypertension, uses for dihydropyridine CCBs include:
    • Nifedipine has some efficacy in treatment of preterm labor.
    • Nimodipine (Nimotop®) has affinity for cerebral blood vessels and appears to reduce morbidity after a subarachnoid hemorrhage.
    • Nicardipine is used IV to prevent cerebral vasospasm associated with stroke. It has higher affinity for vessels in the heart and in the brain.

    The 1990's were filled with "me too" drugs: the benzodiazepines, cephalosporins, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers came onto the market by the droves!

    Of all of these new classes of drugs, none completely dominated the class like amlodipine dominates the dihydropyridine CCB's. It's been years, actually decades, since I have dispensed isradipine (Dynacirc®), nicardipine (Cardene®), and nisoldipine (Sular®), but interestingly enough I've dispensed nimodipine a few times for patients this past year with subarachnoid hemorrhages, due to accidents

    The physician from the rehab hospital was amazed that a local pharmacy had it in stock. Lately, it is amlodipine being dispensed ... by a landslide.

    Have a great day on the bench!!

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    NON-Dihydropyridine Calcium Channel Blockers

    CCBs inhibit the influx of calcium through its channels causing slower conduction through the SA and AV nodes. They slow ventricular rates, in atrial flutter, atrial fibrillation, and PSVT.

    Only diltiazem and verapamil are indicated for heart dysrhythmias. Cardiac muscle is highly dependent on the influx of calcium during each action potential for normal function and rhythm. Impulse generation in the sinoatrial node and conduction in the atrioventricular node may be reduced or blocked by calcium channel blockers

    • Indicated for reduction in symptoms where beta blockers are contraindicated. The reduction in mechanical function reduces oxygen demand in patients with angina.
    • Combination with beta blockers when a beta blocker therapy is not successful
    • Slow release long acting dihydropyridines & non-dihydropyridines are effective in stable angina
    • Decrease systemic vascular resistance and arterial BP by vasodilation of systemic arteries
    • Decreased contractility and oxygen requirements
    • Verapamil & Diltiazem decrease MV02 (myocardial oxygen demand) by decreasing conduction through the AV node, and decreasing heart rate

    Indications for use: treatment and prevention of supraventricular tachycardia. First line agent for prevention of PSVT (paroxysmal supraventricular tachycardia). Also useful for treatment of atrial fibrillation, especially when beta blocker therapy is not tolerated. Diltiazem and Verapamil are more selective for cardiac tissue than are the dihydropyridines. They block tachycardias in the calcium dependent cells especially in the AV node

    Hypertension: In the absence of cardiac disease, there is no compelling reason to consider non-dihydropyridine CCB to be first line therapy. Are useful in patients with obstructive airway disease and in the African American population. They are also useful in patients with angina and atrial fibrillation, with hypertension.

    Diltiazem (Cardizem®, Dilacor®, Tiazac®, Taztia®, Cartia XT®) (tablets approved 1982)
    Available as tablets: 30, 60, 90 and 120mg
    • SR-Capsules: dosed BID : 60-90-120mg
    • CD-capsules: once daily 120,180,240,300,360mg
    • LA –tablets : 120,180,240,300,360,420 mg tablets

    Dosage 120mg- 360mg / day

    Drug Interactions: inhibits cytochrome P-450 enzymes in the liver.
    • Administration with a beta blocker may precipitate heart failure.
    • Quinidine increases the risk of hypotension.
    • May increase digoxin concentration.

    Verapamil (Isoptin®, Calan®, Verelan®, Covera HS®)
    • Immediate release tablets: 40mg, 80mg 120mg tablets dosed 3 times daily.
    • Sustained release tablets: 120,180,240mg
    • Sustained release capsules: 120,180,240,360mg
    • PM capsules: 100, 200, 300mg
    • Dosage:120mg-360mg /day

    Drug Interactions / Special Notes: inhibits cytochrome P-450 enzymes in the liver
    • Administration with a beta blocker may precipitate heart failure
    • Quinidine increases the risk of hypotension
    • May increase digoxin concentration
    • May cause nausea and constipation

    Diltiazem (Cardizem-CD®) & Verapamil (Isoptin® , Calan®, Verelan®)
    • More potent coronary vasodilators (verapamil more than diltiazem)
    • Good choice for supraventricular tachycardias
    • Minimal peripheral vasodilation & side effects
    • May cause bradycardia, and heart block
    • Avoid in patients with LV systolic dysfunction (EF less than 30%), conduction abnormalities or combined with beta blockers.
    • Indicated for angina
    • Indicated for migraine headache prophylaxis
    • Verapamil is indicated for prevention of cluster headache
    • First generation CCB (verapamil & diltiazem) may accelerate progression of heart failure

    Warnings/precautions/ adverse effects (CCB's)
    • May worsen conduction defects, systolic dysfunction
    • Gingival hyperplasia
    • May cause nausea & headache
    • Verapamil: may cause constipation

    Calcium channel blockers and rash:
    • Calcium channel blockers may cause eczema and other skin problems. About 1% of patients get minor skin reactions (rash, itching, photosensitivity) Calcium blockers can cause a delayed eczema rash occurring about 3 months after starting the drug.

    • Patient Education CCB
      • Notify physician if any of the following occur: irregular heartbeat, shortness of breath, swelling of hands and feet, constipation, dizziness, hypotension.
      • Instruct patient in postural hypotension
      • Most of the products in this class are sustained release. Do not open capsules, or chew or crush tablets

      Calcium channel blockers (CCBs) can be divided into two distinct classes, even though they “block calcium”. We have the dihydropyridines and the “non-dihydropyridines”. This session will explore the two non-dihydropyridine calcium channel blockers, diltiazem, and verapamil. These two drugs were very popular in the 1980's when they came out. We had Calan® by Searle and Isoptin® by Knoll that were the verapamil products. On the verapamil front, Marion Merrell Dow had Cardizem®, first as tablets, then SR capsules then CD capsules then LA tablets. Other branded products followed as well, including Taztia®, Dilacor® and Tiazac®.

      Prescribers may be advised to write diltiazem by the brand name to decrease confusion. "Diltiazem 120" can be interpreted as 120mg immediate release tablets (3-4 times daily); SR capsules (twice daily), CD once a day capsules, or LA once a day tablets. This is a potential for medication error with which pharmacists and pharmacy technicians must be keenly aware.

      Have a great day on the bench!!

    April 2021

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    Mechanism: blocks peripheral alpha-1 receptors (post-synaptic)- causes vasodilation of arteries and veins. Alpha-1 receptors are also abundant in the smooth muscle of the bladder neck and prostate. Causes less reflex tachycardia than direct vasodilators (like minoxidil & hydralazine).

    Indications: for patients who have not responded to initial hypertensive therapy. Ideal for older men with BPH.

    Warnings/precautions: Orthostatic hypotension may occur after the first few doses. Minimize by slow titration. Watch for syncope. In the ALLHAT study, the doxazosin arm was discontinued prematurely due an increase of 25% in CV disease outcomes. Caused increase in risk of stroke, CHF and CHD. An alpha blocker is not recommended for initial monotherapy, with the possible exception of older men with symptoms of prostatism and if they are not at high cardiovascular risk.

    Adverse effects
    • Orthostatic hypotension
    • Dry mouth
    • Urinary urgency
    • Constipation
    • Priapism
    Drug interactions

    NSAIDs decrease antihypertensive effects
    Beta blockers and Diuretics increase antihypertensive effects of these agents

    Patient Education:
    • Watch for postural hypotension. Start low. Give dose at bedtime.
    • Watch for drowsiness
    • If priapism occurs seek medical treatment immediately.

    BPH1mg at bedtime1-16mg/day16=HTN
    1mg at bedtime2-20mg
    (in 2-3 doses)
    BPH1mg at bedtime1-20mg20mg/day

    Prescribing information:

    PRAZOSIN: Always a test question for my PA students...which alpha blocker is NOT to be used for BPH. The answer is prazosin (Minipress®), as it has too short of a duration of action. We dispense more prazosin than doxazosin or terazosin!

    Prazosin is used frequently for improving sleep and decreasing nightmares for patients suffering from PTSD (post-traumatic stress disorder). Nearly 20% of veterans who suffer from PTSD are treated with prazosin. There have been studies proving and disproving its efficacy. Although one rigorous study found it no more effective than placebo, it is recommended NOT to change its clinical use, since there is little else for treatment of nightmares.

    Prazosin blocks the alpha1 receptor for norepinephrine, which becomes more sensitive in combat settings (or any trauma). This up-regulation doesn't seem to go away once the stimulus is removed, and nightmares can become problematic.

    Drugs causing Intraoperative Floppy Iris Syndrome:

    Alpha-1 Blockers: both selective and non-selective The iris becomes flaccid and billows in response to intraoperative irrigation currents, causing the potential prolapse of the iris toward phacoemulsification incisions. Ophthalmologists can modify their surgical techniques including using iris hooks, iris dilation rings, viscoelastic devices.

    Ophthalmologists MUST know before surgery that patient has been on alpha blocker therapy. Usual protocol is to stop the medication 7-10 days pre-op. Be sure to check for alpha blocker use with pre-op physicals for cataract surgery!

    Alpha blockers have been mostly reserved for treatment of Benign Prostatic Hypertrophy (BPH), thanks to the ALLHAT study (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial). We use lots of alpha blockers, but mostly for treatment of BPH. The selective alpha blockers (tamsulosin, alfuzosin, silodosin) were purposely excluded from this discussion, as they are not for treatment of hypertension.

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    Mechanism: decreases sympathetic outflow to the cardiovascular system.
    • Clonidine: stimulates alpha-adrenoceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure.
    • Guanfacine: stimulation of central a2-adrenergic receptors. By stimulating these receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels.
    • Methyldopa: conversion into alpha-methylnorepinephrine, which is a potent alpha-2 adrenergic agonist that binds to and stimulates potent central inhibitory alpha-2 adrenergic receptors.
    Indications: use in mild to moderate hypertension has been reduced due to availability of other agents with less side effects.
    • Methyldopa: is primarily used for hypertension during pregnancy.
    • Methyldopa: flu like symptoms. Monitor for hepatic dysfunction. Anemia
    Class adverse effects:
    • Drowsiness, dizziness, dry mouth
    • Depression and sleep disturbances
    • Impotence
    • Orthostatic hypotension
    • Bradycardia
    Drug interactions:
    • Caution with other sedating medications
    • Caution with angina, recent myocardial infarction, and cerebrovascular accident.
    Patient Education: Gradually taper dose. Do not suddenly stop. (rebound hypertension)


    Catapres TTS®
    19740.1mg BID 0.1mg/day patch weekly 0.2-0.6mg (2 divided doses)
    patch 0.1-0.3mg/day
    MethyldopaAldomet®1962250mg BID500-2000 in 2 doses2000mg

    Clonidine has been used for the following:
    • Atrial fib
    • alcohol withdrawal
    • ADD
    • Constitutional growth delay in children
    • Cyclosporin associated nephrotoxicity
    • Diabetic diarrhea
    • Hyperhidrosis
    • Hypertensive urgencies
    • Mania
    • Menopausal flushing
    • Methadone/opiate detox
    • Pheochromocytoma diagnosis
    • Post Herpetic neuralgia
    • Psychosis
    • Reduction of allergen induced inflammatory reaction
    • Restless legs syndrome
    • Smoking cessation facilitation
    • Ulcerative colitis

    My son-in-law, Mark Garofoli and I attended PAINWEEK in Las Vegas a couple of years ago, where Mark did several presentations. We went to the exhibit hall and spoke with the pharmaceutical representatives. One was extolling the wonderful benefits of a new medication for opioid withdrawal disorder, and how effective it was when compared to placebo. Both of us being pharmacists and understanding the mechanisms of action asked the reps, “How did it stand up against clonidine?” The silence was deafening! This product costs $20 per tablet; the cost of clonidine is negligible.

    I remember in the 1980’s dispensing alpha-methyl-dopa (Aldomet®) as the “go to” drug for hypertension. We older pharmacists remember buying Aldomet® 250, Aldomet® 500, and Aldoril® 15 and Aldoril® 25 in bottles of 500! Today when we see methyldopa prescribed, it is usually for pregnant women with hypertension.

    Have a great day on the bench!!

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    Overview of Potassium Sparing Diuretics


    Mechanism of action:
    • Amiloride (Midamor®) and triamterene (Dyrenium®) are cations that directly block sodium channels but do not affect the mineralocorticoid receptor, thus preserving potassium.
    • Spironolactone (Aldactone®) and eplerenone (Inspra®) competitively inhibit the mineralocorticoid receptor, with eplerenone being more specific for that receptor. Eplerenone has less endocrine side effects, especially gynecomastia in males.
    Uses: All four potassium sparing diuretics are weak with respect to diuresis. They are frequently combined with loop diuretics to minimize potassium loss. Years ago, they were combined with thiazide diuretics to enhance hypertension control.
    • Spironolactone and eplerenone: by blocking the mineralocorticoid receptor, these drugs may reduce the adverse effects of excess aldosterone on the heart, making them useful for heart failure. Growing evidence shows that they may mediate some major effects of the Renin-Angiotensin-Aldosterone system activation, such as myocardial remodeling and fibrosis as well as sodium retention and potassium loss at the distal tubules. Aldosterone promotes sodium retention, potassium and magnesium loss, sympathetic activation, parasympathetic inhibition, myocardial and vascular fibrosis, baroreceptor dysfunction, and vascular damage and impairs arterial compliance. The RALES study showed a 29% relative risk reduction in heart failure. Should be considered as a “neurohormonal antagonist” rather than a potassium sparing diuretic.
    • Amiloride: useful for treatment of lithium induced diabetic nephrogenic diabetes insipidus
    Adverse effects: Monitor for hyperkalemia, especially if taking potassium supplementation or ACE inhibitors or ARBS. Triamterene is a potential nephrotoxin, possibly leading to crystalluria and cast formation. Causes kidney stones, which can be oxalate or triamterene stones.

    AmilorideMidamor®Oct 19815mg/day5mg/day20mg
    TriamtereneDyrenium®Aug 196450mg/day50-100mg300mg
    SpironolactoneAldactone®Jan 196012.5-25mg50-100N/A
    EplerenoneInspra®Sep 200212.5-25mg50mg50mg
    Amiloride/HCTZModuretic® 5/50Oct 1981One dailyOne daily2 tabs daily
    Triamterene/HCTZDyazide® 37.5Dec 1965One dailyOne daily2 caps daily
    Spironolactone/HCTZAldactazide 25Jan 1961One dailyTwo daily8 daily

    I remember early on in my career when spironolactone, amiloride, triamterene were the go-to drugs for hypertension. In 1983, we dispensed so much spironolactone (Aldactone®) and spironolactone/HCTZ (Aldactazide®), that we got a free Hoover sweeper!

    We bought potassium sparing diuretics in bottles of 1000 and turned them over in a couple of weeks. We seldom dispense triamterene and amiloride today, and spironolactone is used by cardiologists for heart failure and dermatologists to suppress testosterone in women to help control acne and poly cystic ovary syndrome.

    One of my favorite patients came to the pharmacy a few years back. He was taking spironolactone for heart failure and complained that he was suffering from gynecomastia. He said the pain was so annoying he was ready to try on one of his wife’s bras!

    I wrote the drug name “eplerenone” on a sheet of paper, as he was seeing his endocrinologist the next day. The endocrinologist refused saying it would not help. Being persistent he approached his family doctor, and she made the change to eplerenone. Within a month the gynecomastia resolved, while still maintaining good control of his heart failure.

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    Overview of Loop Diuretics

    LOOP DIURETICS: The “big guns” for edema

    Mechanism:Inhibits the NKCC2 (the luminal Na/K/2Cl co-transporter) in the thick ascending limb of the loop of Henle. This leads to a decrease in total fluid volume through inhibition of sodium and chloride resorption, which causes increased excretion of water, sodium, chloride, magnesium and calcium. Loop diuretics are several times more potent than thiazides, cause less vasodilatation, and are not usually as effective for treating hypertension.

    • When patients are unable to tolerate thiazide diuretics, when they lose effectiveness, and in patients with impaired renal function (less than 30mL/min).
    • Most heart failure patients require more potent Loop diuretics rather than thiazide diuretics.
    • Loops primary agents used to increase excretion of sodium and water
    • Take daily in the morning.
    • If dosed twice daily, take in AM and afternoon.
    • Ideally, furosemide should be taken on an empty stomach (food decreases absorption), Torsemide (Demadex®) is not affected by food.
    Warnings/precautions/ adverse effects:
    • Same effects as thiazides, additionally:
      • monitor for hypovolemia
      • check BUN and serum creatinine
      • watch for ototoxicity (especially if on an ototoxic drug)
      • may cause postural hypotension
      • may cause photosensitivity
    Drug interactions:
    • NSAIDS: blunt loop diuretics response
    • Antiarrhythmics: depleted K+ may cause Torsade’s de Pointes
    • May cause hyperuricemia, and precipitate gout attacks
    • Lithium: diuresis may spike lithium levels
    Patient Education/Counseling:
    • Report muscle cramps, dizziness, excessive thirst, weakness and confusion as these may be signs of over diuresis.
    • Patients should weigh themselves daily (fluid retention)
    • May be allergic if are allergic to sulfa antibiotics.
    • Caution for photosensitivity—recommend sunscreen
    • Potassium supplements may not be needed if taking an ACE inhibitor (lisinopril, etc.)
    • May need to change to potassium-sparing diuretic if hypokalemia persists
    • Control sodium intake
    • Take in the morning. Take with food
    • Notify practitioner if muscle cramps occur
    • Monitor blood sugar levels in diabetics
    • Weight
    • Urine output
    • Blood pressure
    • Blood levels for sodium, potassium, magnesium, creatinine, BUN
    BumetanideBumex®0.25mg BID1mg BID-TID10mg8-10mg
    FurosemideLasix®20mg BID40mg 3-4/day320mg200mg
    Ethacrynic acidEdecrin®50mg/day50mg-200mg/ day (divided dose)400mg400mg

    **MAXIMUM DOSE: dose that when exceeded, does not produce additional diuresis in healthy subjects.

    CHEAT SHEET: bumetanide 1 mg = furosemide 40 mg= torsemide 20 mg = Ethacrynic acid 50 mg

    Hypersensitivity reactions: Furosemide (Lasix®), bumetanide (Bumex®), and torsemide (Demadex®), which are in the sulfonamide class, can cause hypersensitivity reactions, usually manifested as a rash or rarely acute interstitial nephritis, similar to those produced by other sulfonamide drugs. Caution if severely allergic to Sulfa antibiotics, such as Bactrim® or Septra®.
    • Ethacrynic Acid (Edecrin®)- is the “go to” for patients that are refractory to the sulfonamide loop diuretics, or patients that are extremely allergic to the sulfa class (including celecoxib, sulfonylureas, thiazides, etc.). This product is expensive, one tablet of ethacrynic acid costs about as much as 100 tablets of the other loop diuretics!

    In the 1920's while treating syphilis with mercury-based compounds, clinicians noted that they caused excretion of excess fluid. Until the discovery of azetazolamide (a carbonic anhydrase inhibitor) in 1950, the toxic mercury-based compounds were all that was available!

    Chlorothiazide (Diuril®) (1958), yet another sulfa derivative, became the mainstay for heart failure and hypertension. In 1966, the FDA approval of furosemide (Lasix®) took over the treatment of kidney failure and pulmonary edema. Ethacrynic acid (Edecrin®) was approved in 1967 and marketed by Merck.

    In 1983, bumetanide (Bumex®) became the third loop diuretic to be approved. In 1993, torsemide (Demadex®) was FDA approved and marketed by Roche.

    Have a great day on the bench!!

    March 2021

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    Overview of Thiazid Diuretics


    • direct arteriole dilation
    • Reduction in total fluid volume, through the inhibition of sodium resorption in the distal tubules of the nephron
    • Prominent diuretic effect fades over time; however, the antihypertensive effect is persistent.
    • Increases effectiveness of other antihypertensive agents by preventing the re-expansion of plasma volume.
    • Currently recommended for initial therapy of hypertension.
      Diuretics are more effective in African Americans and elderly patients because they are more renin dependent than Caucasians. Thiazide diuretics are preferred over “loop” diuretics because of their extended action.
    • Thiazides are filtration dependent, and only effective in patients with a creatine clearance (CrCl) greater than 30mL per minute.
    • Take early in the day to avoid nocturia
    • Photosensitivity—use SPF >15
    • May increase blood glucose in diabetics
    • Report muscle cramps, may indicate depleted potassium
    • Caution if allergic to sulfonamide drugs.
    Adverse effects
    • May cause hypokalemia, and hypomagnesemia
    • May cause orthostatic hypotension.
    Drug interactions
    • Steroids: cause salt retention and antagonize the actions of thiazides
    • NSAIDS: blunt thiazides response
    • Calcium: increases calcium levels, is protective for osteoporosis
    • Antiarrhythmias: depleted K+ may cause Torasades de Pointes
    • May cause hyperuricemia, and precipitate gout attacks
    • Lithium: thiazides decrease lithium clearance and increase risk of toxicity
    Patient Education: Thiazide diuretics
    • Be sure to monitor: BUN/ creatinine; cholesterol levels, K+ levels, uric acid levels, weight and BP
    • Take in the morning. Take with food
    • Notify practitioner if muscle cramps occur
    • Use sunscreen due to photosensitivity
    • Monitor blood sugar levels in diabetics
    • Watch alcohol intake for OTC drugs
    • May cause gout attacks, notify physician of sudden joint pain.
    Prescribing information: Thiazide diuretics
    • Flattened dose response curve for hypotensive effect. Blood pressure reduction plateaus at 25mg for HCTZ , while adverse potential increases with increasing doses (50mg, 100mg). Full antihypertensive effect may take up to 4 weeks or longer.
    • Very, very inexpensive therapy. 100 tablets less than $8.00
    • Pregnancy: Category-B: indicated when edema is due to pathological causes. Dependent edema resulting from restriction of venous return by the gravid uterus is NOT properly treated with diuretics.
    • The combination of an Angiotensin Converting Inhibitor (ACEI)/ or Angiotensin Receptor Blocker (ARB) with a thiazide diuretic reduces risk of thiazide-induced hypokalemia. Most common combinations are Lisinopril/HCTZ, Losartan/HCTZ and Irbesartan/HCTZ
    • ACEI/ARB ameliorates diuretic-induced activation of the renin-angiotensin-aldosterone system, caused by a thiazide diuretic. This leads to an additive blood pressure reduction
    • Chlorthalidone and indapamide, both thiazide-like diuretics in the same class as HCTZ, have been shown to provide greater antihypertensive efficacy. Both chlorthalidone and indapamide reduce cardiovascular events and mortality compared with hydrochlorothiazide. So that begs the question why do most pharmacists buy HCTZ in bottles of 1000, and we “blow the dust off” the indapamide and chlorthalidone?
    • Metolazone (Zaroxolyn®) is frequently prescribed by nephrologists because it may be effective in patients with renal impairment. Most often used as a “kicker” two or three times a week to augment the diuretic effects of loop diuretics like furosemide (Lasix®).

    Generic/BrandDosage formsTypical adult doseHalf life
    Chlorthalidone (Hygroton®) 25, 50mg tablets12.5- 25mg once daily.50-60 hours
    Chlorothiazide (Diuril®)500mg tablets 250mg/5ml susp 500mg-1000mg per day or divided BID1-2 hours/td>
    Hydrochlorothiazide (HydroDiuril®, Esidrex®) 12.5mg caps; 12.5mg, 25mg, 50mg tabs12.5-50mg/day5.6-14hrs
    Indapamide (Lozol®) 1.25mg, 2.5mg tabs1.25-2.5mg daily16hrs
    Metolazone (Zaroxolyn®)2.5mg, 5mg 10mg tablets2.5-5mg once daily14 hours


    HydroflumethiazideSaluron®7/22/1959Shire LLC


    Thiazide diuretics are 63 years old and still going strong! These agents are timeless, with only three of them used at all today, namely hydrochlorothiazide (HCTZ), metolazone and chlorthalidone.

    With all of the evidence for indapamide and metolazone being superior to HCTZ, we have the HCTZ 12.5mg and 25mg in our "fast moving" section of the pharmacy.

    I can’t think of more than 2 or 3 current patients taking chlorthalidone or indapamide. I remember 40 years ago, when we would buy Enduron® (methyclothiazide) in bottles of 1000 and move them right off the shelf. I also remember buying bulk bottles of Diuril® 500mg as well as HydroDiuril® 100mg tablets.

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    Hypertension and Beyond: A Glance at the Wide Utility of Beta Blockers


    Mechanism: Interfere with sympathetic nervous system to decreases peripheral vasoconstriction
    • Protect heart from over-stimulation by sympathetic nervous system. Blockade of beta receptors antagonizes the increase in sympathetic nervous system activity responsible for the progression of heart failure
    • Over a period of 3-6 months BB produce substantial rises in ejection fraction (averaging 10% absolute increase) and reducing LV size and mass
    • Current guidelines recommend BB with all patients with stable HF due to LV dysfunction unless unable to tolerate. Patients MUST be stable before treatment is initiated
    Beta blockers most effective for heart failure
    • Carvedilol (Coreg®) target dose: 25mg BID
    • Metoprolol succinate (Toprol-XL) target dose 200mg/day
    • Bisoprolol (Zebeta®) 10mg daily
    Titrate all beta blockers slowly (increase dose every two weeks), but try to get patient to target doses.

    • Unless a patient has Coronary Artery Disease (CAD), atrial fibrillation, angina or heart failure, beta-blockers are considered second line therapy for hypertension, especially in patients over age 60.
    • Atenolol has NOT been shown to improve outcomes in hypertension, heart failure, or after a myocardial infarction.
    • Non vasodilating beta blockers are also associated with impaired glucose tolerance, which may lead to an increase risk of new onset Type-2 diabetes. (Carvedilol, labetalol and nebivolol are VASOdilating beta blockers)
    • Labetalol is the preferred antihypertensive in pregnancy. Low concentrations of labetalol appear in breast milk
    • Metoprolol tartrate (Lopressor), propranolol (Inderal) and timolol (Blocadren) penetrate the blood brain barrier, and have proven efficacy for migraine prevention.

    I tell my new heart failure patients that are just starting out on carvedilol (Coreg), that “if I have a miracle drug on my shelf it is carvedilol.”Back in the early 1990’s one of my patients came in with a sheet of paper from his cardiologist. Turns out his cardiologist was Pittsburgh’s most renown heart failure specialist.

    He asked me to review the side effects about carvedilol.The drug was not even on the market yet, and the patient was to be enrolled in a study.He was on the heart transplant list, and this was the last-ditch effort using medication.

    The patient responded well, lived another 20 years, and never needed a heart transplant.The efficacy of that drug is amazing, just getting the patients to have good adherence is the biggest challenge.Every two weeks when the dose is increased, the patient feels wiped out, and many fall short of the 25mg twice daily goal. Keep encouraging their patients to tolerate the initial side effects, because the benefits are amazing!

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    Exploring Differences Between Common Beta Blockers

    Eighteen beta blockers are listed in Up-To-Date's website. I find it beneficial to sort them out into the most common ones on the community pharmacist's shelves.

    I remember early on in my career when propranolol (Inderal®) changed from the round orange, blue, green tablets to hexagonal tablets because the manufacturer's patent expired in July 1985. Now, nebivolol (Bystolic®) is the only branded beta-blocker left on our shelves, and a prior authorization is usually the case if a clinician needs to prescribe it. Over time, beta blockers have proven to be cheap and effective.

    BETA BLOCKERS- The differences...

    Cardioselectivity for Beta-1: All Beta blockers lose their cardio-selectivity at higher doses. Avoid beta blockers in patients with asthma, COPD, and peripheral vascular disease and diabetes unless there are compelling indications, such as ischemic heart disease and prevention of second myocardial infarction (MI).
    • Beta-1 selective drugs include: Acebutalol (Sectral®), Atenolol (Tenormin®), Bisoprolol (Zebeta®), Metoprolol (Lopressor® or Toprol-XL®)
    ISA (intrinsic sympathomimetic activity) in theory may have advantages in beta blockers in patients with borderline CHF, sinus bradycardia or peripheral vascular disease. These agents do not appear to be as protective against cardiovascular events as other beta blockers. They may increase the risk of MI, thus should not be used.
    • Penbutalol (Levatol®) and Pindolol (Visken®) and Acebutalol (Sectral®) have ISA, causing less resting bradycardia and lipid changes
    Lipophilic Beta Blockers: All Beta Blockers cross the Blood Brain Barrier, but the extent to which they enter the brain depends on the lipophilicity. Propranolol (Inderal®) (least cardio selective BB) and Metoprolol (Lopressor®/Toprol-XL®) are relatively lipophilic. More lipophilic BB cause more CNS side effects such as depression.

    Hydrophilic Beta Blockers:
    • Atenolol (Tenormin®) and Nadolol (Corgard®) are more water soluble (weakly lipophilic). Less likely to cause sedation.
    Non-Vasodilating beta blockers:
    • Propranolol (Inderal®), Metoprolol (Lopressor®, Toprol-XL®), Atenolol (Tenormin®), are associated with insulin resistance, and decreased insulin secretion.
    Vasodilating beta-blockers:
    • Carvedilol (Coreg®), Nebivolol (Bystolic®), Labetalol (Normodyne®) do not cause hyperglycemia. Are the best choice for a diabetic patient.

    Mechanism: Beta blockers
    Beta-blockers slow heart rate and reduce myocardial contractility. In hypertensive patients, they reduce total peripheral resistance.

    Proposed mechanisms include:
    • -stimulation of renin secretion is blocked
    • -cardiac contractility is decreased, thus decreasing cardiac output
    • -central sympathetic output is decreased
    • -decrease in heart rate decreases cardiac output
    • -Beta blocker action may combine all the above mechanisms
    Indications for beta blockers:
    • Patients with rapid resting heart rate (a-fib, paroxysmal supraventricular tachycardia)
    • Heart failure, post-MI
    • High coronary disease risk
    • Angina
    • Hypertension
    • Prevention of migraine (propranolol). Documentation of efficacy is less clear for metoprolol, atenolol, and nadolol.
    • Caution with diabetics: Diabetes (watch for “masking” of hypoglycemic symptoms)
    • Caution in patients with Raynauds or peripheral vascular disease
    • Caution in COPD/ asthma or bronchospastic disease
    • Caution in depressed patients—avoid lipid soluble BB (propranolol & metoprolol)
    • Caution in hyperlipidemia; increases LDL and decreases HDL
    Patient Education
    • Report dizziness or hypotension
    • Sedation with lipid soluble beta blockers (propranolol & metoprolol)
    • Avoid rapid withdrawal: taper dose over 14 days.
    • Sexual dysfunctions (impotence & decreased libido)
    NOTES: Beta Blockers:
    • • All beta blockers lower blood pressure to a similar extent, and can be dosed once or twice daily.
    • • Cardioselectivity is dose dependent
    • • May increase triglycerides
    • Carvedilol (Coreg®), Metoprolol (Toprol-XL®), and Bisoprolol (Zebeta®) are the only beta-blockers with mortality evidence for use in heart failure. (However, the COMET study showed that carvedilol is the most effective)
    BETA BLOCKERS— MOST COMMON Non-Selective Beta Blockers
    (beta-1 and beta-2 activity – are more likely to cause peripheral vasoconstriction, bronchoconstriction, delayed recovery from hypoglycemia in Type-1 diabetes, and impair exercise performance. Not a good choice for patients with asthma/COPD)
    DrugLipophilicityHalf LifeIndicationDoseComments
    Nadolol (Corgard®)LOWLONGAngina, HTN, A-fib10-240mg/day
    Propranolol (Inderal®) HIGHShort, but LA formula availableAngina, HTN, tremor, Migraine PxTabs: 10-40mg QID LA-CAPs: 80-160/day max=320mg High risk of fatigue. Low concentrations in breast milk

    BETA BLOCKERS- MOST COMMON beta-1 selective
    (remember beta selectivity is lost at higher doses)

    DrugLipophilicityHalf LifeIndicationDoseComments
    Atenolol (Tenormin®)LOWLONGA-fib for rate control. HTN: no improvement in mortality 25-100mgRenal elimination
    Metoprolol tartrate Immediate release (Lopressor®) ModerateMediumAngina, hypertension, post MI25-400mg
    Metoprolol Succinate extended release (Toprol-XL®) ModerateLONG (once a day) Heart failure, HTN, angina, a-fib12.5-400mgSuccinate is long acting
    Nebivolol (Bystolic®) LOWLONGHTN,5-40mgNot indicated for HF in USA

    BETA-BLOCKERS MOST COMMON alpha-1 antagonist activity
    (these cause peripheral vasodilation)

    DrugLipophilicityHalf LifeIndicationDoseComments
    Carvedilol (Coreg®) Moderate1st-pass metabolism. Moderate Heart Failure, Hypertension, LVD after MI 3.125mg BID to 25mg BID maximum of 50 mg BIDNOT cardioselective
    Labetalol (Trandate®) (Normodyne®)LOWModerateHypertension100mg-400mg BIDNOT cardioselective. Preferred BB in PREGNANCY. Low concentration in breast milk.

    Have a great day on the bench!!

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    Overview of Statins for Hyperlipidemia

    Statins: what would we ever do without them? At one time, diet and exercise and anion exchange resins were all we had to combat hyperlipidemia.

    One of the biggest challenges we all have as community pharmacists is KEEPING patients on statin therapy. We all know that our star ratings are based on diabetics being prescribed statins, as well as adherence to statin therapy. Everyone complains of muscle pain, but a patient along with their doctor should decide based on liver function tests as to whether they should continue therapy.


    Mechanism of Action: HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids.

    Indication: Overwhelmingly the best choice for elevated LDL cholesterol, providing safe and effective LDL lowering by 18- 55%. Also, lower triglycerides, and increase HDL.

    The primary target of lipid-lowering therapy is LDL because there is a strong relationship between elevated LDL and coronary heart disease. Moderate doses of statins, which primarily target LDL, decrease cardiovascular morbidity and mortality by 25% to 35% within five years’ use. Although low HDL and high triglycerides are associated with increased risk for coronary heart disease, evidence of cardiovascular benefit from treating low HDL or high triglycerides is less compelling.

    Warnings/Precautions/Adverse effects:
    • GI adverse effects
    • Headache & dyspepsia
    • Elevated liver enzymes AST and ALT.
      • Do LFT initially, at 12 weeks, then annually.
    • Myopathy: is believed to be low 0.08% (8 per 10,000)
    • Check CK (creatine kinase) before starting therapy. Do not stop statins if less than 3 times upper-limit of normal.
    • Evaluate for increased/excess exercise.
    • 30% of patients on placebo experience muscle pain
    • Evaluate in 6-12 weeks as per the scheme outlined previously
    • May be worse if other drugs are taken concurrently (erythromycin, cyclosporine, niacin, fibrates, antifungals)
    • May lead to rhabdomyolysis: disintegration of dissolution of muscle
    Drug Interactions:
    • Pravastatin (Pravachol®) and Rosuvastatin (Crestor®) are not metabolized by CYP450.
    • Pitavastatin (Livalo®): Not significantly metabolized by CYP450 and may be less likely to be involved in drug interactions.
    • Other statins (simvastatin/lovastatin) have potential for significant drug interactions.
    • Grapefruit juice: co administration with grapefruit juice (8oz or 1 grapefruit)) may increase simvastatin, & lovastatin levels. Separation for food and drug does NOT work. Grapefruit primarily affects intestinal, not hepatic enzymes.
    STATIN COMPARISONS: to get 41% LDL-C lowering:
    Rosuvastatin 5mg= Atorvastatin 20mg= Simvastatin 40mg=Pravastatin 80mg

    Contraindications for statins:
    Itraconazole, Ketoconazole, Posaconazole, Erythromycin, Clarithromycin, Telithromycin, HIV protease inhibitors, Nefazodone, Gemfibrozil, Cyclosporine, Danazol

    Simvastatin dose should not exceed 10 mg with amiodarone, verapamil, or diltiazem. Simvastatin dose should not exceed 20 mg with amlodipine or ranolazine.

    Cholesterol medications are ideally dosed after supper & before bedtime, due to increased cholesterol synthesis during the night. Although rosuvastatin (Crestor®) and atorvastatin (Lipitor®), because of their long half-lives, can be dosed any time, most clinicians advise that all statins be given in the evening for maximum benefit. Pravastatin (Pravachol®), Fluvastatin (Lescol®), Simvastatin (Zocor®) and Lovastatin (Mevacor®) must be dosed in the evening.

    May cause photosensitivity reactions.

    Pregnancy category-X.

    Asian patients may require lower doses of the statins.

    All statins except pitavastatin (Livalo®) are available generically.

    Statins are no longer recommended to be combined with niacin for hyperlipidemia. The FDA pulled approval of this combo to treat hyperlipidemia.

    Statins inhibit CoQ10 formation and many theorize low CoQ10 levels might lead to myopathy. There's no conclusive proof that CoQ10 works for statin induced myopathy but some anecdotal reports suggest it might be helpful. Dosage: If patients want to try CoQ10, suggest starting low and dividing doses over 100 mg. Take two to three times daily to minimize nausea and diarrhea. Interestingly enough, a meta-analysis of 2400 patients showed significant lower levels of Vitamin-D in patients who had statin associated muscle pain.

    Muscle complaints defined:

    Myopathy - a general term related to any muscle complaint

    Myalgia - muscle complaints (i.e., ache, weakness) without elevations in CK. This is the most common myopathy reported with statins

    Myositis - muscle complaints with elevation of CK Rhabdomyolysis - markedly elevated levels of CK, usually greater than ten times the upper limit of normal; usually accompanied by creatinine elevation, brown urine, and urinary myoglobin.

    Have a great day on the bench!!

    February 2021

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    Beyond the Statins: An Overview of PCSK9 Inhibitor Antibodies

    Monoclonal antibodies are notoriously expensive. Whether for the treatment of rheumatoid arthritis or multiple sclerosis, the costs are incredibly high. I smile when I think of these drugs, because they were first introduced at around $1,200 per month.

    Due to poor sales because of formulary coverage, both companies reduced the price of these drugs by 60%. It shows that monoclonal antibody therapy for COMMON diseases needs to be reasonably priced.

    We are seeing more of these drugs being used, thanks to decreased costs. They are highly efficacious, but certainly do not take the place of statin therapy for most patients, with a cost of around $10 per month.

    PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Inhibitor Antibodies
    (Both drugs approved in 2015)

    HOW THEY WORK: The PCSK9 protein interferes with the clearance of LDL-C from the blood. LDL receptors on liver cells remove LDL-C from the blood by binding it and then moving it into the cell for elimination. The lipid-free receptors then return to the surface of the cell. When PCSK9 binds to the LDL receptor, however, the receptor is unable to re-emerge on to the cell surface to remove more LDL-C, which then remains in the blood. By inhibiting the PCSK9 protein, PCSK9 inhibitors essentially improve the liver’s ability to recycle LDL receptors, resulting in a greater number of receptors on the cell surface and enabling more LDL-C to be removed from circulation.

    • They can lower LDL-C by as much as 60% in patients on statin therapy.
    • Reductions in the rates of stroke or myocardial infarction by 50%.
    • Lowers triglyceride levels by 12 to 31 percent
    • Slight increase in high density lipoprotein cholesterol by 5 to 9 percent
    Alirocumab (Praluent®): (approx. $500/month): Indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL- C

    Storage: keep in a refrigerator at 36°F to 46°F in the outer carton in order to protect from light. Warm up to room temperature before injection. Don’t exceed 24 hours of time out of refrigerator. May take up to 20 seconds for injection to be complete.

    Dose: 75mg SQ every 2 weeks. This is usually enough to achieve max lowering of LDL-C. Maximum dose is 150mg every 2 weeks. Available as pre-filled single dose pens, 75mg or 150mg.

    Evolocumab (Repatha®): (approx. $500/month) is used along with diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia, (an inherited condition that causes high levels of LDL), or atherosclerotic heart or blood vessel problems, who need additional LDL lowering.

    Keep refrigerated. May be stored at room temperature for up to 30 days.

    Dose: Primary hyperlipidemia with established clinical atherosclerotic CVD or heterozygous familial hypercholesterolemia: 140 mg every 2 weeks or 420 mg once monthly in abdomen, thigh, or upper arm.

    For both products “maximally tolerated statin therapy” can be interpreted as no statin at all if patients can’t tolerate statins.

    Have a great day on the bench!!

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    Beyond the Statins: Overview of Fibric Acid Derivatives

    For most of our patients elevated triglycerides seem to be directly connected to their poor diet of refined carbohydrates. Pizza, pasta, bread, sugar drinks, cookies, donuts, virtually anything that tastes good can drive up triglycerides. Fibrates are of not much value. Treatment of elevated triglycerides is better left to the dietician, rather than reaching for the fibrates! Diet and exercise are the cornerstone for hyperlipidemia, cardiovascular disease, and diabetes.

    Tricor was first introduced in 1993 (67mg, 134mg, 200mg), and reformulated in 2001 (54mg and 160mg), and again in 2004 (48mg and 145mg), just to protect the patent. To follow up, they introduced Trilipix (fenofibric acid) in 2008, which was their last attempt to breathe life into this product. It bombed.

    Fibrates for High Triglycerides... not so fast

    Triglyceride overview:

    ASCVD: Elevated fasting plasma triglycerides levels are associated with atherosclerotic cardiovascular disease (ASCVD) burden and events such as myocardial infarction and stroke. Triglycerides over 150mg/dl seems to increase the risk of ASCVD. Elevated triglycerides are also associated with insulin resistance, metabolic syndrome, platelet aggregation and low HDL. Lowering TG’s has not been proven to reduce ASCVD events.

    Acute pancreatitis: The risk for acute pancreatitis rises when serum TG levels exceed 500 mg/dL. The risk of developing acute pancreatitis is approximately 5 percent when TG’s exceed 1000mg/dl and up to 20 percent with TGs exceed 2000 mg/dL.

    Medications that can exacerbate hypertriglyceridemia:
    • Oral estrogens
    • Bile-acid sequestrants (Cholestyramine, Colestipol, Colesevelam)
    • Antiretroviral regimens, especially for HIV (especially Protease inhibitors)
    • Second-generation antipsychotic medications such as clozapine (Clozaril) and olanzapine (Zyprexa
    • Nonselective beta blockers (propranolol)
    • Thiazide Diuretics
    • Glucocorticoids
    • Increased consumption of alcohol, sugar-containing beverages and simple carbohydrates


    Mechanism of Action:
    Bind to and stimulate peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor which increases lipoprotein lipase activity, which hydrolyzes triglycerides from VLDL. Other effects include decreased hepatic cholesterol synthesis, and increased cholesterol secretion in the bile \

    Indication: 20 to 50% reduction in triglycerides

    Warnings/ Precautions/Adverse effects:
    • Caution if combined with statins (watch CK, rhabdomyolysis)
    • Take with food to minimize GI upset
    • May increase gallstones - don’t give if patient has gallbladder disease.

    Drug Interactions: Fibrates will increase warfarin effect- reduce warfarin dose by 30%

    Patient Education: Take with food to minimize GI effects

    Products of this Class (Fibrates)
    • Gemfibrozil (Lopid®)
      • 600mg tablets
      • Dosage: 1 tablet BID
      • Prescriber note: Avoid combining Gemfibrozil with statins CONTRAINDICATED.
    • Fenofibrate (Tricor®)
      • Tablets 48mg and 145mg (new formulations)
      • Dosage: 1 tablet daily
      • Other fenofibrate formulations: 54mg, 67mg, 134mg, 150mg, 160mg, 200mg

    Fibric acid derivatives have fallen out of favor.

    NOTE: Statins typically lower TG levels by 5 to 15 percent; however, high-intensity statin therapy can lower TGs by 25 to 30 percent. Most clinicians will increase the statin dose rather than add a fibrate. Fibrates, when combined with statins did not lower risk of non-fatal MI, non-fatal stroke, or CV death. Gemfibrozil is the only fibrate with demonstrated beneficial effects on cardiovascular outcomes, but its use with statins can increase the risk of myopathy and is not recommended. Fenofibrate is not proven, gemfibrozil with statins causes high risk of myopathy and is not recommended.

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    Beyond the Statins: Overview of Ezetimibe and Bempedoic Acid

    Ezetimibe (Zetia®- approved October-2002)

    >Mechanism: works by blocking NCP1L1 (Niemann-Pick C1-Like 1), which blocks intestinal absorption of cholesterol and phytosterols. It is effective in absence of dietary cholesterol because it blocks absorption of cholesterol in the bile.

    It lowers LDL by 18%, and triglycerides by 8%, and raises HDL by 1-5% by itself. When combined with statins it lowers LDL 25%, triglycerides by 14%, and raises HDL by 3%.

    Prescribers Note:
    Most clinicians will try to get a statin on board even if the patient complains of muscle pain. Even giving Atorvastatin 5mg 3 or 4 times a week greatly improves the lipid profile over that of ezetimibe (Zetia®) alone. Ezetimibe may be helpful for avoiding high doses of statins, and therefore possibly decreasing risk of myopathy in patients who do not meet cholesterol goals on low-dose statin therapy alone.

    Warnings/Precautions/Adverse Effects:
    Well tolerated. May see increase in liver transaminases when combined with statins.

    Pregnancy Category-C

    Bempedoic Acid (Nexletol®-approved 2020)

    Mechanism: the first ATPcitrate lyase (ACL) inhibitor, indicated for use as adjunct to diet and maximally tolerated statin therapy. This enzyme is “upstream” from HMG reductase, the enzyme that statins block. First oral, once daily, non-statin in 20 years since ezetimibe. Lowered LDL-C by 17% on background therapy.

    Dose: 180mg once daily, with or without food.
    • Simvastatin: Avoid concomitant use with simvastatin greater than 20 mg.
    • Pravastatin: Avoid concomitant use with pravastatin greater than 40 mg
      • Practice Point: other statins such as rosuvastatin and atorvastatin do not seem to be affected by bempedoic acid and may be a more rational choice./li>
    Warning: may increase blood uric acid levels. Hyperuricemia may occur early in treatment and persist throughout treatment and may lead to the development of gout.
    • Practice Point: Check the profile for allopurinol, febuxostat or colchicine which indicate potential for gout flares. Be sure to contact the prescriber and patient.
    Tendinopathies: bempedoic acid increases the risk for tendon rupture, especially in the rotator cuff, biceps, and Achilles tendons.
    • Practice point: Check patient profile for the following that can increase the risk of tendon rupture: patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders..
    Pennsylvania Medicaid Formulary requires: “Is being prescribed the ACL inhibitor by or in consultation with an appropriate specialist (e.g., cardiologist, endocrinologist, or other provider specializing in lipid disorders.”

    Do not consider Bempedoic acid to be as safe as the PCSK-9 inhibitors (alirocumab (Praluent®), evolocumab (Repatha®). The potential for gout as well as tendinopathies makes it necessary for the prescriber and pharmacist to provide a more intense patient counseling effort. This is especially important for patients with commercial insurance or Medicare-D plans where the prescriber might not need to be a specialist as required for the state Medicaid plans, such as Pennsylvania's.

    Nexletol (bempedoic acid) and Nexlizet (bempedoic acid + ezetimibe) are being detailed to family practice offices as well as the specialists.

    Make sure you are monitoring the uric acid levels, as bempedoic acid might precipitate a gout attack. Most recommendations say check uric acid (and get it under control) before prescribing bempedoic acid.

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    An Overview of Bile Acid Resins

    At the beginning of my career, all we had to lower cholesterol was diet, exercise, and cholestyramine (Questran®). One of my colleagues had a heart attack at the age of 42 years. His wife went to a cooking school in the early 1980’s to learn how to cook heart healthy meals.

    The statins came along about 1987 and for the most part displaced cholestyramine as treatment of hyperlipidemia. Now I see that most of the cholestyramine prescriptions are written by gastroenterologists, and the colesevelam prescriptions are written by endocrinologists!

    Mechanism of Action: Anion exchange resin that binds bile acids in the intestine. Resins are insoluble and non-absorbable. Bile acids are synthesized from cholesterol, and by their removal more cholesterol is taken up from the bloodstream. Bile acids and resins are excreted in the stool.

    Indication: Usually used as adjuncts to statin therapy requiring further lowering of LDL, reduces LDL by 15-30%.

    Warnings/ Precautions/Adverse effects:
    • Constipation- major side effect (30%)
    • Taken right before meals.
    • ELEVATES Triglycerides (negative feedback with liver)
    • Vitamin deficiencies: Bind fat soluble vitamins (A, D, E, K); be sure to monitor for Vitamin-K deficiency
    Drug interactions:
    • Will bind other drugs and decrease their absorption. Colestipol and cholestyramine bind digoxin, warfarin, statins and other ionic charged drugs can be bound
    • Other drugs should be taken 1 hour before, or 4-6 hours after the resins
    Patient Education:
    • Other drugs should be taken 1 hour before, or 4-6 hours after the resins
    • Increase fluid intake and fiber in order to better cope with constipation
    • Large tablet load, unpalatable taste and side effects will impact adherence to this class of drugs
    Products of this Class:
    • Cholestyramine (Questran®, Prevalite®) available in regular and sugar free. Scoop is included
      • Dose = 4gm 1 –2 times daily
      • Dissolve granules in water or juice
    • Colestipol (Colestid®)
      • Tablets (1gm): 2 to 16 tablets daily
      • Granules: 5gm packets, 5 to 30gm/day
    • Colesevelam (Welchol® 625mg)
      • Also used as add-on therapy for Type-2 diabetes. Used along with Metformin, sulfonylureas, and insulin. Bile acids play a role in cholesterol and glucose metabolism (FXR receptor). Reducing bile acid absorption can improve both. Lowers HbA1c about 0.5%- 0.8%; Lowers LDL up to 20%.
      • CAUTION: in patients with triglycerides over 300 mg/dL. Avoid use if triglycerides exceed 500 mg/dL. May increase triglycerides up to 10% especially when combined with insulin or sulfonylureas.
      • Dose: 3 tablets BID or 6 tablets as a single dose or 3.75gm packets once daily
      • Colesevelam does NOT bind digoxin, warfarin, or statins

    Pruritus may develop in patients with cholestasis due to any cause. Elevated bile acids in the skin can cause itching. Cholestyramine (4-16 grams per day) can be considered as first line therapy. Colestipol can also be considered. Best if dosed before and after breakfast in patients with an intact gallbladder to enhance the excretion of the bile pruritogens, which seem to accumulate in the gallbladder during the overnight fast.

    Cholestyramine binds toxins A and B excreted by Clostridium difficile. Cholestyramine does not alter the gut flora but may be helpful as adjunctive therapy. Now that vancomycin is considered first line therapy for C. dif, caution must be exercised when using cholestyramine, as it may bind vancomycin rendering it less effective. If both are given together, be sure to separate by at least 2-3 hours.

    Some diaper rash compounds include cholestyramine to bind up bile acids, which can cause direct irritation. Nationwide Children’s Hospital uses a 20% Cholestyramine/Petrolatum preparation, consisting of cholestyramine light (80%) [25grams] combined with petrolatum base [75grams]. Shelf life was 180 days.

    Para Have a great day on the bench!!

    January 2021

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    Role of Niacin in the Management of Hyperlipidemia

    Understanding Niacin therapy always gives me a better appreciation for treating hyperlipidemia. I always tell my students that “Niacin makes the numbers look pretty but does nothing to extend life.”

    Niacin raises HLD, lowers LDL and triglycerides, but doesn’t do anything to decrease CV events. You have to wonder what it is that the statins do that is so “magical”. When statins make the numbers look pretty, patients live longer. I have to wonder if further research will show that statins do more than play the numbers game. Hyperlipidemia is clearly more than a numbers game!

    The goal of treating hyperlipidemia is to decrease the concentration of free LDL in the blood that can cause fatty streaks and plaques and to increase HDL which works to reverse the formation of fatty streaks and plaques.

    LDL: low density lipoprotein –a genetic link exists (bad cholesterol)
    • Oxidized LDL becomes atherogenic
    HDL: high density lipoprotein- no genetic link (“good cholesterol”)
    TG: triglycerides-a genetic link exists.
    • Oxidizes LDL, lowers LDL clearance, causes inflammation—a genetic link exists
    The overall goal is to decrease the risk for a cardiac event or a stroke.
    • For every 1% reduction in total cholesterol, total CV mortality is reduced by 1.5%
    • For each 1% decrease in LDL there is a 2% decrease in risk of CV events
    • For each 1% increase in HDL there is a 3% decrease in risk of CV events
    Major risk factors that modify LDL goals:
    • Cigarette smoking
    • Hypertension (BP >140/90 mmHg or on antihypertensive medications)
    • Low HDL cholesterol
    • Family history of premature CHD
      1. Male first degree relative <55 years old
      2. Female first degree relative <65 years old
    • Age
      1. Men > 55 years old
      2. Women > 55 years old

    NICOTINIC ACID (Niacin) Vitamin B3
    Mechanism of Action for hyperlipidemia
    Decreases the production and release of very low-density lipoprotein (VLDL). Niacin also decreases the release of free fatty acids from adipose tissue into the circulation, which is the primary producer of circulating FFA’s.

    • Niacin (1.5-4.5gm/day) - lowers LDL by 5-25%, increases HDL 15-35%, and decreases triglycerides by 10-50%. Sounds like a winning combination… except…
    • Never monotherapy (low-cholesterol, low-fat diet)
    Warnings/ Precautions/Adverse effects:
    • Although Niacin is arguably the most effective drug for improving the entire lipid profile it is difficult for patients to tolerate.
    • Causes cutaneous flushing
      • Can be overcome by one Aspirin 325mg 30 minutes before niacin (enteric coating 1 hour).
    • Start low and go slow with niacin dosing
    • Take with food
    • GI upset
    • Liver toxicity
    • May cause mild worsening of glucose intolerance.
      • Diabetics may experience a 25% increase in serum glucose levels.
    • May raise uric levels and precipitate gout.
    Patient Education:
    • Major side effect is cutaneous flushing.
    • Take with food to decrease GI upset, right before bed..
    • Swallow whole, with cold water.
    • Avoid sudden changes in posture. May cause dizziness.
    • Avoid alcohol and hot drinks during administration.
    • Increase blood glucose monitoring if diabetic.
    • Watch niacin content in multivitamin.
    Products of this Class:
    • Niaspan® 500, 750 and 1000 (generic available, but still expensive)
    • gen=$60/90 tablets
    • brand= 990.00/90 tablets
    • Adult dose: start at 500mg at bedtime for 1-4 weeks. Then 1000mg at bedtime for 5-8 weeks then titrate to response and tolerance. Doses over 2000mg/day are not recommended
    Other forms of Niacin:
    • Can be either nicotinic acid or nicotinamide
    • Nicotinic acid is the only form proven to lower LDL
    • Immediate Release Niacin
      • Over-the-counter
    • Niaspan ER®
      • Less flushing, but long-term effects unknown
    • “Slow” Niacin- over the counter
      • Not used for the treatment of Dyslipidemia
      • Typically, nicotinamide
      • Hepatotoxicity

    BAD PRESS FOR NIACIN! (September 2014): “Added to a statin Niacin does NOT improve cardiovascular outcomes more than a statin alone when LDL is around 70 mg/dL. Adding niacin to bump up HDL makes number look better but doesn’t improve outcomes.” (AIM-HIGH study)

    SAFETY: For every 1000 patients treated for about 4 years with a statin plus niacin and an anti-flushing agent, about 18 more will develop diabetes and 37 more diabetics will have worse glycemic control...compared to patients on a statin alone.

    RECOMMENDATION: Niacin is associated with dyspepsia, diarrhea, rash, muscle pain, and flushing with possibly more infections and GI bleeding. If they have low LDL and stable CV disease, recommend stopping the Niacin

    URBAN LEGEND: Niacin to flush THC for drug testing? Doesn’t work, high doses lead to liver toxicity. Have a great day on the bench!!

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    Overview of Anticoagulation Management

    A lot of noise was made when the Factor Xa drugs came out and there was no reversal agent. We all feel comfortable with Vitamin-K reversing the effects of warfarin, but that can take a couple of days. Just simply stopping the Factor Xa inhibitors will produce similar results! Now that we have monoclonal antibodies to reverse dabigatran and the Xa inhibitors that worry should be gone.

    A common question, though, in the family practice setting is when someone should stop their anticoagulant or antiplatelet therapy. The chart below provides guidance on that front:

    Asprin7-10 days before
    Prasugrel (Effient®)7-10 days before
    Clopidogrel (Plavix®)5 days before
    Ticagrelor (Brilinta®)5 days before
    Warfarin (Coumadin®)5 days before
    Dabigatran (Pradaxa®)12-17 hours1-2 days before
    3-5 days if CRCl is less than 50
    Rivaroxaban (Xarelto®)5-9 hoursAt least 24 hours (ideal=48hr)High risk= 2 days
    Apixaban (Eliquis®)8-15 hoursAt least 24 hours (ideal-48hr)High risk= 2 days
    Edoxaban (Savaysa®)6-11 hoursAt least 24 hours (ideal-48hr)High risk= 2 days

    WHEN to RESTART: Most experts say to restart therapy 24 hours after a low bleeding risk procedure. Most agree that the anti-platelet drugs cannot be reversed.

    ASPIRIN reversal… sort of
    Intravenous DDAVP may be beneficial in some cardiac surgical patients with intractable microvascular bleeding due to platelet dysfunction that may be caused by aspirin use.

    Vitamin-K: Reversal agent for Warfarin Treatment: Stop drug.
    • If minor bleeding progresses to major bleeding: Administer Vitamin-K at 5 to 25mg parenterally. May cause prolonged resistance to warfarin.
    • If INR is between 5 to 9, a low dose of oral Vitamin K (2.5mg) is given
    • Greater than 9 with no bleeding: give 5 mg orally. Will reduce the INR within 12 to 24 hours.
    Idarucizumab (Praxbind®)- reversal agent for dabigatran
    • Idarucizumab is a humanized monoclonal antibody fragment (Fab) indicated in patients treated with idarucizumab when reversal of the anticoagulant effects of dabigatran is needed:
      • For emergency surgery/urgent procedures
      • In life-threatening or uncontrolled bleeding
    Coagulation factor Xa (recombinant), inactivated-zhzo) (Andexxa®)
    • ANDEXXA® is indicated for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
    • This indication is approved under accelerated approval based on the change from baseline in anti-Factor Xa activity in healthy volunteers. An improvement in hemostasis has not been established. Continued approval for this indication may be contingent upon the results of studies to demonstrate an improvement in hemostasis.
    Limitation of use:
    • ANDEXXA® has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any Factor Xa inhibitors other than apixaban (Eliquis®) and rivaroxaban (Xarelto®).
    Prothrombin Complex Concentrate (PCC) (Kcentra®)

    Kcentra® is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (warfarin) therapy in adult patients with acute major bleeding or the need for urgent surgery or other invasive procedure..

    Administration route: intravenous use only. Online dosing calculator available.
    • Administer Vitamin-K to maintain Vitamin K-dependent clotting factor levels once the effects of Kcentra® have diminished
    Source: human plasma. The risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent (mad cow disease), is possible

    Plasma is frozen within hours after donation in order to preserve the clotting factors. The shelf life of FFP is 12 months, but it can be extended to 7 years if stored at − 65 °C (-85°F). Most often used to treat bleeding disorders when a clotting factor or multiple factors are deficient, and no factor specific concentrate is available.
    A unit of FFP contains near normal levels of all factors, including 400mg of fibrinogen. It increases factor levels by 3%

    Indications for use for FFP
    • Treatment of multiple or specific coagulation factor deficiency, with abnormal PT or APPT. Either congenital or acquired (related to drug treatment)
    • Can be used for prophylaxis for planned surgical procedures.
    • Patients with massive transfusion who have clinically significant coagulation deficiencies.
    Patients on warfarin who are bleeding or need to undergo an invasive procedure before Vitamin-K could reverse the warfarin effect or who need to have anticoagulation therapy after the procedure.

    Have a great day on the bench!!

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    Virchow’s Triad—risk factors for venous thrombosis
    Atrial fibrillationSmokingObesity
    Varicose veinsCholesterol plaquesPregnancy
    Prolonged immobilizationChronic high BPCancer/Chemotherapy
    Genetic factors (Factor-V)
    Oral contraceptives

    Direct oral anticoagulants (DOACs) are oral medications that specifically inhibit factors IIa or Xa. They are also known as new (or novel) oral anticoagulants (NOACs) or target-specific oral anticoagulants (TSOACs). DOACs are the preferred name according to the International Society of Thrombosis and Haemostasias

    Where DOAC’s work:
    Prothrombin---- ((Xa))------ Thrombin (Rivaroxaban works here)
    Fibrinogen----((Thrombin))-----Fibrin (Dabigatran works here)
    Fibrin does the cross linking to stabilize the clot that is formed

    DABIGATRAN (PRADAXA®) (released- November 2010)

    Mechanism: Direct Thrombin Inhibitor. Dabigatran was the first ORAL anticoagulant to be introduced in over 50 years!! Referred to as a “univalent direct thrombin inhibitor” that binds directly to the active site on factor IIa (thrombin). Thrombin is a naturally occurring enzyme in our circulatory system that converts fibrinogen into fibrin, which is an important step in clot formation. By tying up thrombin, clots are not so readily formed.

    Dosage: 150mg BID / 75mg BID if CrCl is 15-30mL/min
    Advantages compared to warfarin:
    • Prevents more strokes, including hemorrhagic (5/1000 a/fib patients/year)
    • Extensive monitoring not necessary
    • Fewer food and drug interactions
    • Less intracranial bleeding
    Disadvantages compared to warfarin:
    • COST: $15/day costs more than warfarin + monitoring
    • TWICE DAILY DOSING must have excellent patient compliance
    • GI upset- give with food. Increase GI bleed
    Prescribing info: Make sure INR is below 2 before starting therapy.
    • Some drug interactions with P-glycoprotein inhibitors (Ketoconazole, Clarithromycin, others)
    • Rifampin speeds metabolism.
    • Due to costs, this drug is ideal for patients with uncontrolled INR on warfarin therapy.

    Role of Factor Xa: Factor Xa is responsible for the conversion of prothrombin to thrombin. Blocking Xa blocks that conversion to thrombin and clot formation is impeded.

    Rivaroxaban (Xarelto®) available August-2011 (490.00/month)
    The first oral, selective inhibitor of Factor Xa approved by the FDA

    Nonvalvular Atrial Fibrillation:
    • For patients with CrCl >50 mL/min: 20 mg orally, once daily with the evening meal
    • For patients with CrCl 15 - 50 mL/min: 15 mg orally, once daily with the evening meal
    Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE:
    • 15 mg orally twice daily with food for the first 21 days for the initial treatment of acute DVT or PE. After the initial treatment period, 20 mg orally once daily with food for the remaining treatment and the long-term reduction in the risk of recurrence of DVT and of PE. Reduce to 10mg after 1 year.
    • Prophylaxis of DVT Following Hip or Knee Replacement Surgery: 10 mg orally, once daily with or without food
    • to reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation
    • for treatment of deep vein thrombosis (DVT)
    • for treatment of pulmonary embolism (PE)
    • for reduction in the risk of recurrence of DVT or PE
    • for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery (10mg daily)
    • for prophylaxis of venous thromboembolism (VTE) in acutely ill
    • to reduce the risk of major cardiovascular events in patients with chronic coronary artery disease (CAD) or peripheral artery disease
    • Convenient once-daily, oral dosing
    • No routine monitoring of INR or other coagulation parameters is required. Fast onset.
    • AVOID use in severe renal impairment (creatinine clearance <30 mL/min).
    • AVOID in patients with hepatic impairment
    • AVOID drugs that Inhibit Cytochrome P450 CYP3A4 Enzymes and Drug Transport Systems such as P-gp and strong CYP3A4 inhibitors, which cause significant increases in rivaroxaban exposure. May double dose if giving concurrently with P4503A4 inducer.
    • for prophylaxis of venous thromboembolism (VTE) in acutely ill
    • to reduce the risk of major cardiovascular events in patients with chronic coronary artery disease (CAD) or peripheral artery disease
    (October 2018) Rivaroxaban XARELTO® is indicated, in combination with aspirin, to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).
    • • Dose is 2.5mg BID + 81mg aspirin/day
    Apixaban (Eliquis®) (approved Dec 28, 2012) ($485.00/month)

    ELIQUIS® is a factor Xa inhibitor anticoagulant indicated:
    • to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
    • for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery.
    Apixaban Indications and Dosages: Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation (NVAF): The recommended dose is 5 mg orally twice daily.

    In patients with at least 2 of the following characteristics reduce dose to 2.5mg twice daily:
    • Age: over age 80,
    • body weight less than 60kg (132lbs),
    • serum creatinine ≥1.5 mg/dL
    • Greater than 9: give 5 mg orally.? Will reduce the?INR within 12 to 24 hours
    Indications and dosage:
    • Prophylaxis of DVT following hip or knee replacement surgery: The recommended dose is 2.5 mg orally twice daily.
    • Treatment of DVT and PE: The recommended dose is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily.
    • serum creatinine ≥1.5 mg/dL
    • Reduction in the risk of recurrent DVT and PE following initial therapy: The recommended dose is 2.5 mg taken orally twice daily.

    Drug interactions: Warfarin is metabolized by the P450 enzyme system.? Lots of drug interactions.
    • P450 inhibitors (blockers): Azole-antifungals, some HMG CoA reductase drugs, erythromycins, etc.
    • P450 inducers: carbamazepine, barbiturates, phenytoin
    • Can be displaced from binding sites: loop diuretics, valproate
    • Platelet aggregation: NSAIDS can enhance warfarin’s effect.

    A fib: for every 1000 patients treated per year, apixaban prevents three more strokes, avoids ten major bleeds, and prevents four deaths compared to warfarin

    Edoxaban (Savaysa®) (2015) ($400/month)

    Treatment of NVAF: Assess CrCL before initiating therapy. The recommended dose is 60 mg once daily in patients with CrCL >50 to ≤ 95 mL/min.
    • Do not use SAVAYSA in patients with CrCL over 95 mL/min (sorry, your kidneys are “too” good for this drug!)
    • Reduce dose to 30 mg once daily in patients with creatinine clearance 15 to 50 mL/min
    Treatment of DVT and PE: The recommended dose is 60 mg once daily. The recommended dose is 30 mg once daily for patients with CrCL 15 to 50 mL/min or body weight less than or equal to 60 kg or who use certain P-gp inhibitors.

    With nearly 50% of our warfarin patients having uncontrolled INR's, DOACs have been a Godsend. They do not require extensive monitoring, do not hang around very long in the body, and have excellent efficacy.

    One of the biggest challenges we see, however, is the cost of these medications. Adherence becomes a challenge when patients struggle to pay even a percentage of the costs of these medications.

    Rudolf Virchow (1821-1902) was a German physician who is credited for elucidating the origins of thromboembolism. In fact, he coined the term “thrombosis” which is the process by which a clot forms in a blood vessel as well as the term “embolism”, which is a clot that has moved and blocks off a vessel. Virchow also had a brilliant career in which he clarified how cells divide, as well being a strong social medicine advocate. Considered by many to be the most brilliant physician of the 1800’s and the ‘father of cell pathology’, he even has a lymph node named after him!

    In the next session, we will discuss when to stop these drugs before elective surgical procedures. Have a great day on the bench!!

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    Anticoagulation Overview: Vitamin-K Antagonists (Warfarin)

    Warfarin? (Coumadin®) tablets: (approved by FDA June 8, 1954)
    Mechanism of Action: Vitamin K antagonist: produces its pharmacological effect by interfering with the interconversion of Vitamin-K and its 2,3 epoxide.? Leads to depletion of Factors: II, VII, IX and X (produced in liver)?and anticoagulant proteins C & S.?

    Dosage: at least 4 to 5 days are necessary before a patient is anti-coagulated.
    Initial Dosage: 5mg / day in normal patients.? The INR should be 2 in four to five days.
    • 2.5 to 4mg for elderly or patients with liver disease
    • 7.5 to 10mg for young, healthy or obese patients
    • Most clinicians titrate warfarin doses by trial and error
    • Now the FDA is suggesting lower doses for patients with certain genetic variations.
    Genetic Variations in Warfarin:
    • CYP2C9 activity indicates a slow or fast metabolizer. A slow metabolizer may need a lower maintenance dose and take longer for their INR to get to steady state
    • Vitamin K epoxide reductase activity (VKORC1) tells whether a patient is sensitive or resistant to warfarin’s effects.
    Adverse effects bleeding
    Treatment stop the drug
    • If minor bleeding progresses to major bleeding: Administer Vitamin-K 5 to 25mg parenterally. May cause prolonged resistance to warfarin.
    • 7.5 to 10mg for young, healthy or obese patients
    • MIf INR is between 5 to 9, a low dose of oral Vitamin K (2.5mg) is given
    • Greater than 9: give 5 mg orally.? Will reduce the?INR within 12 to 24 hours
    Contraindications: pregnancy Category X
    Drug interactions: Warfarin is metabolized by the P450 enzyme system.? Lots of drug interactions.
    • P450 inhibitors (blockers): Azole-antifungals, some HMG CoA reductase drugs, erythromycins, etc.
    • P450 inducers: carbamazepine, barbiturates, phenytoin
    • Can be displaced from binding sites: loop diuretics, valproate
    • Platelet aggregation: NSAIDS can enhance warfarin’s effect.
    Drug monitoring: Warfarin is metabolized by the P450 enzyme system.? Lots of drug interactions.
    • Initial: INR should be done daily while in the hospital.
    • Every 2 or 3 days if not hospitalized
    • Once stabilized, monitor every 4 to 6 weeks
    • TARGET INR is between 2 and 3 for most conditions requiring anticoagulation therapy

    TEACHING POINTS FOR Warfarin ) Consult pharmacist or practitioner for recommendations for OTC medications?
    Bleeding:? have lots of Band-Aids; use electric razors
    FOOD–drug interactions:? Be careful with diets and Vitamin K rich foods.?? Patients are often told to avoid foods high in vitamin K because of warfarin antagonism. A diet too low in vitamin K makes it MORE difficult to manage INR, because any change in dietary vitamin K can cause large fluctuations in INR. Encourage patients to eat a well-balanced consistent diet.
    Note: Warfarin patients are at the goal INR only 55% of the time (yikes!)
    –BEFAST: teach your patients signs and symptoms of a stroke, pulmonary embolism, deep vein thrombosis and heart attack:

    Signs and symptoms of a Stroke—BE FAST!
    • B -Balance: sudden loss of balance, headache, or dizziness
    • E -Eyes: trouble seeing out of one or both eyes
    • F -Face: Uneven smile or expression, facial droop or numbness in the face
    • A -Arms: weakness, numbness, one arm drifts down
    • S -Speech: slurred, mute, inappropriate words or strange speech
    • T– Time: seek help immediately. Immediately call 9-1-1.
    Signs and Symptoms of Pulmonary Embolism (PE)
    • Dyspnea: Difficulty breathing or shortness of breath. Usually sudden and severe
    • Hemoptysis: Coughing up blood
    • Diaphoresis: Abnormal?sweating
    • Cyanosis: Nails or lips turning blue
    • Tachycardia: Rapid heartbeat
    • Pain: Unexplained sharp, severe?pain in the chest?and/or back
    • Syncope: Loss of consciousness
    Signs and Symptom of Deep Vein Thrombus (DVT)
    • throbbing or cramping pain in 1 leg (rarely both legs), usually in the calf or thigh
    • swelling in 1 leg (rarely both legs)
    • warm skin around the painful area
    • red or darkened skin around the painful area
    • swollen veins that are hard or sore to the touch

    Signs and symptoms of Heart Attack in WOMEN
    Usually in female patients multiple symptoms may occur:
    • Chest pain: or fullness in the chest (an elephant sitting on my chest!)
    • Nausea or stomach pain: feeling like the need to vomit. More commonly seen in women
    • Anxiety: feeling like something is wrong, but cannot put your finger on it
    • Arm pain: pain in the arm, leg, or jaw. A woman may feel numbness radiating down the left arm, and this pain or sensation can pread elsewhere in the body, especially the shoulders
    • Dyspnea: shortness of breath or difficulty with breathing
    • Cold sweats: resulting in cold clammy skin
    • Dizziness: sudden onset of lightheadedness, room spinning is usually combined with other symptoms on this list
    • Extreme fatigue: unexpected sluggishness or exhaustion
    • Heart palpitations: heart skips a beat or fluttering sensation

    Signs and symptoms of Heart Attack in Men
    Usually in male patients the following symptoms occur:
    • Pain or tingling in back, neck, shoulder, or jaw
    • Chest pain
    • Sweating
    • Shortness of breath

    The history of the discovery and marketing of warfarin (Coumadin®) is a most fascinating story that begins in the pastures of the northeast:

    Numerous cows in the 1920’s died after routine minor surgical procedures such as castration or dehorning. A Canadian veterinarian named Frank Shofield astutely reasoned that this hemorrhaging could be attributed to animals that ate silage that had rotten sweet clover.? This hemorrhaging became known as “sweet clover disease.”

    Dr Karl Paul Link, a chemist from Wisconsin, started his own investigation into the curious problem in 1933. He published an article in Circulation describing the effects of the rotted sweet clover. Dr Link’s work was supported by the Wisconsin Alumni Research Foundation (WARF), which is the root name for warfarin.? Dr Link’s student Harold Campbell isolated the anticoagulant dicoumarol in 1939.?At first this compound was sold as a rat poison, and it wasn’t until the 1950’s that Endo Pharmaceutical began marketing warfarin for human use.

    While on vacation in 1955, President Eisenhower was given warfarin after a heart attack, which vaulted this drug to national prominence.? Warfarin poisoning was also postulated to have caused the cerebral hemorrhage and gastrointestinal bleed that lead to the demise of Russian dictator Josef Stalin.

    My daughter Gretchen gave me a 1959 drug handbook, which listed the available strengths of Coumadin as 1mg, 5mg and 25mg!

    Have a great day on the bench!!

    December 2020

    Micro-Learning CE Associated - Click Here For Details

    A Overview of Heparin and Low Molecular Weight Heparins

    HEPARIN First available 1936
    Mechanism of Action: derived from bovine lung or porcine intestinal mucosa. Heparin binds to Antithrombin III and results in an inactivation of clotting factors IXa, Xa, XIIa and Thrombin (IIa). By inactivating thrombin, it inhibits the thrombin induced factors V and VIII. Not only does Heparin prevent the growth and propagation of the formed thrombus, but it also allows the patient’s own thrombolytic system to degrade the clot. Heparin may also have a direct effect on thrombolysis.

    Dosage: each hospital develops its own nomograms that are specific for the reagent and instrument used to validate that nomogram. Is administered IV or SC.
    Adverse effects & contraindications: bleeding is the primary adverse effect. Watch for nosebleeds, hematuria, or tarry stools. Minimal renal elimination, can be used for renal insufficiency or renal failure.

    HIT: Most common cause of DRUG INDUCED neutropenia. Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of exposure to heparin (ie, unfractionated heparin, low molecular weight [LMW] heparin) that occurs in up to 5 percent of patients exposed, regardless of the dose, schedule, or route of administration. More common with heparin.

    Reversal: Protamine sulfate 1% solution will neutralize heparin. Each mg of protamine neutralizes about 100 USP heparin units. Works in 5 minutes and is active for 2 hours. Should give via slow IV infusion over 10 minutes. Heparin also has a very short half-life of 60-90 minutes.

    • Use caution with elderly women; they are twice as likely to experience major bleeding than men.
    • Severe uncontrolled hypertension is a contraindication.
    • Pregnancy category-C

    Drug interactions: interactions do occur with NSAIDS, digitalis etc. Since tight monitoring is required, dosage adjustments are easily made.

    Drug monitoring: most common: APTT (Activated Partial Thromboplastin Time), is widely used, quickly done and reproducible. Do APTT six hour after bolus dose, or after any dosage change then every 6 hours until a therapeutic APTT is reached. Then evaluate every 24 hours. APTT= normal range is 25-35 seconds. Ranges vary from lab to lab. Heparin induced APTT is 1.5 to 2.5 times normal.


    Enoxaparin (Lovenox®) approved 1993
    injection 30mg/0.3ml, 40/0.4ml, 60/0.6ml, 80/0.8ml, 100/1ml, 120/0.8ml, 150/ml & 300mg/3ml

    Mechanism: inhibits factor IIa and to a much greater extent Xa.
    • DVT surgical prophylaxis: (dose dependent on surgical site)
    • DVT treatment with or without PE:
    • Outpatient treatment: patients with acute DVT without PE who can be treated at home. Typical outpatient dose: is 1mg/kg subcutaneously every 12 hours.
    Adverse effects & contraindications: minor bleeding, gingival bleeding, watch for GI or urogenital bleeding.

    Reversal: Protamine: give 1mg for every 1mg of enoxaparin. Protamine neutralizes only 60-75% of antithrombotic activity. Not recommended if LMWH was given more than 12 hours earlier.

    Pregnancy category B. LMW does not cross placenta. Appears to be safe to use during pregnancy. Good alternative to heparin when long term anticoagulation is necessary.

    Caution with NSAIDS, they can increase bleeding.

    Drug Monitoring: because of predictable responses, routine monitoring of APTT is not necessary. Have baseline PT, CBC, Creatinine then periodic monitoring of platelets and fecal occult blood. Patient education: (enoxaparin)
    • Contact practitioner if bleeding, bruising, dizziness itching, rash or fever occurs
    • Injections are given around the navel, upper thigh, or buttocks. Change site daily
    • Inject under skin not into muscle
    • If excessive bruising occurs at injection site it may be lessened by an ice cube massage on the site prior to injection.
    NOTE: other low molecular weight heparins are available, but enoxaparin (Lovenox®) is the most commonly used. Here are the others:
    • Dalteparin (Fragmin®)
    • Tinzaparin (Innohep®)
    • Fondaparinux (Arixtra®)

    Have a great day on the bench!!

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    A Broad Overview of Antiplatelet Therapy

    ASPIRIN (patented: 1899)
    Mechanism: Acetylation of platelet cyclooxygenase prevents synthesis of Thromboxane A2, (a prostaglandin derivative) which is a potent vasoconstrictor, and inducer of platelet aggregation and platelet release reaction. Aspirin inhibits platelet aggregation for the life of the platelet (7 to 10 days).

    Men benefit more: cardiovascular protection
    Women benefit more: stroke prevention

    Dosage: American Heart Assn. Recommends 75mg to 325mg/ day
    Adverse effects & contraindications: GI bleeding. Avoid with asthma.
    Drug interactions: Warfarin (however, this may be beneficial)
    Drug monitoring: check for signs and symptoms of bleeding such as dark stools
    Patient education: Take with food. Use enteric coated tablets. Take low dose

    Mechanism: inhibits platelet aggregation and activation by blocking the P2Y12 adenosine diphosphate (ADP) receptor on the platelet surface. This inhibition is irreversible and lasts throughout the lifespan of the platelet (5-7 days).

    Clopidogrel (Plavix®)
    75mg tablets (FDA approved 1997)
    Dosage: one tablet (75mg) daily, with or without food.
    Clopidogrel is a pro-drug needing activation by the CYP450-2C19 pathway.
    • Indicated for recent MI, or stroke, or established peripheral arterial disease. Reduces the rate of new ischemic stroke, new MI and other vascular deaths.
    • Acute coronary Syndrome (ACS): for patients with acute coronary syndrome (unstable angina, non-Q-wave MI) including patients who are managed medically and those to be managed with percutaneous coronary intervention (with or without stent) or Coronary Artery Bypass Grafting (CABG)
    Mechanism: inhibits platelet aggregation for the life of the platelet (5-7 days)
    Adverse effects: increased bleeding risk
    Contraindications: active bleeding (GI) or intracranial hemorrhage
    Drug interactions: administer with caution for NSAID patients (increased GI bleeding risk)
    • About 30% of Caucasians are poor CYP450- 2C19 metabolizers
    • Omeprazole (Prilosec®) blocks this pathway and may reduce effectiveness of clopidogrel. Pantoprazole (Protonix®) is the least likely in this drug class to interact
    Patient education: Discontinue 7-10 days before surgery if so directed. Most clinicians when combining with aspirin, will use the 81mg (low dose).

    In some cases, there is no benefit to aspirin/clopidogrel than aspirin therapy alone:
    • Cardiovascular risk factors only: aspirin + clopidogrel: combo NOT beneficial
    • Established cardiovascular disease: aspirin + clopidogrel: combo NOT beneficial
    • Acute coronary syndrome: aspirin + clopidogrel: combo is beneficial
    • After a stent: aspirin + clopidogrel: combo is beneficial

    Prasugrel (Effient®)
    FDA approved in 2009. Prasugrel seems to be more effective than clopidogrel for reducing cardiovascular events in some acute coronary syndrome patients undergoing angioplasty. Carries a higher bleeding risk than clopidogrel.

    Compared to clopidogrel:
    • Higher bleeding risk. Avoid in patients with prior TIA or prior stroke.
    • Not affected by 2C19 activation (minimal drug interactions with omeprazole)
    • Combine with aspirin after angioplasty
    • Avoid if over 75, unless high risk
    • More effective than clopidogrel after angioplasty-more bleeding!
    • Discontinue 7 days before surgery
    Dosage: 5mg per day if under 60kg / 10mg if over 60kg


    What about STOPPING aspirin, clopidogrel, prasugrel, and ticagrelor? The first challenge is no clear evidence determines the most effective duration for dual antiplatelet therapy (DAPT) after drug-eluting stents.

    Risk of stopping aspirin, clopidogrel, or other antiplatelet drugs too soon:
    NOTE: serious consequences can occur for patients on aspirin for secondary prevention, or on aspirin plus clopidogrel for acute coronary syndrome or after a stent, if they stop their drug therapy too soon.

    Platelet rebound effect-Stopping Aspirin therapy:
    • Stopping aspirin even short-term may increase the risk of heart attack and stroke possibly due to a rebound effect.
    • Stopping aspirin seems to stimulate the production of new platelets and increase binding of fibrinogen. This rebound effect lasts at least 8 to 10 days after stopping therapy.
    • More surgeons will continue aspirin if bleeding risk is low especially if the patient's risk of thrombosis is high.
    • Aspirin prevents clotting while it is being taken, but abruptly stopping it triples the risk of stroke and increases the risk of other cardiovascular adverse effects.
    • Stopping aspirin in patients with a prior MI leads to 4 extra MIs per 1000 patients per year.
    • Stopping clopidogrel (Plavix®) within 30 days after a drug-eluting stent results in 25% of patients having a stent thrombosis instead of just 1%.
    • For stents, continue aspirin plus clopidogrel (Plavix®), prasugrel (Effient®), or ticagrelor (Brilinta®):
      • 30 days after a bare metal stentl
      • 1 year after a drug eluting stent
      • Many clinicians will keep patients on dual therapy longer if the bleeding risk is low

    • Surgery: If the drug must be stopped, stop clopidogrel, ticagrelor, or aspirin 5 days prior and prasugrel 7 days before surgery. Continue aspirin for all but the riskiest surgery.

    • Adherence is critical for all antiplatelet therapy. Triple risk of heart attack if stopped too soon.
    • Aspirin is serious medicine, do not stop without talking to your doctor

    Aspirin is serious therapy. As such, prescribers are encouraged to actually write prescriptions for aspirin therapy. First, prescribed aspirin therapies are covered on many state Medicaid programs. Secondly, it underscores the importance of this therapy and provides valuable adherence data with respect to refills.

    I often wonder how long it would take to get Aspirin through the FDA approval process today, given its side effect profile. Most pharmacists are aware that Aspirin is really the trade name that Bayer gave acetyl salicylic acid, which had its origins from willow bark. Interestingly enough, aspirin came onto the market one year after heroin was marketed, also by the Bayer company in Germany.

    Have a great day on the bench!!

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    An Overview of Platelets and Coagulation

    Antiplatelet Therapy
    As pharmacists, we provide prescription therapy directed at clot prevention. Many of us older pharmacists remember a 60-Minute “hatchet job” done to our profession in the 1980’s when a staged patient was buying a bottle of aspirin, while the pharmacist dispensed his warfarin prescription.

    I remember an expert saying that this was a big “no-no”. We all learned in pharmacy school that warfarin and aspirin should never be given together… those were the days!! Today, it is rather commonplace to see triple therapy consisting of an anticoagulant, and two antiplatelets (aspirin/clopidogrel). It just depends on the source of the clot.

    Some older patients are at higher risk for conditions that require two antiplatelet drugs plus anticoagulation.

    An example of such a patient:
    • coronary stent patient (needs Aspirin + clopidogrel (Plaxix®)
    • plus has atrial fibrillation or mechanical valve or Venous thromboembolism (VTE) (needs Warfarin)

    In this case, TRIPLE therapy is warranted because there are 2 different kinds of clots:

    White clot:
    • Mostly platelets
    • Usually forms in the arteries (high pressure)
    • Use antiplatelet therapy such as Aspirin, Clopidogrel, prasugrel, or ticagrelor
    • Protective against MI and stroke
    Red clot:
    • Rich in red blood cells and fibrin
    • Usually forms in the veins or atrium (low pressure)
    • Use Anticoagulant therapy such as warfarin
    • Protects against DVT (deep vein thrombosis) and PE (pulmonary emboli)

    PLATELETS: stop the bleeding!
    Platelets initiate hemostatic mechanisms that repair injured blood vessels. The platelet is a circulating disc-shaped cell that does not contain a nucleus. Many references refer to them as “blood cell fragments.”

    ROLE OF PLATELETS: As pharmacists, we provide prescription therapy directed at clot prevention. Many of us older pharmacists remember a 60-Minute “hatchet job” done to our profession in the 1980’s when a staged patient was buying a bottle of aspirin, while the pharmacist dispensed his warfarin prescription.

    Activated platelets do the following:
    • Adhesion to the site of injury
    • Activation and secretion
    • Aggregation- form clumps to “plug the leaks”
    • Interaction with coagulation factors especially with factor VIIa to promote local coagulation, and ultimately the generation of thrombin, the most potent of the platelet agonists.
    Antiplatelet mechanisms of action… ways to block platelet activity:
    • Blocking the thrombin receptor (PAR-1): think vorapaxar (Zontivity®), which was removed from the US market
    • Blocking ADP binding at the P2Y1 and P2Y12 receptors: think clopidogrel (Plavix®), prasugrel (Effient®) and ticagrelor (Brilinta®)
    • Blocking prostaglandin synthesis: think aspirin and other non-selective COX-1 inhibitors
    • Blocking cyclic AMP: think dipyridamole

    How many?
    A normal platelet count ranges from 150,000 to 450,000 platelets per microliter of blood.
    • Having more than 450,000 platelets is a condition called thrombocytosis or thrombocythemia
    • Having fewer than 150,000 is known as thrombocytopenia.

    Last week my 4-year-old grandson Luke and I were out for a walk. He said, “Let’s take a shortcut over to the other road.” We walked through some brush, and Luke got scratched by a briar. He looked at his scratch and saw the blood and said, “We need to go home and have Mom put a Band-aid on it.”

    I told him, “You’ll be fine; your platelets will take care of it.” He asked me what a platelet was, and I explained that was like your body’s own Band-aid that stops the bleeding. For the next 3 days we watched every platelet video on YouTube! He sustained another scratch, and told me it was so big that he needed “two platelets” to fix it… I guess my Band-aid analogy painted the wrong picture.

    We are beginning to cover Cardiology meds, which would seem appropriate given the sudden interest in platelets in my family!

    Have a great day on the bench!!

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    An Overview of Herpes and Zoster Treatment

    Acyclovir (Zovirax®)
    Available as: capsules 200mg; tablets 400mg & 800mg and 200mg/5ml
    Mechanism: requires 3 phosphorylation steps for activation. Is selectively activated and accumulates only in infected cells. It inactivates DNA polymerase.
    Indication for Use:
    • Initial and recurrent HSV I and II
    • Treatment of herpes Zoster (shingles)
    • Treatment of varicella (chickenpox)
    • IV used for treatment of herpes simplex encephalitis, neonatal HSV and serious HSV or VZV infections
    • Initial genital: 400mg 5 times daily for 7-10
    • Mucocutaneous oral labial: 400 mg 5 times daily for 5 days
    • Recurrent: 800mg three times daily for 2 days or 400mg three times daily for 5 days
    • Suppression: 400mg twice daily
    • Zoster: 800mg 5 times daily for 7 days. (start within 24 hours of rash)
    • Varicella: 20mg/kg (800mg MAX) four times daily for 5 days. (generally, treatment not recommended)
    • Pregnancy: Category-B
    • Treatment for Zoster is MOST effective when initiated within 48 hours of onset of rash. After 72 hours of onset, minimal benefit.
    • Renal impairment: dosage adjustment required
    Adverse Effects:
    • Photosensitivity may occur
    • Stevens-Johnson syndrome
    • GI: diarrhea and nausea
    Drug Interactions:
    • May elevate theophylline
    • May lower levels of Phenytoin and Valproic acid
    Patient Education:
    • Avoid sexual intercourse when visible herpes lesions are present.
    • Oral Acyclovir does NOT eliminate latent HSV, and is not a cure
    • May cause photosensitivity, wear sunscreens and protective clothing.
    • May take with or without food

    Famvir® (Famciclovir)
    Available as: tablets 125mg, 250mg & 500mg
    Mechanism: Gets bio-transformed to penciclovir which is active against HSV I & II, and VZV. Inhibits viral DNA synthesis.
    Indication for Use:
    • Zoster: 500mg every 8 hours for 7 days
    • Recurrent genital herpes: 1GM twice daily for 1 day
    • Herpes Simplex (oral or genital) 250mg three times daily for 7-10 days
    • Suppression: 250mg twice daily for up to 1 year
    • Mucocutaneous oral labial: 500mg twice daily for 7 days
    • Famciclovir has been approved as the first and only antiviral to shorten duration of cold sore outbreak with a single dose:
    Dosage: Famciclovir 500mg: Three tablets (1500mg) as a single dose at earliest sign or symptom of a cold sore.

    • Pregnancy: Category-B
    • Initiate therapy ASAP
    Adverse Effects:
    • Headache
    • Nausea & vomiting
    Patient Education:
    • Initiate therapy ASAP (within 6 hours of outbreak)
    • May take with or without food

    Epithelial Keratitis dosing for oral antiviral agents.
    Click Here for AAO Treatment Guide
    • Acyclovir (Zovirax®): 400mg 3-5 times daily for 7-10 days OR
    • Valacyclovir (Valtrex®): 500mg twice daily for 7-10 days OR
    • Famciclovir (Famvir®) 250mg BID for 7-10 days

    Viruses are non-living particles that require a host cell in order to replicate. They must be inside a host cell to cause infection, by overtaking that cells ‘machinery’. The virus is surrounded by a protein coat or capsid and contains only a few dozen genes either in the form of RNA or DNA that contain the information necessary for replication.

    Some viruses such as the common cold are self-limiting, resolving in 7 to 10 days. Other viruses such as HIV can cause serious and sometimes fatal disease and require aggressive therapy. Challenges in drug therapy are due to rapid mutation which can quickly render drugs ineffective. Due to the intracellular nature of the viruses, it is difficult for medications to find their “targets” inside normal living cells.

    Depending upon whether the HSV-1 virus attacks the oral mucosa, or HSV-2 attacks the genital mucosa, the doses for the three antivirals are different.

    For Zoster (shingles), caused by a varicella virus, think highest dose for longest duration. Most important with the treatment of these viral infections, start treatment early, ideally within 48 hours of onset of symptoms.

    Didn’t you forget something?? Topical treatment of Herpes infections.
    The short answer is no I didn’t. All of the topical products whether for cold sores, genital herpes or herpes eye infections are expensive and need to be applied frequently, at least 5 times per day.

    With the oral dosage forms being available as generics, there is no need whatsoever to prescribe these less than effective and overpriced products.

    Have a great day on the bench!!

    November 2020

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    An Overview of Influenza Treatment


    • Amantadine (Symmetrel®) not recommended
    • Rimantadine (Flumadine®) not recommended
    At one time these drugs were recommended for treatment of Influenza-A. Since 2006, the CDC has not recommend using these drugs due to resistance to Type-A flu strains.


    Zanamavir (Relenza®) approved July 1999 (WAC=$59.00)
    inhibits neuraminidase, with the possibility of alteration of virus particle aggregation and release.

    Indications for use:
    Treatment of both Type A and Type-B influenza. Will decrease symptoms by 1.3 days if started within 48 hours of viral symptoms.

    Warnings / Precautions / Adverse effects:
    May see pulmonary effects in asthma and COPD patients. Have albuterol ready for rescue as this drug may induce bronchospasm. Not recommended for this patient group. May see mild gastrointestinal distress such as nausea, vomiting and diarrhea.

    Patient Education:
    • If asthmatic or COPD, have Albuterol inhaler ready.
    • Instruct patient on use of delivery system.
    • Must complete 5-day course even is symptoms disappear
    • Does not reduce the transmission of virus to others.
    • Take 2 doses first day of treatment, if there are 2 hours between doses. Then every 12 hours.

    Representative Products:
    Relenza® (zanamivir) diskhaler: Adults: 2 inhalations twice daily. Age 7 years to adult.

    OSELTAMIVIR (Tamiflu®) approved 1999
    Inhibits neuraminidase, with the possibility of alteration of virus particle aggregation and release. Is a prodrug, is pharmacologically similar to zanamivir

    Indications for use:
    Influenza type A and B. Begin within 48 hours of symptoms. May reduce symptoms by 1 day.

    Warnings / Precautions / Adverse effects:
    Nausea, vomiting, vertigo and insomnia

    NOTE: CDC warning: November 13, 2006
    The FDA approved a labeling supplement to include a precaution about neuropsychiatric events for Tamiflu®. Self-injury and delirium have been observed in Japan primarily among pediatric patients. Monitor pediatric patients for signs of unusual behavior.

    Patient Education:
    Start therapy as soon as possible.
    Not a substitute for the vaccine

    Representative Products:
    Tamiflu® 75mg capsules and powder for suspension 12mg/mL (available generically) Adults: 75mg twice daily for 5 days.
    Adults: 75mg twice daily for 5 days.
    Children: based on body weight:
    • If younger than 1 yr old: 3 mg/kg/dose twice daily

    If 1 yr or older, dose varies by child’s weight:
    • 15 kg or less, the dose is 30 mg twice a day
    • >15 to 23 kg, the dose is 45 mg twice a day
    • >23 to 40 kg, the dose is 60 mg twice a day
    • >40 kg, the dose is 75 mg twice a day

    CHEMOPROPHYLAXIS with Tamiflu and Relenza
    FormulationsAdult DosePediatric dose
    Oseltamivir (Tamiflu)30,45,75mg caps and 6mg/ml oral suspProphylaxis: 75mg/day Treatment: 75mg BIDProphylaxis: 30-75mg/day Treatment 30-75mg BID
    Zanamivir (Relenza)5mg/blister inhalerProph: 2 inh once daily Treat: 2 inh BID x5Proph: over 5yrs: 2 inh QD Treat over 7 yo: 2 inh BID

    COST of Tamiflu: $180.00/ 10 capsules 75mg
    Cost of generic (oseltamivir): $40.00/10 caps 75mg

    Baloxavir marboxil tablets (XOFLUZA® ) approved 2018 Cost: $180.00/dose
    Mechanism of action:
    is a polymerase acidic (PA) endonuclease inhibitor, an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene transcription, resulting in inhibition of influenza virus replication

    Indications for use:
    for the treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours. Shortens flu symptoms versus placebo by about one day.

    Take a single dose of XOFLUZA® orally within 48 hours of symptom onset with or without food
    • 80kg and over: take 80mg dose.
    • 40kg-80kg: take 40mg as a single dose.
    • On average, patients recovered from flu symptoms in 2.3 days---(54 hours versus 80 hours) by about one day.
    • Does not reduce the transmission of virus to others.
    • Reduces viral load faster than oseltamivir, but not sure that reduces spread of flu.

    Warnings / Precautions / Adverse effects:
    • No changes at QT interval, even at twice the dose.
    • Avoid co-administration of XOFLUZA® with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc).
    • The dose of XOFLUZA® depends on weight
    • Avoid if pregnant
    • Reduces viral load faster than oseltamivir, but not sure that reduces spread of flu.


    HIGH RISK PATIENTS:: Clinicians should start antiviral treatment as soon as possible for adults and children with documented or suspected influenza, vaccinated or not, who meet the following criteria:
    • Persons of any age who are hospitalized with influenza.
    • Outpatients of any age with severe or progressive illness, regardless of illness duration.
    • Outpatients who are at high risk of complications from influenza, including those with chronic medical conditions and immunocompromised patients. Think diabetes, obesity, chronic kidney disease, chronic heart disease, chronic lung disease (asthma, COPD)
    • Children younger than 2 years and adults ≥65 years.
    • Pregnant women and those within 2 weeks postpartum

    LOW RISK PATIENTS:: Outpatients with illness onset ≤2 days before presentation (C-I).
    • Symptomatic outpatients who are household contacts of persons who are at high risk of developing complications from influenza, particularly those who are severely immunocompromised (C-III).
    • Symptomatic healthcare providers who care for patients who are at high risk of developing complications from influenza, particularly those who are severely immunocompromised

    (Of course, PREVENTION is the best approach)
    • Vaccination: best if given in October and November
    • Avoid close contact with sick people
    • Stay home if you are sick
    • Cover mouth and nose when coughing or sneezing
    • Wash your hands---OFTEN! Viruses can survive on surfaces for 2-8 hours.
    • Avoid touching eyes, nose, mouth
    • Looks like we need to add masking and social distancing to this list given the low transmission rate in the Southern Hemisphere in 2020.

    • Bedrest
    • Fluids
    • Humidification of air

    • Cough suppressants, analgesic. Symptom management.
    • Absolutely no aspirin in patients under age 18.

    We’ve seen a significant decrease in the influenza spread in the southern hemisphere, most likely due to social distancing, masking, working from home and on-line learning. All of the efforts made to decrease the spread of the COVID-19 virus are greatly impacting the spread of the seasonal influenza virus. Patients seem a lot more interested in getting their flu vaccinations this year. I’ve noticed a huge uptick in patient who were “first timers”.

    Many universities will end their fall term before Thanksgiving, and the students will not return to campus until 2021. This should greatly help decrease the “holiday germ exchange” where students would go home collect their Thanksgiving germs, bring them back to campus, spread them around, and everyone could bring home fresh germs for Christmas.

    All of the efforts made to decrease the spread of the COVID-19 virus are greatly impacting the spread of the seasonal influenza virus. Patients seem a lot more interested in getting their flu vaccinations this year. I’ve noticed a huge uptick in patient who were “first timers”.

    Finally, some good news for 2020! But patients will inevitably be diagnosed with influenza in the coming season. So, what do we do?

    Have a great day on the bench!!

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    Flu shots? Did you get yours?

    Who should get the flu vaccine?
    That’s easy… virtually everyone from age six months and up, regardless of pregnancy status. Patients with laboratory confirmed COVID 19 infection, symptomatic or not, should not get the influenza vaccination until they are no longer acutely and do not require isolation.

    On average, about 45% of the United States citizens get their annual flu shot.
    Healthcare workers: last year 80.6% of all healthcare workers got the vaccine. By occupation, flu vaccination coverage was highest among physicians (98%), nurses (92%), pharmacists (90.6%), and nurse practitioners and physician assistants (88.8%). (source: CDC.gov)

    Efficacy of last year’s vaccine:was estimated to be 45% with 50% accuracy for the Influenza-B and 37% for Influenza-A

    For 2020-2021, trivalent (three-strain) egg-based vaccines are recommended to contain:
  • A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus (updated)
  • FA/Hong Kong/2671/2019 (H3N2)-like virus (updated)
  • B/Washington/02/2019 (B/Victoria lineage)-like virus (updated)

  • Quadrivalent (four-strain) egg-based vaccines, which protect against a second lineage of B viruses, are recommended to contain:
  • the three recommended viruses above, plus B/Phuket/3073/2013-like (Yamagata lineage) virus. (remains unchanged from 2019-2020 vaccine)

  • US DRUG NAMES (egg based):Afluria Quadrivalent; Fluad Trivalent; Fluad Quadrivalent; Fluarix Quadrivalent; Flucelvax Quadrivalent; FluLaval Quadrivalent; Fluvirin; Fluzone High-Dose; Fluzone Quadrivalent

    For 2020-2021, cell- or recombinant-based vaccines are recommended to contain:
    • A/Hawaii/70/2019 (H1N1)pdm09-like virus (updated)
    • A/Hong Kong/2671/2019 (H3N2)-like virus
    • B/Washington/02/2019 (B/Victoria lineage)-like virus
    • BB/Phuket/3073/2013-like (Yamagata lineage) virus

    There are two egg-free vaccines available in the US. Flublok Quadrivalent is recombinant and Flucelvax Quadrivalent is cell-based.

    Flu vaccines for patients over age 65:
    • Fluzone High-Dose Quadrivalent® contains four times the amount of antigen as the standard-dose inactivated flu vaccine, producing better protection in the elderly population. In a NEJM study Fluzone High Dose was found to be 24% more effective in preventing flu in adults 65 years and older relative to a standard-dose vaccine.
    • FLUAD® Influenza Vaccine, Adjuvanted: For active immunization of persons 65 years of age and older against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. (Source: fda.com) Medicare beneficiaries 65 years and older found that trivalent FLUAD provided greater protection against flu-related hospitalizations than standard-dose, egg-based flu vaccine.

    Adjuvants are ingredients of a vaccine that elicits a more robust immune response. Adjuvants also can reduce the amount of virus needed for production of a vaccine and still give adequate immune response.

    Share the following talking points with your patients:
    • During the preparation of inactivated influenza vaccines, the vaccine viruses are made noninfectious (inactivated or killed). Therefore, it cannot cause influenza.
    • The flu vaccine is administered intramuscularly by injection.
    • The flu vaccine takes two weeks to provide a full immune response.
    • The flu vaccine is licensed for use among persons aged >6 months, including those who are healthy, pregnant, and those with chronic medical conditions.

    What will this year’s flu season look like?
    • Flu season: influenza activity remained at lower levels than expected for this time of the year, though increased detections were reported in some countries. In the temperate zones of the southern hemisphere, the influenza season remained low or below baseline. Despite continued or even increased testing for influenza in some countries in the southern hemisphere, very few influenza detections were reported.
    • In the temperate zone of the northern hemisphere, influenza activity remained below inter-seasonal levels. (Source: World Health Organization)
    • It appears that all of the mitigation efforts to stop the spread of COVID-19 are having a significant impact on influenza spread. Children naturally spread influenza, and with many of them staying at home and attending school virtually, it seems to have impact on the decreased spreading of influenza. Social distancing, wearing face masks, limiting size of gatherings and travel restrictions all have impacted the rates of influenza illness.
    Once again, I relied heavily on my daughter Dr. Gretchen Garofoli to do the proofreading and additions to this column. She does outstanding presentations for her students as well as freeCE.com.

    I was amazed that the physicians and nurses had a higher immunization rate than did the pharmacists. Whenever you call most chain pharmacies, they answer the phone “Hi this is “Big Box Drug store, we are offering flu shots.” Every pharmacy is actively promoting flu shots to their patients, with increased availability and flu shot clinics. Certainly, we as pharmacists know of the availability of flu shots.

    I’m hoping that the very mild flu season is a harbinger of what we have in the Northern Hemisphere this flu season. Most agree we need a break from viruses. Wear your mask, wash your hands, and social distance!

    As Gretchen is doing, I would encourage you to get actively in your community and pharmacies providing flu shots, especially as patients are more concerned than ever with vaccinations. Throw in a Tdap, and a pneumonia shot while you're at it!!

    Have a great day on the bench!!

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    Influenza: The Basics

    FLU SEASON: starts in October and November and greatly increases in December and January with the highest peak occurring in February in the Northern Hemisphere. Here are some flu basics that we clinicians need to become familiar with:
    • Flu is caused by an RNA virus of the orthomyxovirus family.
    • Antigenic drift: Frequent minor changes in antigenic structure of the virus. This can reach epidemic proportions, but not every year. This is what requires minor adjustments in the vaccine formulation.
    • Antigenic shift: Major change in one or both major antigens in Influenza-A resulting in different subtype. This can result in major pandemics in all ages.
    • Subtypes based on 2 surface antigens hemagglutinin (H) and neuraminidase (N).
    • Four types of hemagglutinins cause disease in humans and virus attachment to cells (H1, H2, H3, H5). There are 16 known hemagglutinin proteins (Labeled H1- H16).
    • Two types of neuraminidase cause disease in humans and have a role in viral penetration of cells. (N1, N2) There are 9 known variants of the neuraminidase proteins.
    • Causes moderate to severe disease in all ages and can be transmitted in other animals.
    • Most commonly associated with global pandemics
    • Three subtypes of Influenza A have maintained a presence in the human population:
      • H1N1, H1N2, and H3N2
      • *Note: Avian flu is the H5N1 subtype which is infamous for its transmission from infected fowl to humans.
    For 2020-2021, trivalent (three-component) egg-based vaccines are recommended to contain:
    • A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus
    • A/Hong Kong/2671/2019 (H3N2)-like virus
    • B/Washington/02/2019 (B/Victoria lineage)-like virus
    Quadrivalent (four-component) egg-based vaccines, which protect against a second lineage of B viruses, are recommended to contain:
    • the three recommended viruses above, plus B/Phuket/3073/2013-like (Yamagata lineage) virus.
    • US DRUG NAMES (egg based): Afluria®; Afluria Quadrivalent®; Fluad®; Fluarix Quadrivalent®; Flucelvax Quadrivalent®; Flucelvax [DSC]®; FluLaval Quadrivalent®; Fluvirin®; Fluzone High-Dose®; Fluzone Intradermal Quadrivalent®; Fluzone Quadrivalent®; Fluzone [DSC]®
    For 2020-2021, cell- or recombinant-based vaccines are recommended to contain:
    • A/Hawaii/70/2019 (H1N1)pdm09-like virus (updated)
    • A/Hong Kong/45/2019 (H3N2)-like virus (updated)
    • B/Washington/02/2019 (B/Victoria lineage)-like virus (updated)
    • B/Phuket/3073/2013-like (Yamagata lineage) virus
    The only product available for this flu season is Flublok Quadrivalent®. There are no egg proteins in this product.

    Medication Guide and/or Vaccine Information Statement (VIS) In the U.S, the appropriate CDC-approved Vaccine Information Statement (VIS) must be provided to the patient prior to administering each dose of this vaccine; VIS is available at http://www.cdc.gov/vaccines/hcp/vis/vis-statements/flu.html.

    WHO IS THE ACIP?: ACIP comprises medical and public health experts. The ACIP meets three times a year to develop recommendations on how to use vaccines to control disease in the United States. The recommendations include the age(s) when the vaccines should be given, the number of doses needed, and the amount of time between doses.
    • Oseltamivir-resistant influenza A (H1N1) strains have been identified in the United States and some other countries. However, oseltamivir or zanamivir continue to be the recommended antivirals for treatment of influenza because other influenza virus strains remain sensitive to oseltamivir, and resistance levels to other antiviral medications remain high.
    Influenza –B
    No subgroups.
    Only affects humans and causes a milder disease usually in children.

    Rarely reported in humans. Does not cause significant infections in humans.

    • Major complication is pneumonia, Reyes syndrome, worsening of chronic bronchitis and death.
    • One of the leading causes of vaccine-preventable disease. 20-40K deaths during epidemics.
    • Rates of disease highest in elderly (over 65 years old), less than 2 years of age, and people of any age with medical conditions.
    • Penetrates the epithelial cells of the respiratory tract and destroys the host cell.
    • Virus is shed in respiratory secretions for 5 to 10 days, and transmission is through direct person to person droplet contamination or contact.
    • Incubation period is approx. 2 days
    • Clinical features: abrupt onset, fever, myalgia, sore throat, nonproductive cough, headache.
    • Disease peaks between December and March in the Northern Hemisphere.
    Comparison of Symptoms Between Common Cold and Influenza
    Symptom/ParameterCommon ColdInfluenza
    FeverUncommon (low grade)Common 100-104F
    Myalgia, arthralgiaUncommonCommon and severe
    HeadacheUncommon and mildCommon and severe
    Dry coughMild to moderateCommon and severe
    Malaise and weaknessMildSevere
    Fatigue LevelMild, short livedSevere long lasting 2-3 wks
    Nasal congestionCommonOccasional
    Sore throatCommonOccasional
    Vaccine availablenoYes (yearly)
    Incubation period12 hours to 5 days (avg=2d)1-4 days (average=2 days)
    Contagious period1 day before & 5 days after1 day before & 5 days after
    ComplicationsSinus congestionBronchitis, pneumonia

    My daughter Gretchen Garofoli sits as the Coordinator of the American Pharmacists Association Immunizing Pharmacists SIG Community. She is very active at West Virginia University teaching and promoting immunization. She lectures across several platforms, especially FreeCE.com where she is their immunizing expert.

    As Gretchen is doing, I would encourage you to get actively in your community and pharmacies providing flu shots, especially as patients are more concerned than ever with vaccinations. Throw in a Tdap, and a pneumonia shot while you're at it!!

    Have a great day on the bench!!

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    Overview of Antibiotic-Induced Clostridioides difficile Infection

    C. dif infections... what a way to wrap up antibiotics!

    Clostridioides (Clostridium) difficile is an anaerobic gram-positive spore and toxin producing bacillus first discovered in 1935. In the 1970’s, its role was elucidated in antibiotic associated diarrhea. It is one of the most common and problematic nosocomial infections to contain. As “C. diff” multiplies, it produces two toxins (A and B) that cause diarrhea and colitis. 027/NAP1/BI isolates are the most virulent and produce 20 times more A and B toxins in vitro.

    Incidence: Between 2001-2010, the CDC analyzed data from 2.2 million hospital discharges. 700,000 patients were admitted for Clostridioides difficile infection (CDI) and nearly 1.5 million others acquired the infection while hospitalized for other reasons. CDIs increased from 4.5 to 8.2 per 1,000 discharges across the study period. Overall, 7.1% of infected patients died. Additionally, patients who acquired the infection while hospitalized were more than twice as likely to die than patients who were admitted for treatment of principal infection, a trend that increased during the study.

    Risk factors for developing CDAD (Clostridioides difficile associated diarrhea) include:
    • Antacid drugs (especially Proton pump inhibitors—omeprazole, esomeprazole)
    • Previous exposure to antimicrobial agents: Virtually all antibiotics have been associated with CDAD, but historically these drugs have posed the greatest risk. Aminopenicillins, cephalosporins, clindamycin and fluoroquinolones are frequently being implicated as risk factors. Fluoroquinolone administration for as short as 1-3 days whereas most antibiotics associated with CDAD take more than 3 days to occur. Remember this major side effect when counseling patients when dispensing levofloxacin (Levaquin®) ciprofloxacin (Cipro®), and moxifloxacin (Avelox®)
    Treatment of C. difficile (source: Sanford guide 2020)
    • First line: Vancomycin (Vancocin®) 125mg capsules four times daily for 10-14 days
    • Second line: Fidaxomicin (Dificid®) 200mg twice daily for 10 days (cost:$4100)
    • Third line: Metronidazole 500mg three times daily is only to be used if patient is not able to afford vancomycin or fidaxomicin
    • Adjunct therapy: Some clinicians use cholestyramine (Questran) 4gm 3 or 4 times daily to bind the toxins released by C.dif. Be sure to separate from vancomycin therapy by 2-3 hours to avoid binding.
    • Adjunct therapy: Saccharomyces boulardii (Florastar/ Stabile-GI) has the best efficacy of all probiotics for C. dif diarrhea.
    • Fecal transplant can be tried if reoccurrence, where an infusion of stool from a healthy donor is usually given rectally by enema or colonoscope. Some success has occurred when given by NG tube. Has the highest rate of efficacy.
    Zinplava® bezlotoxumab: approved 2016
    • human monoclonal antibody that binds to Clostridioides difficile toxin B, indicated to reduce recurrence of Clostridioides difficile infection (CDI) in patients 18 years of age or older who are receiving antibacterial drug treatment of CDI and are at a high risk for CDI recurrence.
    • Limitation of Use: ZINPLAVA is not indicated for the treatment of CDI because it is not an antibacterial drug. ZINPLAVA should only be used in conjunction with antibacterial drug treatment of CDI
    Prevention of Difficile:
    • Alcohol wipes and gels do not stop the spread. C. difficile is spread by spores, and the spores are relatively resistant to alcohol and other antiseptics. Wash hands with soap and water. Artificial fingernails are impossible to clean adequately, even after vigorous scrubbing or use of an antimicrobial soap. Healthcare workers are advised not to wear artificial nails, if in contact with C. dif patients.
    • Bleach wipes: good bathroom hygiene is effective in controlling C. dif. Patients should wipe down the toilet seat after each use with bleach wipes. Note that commercially available Clorox® wipes (yellow and green can) do not contain bleach. However, Clorox® “HealthCare” wipes contain bleach, and can be used for disinfection in the bathroom. See www.clorox.com for recipes to make your own solution. Don’t use paper towels, as they degrade the solution. https://www.clorox.com/resources/coronavirus/how-to-make-your-own-disinfecting-solution/
    • Antibiotic stewardship is a must! Use antibiotics only when absolutely necessary to avoid potential for C. dif.
    We pharmacists frequently dispense antibiotics, and sometimes we question the rationale. Now that the fluoroquinolones are very cheap, clinicians seem to jump on them. The current resistance rate for Strep pneumo (respiratory infections) for azithromycin (Z-pak) is around 47%. The current resistance rate for E. coli (urinary tract infections) for Trimeth/Sulfa is 21% and for Cipro/Levofloxacin is 27%.
    Besides the huge problem of antibiotic resistance, the development of Clostridioides difficile infection (CDI) is yet another problem that can be created with indiscriminate antibiotic use.

    Have a great day on the bench!!

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    Clindamycin Overview


    Binds exclusively to the 50S ribosomal subunit and suppresses protein synthesis. Clindamycin is 90% bioavailable after oral administration.

    Indications for use:
    Treatment of serious infections due to susceptible strains of streptococcus & staphylococcus. Very effective for Gram positive and Anaerobes. Penetrates well into the bone even in absence of inflammation.

    Common use: dental infections, anaerobic intra-abdominal infections, Methicillin resistant staph aureus (CA-MRSA).
    2nd choice for dental prophylaxis: adults 600mg one hour before appointment. Toxic shock syndrome: inhibits production of staphylococcal toxin associated with the toxic shock syndrome, used along with vancomycin.

    PSEUDOMEMBRANOUS COLITIS: fatal colitis characterized by severe persistent diarrhea. Toxins caused by Clostridioides difficile cause antibiotic associated colitis. When significant diarrhea occurs, STOP the drug. Don’t give anti-peristaltic meds. This condition can begin even after the cessation of Clindamycin.
    This condition is treated with Vancomycin, Fidaxomicin or Metronidazole.

    Pregnancy Category: B

    Side effects:
    Colitis & diarrhea

    Drug Monitoring:
    Watch for pseudomembranous colitis.

    Patient Education:
    Do not treat diarrhea without notifying the prescriber
    May take Clindamycin with food and full glass of water

    Most common Drugs & dosage of this class
    Clindamycin (Cleocin®)
    Available as capsules: 150mg, 300mg. Suspension: 75mg/5ml
    Suspension needs to be reconstituted. Do NOT refrigerate. Good for 14 days.
    Dosage: Serious infections: 150mg- 300mg every 6 hours
    More serious: 300mg-450mg every 6 hours.
    Child 8-16mg/kg divided in 3 or 4 equal doses.
    Dental prophylaxis: 600mg 1 hour before appointment

    Clindamycin is also used topically for treatment of acne.
    Available as 1% lotion, cream, gel and solutions. Apply twice daily.
    Also available as: Cleocin® Vaginal cream and suppositories.

    Clindamycin (Cleocin®), we learned in Pharmacy School back in the late 1970’s, was a most welcome addition to the infectious disease clinician’s armamentarium because it penetrated the vasculature of infected bone. It was pretty well elucidated at that time that there was a significant risk of Clostridioides difficile infection, and abundant caution was recommended.

    To quote the American Association of Endodontists (AAE) for patients that cannot take penicillins or cephalosporins, they offer this warning:

    “For patients with a true allergy to penicillin, the primary alternative antibiotic recommendation has changed. It is now azithromycin with a loading dose of 500 mg, and then 250 mg for four additional days.”

    “Clindamycin now has a U.S. Food and Drug Administration black box warning for Clostridioides difficile infection, which can be fatal. Therefore, it is only indicated if the patient cannot take azithromycin.”

    “For all patients on antibiotics, the antibiotic treatment is discontinued as soon as definitive treatment and improvement of the condition occurs (as short as three days), rather than to the full course of the prescription.”

    With the dental warnings from the AAE, I suspect we will be seeing a lot less oral clindamycin.

    Clindamycin, which was derived from lincomycin was approved by the FDA in the late 1960’s. Lincomycin (Lincocin®) is a natural product made by Streptomyces lincolnensis, an actinobacterium. Generic Clindamycin capsules became available in 1989.

    Have a great day on the bench!!

    October 2020

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    Role of Nitroimidazoles in Practice


    METRONIDAZOLE (Flagyl®) (1963)

    Disrupts structure of RNA and DNA, and cellular proteins of organism.

    Indications for use
    • Highly effective against ANAEROBES (mostly gram negative)
    • 3 types of protozoal infections: giardiasis, amebiasis, trichomoniasis
    • Clostridium difficile (C.dif) infections if cost is a concern, however we are seeing more resistance, and metronidazole is no longer considered first line therapy.
    • used in combination for H. pylori infections
    • bacterial vaginosis
    • used for intra-abdominal infections
    • “They clean-up what the big classes of drugs (FQ, ceph, pen, macrolides) miss!”
    Most common uses:
    • Abdominal infections, vaginosis, trichomoniasis, GI infections such as amebiasis, Giardia duodenalis (also termed G. lamblia) Helicobacter pylori, C.dif
    • Topical therapy can be used for treatment of acne rosacea and bacterial vaginosis
    Pregnancy Category B (however, some references say don’t use 1st trimester)
    Disulfram reactions (nausea, flushing, vomiting with alcohol)
    Neurological effects (rare) seizures, peripheral neuropathy
    Metallic taste
    Nausea, vomiting & diarrhea

    Side effects:
    Metallic taste
    Nausea, vomiting & diarrhea

    Patient Education:
    Avoid alcohol
    Report any neurological effects to prescriber
    Complete course of therapy as prescribed
    May darken urine
    May cause unpleasant metallic taste.

    Most common Drugs & dosage of this class
    Metronidazole (Flagyl®)
    Dosage: Adult 250- 500mg every 6 to 8 hours for 7 to 10 days.
    Trichomoniasis: 1- day treatment: 2GM in one day, as a single or divided dose.
    Child dose: consult literature. Based on type of infection.

    Metrocream® & Metrogel®
    Used topically once or twice daily.
    Used for rosacea

    Metrogel Vaginal®
    Bacterial vaginosis: 1 applicatorful once or twice daily for 5 days. Be sure to specify route of administration when prescribing topical therapy.

    TINIDAZOLE (Tindamax®) 2004
    Is a second generation nitroimidazole
    • Treatment of trichomoniasis caused by Trichomonas vaginalis. (2GM single dose)
    • Treatment of giardiasis caused by Giardia duodenalis (also termed G. lamblia) (2gm single dose)
    • Treatment of intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica (2gm daily for 3-5 days)
    • Treatment of bacterial vaginosis (Gardnerella vaginitis) (2gm daily for 2 days)
    Side effects: like metronidazole; also avoid first trimester of pregnancy, avoid alcohol.

    SECNIDAZOLE (Solosec®) (2017)
    • Bacterial vaginosis. Dose one single gram packet of granules taken with food.
    Side effects: The most common side effects of secnidazole include yeast infection, headache, nausea, altered taste, vomiting, diarrhea, abdominal pain, and vaginal itching

    Note: does not seem to affect alcohol metabolism like tinidazole and metronidazole. There are no restrictions on alcohol use with secnidazole.

    Nitroimidazoles have been available since 1963. Metronidazole counseling is a must and most of us are well engrained to counsel patients about the absolute need to avoid alcohol. Often, people are bothered by the metallic taste from metronidazole.

    Even though tinidazole is available generically, and costs less than $30 per course of therapy it never got much attention, because metronidazole is so effective and cheap.

    One use of the metronidazole is for giardiasis. Giardiasis is extremely common, with 95% of all fresh surface water being contaminated. I remember as a kid going fishing with my Grandpa and we always drank out of a spring or creek, as long as it “didn’t smell bad”! Today, all fresh water needs to be purified before drinking. Here in Central Pennsylvania you’ll still see people with their plastic water jugs getting “fresh mountain spring water.” Keep the metronidazole handy!!

    Have a great day on the bench!!

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    Role of Nitrofurantoins in the Treatment of Urinary Tract Infections


    Nitrofurantoin history
    Approved by the FDA in 1953, nitrofurantoin became standard therapy for lower urinary tract infections (UTI) until the late 1970s. Other antibiotics, such as the fluoroquinolones, became available and its use decreased substantially. Since 2011, nitrofurantoin was again recommended as first-line therapy for lower UTI due to increasing resistance to fluoroquinolones.

    MAY disrupt carbohydrate metabolism. May inhibit cell wall synthesis. Low doses are bacteriostatic; high doses are bactericidal. Therapeutic serum & tissue concentrations are not achieved, except in the urinary tract. Poorly absorbed. 90% is renally eliminated, achieving high urine concentrations.

    Indications for use
    Effective against many Gram (+) and Gram (-) including some strains of E.coli, P.mirab, Klebsiella, S.aureus, Enterobacter. Nitrofurantoin macrocrystals (Macrodantin®) may also be used for prevention of urinary tract infections. Dose is one capsule at bedtime or one capsule after each act of intercourse.

    Prescribing tips or more like “when not to prescribe”:
    • AVOID nitrofurantoin in patients with creatinine clearance less than 60mL/minute due to an increased risk for pulmonary toxicity, neuropathy, hepatotoxicity.
    • AVOID nitrofurantoin if early pyelonephritis is suspected, because serum concentrations doesn’t get high enough to treat systemic infections.
    • AVOID in the first trimester of pregnancy
    • AVOID last week of pregnancy due to potential for hemolytic anemia in newborn. Neonates had a higher rate of neonatal jaundice.
    • AVOID in complicated UTI
    Pulmonary reactions: manifested by sudden onset of dyspnea, chest pains, cough, fever & chills. Prolonged use can cause pulmonary fibrosis.
    Hemolysis can occur if the patient is Glucose-6-phosphate dehydrogenase (G-6-PD) deficient.

    Pregnancy Category B: AVOID last week of pregnancy due to potential for hemolytic anemia in newborn.

    Side effects
    GI upset is common. Give with food.
    Headache, dizziness, confusion.
    Dermatologic: exfoliative dermatitis

    Patient Education-Nitrofurantoins:
    Complete full course of therapy.
    Take with food or milk
    May cause brown discoloration of urine
    Notify physician if breathing difficulties, skin rashes or tingling in fingers & toes.

    Most common Drugs & dosage of this class
    • MacroBid (nitrofurantoin macrocrystals monohydrate)
      Dosage: 100mg BID with food.
    • Macrodantin (nitrofurantoin macrocrystals) 50mg and 100mg
      Dosage: QID with food. (is most commonly used for Urinary Tract Infection prophylaxis)
    Other Urinary Tract Antiseptics:
    • Methenamine Hippurate (Hiprex®)- is the salt of hippuric acid and methenamine. Available as 1 gram tablets.
    • Methenamine Mandelate (Mandelamine®)- is the salt of mandelic acid and methenamine, available as 500mg and 1gm tablets. Dose 1gm four times daily.
    Mechanism: an inactive weak base, slowly hydrolyzes in acidic urine to ammonia and the nonspecific antibacterial, formaldehyde. Formaldehyde is thought to act by denaturation of protein. It becomes effective when urinary pH is less than 5.5, so frequently Vitamin-C (ascorbic acid) 4-12 grams may be given to acidify the urine and increase efficacy.

    Used only for prophylaxis of UTI, not treatment.

    Of course, I always recommend generic drugs be prescribed. However, I tell my students that this drug should be prescribed by brand name and let the pharmacist substitute to the generic equivalent.

    We frequently get prescriptions for “Nitrofurantoin macrocrystals 100mg-one capsule BID” which is Macrodantin® which is dosed four times daily, or once daily for prophylaxis. We have to call the doctor’s office for clarification.

    We also get “Nitrofurantoin Macrocrystals Monohydrate 100mg HS for prevention” which is MacroBID®, which is not used for prophylaxis, but treatment. When prescribing on an EMR or Pharmacy software it is best to search by “MacroBID®” or “Macrodantin®”

    I had not dispensed any methenamine for at least 30 years, and currently I have 2 women on this drug for prevention. For treatment/prevention of UTI, it seems the “antique drugs” are more efficacious. Our local resistance rates for nitrofurantoin for E. Coli is 7%, where the resistance to fluroquinolones is 27% and resistance to Sulfamethoxazole/Trimethoprim is 25%.

    Sanford guide recommends NOT using fluoroquinolones if resistance rates are over 10%, and not using Sulfa if the resistance rate is over 20%. At the clinic our “go to” is Macrobid® (nitrofurantoinMM) 100mg twice daily for 7 days, once the risk of pyelonephritis is ruled out.

    Have a great day on the bench!!

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    Overview of Fluroquinolones

    Mechanism: involves inhibition of DNA topoisomerase. Disrupts DNA cell replication.
    Fluoroquinolones are considered bactericidal.

    Indications for use:
    Excellent Gram positive & gram-negative coverage. Activity against Pseudomonas. Coverage of Anaerobes is poor.

    • May cause QT prolongation. Caution with elderly or any patient taking drugs that prolong the QTc interval. (FDA Black Box warning)
    • Photosensitivity reactions can occur. Use a sunscreen.
    • Mental health: may cause mood or behavior changes such as nervousness, confusion, agitation, paranoia, hallucinations. (FDA Black Box warning)
    • May worsen symptoms of myasthenia gravis. (FDA Black Box warning)
    • Tendonitis: may not give to patients under 18! (FDA Black Box warning)
    • Avoid in pregnant women, nursing women & children due cartilage erosion in growing bone tissue. (FDA Black Box warning) Pregnancy Category D
    • Pseudomembranous colitis (Clostridium difficile associated diarrhea) FQ have been implicated in causing surges of the highly toxic 027/BI/NAP1strain of C. dif.
    • May affect blood sugar levels, especially in diabetics (esp. renal impaired). HYPOglycemia can occur within the first 3 days. HYPERglycemia usually doesn't show up until after 3 days. Advise extra blood sugar monitoring. (FDA Black Box warning)
    • 2018: increased risk of the aorta (the main artery of body) rupturing, causing massive bleeding and potentially, death.
    Side effects: rash, urticaria, photosensitivity

    Drug Interactions:
    Do not take with antacids, multivitamins, iron, calcium, magnesium, for at least 2 hours.
    Increases theophylline levels
    May increase prothrombin time or INR (warfarin interaction)

    Patient Education:
    • Use sunscreen if outside.
    • May take with food to decrease GI upset.
    • Avoid iron, magnesium, calcium, zinc or any divalent or trivalent ions.
    • Finish the entire course of therapy.
    Most common Drugs & dosage:

    Ciprofloxacin (Cipro®) FDA initial approval 1987
    Available as: 250mg, 500mg 750mg and XR 500mg & XR 1000mg tablets

    Typical dosage: 500mg every 12 hours
    • Primary use today is for urinary tract infections, skin/soft tissue and GI infections. Not for respiratory infections. Not for gonorrhea infections.
    • Historical note: In August 2000, the FDA approved ciprofloxacin for management of postexposure inhalational anthrax. First antimicrobial drug approved by the FDA for use in treating an infection due to a biological weapon.
    Levofloxacin (Levaquin®) (FDA approved: 12/1998)
    Available as: tablets 250, 500mg & 750mg also available as liquid (25mg/ml)
    Dosage: 500mg q24 hours for 10 days
    • Can be used for both UTI and respiratory infections
    • For sinusitis, may give 750mg daily for 5 days. The higher peak concentrations of levofloxacin provide more rapid and complete killing of pathogens, which may decrease the emergence of resistance.
    • Hospital discharge: IV to PO mg for mg
    Moxifloxin (Avelox®) (FDA approved 1999)
    available as 400mg tablets
    Dose: 400mg every 24 hours
    • Little renal penetration, used only for respiratory infection, and skin and soft tissue infections. Minimal value for urinary tract infections.
    • Does NOT cover pseudomonas.
    Delafloxacin (Baxdela®) --- FDA approved 2018
    “the exception to all of the fluoroquinolone rules”
    Dosage: 450mg orally every 12 hours ($675.00/ 5 days therapy) or 300mg IV q12h

    • Is an anionic fluoroquinolone antibiotic for treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSI’s)
    • More active than other FQ’s against Gram positive organisms such as multi drug resistant
      Strep pneumo and MRSA (methicillin resistant S. aureus).
    • Like other FQ: May cause tendinopathy.
    • Avoid polyvalent cations with administration.
    Special Notes:
    • Does not prolong QTc interval
    • Does not cause photosensitivity
    Gemifloxacin (Factive) – FDA approved 2003
    Was used for exacerbations of chronic bronchitis but is seldom used due to causing red exfoliative rash.

    And, you seasoned pharmacists remember the FIRST fluoroquinolone:

    Norfloxacin (Noroxin®) by Merck October 1986
    Only used for urinary tract infections, rarely used today.

    We see major resistance to fluoroquinolones. Here are some resistance stats from my backyard: Escherichia coli accounts for 75-95% of urinary tract infections.
    Streptococcus pneumoniae was a big player in the pre-antibiotic era, thanks to child immunizations it is seen less frequently. However, is the most common agent in hospitalizations.

    USA 2017UPMC Altoona
    Altoona, PA
    Mount Nittany,
    State College PA
    E. coli resistance25%27%16%
    Strep pneumo resistance1%5%0%

    Altoona, PA where I practice is a community with an older population. State College PA, home of Penn State is a more affluent, healthier, younger, and better educated community, less likely to demand or need antibiotic therapy. There is a distance of about 35 miles between the two municipalities, but a major gap in fluoroquinolone resistance.

    Special thanks to Ukwen Akpoji, from the Cleveland Veterans Hospital, John Rossi from Mount Nittany and the staff at UPMC Altoona Pharmacy.

    Once again, my fellow pharmacists, including my wife Denise, were helpful in guiding me through this overview. Ukwen Akpoji, Pharm D. provided some interesting data about the prevalence of resistance in the United States. He commented, “E. coli resistance to fluoroquinolones is about 30% at our VA (we have a unique population which may not be relatable to community).” With Ukwen’s population being much older and sicker, we might expect to see even higher resistance rates in other patient populations. Is there any wonder that the Cleveland Veterans Hospital needs a pharmacist specialized in antibiotic stewardship?

    At the clinic that I staff, we have changed our protocol for treatment of urinary tract infections, making nitrofurantoin the agent of choice for uncomplicated UTI’s due to resistance as well as the significant adverse effects of the fluoroquinolones.

    I remember as a young pharmacist when Noroxin® and Cipro® became available in the late 1980’s. They were a Godsend, as the patients no longer needed to be hospitalized to be treated with aminoglycosides for Pseudomonas infections. After 30 years of use, we have seen numerous side effects that require us to reign in overuse.

    Have a great day on the bench!!

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    Overview of Sulfonamide Antibiotics


    Sulfonamide mechanism:
    • Sulfa drugs compete with para-amino-benzoic-acid (PABA) to block its conversion to dihydrofolic acid (DHFA)
    • Trimethoprim: block conversion of dihydrofolate to tetrahydrofolate
    Bacteria are obligate folic acid synthesizers, while humans obtain folate through dietary sources.

    Septra DS®, Bactrim DS® 800/160 and Bactrim® & Septra® (single strength) 400/80
    Liquid: 200mg SMZ/ 40mg TMP

    Adults: Septra DS®, BID for 7-10 days
    Child: 40mg/kg SMZ divided BID for 10 days.

    Indications for use:
    • Acute and chronic cystitis.
    • UTI caused by E.coli.
    • Used to treat P. Carinii infections (PCP pneumonia)
    • Also, for post-transplant antibiotic prophylaxis of PCP pneumonia
    • Methicillin resistant Staph aureus
    • Upper Respiratory Infections, Acute bronchitis
    • Acute otitis media (second line)
    • Lice- the combination of topical permethrin (Nix®) and oral (TMP/SMX) was a better second line treatment for head lice infestation than was PER alone. Monitor for adverse effects
    Warnings/Precautions: sulfonamides are perhaps the most allergenic of all antibiotics.
    About 3% - 4% of patients develop allergic reactions to sulfonamide antibiotics, also popularly known as "sulfa" antibiotics.
    • Sulfonylarylamines (the sulfa antibiotics: sulfamethoxazole, sulfisoxazole) along with the HIV protease inhibitors amprenavir and fosamprenavir)
    • NONsulfonylarylamines (loop diuretics, thiazide diuretics, sulfonylureas, celecoxib (Celebrex), acetazolamide, etc)
    • Sulfonamide moiety-containing drugs (e.g., sumatriptan, sotalol, and topiramate, etc)
    NONsulfonylarylamine and sulfonamide moiety-containing drugs need NOT be routinely avoided in patients with a history of allergy to sulfonylarylamines. However, these warning flags appear on most computer systems, and gently warn patients to watch for rash etc.

    Carries the highest risk of toxic epidermal necrolysis of the antibiotic classes. Can cause Stevens Johnson syndrome, hepatic necrosis, agranulocytosis. More likely to occur in HIV patients.

    Pregnancy Category-C:
    • Avoid in the first trimester of pregnancy since trimethoprim is a folic acid antagonist, and may have an association with folate-sensitive birth defects
    • Avoid at term. Can cause jaundice, hemolytic anemia and kernicterus. Both sulfa and trimethoprim easily cross placenta. Premature infants and infants with hyperbilirubinemia.
    Glucose-phosphate dehydrogenase deficiency: Any patient with G-6-PD (glucose-6- phosphate dehydrogenase) deficiency is at increased risk for adverse effects.

    Side effects:
    Photosensitivity (wear sunscreen!)
    GI upset including Nausea, Vomiting, Diarrhea
    Crystaluria— encourage patient to drink plenty of fluids.

    Drug Interactions: (Sulfa drugs)
    Warfarin: may prolong prothrombin time---significant drug interaction (increasing warfarin effect)
    Diuretics: in elderly can cause thrombocytopenia
    Potassium: may cause elevated potassium (hyperkalemia):
    Trimethoprim is structurally like the potassium-sparing diuretic amiloride. It competitively inhibits the sodium channels of the epithelium in the distal nephron, thereby impairing renal potassium excretion.

    Drug Monitoring:
    Watch for blood dyscrasias.
    Don’t give to patients with G-6-PD deficiency
    Watch for hypersensitivity reactions
    Adjust dose for a creatinine clearance of less than 30 mL/min
    Patient Education:
    Take full course of therapy. Drink large glass of water with each dose.

    Most Common Drugs & Dosage of This Class:
    Septra SS®, Septra DS®, Bactrim SS®, Bactrim DS® are most commonly used.
    5:1 ratio SMX to TMP
    • Double strength: 800mg sulfamethoxazole +160mg trimethoprim
    • Single strength: 400mg sulfamethoxazole + 80mg trimethoprim
    • Suspension: 200mg sulfamethoxazole + 40mg trimethoprim per teaspoonful

    The sulfonamides have a most interesting history. In the 1930’s sulfonamides became popular as one of the first true antibacterial agents, an outcropping from the dye industry. Demand for this product in a liquid form was met by the Massengil company by dissolving the powdered antibiotic in diethylene glycol—anti-freeze. Lethal kidney failure ensued.

    In just two months during September and October 1937, this drug was responsible for the deaths of more than 100 people in 15 states, from Virginia to California. The drug and the deaths led to the passage of the 1938 Food, Drug, and Cosmetic Act, which increased FDA’s authority to regulate drugs. Up until that point, drugs did not need to be proven safe, just labeled correctly.

    It was not until the Kefauver Harris Amendment in 1962 that assured efficacy. It took until I was 4 years old until the government made the drug companies show that their drugs worked! The Kefauver-Harris amendments were necessary due to the thalidomide tragedy that devastated Great Britain but was never approved in the United States.

    We seasoned pharmacists remember Gantrisin® (sulfasoxazole), Gantanol® (Sulfamethoxazole) and AZO-Gantanol®(phenazopyridine/Sulfamethoxazole). Today, most of us see only Trimeth/Sulfa, which early on in my career was co-marketed by Burrough Wellcome (Septra®) and Roche (Bactrim®).

    Have a great day on the bench!!

    September 2020

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    Overview of Macrolide Antibiotics

    Erythromycin was first isolated in 1952 from the bacteria Saccharopolyspora erythraea
    Mechanism: may be bactericidal OR bacteriostatic. It binds to the 50S ribosomal subunit of the 70S ribosomal unit, thus inhibiting protein synthesis

    Indications for use: effective against many gram-positive bacteria, including strep (Streptococcus pneumonea) Corynebacterium, Neisseria & some strains of Mycoplasma, Legionella, Treponema & Bordetella. Some penicillin-G resistant S. aureus are susceptible to erythromycins. Are preferred drugs for Mycoplasma pneumoniae, Campylobacter, Legionnaires, Chlamydia, diphtheria & pertussis.

    Most common uses: Upper Respiratory Infection, Community Acquired Pneumonia, Chlamydia, atypicals.

    Gastrointestinal distress (nausea, vomiting & diarrhea) occurs with all Erythromycins
    Allergies are rare, may see skin eruptions, fever, and eosinophilia
    Cholestatic hepatitis can occur (rare)
    Hepatotoxicity can develop with estolate salts of Erythromycin
    P450 blockers (except Azithromycin). Therefore, they may increase the effects of warfarin, digoxin & theophylline, some cholesterol drugs (simvastatin, atorvastatin).

    Side effects:
    Pseudomembranous colitis
    GI upset because it stimulates GI motility & increase pain and cramping

    Drug Interactions: Erythromycin and clarithromycin are CYP-P450 inhibitors. Both are 14 membered macrolides. Azithromycin is a 15 membered ring NOT metabolized by P-450 system, but excreted in the bile and then the feces, with very little unchanged drug appearing in the urine

    Patient Education:
    Take with food
    Take course until completed
    Watch for signs of liver dysfunction (pale stools, muscle cramps, yellowing of skin etc.)

    Most common Drugs & dosage of this class:

    Erythromycin base (Erytab®) (Erythrocin®) (old drug—extremely expensive $10-$17/tablet)

    Azithromycin (Zithromax®)
    Azithromycin was discovered by Pliva a Yugoslavian drug company. Pliva cross licensed azithromycin to Pfizer who launched it under the brand name Zithromax® in 1991
    Available as tablets: 250mg & 500mg. Suspension 100mg/5ml & 200mg/5ml
    Zithromax TriPack: 500mg tablets – one daily for 3 days
    Zithromax Zpack 250mg: Take 2 tablets first day. Then 1 tablet daily days 2—5.
    Child: 10mg/kg on day 1 then 5mg/kg on days 2-5.
    Otitis media can be given as 30mg/kg as a single dose.
    Pregnancy Category B

    Azithromycin has a half-life of 63 hours so coverage occurs for 5 days after the last dose.
    Once day doses (1gm) are also indicated for : Chlamydia, Chancroid, Non-gonococcal urethritis. Gonococcal is a 2gm dose.
    • NOT metabolized by cytochrome-p450 enzyme system
    • No dosage adjustment needed if renally impaired
    • Caution: may prolong QT interval—caution with heart patients especially if bradycardia, or other QT-prolonging drugs.
    • RESISTANCE: is a major problem with azithromycin. The current resistance rate for Strep pneumo (respiratory infections) for azithromycin (Z-pak) is around 47% in Altoona, PA.
    Clarithromycin (Biaxin®)
    Clarithromycin was developed by scientists at the Japanese drug company Taisho Pharmaceutical in the 1970s. Clarithromycin was developed to overcome the acid instability of erythromycin.
    Available as tablets: 250mg, 500mg and XL-500mg. Suspension 125 & 250/5cc
    Adults: 500mg twice daily with food or Biaxin XL 500mg: 2 tablets once daily.
    Child: 15mg/kg/day divided twice daily, every 12 hours for 10 days. Nasty bitter taste.

    Pregnancy Category: C
    ** more effective than Erythromycins against staph & strep. Also effective against Toxoplasmosis & Cryptosporidium species.
    Given with lansoprazole & omeprazole to eradicate Helicobacter pylori.
    • Cut dose in half if creatinine clearance is less than 30ml/min
    • Causes metallic taste in mouth
    • Caution: may prolong QT interval—caution with heart patients especially if bradycardia, or other QT-prolonging drugs.
    POTENT blocker of CYP450-3A4, and P-glycoprotein
    Increases warfarin (Coumadin®) levels—may cause increased bleeding risk.

    I remember in pharmacy school (now 40 years ago) one of my professors saying that the safest group of drugs were the erythromycins. They were reportedly “easy to dose, did not have drug interactions and didn’t cause resistance!” One out of three is correct.

    Macrolide resistance is a real problem. I spend a fair amount of time discussing macrolide resistance with my students, because azithromycin is “designed” to cause resistance.

    The package insert states that it is 5 days’ worth of meds that fights infections for 10 days. Using our simple pharmacokinetics, we see that after 10 days, the azithromycin levels would fall below the minimum inhibitory concentration (MIC), which is where resistance occurs.

    Since azithromycin has a half-life of 63 hours, and it takes 5 half-lives to get to a negligible amount, it would take 13 days after the last dose (day-5) to have a negligible amount (day-18). At a minimum, the levels of azithromycin fall under the MIC for at least 8 days! Simple pharmacokinetics show us why it is a flip of the coin whether an azithromycin pack will benefit our patients.

    Have a great day on the bench!!

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    Tetracycline Overview


    Mechanism: Tetracyclines are bacteriostatic. They inhibit bacterial protein synthesis, working on ribosomal RNA.

    Indications for use:
    Covers most staph & strep strains, enterics, mycoplasma, spirochetes, rickettsiae, Chlamydia

    Drug of choice: acne & chlamydia, Rocky Mountain Spotted Fever, and Borrelia burgdorferi (Lymes)
    Doxycyline is approved for malaria prophylaxis.
    Doxycyline is less nephrotoxic and may be preferred in patients with renal disorders, as the drug is almost entirely excreted through the feces.
    Both Minocycline and Doxycycline are long acting with a half-life of 16 hours.

    • do not give with antacids, calcium, iron. (drug will not get absorbed)
    • photosensitivity
    • dental staining (not to be used in prepubertal children) ***
    • do not use in pregnant women or if breast feeding
    • May cause pseudotumor cerebri, a condition in which intracranial pressures increase
    Drug Interactions: any divalent or trivalent cations (magnesium, calcium, iron etc)
    • Decreases effectiveness of bactericidal antibiotics
    • May decrease effectiveness of oral contraceptives
    • Warfarin: increases effect. Increased bleeding risk.
    Class Side effect of tetracyclines: hepatotoxicity, nephrotoxicity, photosensitivity, dental staining, Pseudomembranous colitis is rare for this class of drugs

    Patient Education:
    • Avoid dairy products if using tetracycline. Does not seem to affect doxycycline.
    • May take with food to decrease GI upset
    • Wear sunscreen
    Most common Drugs & dosage of this class
    Available as capsules 250mg & 500mg
    Dosage 250-500mg four times daily

    Doxycycline hyclate (Vibramycin®) Doxycycline monohydrate (Monodox®):
    Available as capsule=50mg & 100mg & 100mg tablets
    Dosage: 200mg first day, then 100mg daily for 10days. May use 100mg BID for 10 days.
    Minimal food drug interaction with doxycycline. Absorption is delayed.
    Common uses: Acne, Lyme disease, Upper Respiratory Infection, Community Acquired Pneumonia, Chlamydia, Community Acquired Methicillin Resistant Staph Aureus (CA-MRSA) Rocky Mountain Spotted Fever (RMSF)
    Not so common uses: bioterrorism: plague, anthrax, tularemia.

    ***Doxycycline is the most effective antibiotic for the treatment of suspected rickettsial infections, including Rocky Mountain spotted fever (RMSF). Delay in treatment of rickettsial diseases may lead to severe illness or death. Children are five times more likely than adults to die from RMSF.
    Misperceptions about the use of doxycycline for children prevent kids from getting lifesaving treatment. The old tetracyclines indeed cause dental staining and that warning in 1970 was given to the tetracycline family, even though it is NOT appropriate for doxycycline.
    Smile and take your DOXYCYCLINE: Doctors often avoid prescribing doxycycline to young children because of a warning that tooth staining may occur when used in children less than 8 years old. In a recent study, experts at the CDC and Indian Health Service (IHS) found that short courses of the antibiotic doxycycline can be used in children without causing tooth staining or weakening of tooth enamel.

    Doxycycline capsules: I always recommend and dispense doxycycline hyclate tablets. The doxycycline 100 mg capsules are huge and a potential choking hazard. I have had a couple of students who shared with me that had esophageal varices from doxycycline capsules getting stuck in their throat. My wife had a GI doctor share with her that he has seen this happen all to frequently and can be greatly reduced by exclusively dispensing the tablets.

    Doxycycline monohydrate (Monodox®):
    Available as tablets and capsules. Were believed to cause less GI upset. Not really proven.

    Minocycline (Minocin®):
    Available as capsules 50mg, 75mg & 100mg
    Dosage: 200mg stat; then 100mg BID q12h
    Minocycline may cause vestibular disorders, resulting in dizziness.
    Minocycline may cause pigmentation of skin & mucus membranes.

    How well I remember Achromycin-V® being dispensed for $4.00 for 100 capsules when I first started my career. Today the wholesale acquisition cost is almost $4.00 PER CAPSULE, and that price has dropped in half since last year! Remember 6 years ago when doxycycline was $4 per tablet cost, and now it is inexpensive again?

    Here’s an unusual use for tetracycline: It can be used as a biomarker in animals (and humans too!) The bait can be fed to the animal and then an allotted portion of time is allowed to pass. The critter (bear, raccoon etc) is given a second dose of tetracycline containing bait.

    A tooth is then extracted, sectioned in half and the “rings” of tetracycline can be measured and the animal’s growth can be measured. Tetracycline can also be used to measure vaccine distribution in wildlife, using tetracycline as a biomarker.
    Chlortetracycline was the first member of the tetracycline family, discovered in 1948. Aureomycin ophthalmic ointment was FDA approved in 1950. Tetracycline was first approved by the FDA in 1953, the patent given to Lederle Labs for the brand name of Achromycin-V®. Doxycycline was approved by the FDA in 1967 with the brand name of Vibramycin®. Minocycline (Minocin®) was approved by the FDA in 1971, the last tetracycline to be approved.

    Have a great day on the bench!!

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    Penicillin Allergy? Let’s Make Sure!

    Table 1. Classifications of β-lactam Reactions
    Levine ClassificationGell & Coombs ClassificationTime to Onset, hMediator(s)MechanismClinical Signs
    ImmediateType I≤1PCN-specific IgE antibodiesHistamine and vasoactive stormAnaphylaxis; angioedema; bronchospasm; urticaria (hives)
    Non-immediateType II≥72IgG, complementAntigen bound to hapten and fixed in tissue; increased clearance of RBCs, PltsGoodpasture's syndrome; PCN-related hemolytic anemia
    Type IIIIgG, IgM immune complexesTissue deposition of immune complexesSystemic Lupus; Penicillin-induced serum sickness
    Type IVT-cellsActivated T-cellsMorbilliform eruptions, contact dermatitis; Rarely more serious: e.g., Stevens-Johnson Syndrome
    So, penicillin allergies come in variations, with the Immediate Type-1 being the most serious. Those are the ones that physicians and pharmacists need to be most concerned about.

    So what’s the Big Deal… we have clindamycin and fluoroquinolones. From head to heart to skin infections (notably methicillin-susceptible Staphylococcus aureus or MSSA), beta-lactams like cephalosporins and penicillins are the drugs of choice. If they are “taken off the table,” we are forced to use broad-spectrum antibiotics like clindamycin and fluoroquinolones. Fluoroquinolones and clindamycin may not only be less effective for eradicating the bacteria (leading to antibiotic resistance), but also are a major cause of Clostridium difficile diarrheal infections!
    First-generation cephalosporins are commonly prescribed for surgical site infection (SSI) prophylaxis for almost all surgeries, either as monotherapy or as combination therapy. Preserving first-generation cephalosporins through antibiotic stewardship is critical to future patient care.

    Beta-lactam Cross-Reactivity: An OChem Rerun
    Cephalosporins are related to the structure and antimicrobial activity of penicillins. Both groups of antibiotics possess the core four-membered β-lactam ring. Cephalosporin cross-reactivity potential is related to the structural R1 side chain.
    For example, amoxicillin shares the same R1 side chain as ampicillin, cephalexin (Keflex®), cefadroxil (Duricef®), and cefaclor (Ceclor®). Patients allergic to penicillins should avoid cephalosporins with identical R1-group side chains. The third-generation cephalosporins, such as cefdinir (Omnicef®), cefpodoxime (Vantin®) and ceftriaxone (Rocephin IM/IV®), do not have R1 side chains that match the penicillins, so there is minimal chance of cross-reactivity.

    You Can Help to Set the [Allergy] Record Straight! Almost 80% of patients with IgE-mediated reactions lose their hypersensitivity after 10 years! Asking questions about their reaction symptoms, time since the initial reaction and whether they have taken other beta-lactam antibiotics since can be useful to “de-label” and remove allergies from the patients’ records. As pharmacists, we have a unique opportunity to ensure accurate documentation! We must make sure that when we document a patient-reported “allergy,” we delineate between allergies and side effects:
    • Allergy is an adverse drug reaction mediated by an immune response (e.g., rash, hives).
    • A side effect is an expected and known effect of a drug that is not the intended therapeutic outcome (GI upset, diarrhea).
    I've precepted 65 students now and am amazed with their success. Last week Ukwen Akpoji reached out to me and offered a guiding hand through the challenges of antibiotic stewardship, as well as navigating through patient reported allergies.

    With his experiences in that field, I am able to provide you some very useful information with regards to antibiotic use.

    “I’m allergic to penicillins. The last time I took Augmentin, I got horrible upset stomach and diarrhea. I can’t take penicillins.”

    How many times does that happen in our primary care and community pharmacy settings? Fortunately for me, I’ve precepted 65 students now, and some have become experts in their respective fields. Student #34 Ukwen Akpoji is such a superstar in the field of antibiotic stewardship. He shared the following with me for this session:

    Over 30 million people in the United States report a penicillin drug allergy. Less than 5% of these patients mount a type I hypersensitivity reaction mediated by IgE antibodies (i.e. anaphylaxis, angioedema, bronchospasm, etc.). These are histamine-related mechanisms, which is why diphenhydramine (Benadryl) usually helps relieve symptoms.

    Have a great day on the bench!!

    Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of Penicillin Allergy: A Review. JAMA. 2019;321(2):188-99. https://pubmed.ncbi.nlm.nih.gov/30644987/
    Chaudhry SB, Veve MP, Wagner JL. Cephalosporins: A Focus on Side Chains and β-Lactam Cross-Reactivity. Pharmacy (Basel). 2019;7(3):103. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789778/

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    Cephalosporins Overview

    Mechanism: like their closest cousins the penicillins, cephalosporins bind to proteins in the cell wall, enabling it to inhibit cell wall synthesis of the bacteria, causing cell wall lysis and cell death (bactericidal).

    Indications for use:
    Differs between 1st, 2nd, and 3rd generation cephalosporins.

    Gram positive activity, staph aureus, S.epidermidis, Strep pyogenes, Strep pneumoniae.
    Not active against MRSA/ MRSE.
    Some strains of Klebsiella, P.mirabilis, E.coli, Shigella (Gram Negatives)
    Primarily cover gram positive organisms: methicillin-sensitive S. aureus, group A strep
    Some gram-negative coverage: E. coli, Klebsiella species, P. mirabilis
    Poor anaerobic coverage

    Most Common 1st Generation Cephalosporins
    Cephalexin (Keflex®)
    • Available as: capsules 250mg & 500mg. Suspension: 125mg/5ml & 250mg/5ml
    • Adult dosage: 250- 500mg every six hours
    Cefadroxil (Duricef®)
    • Available as 500mg capsules & 1GM tablets. Suspension: 125/5ml; 250/5; 500mg/5ml
    • Adult dose: 1 to 2 gm per day in single or divided doses
    Most Common use: Methicillin Sensitive Staph Aureus (MSSA) skin/soft tissue. Urinary Tract Infection. Surgical prophylaxis

    2nd Generation
    Gram positive: same as above
    Gram negative: more extensive including: Acinetobacter, Citrobacter, Enterobacter, Neisseria, Proteus, E.coli & Klebsiella, Haemophilus influenza,

    Cefuroxime and cefprozil cover S. pneumoniae.
    Enhanced coverage of gram negative organisms: H. influenza, M. catarrhalis, Neisseria species
    Some anaerobic coverage. Cefoxitin and cefotetan cover B. fragilis.

    2nd Generation Cephalosporins
    Cefaclor (Ceclor®)

    Cefuroxime (Ceftin®) is a second-generation cephalosporin that maintains gram-positive activity of first-generation cephalosporins and adds activity against Proteus mirabilis, Hemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, and Moraxella catarrhalis
    Available tablets 125mg, 250mg, 500mg. Suspension: 125mg & 250mg/5cc
    Dosage: Adults 250mg-500mg every 12 hours, with meals
    Common use: Cefuroxime: Upper Respiratory Infection (URI), UTI, Lyme early stage, Otitis media, sinusitis.

    FIRST AND SECOND GENERATION cephalosporins have no activity against Listeria, Atypicals, MRSA, and Enterococci!

    3rd Generation: broad spectrum, most resistant to cephalosporinases.
    Some penetrate the CSF
    Gram positive: decreased compared to first & second generation
    Gram Negative: extensive coverage for Citrobacter, Enterobacter, Neisseria, Hemophilus, Serratia, with some Pseudomonas activity.
    Third-generation agents have enhanced activity against both gram-positive and gram-negative bacteria compared to 1st and 2nd generation.

    3rd Generation Cephalosporins
    Cefdinir (Omnicef®)
    Available as 300mg capsules susp:125mg/5cc & 250mg/5cc
    Dosage: Adults 300mg q12
    Child: 14mg/kg/day divided BID Suspension good for 10 days after reconstitution.
    Major Counseling point: Will turn stools red! occurs when cefdinir
    combines with iron to form a precipitate that gives stool a characteristic discoloration

    Cefpodoxime (Vantin®)
    Available as tablets: 100mg & 200mg. Suspension: 50mg/5cc & 100mg/5cc
    Dosage: Adults: 200-400mg/day divided BID. For skin may increase to 800mg/day

    Ceftriaxone (Rocephin®)
    Available only as injection: 500mg and 1gm injection GIVE IM or IV
    Adults: 1-2 gm daily. Pediatrics 50-75mg/kg. Max=2gm/day
    Dosed once a day. Avoid injection with calcium salts, precipitates in lungs and kidneys.

    COMMON USES: Third Generation Cephalosporins
    • Cefdinir: otitis media; upper respiratory infection.
    • Ceftriaxone: Lyme’s, otitis media, gonorrhea, upper and lower respiratory infections. skin infections
    • Some anaerobic coverage. No agents cover B. fragilis
    Warnings/Precaution: Crossover Allergy
    Cross-reactivity between penicillins and cephalosporins is less than 1%, (instead of 10% as previously thought) which is less likely with second- and third generation cephalosporins than first-generation cephalosporins.
    • Cefdinir (Omnicef®), cefuroxime (Ceftin®), cefpodoxime (Vantin®) or ceftriaxone (Rocephin®), are a safe choice because they do not have the “penicillin-like” side chains.
    Side effects: Cephalosporins
    Hematologic abnormalities: Some cephalosporins contain a methlythiotetrazole (MTT) side chain that increase risk of bleeding (hypoprothrombinemia)
    Rare: nephrotoxicity & hepatic enzyme abnormalities

    Drug Interactions
    Possible disulfiram reaction
    Probenecid inhibits tubular secretion

    Patient Education:
    Watch for severe penicillin allergy patients
    Take with food or milk
    Complete course of therapy

    As we previously discussed with the onset of penicillin therapy, bacterial resistance rapidly became problematic. Penicillinase producing staphylococci were wreaking havoc in the hospitals.

    Fortunately, in 1945 an Italian pharmacologist named Giuseppe Brotzu discovered an antibiotic-producing species of Cephalosporium (now Acremonium), isolated from a sewage outfall in Sardinia! Dr. Brotzu’s visit to a sewer pipe led to the discovery of one of the most used antibiotic classes today.

    As far as my historical experiences go, I remember when Eli Lilly’s brand of cephalosporin (Keflex®) was the first $1.00 per capsule back in 1979. As an intern, I remember Louie Rinovato, my preceptor, saying he doubts that the prices can go much higher! We were just at the beginning. Thanks to generics today, you can buy 100 capsules for what ten capsules of Keflex cost back in 1979!

    Have a great day on the bench!!

    August 2020

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    Penicillin: Still in Use 75 Years Later!

    Mechanism: penicillin binds to proteins in the cell wall, enabling it to inhibit cell wall synthesis of the bacteria, causing cell wall lysis and cell death. Beta-lactam antibiotics (penicillins and cephalosporins) inhibit the growth of sensitive bacteria by inactivating penicillin binding proteins, which are involved in cell wall synthesis. Penicillins are bactericidal.
    Resistance: has been a problem since the introduction of penicillin in the 1940’s.
    • The binding sites can adapt and alter the permeability of the outer membrane
    • Decreasing affinity of the target site can be altered.
    • Resistance to the beta-lactam antibiotics is also due to production of enzymes that cleave penicillins (penicillinases), cephalosporins (cephalosporinases), or both (beta-lactamases)
    Indications for use
    Are highly effective against gram positive cocci and some gram-negative cocci. Little effect on GM- rods.
    • Penicillin-G is 5 to 10 times more active than Penicillin-V against gram negatives & some anaerobes.
    • Are ineffective against Staph aureus, due to beta-lactamase produced by staph.
    • Penicillinase resistant penicillins are not hydrolyzed by beta-lactamase.
    • Are drugs of choice for non-resistant Staph & strep. N. meningitidis, B. Anthracis.
    • Most common use: syphilis, susceptible pharyngitis and endocarditis and dental infections.
    • C. tetani, C. Perfringens, Listeria, Syphilis.
    * Hypersensitivity reactions in 3 to 10 % (rash 4-8%) ; Anaphylaxis in 0.01% to 0.05% Rarely N/V with oral use

    Side effects: very rare- neurotoxicity at high doses. Neutropenia & nephrotoxicity. Broader spectrum penicillins: Amoxicillin can cause diarrhea due to disruption of normal GI flora.

    Drug Interactions: Probenecid increases blood levels.

    Patient Education: Finish entire prescribed dose. Report any rash to practitioner

    Most common Drugs & dosage of this class:

    Penicillin VK (PenVeeK® & V-Cillin-K®)
    Available as tablets: 250mg & 500mg. Liquid= 125mg/5ml & 250mg/5ml
    Liquid is reconstituted by pharmacist. Good for 14 days after mixing. Does have a bitter taste after reconstitution.

    Dose: 250mg-500mg two to four times daily.
    Pediatric:25-50mg/kg/day divided in 4 doses, every 6 hours.

    Penicillin parenteral is still measured in units.
    One unit of penicillin represents the specific activity in 0.6 mcg of sodium penicillin.
    1 mg of penicillin sodium represents approximately 1667 units of penicillin.
    Therefore, 250mg of Penicillin- 400,000iu

    Penicillin G (Pen G & Bicillin L-A)
    Penicillin G is a natural penicillin that is most commonly given intramuscularly (IM)
    • Penicillin G comes in two unique IM formulations: Benzathine Pen G and Procaine Pen G
    • These IM Repository formulations allow for steady release of medications at therapeutic doses for extended intervals
    • Great option for kids that a practitioner is worried that a caregiver may forget doses or non-compliant patients
    • Most common formulation/use: Benzathine Pen G 2.4 million units IM as a single dose for syphilis
    Penicillinase resistant Penicillins (“anti-staph penicillins”):
    Examples: methicillin, oxacillin (1971), cloxacillin (1971) & dicloxacillin (1968).
    Good for methicillin sensitive strep and staph. (not good for enterococci)
    Are not affected by beta-lactamase.
    Generally used for skin and soft tissue infection

    Extended Spectrum Penicillins
    Have a broad spectrum of coverage, but most importantly … Pseudomonas aeruginosa
    Because extended spectrum penicillins are sensitive to Beta-lactamase, they are coupled with Beta-lactamase inhibitors
    Examples: Piperacillin/tazobactam (Zosyn®) and Ticarcillin/clavulanate (Timentin®)
    Piperacillin/tazobactam (Zosyn®) is the safer option that is most commonly used
    Ticarcillin has been associated with electrolyte abnormalities and platelet inhibition Dosing and dosing intervals vary based organism/location of infection.

    I am amazed to read the stories of how the United States “ramped up” the manufacturing of penicillin to meet the demands of World War Two.

    It was indeed an international effort between the United States and Great Britain. Great Britain had the scientists and the technology, but their industrial complex was leveled due to the bombings.

    The US had the land and the fermentation tanks and equipment; with the help of British scientists, penicillin was rapidly produced. The most interesting part of the account I read, was in their search for a penicillin strain they spent most of their efforts with soil screenings.

    The big breakthrough came when the most productive strain was isolated on a rotten cantaloupe in the Peoria fruit market! My wife who describes cantaloupe as smelling like “dirty gym socks” was pleased to learn that her least favorite fruit has an extremely useful purpose!

    Have a great day on the bench!!

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    Anti-Infective Prescribing: The Ground Rules

    • Antibiotics are the only drug where use in one patient can impact the effectiveness in another.
    • If everyone does not use antibiotics well, we will all suffer the consequences.
    • Antibiotics are a shared resource, (and becoming a scarce resource).
    • Using antibiotics properly is analogous to developing and maintaining good roads.
    • Available data demonstrates that we are not doing a good job of using antibiotics in in-patient settings.
    • Several studies show that a substantial percentage (up to 50%) of in-patient antibiotic use is either unnecessary or inappropriate.
    • anti-infective: applies to any drug that is effective against pathogens.
    • antibiotic: technically refers to natural substances produced by a micro-organism that can kill other micro-organisms. However, most of us use antibiotic, anti-infective and antimicrobial interchangeably.
    • bacteriostatic: do not actually kill the bacteria but slow the growth of the organism. The body’s immune system can then dispose of the bacteria. Most bacteriostatic antibiotics disrupt protein synthesis.
    • bactericidal: kill the bacteria outright, usually by interruption of cell wall synthesis
    • minimum inhibitory concentration (MIC): concentration of an antibiotic which prevents growth of the culture.
    • minimum bactericidal concentration (MBC): the concentration that kills 99.9% of the inoculum. Often the MBC is 2 to 8 times that of the MIC
      • Antibiotics for which achievable blood concentrations regularly exceed the MBC of common pathogens are classified as BACTERICIDAL.
      • Antibiotics whose blood concentrations readily exceed MIC but usually do not exceed the MBC are classified as BACTERIOSTATIC.
      • Antibiotics whose blood concentrations do not reach MIC are RESISTANT.
    • time/kill curve: time dependent killing: little or no enhancement of bactericidal activity with drug concentrations above the MBC. Killing depends on maintaining the concentrations above the MBC for as much of the dosing interval as possible. Time kill curves are used to determine whether an antimicrobial is bactericidal or bacteriostatic.
    • post-antibiotic effect: when bacteria are exposed to an antibiotic at concentrations above MIC, the antibiotic is then removed.Bacterial replication does not resume as normal, for a variable period of time (usually hours) after removal of the antibiotic. The post antibiotic effect provides a rationale for pulse dosing of antibiotics. Serum antibiotic concentration falls below the MIC, for part of the dosing interval, the PAE may prevent bacterial multiplication during the brief time when the serum antibiotic concentration falls below the MIC before the next antibiotic dose.
    • superinfection: secondary infections caused when microorganisms normally present in the body are killed by the antibiotic. These normal organisms called host flora (or normal flora) inhabit the skin, upper respiratory, GU, and GI tract.
      • Examples: candida vulvovaginitis after amoxicillin therapy
      • C. difficile: after clindamycin therapy (or any broad-spectrum antibiotic)
    DNA synthesis inhibitor:
    RNA Synthesis inhibitor:

    Protein synthesis inhibitors:


    Cell wall synthesis inhibitors:

    Cell membrane inhibitors:
    Isoniazid (bacteriostatic if stationary phase; bactericidal if growing) Amphotericin-B (fungicidal or fungistatic depending on concentration & organism)

    Protein synthesis inhibitors:

    I teach anti-infective therapy in the Summer semester at St. Francis in the Physician Assistant program. Knowing how much information is crammed in the Physician Assistant’s heads that year, I thought it would be prudent to cover antibiotic therapy.

    What do oxycodone, diazepam, penicillin, and ciprofloxacin have in common? I tell my students that antibiotics, benzodiazepines and opioids are drugs that we not only prescribe for the individual patient, but for society as well.

    Because benzos and opioids are considered as drugs with potential abuse, we must take precautions to minimize dependence and addiction and make certain that these drugs are not diverted. Diversion of opioids and benzos can become a societal problem.

    We must also be prudent in prescribing antibiotic therapy for our patients because they can create resistance to bacteria. Increasing bacterial resistance through reckless prescribing can cause an increase in resistant organisms in which current antibiotics can be futile.

    We have to look no further than the infamous “Z-pak” (Azithromycin) which, in our area, has a 48% resistance rate for Strep pneumo, a very common respiratory pathogen. It is a “flip of the coin” as to whether the “Z-pak” will cure your next community acquired pneumonia. Not being able to cure pneumonias in our patients is a societal problem as well.

    Have a great day on the bench!!

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    Migraine Headache Prevention is Easy…Unless We Are Looking at Real Patients!


    DepressionTCA, SSRI, SNRIBeta-blockers
    Bi-Polar disorderValproate, TopiramateTCA, SSRI, SNRI
    AnxietyTCA, SNRI, BB
    Sleep disturbancesTCABB
    FibromyalgiaTCA, SSRI, SNRIBB
    ObesityTopiramate, SNRITCA, Valproate, SSRI
    EpilepsyTopiramate, ValproateTCA, SSRI, SNRI
    RaynaudsCCBBB, Ergots
    Over Age 60BB (due to stroke risk)
    SmokersBB (due to stroke risk)
    Uninsured patientsCGRP blockers $$$
    PregnancyCaution with all therapies. CCB seem to be safestTopiramate, Valproate

    TCA= Tricyclic Antidepressants such as Amitriptyline (Elavil) and Nortriptyline (Pamelor)
    SSRI= Selective Serotonin Reuptake Inhibitors such as fluoxetine (Prozac®), sertraline (Zoloft®)
    SNRI= Serotonin-norepinephrine reuptake Inhibitor such as venlafaxine (Effexor®), duloxetine (Cymbalta®)
    BB= Beta blockers such as metoprolol (Toprol-XL®, Lopressor®) and propranolol (Inderal®)
    CCB= Calcium Channel Blockers such as verapamil (Isoptin®)
    CGRP= Calcitonin gene-related peptide blockers such as Ajovy®, Aimovig®, Emgality®

    Evidence based guidelines adopted by the AAFP, AAN
    • NSAIDS as FIRST LINE Therapy
    • Triptans (or Dihydroergotamine???) indicated for those who fail to tolerate or respond to NSAIDS
    • NO evidence to support the use of butalbital compounds (Fioricet®)
    • Little evidence to support use of isometheptene compounds (Midrin®)
    • Opioids reserved for use when other medications cannot be used. (Cardio patients)
    Remember when prescribing:
    • Drug overuse is a problem with sub-optimal therapy. Best to use the “one and done” approach. Think of using only Sumatriptan 100mg or Rizatriptan 10mg, rather than redosing with a lower strength.
    • Don’t take acute drugs more frequently than 5 half lives. Sumatriptan and Rizatriptan’s half-life is 2.5 hours.
    • How often do you experience a headache of any severity per month?
    • How often do you experience severe or disabling headaches per month?
    • Has there been any change in either of these headaches over the past six months?
    • How often do you take Rx or OTC meds per month?
    Questions that don't work:
    • How many migraines per month?
    • On a scale of 1-10 how severe?
    As we health care professionals can attest, very seldom does a patient come in with only one chief complaint with no comorbidities. If that were the case, patients could go to a vending machine hit the migraine prevention button and the pills would magically drop out!

    Because of these complex patients, providers such as PA’s and physicians as well as pharmacists must always look at the entire patient and their comorbidities before selecting any therapy.

    Beta blockers are first line therapy for migraine prevention, unless the patient has bradycardia, hypotension, erectile dysfunction, fibromyalgia, depression, a smoker, or over 60 years of age. Hardly qualifies as “first line therapy” in a significant portion of the population.

    As one of the professors at St. Francis says, “Patients don’t come into the clinic with A, B, C or D selections on their forehead!”

    Have a great day on the bench!!

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    Treatment of Cluster Headaches


    Cluster headache: a form of migraine often characterized by brief, but frequently recurrent bouts of severe headache. Frequently referred to as “suicide headaches”. Headaches may last from 45 minutes to 3 hours, maximum. May occur every other day or up to 8 times per day, even the same time each day known as circadian periodicity.
    • Patients will not lie down; they are extremely agitated and incapacitated. They walk and pace and have been known to bang their head off a wall to deflect the pain.
    • Clusters may occur in groups of up to 8 a day lasting for weeks or months.
    • Pain is intense, concentrate on 1 side of head, accompanied by “Cranial autonomic symptoms” such as tearing of the eye, runny nose, fullness of the ear and a droopy eye on the same side.
    Origin: hypothalamus, near where circadian rhythm is governed.
    Typical patient: is a middle-aged male who smokes.

    Oxygen: Flow rate is 12 liters per minute inhaled through a mask, sitting upright is safe and inexpensive, and works within 15 minutes. However, Medicare will NOT pay for oxygen for treatment of episodic cluster headache, even though it is the standard of care. (Fortunately for most, oxygen therapy is affordable.)

    Fast acting triptans: such as injectable sumatriptan (Imitrex®) 6mg subcutaneously, or sumatriptan 20mg nasal spray, or zolmitriptan (Zomig®) nasal spray 5mg. Sumatriptan injection and nasal spray are available as generics. Zomig® is brand only.

    Ergotamine preps: same as migraine dosage. Will help some patients. Save for patients who can’t use a triptan. Same dosage as migraines
    Migranal® nasal spray 4mg/ml. ($315.00/dose)
    • Dosage: 1 spray (0.5mg) each nostril every 15 minutes for a maximum of 4 sprays.
    • Don’t exceed 3mg/day (6 sprays)
    • Don’t exceed 4mg/week (8 sprays)
    D.H.E.® injection: ($250.00/dose) DHE is usually given as a 1 mg intravenous bolus and may be repeated at one hour, with a maximum dose of 3 mg in 24 hours. Maximum= 3ml per 24hr if SC or IM. 2ml max if IV =6ml per week.

    Octreotide (Sandostatin®): may be effective in the treatment of acute cluster headaches.
    Dose: single dose of subcutaneous octreotide (100 mcg)

    Butorphanol (Staldol®) nasal spray: C-IV
    • Narcotic administered as a nasal spray. May provide relief esp. if nausea.
    • One nasal spray; wait 90-120 minutes before deciding to administer another dose.
    • Side effects: watch for drowsiness, may be habit forming.
    Lidocaine: Some success with intranasal Lidocaine. Lidocaine is hard to administer, and mixed results (33% efficacy).


    Calcium channel blockers: Verapamil is the drug of choice. Use highest tolerable dose, (max=320mg/day). Watch for: incidence of electrocardiographic (ECG) abnormalities, including heart block and bradycardia. Best to do an ECG before starting therapy, and with dosage increases over 480mg.
    Watch for: edema, gastrointestinal discomfort, constipation, dull headache, and gingival hyperplasia

    Lithium: can be used but save for patients not responding to verapamil.
    Be sure to inform patient about side effects:
    • Drink 8 to 12 glasses of water a day. Watch for dehydration.
    • Take with food to minimize GI upset.
    • Therapeutic blood levels: maintenance 0.6 to 1.2 mEq/L
    Ergotamine preparations: are of limited value for prevention

    Corticosteroids- can be effective. Reserve for patients who don’t respond to verapamil. Usual dose: oral prednisone 60 to 100 mg once a day for at least five days, and then tapering by decreasing the dose 10 mg every day

    Melatonin: can help some patients. 10mg in the evening. This makes sense because melatonin levels are decreased in some patients with cluster headache.

    Anticonvulsants: Gabapentin (Neurontin®), Topiramate (Topamax®), and Divalproex (Depakote ER®) have all shown promise. Use doses as for migraine prophylaxis.

    Galcanezumab (Emgality®) Galcanezumab is a calcitonin gene-related peptide (CGRP) antagonist indicated in adults for
    • Preventive treatment of migraine AND
    • Treatment of episodic cluster headache (approved June 2019)
    • ligand antagonist a with a 25- to 30-day half-life
    NOTE: inform patients continue preventative treatment for 4 to 6 weeks after remission, to make sure cycle has ended
    Good resource: American Migraine Foundation

    I asked my neighbor at the pharmacy, Curt, who owns Penn-Med, what a non-rebreathing mask was, and he told me it was a typical oxygen mask. A rebreathing mask has the bag attached to the mask. When I asked him about providing oxygen to patients who suffered from cluster headaches, he told me of the reimbursement challenges of providing this service to patients who had normal pulse-ox readings. Yet another time when bureaucracy gets in the way of providing optimal care.

    Curt has a son who is a physical therapist, who specializes in treating migraine headaches by using physical therapy. His son can tell within three visits whether PT is going to be of any help or not. A lot of women are getting much needed relief with this specialized form of physical therapy.

    Have a great day on the bench!!

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    Herbal and Complementary Therapy for Migraine Prevention


    Butterbur: well-studied natural medicine. Treatment of both allergic rhinitis and for preventing migraine headache.
    Postulated mechanism: antispasmodic effects on smooth muscle and vascular walls. Possible anti-inflammatory effects by inhibiting leukotriene synthesis. The American Academy of Neurology (AAN) and American Headache Society (AHS) recommends petasites butterbur (50-75 mg bid), with a Level-A recommendation.
    Side effects: May cause GI upset, primarily burping as well as headache, itchy eyes, diarrhea, breathing difficulties, fatigue, and drowsiness.
    Caution: The raw, unprocessed butterbur plant contains chemicals called pyrrolizidine alkaloids (PAs). PAs can cause liver damage and possibly cancer. Only butterbur products that have been processed to remove PAs and are labeled or certified as PA-free should be used, for up to 16 weeks.

    Feverfew: reduces the frequency of migraines, and when migraines do occur, they tend to have less severe symptoms of pain, nausea, vomiting, and sensitivity to light and noise. AVOID if allergic to ragweed. AAN recommends feverfew (50-300 mg bid) with a Level-B recommendation. There is conflicting evidence about the efficacy of feverfew for migraine prevention.
    Side effects: nausea, digestive problems, and bloating; if the fresh leaves are chewed, sores and irritation of the mouth may occur. Avoid if pregnant. May interact with anticoagulants.

    Riboflavin: migraine prevention is its role in mitochondrial function because migraines could be partly due to mitochondrial dysfunction. Riboflavin is required as a precursor for factors needed for electron transport in mitochondria. Needs to be dosed at 400mg per day and takes at least 3 months to show efficacy. Vitamin B-2 is available in 100mg tablets, over the counter. In one study, the number needed to treat (NNT) for efficacy was 2.3 University of Pittsburgh. Well tolerated, discolors urine bright yellow.

    Magnesium: has been used for treatment and prevention of migraine headache. Some research shows that taking high-dose oral magnesium reduces the frequency and severity of migraine. Magnesium deficiency is related to factors that promote headaches, and people who get migraines seem to have lower levels of magnesium. The strongest evidence for magnesium’s effectiveness is in patients who have migraines with aura. It is believed magnesium may prevent the wave of brain signaling, which produces visual and sensory changes seen with aura. The guidelines from the AAN and the AHS say that magnesium is probably effective and should be considered for migraine prevention. Good choice for menstrual migraine.

    Dose is 400mg by mouth of Magnesium Oxide per day. IV magnesium can be used to abort an irretractable headache. Is in Pregnancy Category-A.
    Side effect: No surprise that diarrhea was the most common side effect.

    Coenzyme Q10 also affects mitochondrial function. Impaired oxygen metabolism and low cellular energy levels caused by faulty mitochondrial function might play a role in migraine headache pathogenesis. Coenzyme Q10 taken in a dose of 100 mg of three times daily appears to reduce migraine attack frequency, headache-days, and days-with-nausea. According to recent clinical research, the number needed to treat for one person to experience a 50% reduction in migraine attack frequency is three. Depending on the brand, it may cost up to $30 per month.

    Just because I know one of my most attentive readers wants to know...

    What About Medical Marijuana?
    Here are the highlights from an article in the Journal of Pain:
    Headache and migraine ratings were reduced by nearly 50% after using cannabis. Men reported larger reductions in headache after cannabis use than women. Cannabis concentrates were related to larger reductions in headache than flower. Evidence for tolerance to effects of cannabis on headache and migraine was detected. Evidence for medication overuse headache was not detected. This article shows a reduction in number of headaches and frequency. 40% of patients for whom medical cannabis was recommended for migraine reported a positive effect, with a decrease in migraine frequency from 10.4 to 4.6 migraines/month. Journal of Pain

    My students of St. Francis frequently hear me downplay complementary medications to treat or prevent disease. Especially with herbal therapy, there is no standardization in the United States.

    Products can vary from store to store since we do not have any system like the Komission-E monographs like Germany has, that spells out everything about purity and safety of herbal products. The only government help we have is just with the labeling of the products.

    When I see that butterbur must have the pyrrolizidine alkaloids removed to prevent liver toxicity and cancers, it makes me very reluctant to recommend the product given the lack of standardization of herbs.

    I am amazed, though, with the levels of efficacy shown by using riboflavin in the 400mg dose along with the magnesium oxide 400mg dose. The key is to have our patients use it for at least 3 months. Ah, the challenges of medication prescribing… getting our patients to “buy into” therapies that don’t show immediate benefit!

    Have a great day on the bench!!

    July 2020

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    Migraine Prophylaxis: Commonly Used Agents



    Risk Factors
    • Stress (Note: Neurology April 2014 says stress reduction INCREASES migraine)
    • Menses
    Sensory Stimuli
    • Foods/stimulants
    • Weather fronts
    • Chronobiologic changes
    • Protective Factors
    • Stress management
    • Biofeedback
    • Regular Sleep & meals
    • Regular exercise
    • Adequate Hydration
    • Regular work/ school
    Indications for Pharmacological prevention
    Headache Frequency: greater than 8 days/ month or 2 days/week
    Significant disability MIDAS (Migraine Disability Assessment) > 10 or HIT-6 > 60 (measures of headache disability)
    Complications with Migraines
    Acute therapies are ineffective
    Migraine related complications

    Success: is defined as working in 50% of the patients to decrease headaches by 50%
    Expect at least 6 weeks to see benefit from migraine prophylaxis

    Neuronal hyperexcitability predisposes individuals to migraine
    Increased neuronal hyperexcitability may be multi factorial
    Abnormal glutamate metabolism
    Deficiency of systemic and brain magnesium
    Abnormal calcium channels that influence presynaptic neurotransmitter release.
    Migraine may be prevented by reducing neuronal hyperexcitability.

    Encourage patients to identify and avoid triggers... skipping meals, disrupted sleep, stress, alcohol, wine, cheese, aspartame, etc. Men are 35% more likely to report overexertion as a migraine trigger. Men are more sensitive to light. Women are more sensitive to triggers of smell and are more likely to become nauseous.

    a) Beta blockers (considered first line for prophylaxis)
    These beta-blockers are lipid soluble and can penetrate the blood brain barrier
    • Propranolol (Inderal®)
    Dosage: 60mg to 360mg daily
    Side effects: fatigue, lassitude, depression, insomnia, postural symptoms
    • Metoprolol tartrate (Lopressor®) or metoprolol succinate (Toprol-XL®)
    Dosage: 50-200mg daily
    Side effects: same as propranolol

    Best to avoid beta blockers in smokers and patients over age 60

    b) General analgesics/NSAIDs (second line)
    • Aspirin 650-1950mg per day.
    • Naproxen 250mg to 550mg –twice daily
    Caution: regular use might lead to chronic headache.
    Avoid: CV disease, GI risk, hypertension

    c) Antidepressants (second line)
    • Amitriptyline (Elavil®) tablets
    Dosage: 25-75mg at bedtime (up to 150mg)
    Side effects: drowsiness, anticholinergic side effects, weight gain.
    Contraindicated in cardiac patients. Amitriptyline is the only tricyclic that has proven efficacy for migraine. No data on using other TCA’s
    • Venlafaxine (Effexor®) (second line)
    Side effects: headache, nervousness, insomnia, weight gain, GI disturbances.
    Caution: if hypertensive or recent heart attack.

    d) Calcium channel blockers (3rd line)
    • Diltiazem (Cardizem®, Cardizem CD®, Cardizem LA®)
    Dosage: 90-180mg daily
    Side effects: headache
    • Verapamil (Isoptin® or Calan SR®)
    Dosage: 80-160mg daily (up to 320mg/day)
    Side effects: Constipation, peripheral edema & cardiac conduction disturbances.

    Dr Robert Kaniecki: Headache Seminar: “Calcium channel blockers are not very effective”

    e) Anticonvulsants:
    • Topiramate (Topamax®) 25mg, 50mg , 100mg, 200mg
    Dosage: 25 to 150mg (Latest information suggests 50mg BID is sufficient)
    Side effects: confusion, weight loss, paresthesia, kidney stones
    Caution: over 200mg a day might decrease effectiveness of oral contraceptives
    • Divalproex (Depakote ER®)
    Dosage: Depakote ER® 500mg once daily for 7 days. Then increase to 1000 mg once daily. Do not crush or chew tablets.
    Side effects: weight gain, hair loss, tremor, diarrhea, and abdominal pain. During first 6 months of treatment watch for thrombocytopenia & hepatic failure.
    • Gabapentin (Neurontin®) -NOT effective- no better than placebo
    Dr. Robert Kaniecki: Headache Seminar:
    • Phenytoin, carbamazepine, phenobarbital are ineffective
    • Give 20% to 25% of maximum daily dose.
    f) Cyproheptadine (Periactin®)

    Often used for children

    4mg tablets, syrup: 2mg/teaspoon
    An antihistamine, with anti-serotonin properties
    Side effects: drowsiness, weight gain.
    Dosage: 4mg three times daily. Maximum 32mg/day

    Migraine headaches are disabling. Patients often want relief to not only get rid of them (with ‘-ditans’, ‘-triptans’ and ‘-gepants’) but also to keep the headaches from occurring in the first place. I find it amazing that success is defined as this: Half of your patients have half of the intensity/frequency of their headaches!

    Two weeks ago, we covered the CGRP inhibitors, all which cost around $725.00 per month. Virtually everything in this week's column is usually less than $20.00 per month.

    Have a great day on the bench!!

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    Treatment of Migraine Headache in Special Populations


    Treatment of Migraine Headache in Children

    In children, the pain is most often bilateral. Symptoms include photophobia (sensitivity to light), phonophobia (sensitivity to sounds), nausea, vomiting, and movement sensitivity.
    • Treatment (acute): Ibuprofen (7.5 - 10 mg/kg) max=800 mg.
    • Acetaminophen (2nd choice). Dose: 15 mg/kg up to 1000 mg.
    • If not effective, try sumatriptan (Imitrex®) nasal spray. Use 10 mg for kids weighing 44 -85lb. Use 20 mg for kids over 85 pounds.
    • Children age 6 to 10 years old weighing less than 110 lbs. should begin with the smallest available dose of triptan. (Sumatriptan-25mg)
    • Treat early for maximum effectiveness.
    Treatment of migraine headache in Pregnancy
    Migraine treatment of choice for pregnant patient: 1000mg Acetaminophen + 10mg metoclopramide.
    Second line: May also use butalbital/APAP/caffeine or Acetaminophen/codeine #3.

    REBOUND HEADACHES (MOH: Medication Overuse Headache) Key points:

    Diagnostic criteria include:
    • Headache - 15 or more days per month in a patient with a pre-existing headache disorder
    • Regular overuse for more than three months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache:
    Overuse of headache medications whether Rx or OTCs for just a few months can make their headaches worse when patients take meds frequently for migraine or tension headaches.

    Here are the drugs most likely to cause medication overuse headaches (MOH) and their % of reported incidence.

    Caution patients to avoid using:
    • butalbital/ acetaminophen (Fioricet®) for 5-8 or more days/month (causes 48% of MOH)
    • acetaminophen (Tylenol®) (causes 46% of MOH)
    • an opioid for 8 or more days/month (causes 33% of MOH)
    • aspirin analgesics (Excedrin®, Bufferin®), (aspirin causes 32% of MOH)
    • Triptans: do not use more than 10-14 days per month. That is why drugs like sumatriptan are packaged in 9 tablet boxes. (Triptans cause 18% of MOH)
    • NSAIDs (Motrin®, Aleve®) for 10 or more days/month. (10% of MOH)
    • Strategy for treating medication overuse headache:
      • Stop abruptly the over-used meds like NSAIDS and triptans
      • Taper butalbital and opioids.
    Treatment of withdrawal headaches:
    symptoms: worsening headache, anxiety, nausea or vomiting, disturbed sleep present for several days or longer.
    Select a drug from another class
    Antiemetic if needed- prochlorperazine (Compazine®) or metoclopramide (Reglan®) helps with nausea AND headache pain.
    Prednisone 100 mg/day for 5 days helps with inflammation but not pain.

    • Chart your symptoms, even those that seem unrelated to headaches.
    • Be sure to include dates, times, and weather.
    • Chart what you were doing, eating, or drinking before the headache began. Log the duration of the headache.
    • Log the medications you took to treat the headache and their efficacy
    AVOID opioids and butalbital for headache treatment!!
    USE prophylactic therapy, which will be discussed in the next session.

    I was a leader of a Boy Scout Troop for almost 20 years. When I think of migraine headaches in kids one of my Scouts stands out. He got a migraine at almost every campout. Whether it was the smoke from the fire or just fatigue, he frequently went home with a massive headache.

    It taught me to remind every patient to keep a good headache diary and to isolate the trigger and do your best to avoid them.

    Rebound headaches can be challenging too. Sometimes the very therapies that are prescribed can be the most important contributory factor to causing rebound headaches.

    Have a great day on the bench!!

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    Acute Relief of Migraine Without ‘Triptans’


    ‘Gepants’ are small molecule drugs which block the CGRP receptor and are effective at both relieving migraines and preventing them. ‘Gepants’, unlike the heavier monoclonal antibodies, rapidly penetrate the brain, so they work quickly; however, they are metabolized in the liver so there is a higher potential for interactions and possibly liver damage. Consider use after patients fail on two triptans, or can’t take triptans due to cardiovascular issues. Two have been approved to date:

    Ubrogepant (Obrelvy®) 50mg and 100mg tablets: Approved Dec 23, 2019
    Dose: 50 to 100mg with or without food, at first sign of migraine headache. If needed a second dose can be taken after 2 hours. Maximum daily dose is 200mg.
    Can be used to treat up to 8 migraines a month.
    Drug interactions: caution with strong CYP450-3A4 inhibitors or inducers. See package insert for liver failure, strong and moderate inducers or inhibitors of CYP450-3A4. Avoid in renal failure.
    Adverse effects: nausea, somnolence, dry mouth, dizziness, or upper respiratory tract infections between 2-5% of patients.
    Good news: no cardiovascular warnings, not controlled, not habit forming, savings card program.
    Bad news: cost is over $90 per pill

    Rimegepant sulfate (Nurtec ODT®): Approved Feb 27, 2020.
    Dose: 75mg one tablet as a single dose. Maximum is one tablet daily.
    Drug interactions: Avoid with strong CYP3A4 inhibitors, strong or moderate CYP3A4 inducers. Refer to package insert.
    Adverse effects: Nausea and vomiting
    Good news: no cardiovascular warnings, not controlled, not habit forming, savings card program.
    Bad news: cost is over $90 per pill

    Atogepant: A third ‘gepant’, atogepant, is currently being studied for use as a migraine preventive.

    Lasmiditan (Reyvow®) is a newly approved (October 2019) migraine abortive tablet. Available: 50- and 100-mg tablets, is a controlled (Schedule V) substance.
    Ditans: Referred to as a Neurally Active Anti- Migraine Agent (NAAMA); it is a specific 5HT1F agonist. Lasmiditan has much higher affinity for the 5-HT1F receptor than for the vasoconstrictor 5-HT1B receptor. No constriction of the coronary or cerebral vessels and offers an alternative for those who cannot take the triptans. No better or no worse with respect to efficacy compared to triptans.
    Warnings: do not drive for 8 hours after dosing, due to drowsiness even if not feeling impaired. Watch for serotonin syndrome.
    Take home: The efficacy of lasmiditan proves that vasoconstriction is not essential for acute migraine therapy and thereby points, in addition to a well-established trigeminal contribution, to central neuronal mechanisms in migraine pathophysiology.

    I tell my student pharmacists of a quote I once heard about health care. "Five years after you graduate, 50% of what you learned in pharmacy school will be obsolete." Neurology, more than any other discipline, supports that quote.

    In just the past 18 months we have had 7 drugs approved for the treatment of migraine headache. There are 4 CGRP monoclonals we discussed last week, 2 ‘gepants’ and one ‘ditan’!

    What fascinates me with this class of drugs is their lack of influence on the blood vessels. We all believed that the vasodilation was the cause of migraines and by "shrinking" those vessels we stopped the process. If that is the case, how do we explain ‘ditans’, ‘gepants’ and non-steroidal anti-inflammatory drugs having such efficacy in migraine treatment?

    As far as the brain goes, we are still in the infancy stage of our understanding of this amazing organ!

    Have a great day on the bench!!

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    Headache Prevention with CGRP Therapy


    CGRP (calcitonin-gene-related peptide) when released causes intense inflammation in the coverings of the brain (the meninges), and for most migraine patients, causes the pain of a migraine attack. This peptide causes vasodilatation which causes several pain processes, most notably migraine headache.

    Mechanism: drug therapy is directed against calcitonin gene related peptide (CGRP) or its receptor for the preventive treatment of migraine and cluster headache. Calcitonin gene-related peptide (CGRP) is a vasoactive peptide, involved in dilation of cerebral and dural blood vessels. Widely distributed throughout the body, CGRP levels in serum increase during migraine or cluster headache.


    Erenumab-aooe (Aimovig®) 70mg ------cost $725/month approved April-2018
    Dosing: Recommended dosage for migraine prophylaxis is 70 mg once monthly given as a subcutaneous injection; some patients may benefit from a dosage of 140 mg once monthly. The 140 mg dose is administered once monthly as two consecutive injections of 70 mg each.
    Mechanism: CGRP-receptor antagonist (it blocks the CGRP receptor)
    Efficacy: the number of migraine days per month was reduced by 3.2 in the 70 mg erenumab-aooe group; 3.7 in the 140 mg erenumab-aooe group, and 1.8 in the placebo group.
    Half-life: 28 days
    Time to peak: 6 days
    Side effects: injection site reaction and constipation. Constipation may be significant, best to avoid in patients already suffering from constipation, or taking constipation inducing meds (TCA’s, opioids)
    Storage: Store under refrigeration. Allow to come to room temperature for 30 minutes before administration

    Fremanezumab-vfrm (Ajovy®) ----cost 725.00 per month. Approved Sept-2018
    Dosing: For migraine prophylaxis: Two subcutaneous dosing options are available to administer the recommended dosage:
    • 225 mg monthly, or
    • 675 mg every 3 months (quarterly) Given as 3 consecutive injections.
    Mechanism: Fremanezumab-vfrm attaches to the CGRP molecule, preventing it from activating CGRP receptors by distorting the CGRP protein so that less of it can connect to the receptors.
    Half-life: Estimated at 31- to 39-days Storage: Remove from the refrigerator. Prior to use, allow AJOVY to sit at room temperature for 30 minutes protected from direct sunlight.

    Galcanezumab (Emgality®) cost= $725/month Sept 2018
    Mechanism: calcitonin gene-related peptide (CGRP) antagonist that attaches to the CGRP molecule, preventing it from activating CGRP receptors by distorting the CGRP protein so that less of it can connect to the receptors. Galcanezuman is ligand antagonist.
    Half-life: 25- to 30-days
    Administration: SC injection.
    Indications and Dosage:
    Two adult indications:
    • Preventive treatment of migraine: First dose is a loading dose of 240 mg, or 2 injections of 120 mg each, which may be administered in the doctor’s office, or by the patient. After that inject 1 dose each month.
    • Treatment of episodic cluster headache (approved June 2019) The recommended dosage is 300 mg (three consecutive subcutaneous injections of 100 mg each) at the onset of the cluster period, and then monthly until the end of the cluster period.
    Aimovig®, Ajovy®, Emgality®:
    • All thee were approved between May and September 2018
    • All three cost the same $725.00 per injection. All have copay coupons for commercial insurance.
    • All three can be injected in the abdomen, upper thigh, or upper arm. All list injection site reactions as side effects
    • Aimovig® contains latex, the others are latex-free.
    • Only Emgality®, thus far is approved for cluster headache treatment. It also is available as an auto-injector (like the Trulicity® device)
    Eptinezumab-jjmr (Vyepti®) approved February 2020
    Mechanism: attaches to the CGRP molecule, preventing it from activating CGRP receptors by distorting the CGRP protein so that less of it can connect to the receptors.
    Administration & Dosage: IV infusion in a health care setting, every 3 months. Do not push IV.
    The recommended dosage is 100 mg administered by IV every 3 months; however, some patients may benefit from a dosage of 300 mg administered by IV every 3 months. No loading dose needed. Infuse over a 30-minute period.

    How well I remember in the early 1990’s when sumatriptan became available! Migraine sufferers before that time had Fioricet®, Fiorinal®, Midrin®, and Cafergot®. None of these products are recommended today. Now we have the CGRP blockers for acute migraine relief as well as prophylaxis.

    Will this new class of drugs be the wonder drugs of migraine therapy? So far patients either love them or hate them. I had one patient who had not met his deductible and had a $450 copay. He said, “for this ability to have a normal month I’m fine with paying $15 per day.” Now that he met his deductible his copay is $35 and both pharmacist and patient are a lot happier!

    Have a great day on the bench!!

    June 2020

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    The Use of Selective Serotonin Receptor Agonists in the Management of Migraine Headache


    TRIPTANS: The medications we discussed last week that we are not supposed to use for migraine headache treatment, were the mainstay of therapy until the early 1990’s. In December of 1992 Imitrex (sumatriptan) injection was approved by the FDA, and the oral dosage form was approved in June of 1995. This profoundly changed acute migraine headache treatment. No more caffeine/ergotamine and oxycodone for migraine treatment, and doctors stopped prescribing both of these drugs in the mid 1990’s for headache.

    Mechanism: activate 5HT1b and 5HT1d and 5HT1f, which make them laser focused for migraine treatment. The net effect of triptans is to constrict cranial blood vessels and suppress inflammatory neuropeptides.
    Even though these drugs are laser focused for migraine treatment, 7-30% of patients will not respond to triptans. When this occurs consider allodynia, where triptans are used after aggressive dosing of non-steroidal anti-inflammatories (NSAIDs).

    Adverse effects: tingling, paresthesias, sensation of warmth in neck & head chest and limbs. Do not use triptans within 24 hours of ergots or other triptans.

    Contraindications: ischemic heart disease, myocardial infarction, uncontrolled hypertension, other heart disease. To reduce the potential for angina, do not give if risk factors: obesity, diabetes, hypercholesterolemia, as well as smokers, men over 40 and post-menopausal women.

    Selective Serotonin Receptor Agonists (Triptans):
    Axert®AlmotriptanTablets 6.25, 12.512.5mg; repeat in 2 hours25mg3.5 hours60 min
    Imitrex®SumatriptanAvailable StrengthTablets 25, 50, & 100mg200mg2.5hr60-120 min
    Nasal spray 5mg, 20mg5 or 20mg. Repeat in 2 hours40mg15-20 min
    Inject 6mg/.5ml New:4mg/.5ml6mg, repeat in 1 hour12mg10-15 min
    Treximet®Sumatriptan + naproxen85/5001 tablet; may repeat in 2 hours. Max 2/day170/1000mg60-120 min
    Relpax®EletriptanTablets 20 & 40mg20mg-40 Repeat in 2 hours80mg5hr60 min
    Frova®Frovatriptan2.5mg2.5mg repeat in 2 hours7.5mg25 hours (longest)60-120 min
    Maxalt®RizatriptanTablet/wafer 5mg, 10mg5 or 10mg. Repeat in 2 hours30mg2-3 hours30 min
    Zomig®ZolmitriptanTablet/wafer 2.5mg, 5mg2.5-5mg repeat in 2 hours10mg2.5-4 hours45 min
    Amerge®Naratriptan1mg & 2.5mg1mg or 2.5mg repeat in 4 hours5mg6 hours60 min

    COST: all the products above are available as generics. However due to competition, or lack thereof, there is great variability in pricing of the generics. Sumatriptan and Rizatriptan are the cheapest, with almotriptan and frovatriptan being the most expensive.

    OK I give up why do we need 7 different triptans??????
    • If you fail on a triptan, the second choice might work better
    • Faster onset—injections work quicker (10-15 minutes) so do nasal sprays (15 minutes). Also, good if patient is vomiting. (note that orally disintegrating tablets do NOT work faster).
    • Long half-life drugs like Frovatriptan and Naratriptan may be more useful for menstrual migraines—more useful for prevention than to abort a headache.
    The Headache Specialist says, “Using TRIPTANS for Migraines”:
    • Reduces all aspects of migraine disability
    • Minimal or no sedation
    • Intrinsic antiemetic properties
    • Drug induced headache is uncommon if use optimally. (Use high dose early)
    • Use 1 pill per headache
    One of the best pieces of advice we can give our patients came from a headache seminar I attended was “Take one and you are done.” The specialist also advised to take the maximum dose available to get rid of the headache. “Hit the headache hard and early on.”

    Most patients know when a migraine is coming, and at the first sign they should take a full dose of a triptan. The specialist stated he had no time for sumatriptan 25mg or the 50mg.

    He also recommended “cleaning up” the inflammatory neuro peptides with NSAID therapy, such as ibuprofen or naproxen, both high doses. Triptans have indeed changed the management of migraine headaches, especially now that the class is very affordable.

    Have a great day on the bench!!

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    Ergots and Opioids: No Place in Migraine Management

    Ergotamine preparations
    Mechanism: in the cranial arteries, it promotes constriction and decreases pulsation.
    Migraine activity might be due to agonist activity at serotonin receptor subtypes
    5-HT1b and 5HT1d
    Adverse effects: can stimulate the chemoreceptor trigger zone and cause nausea and vomiting in 10% of patients. Weakness in legs, myalgia, numbness & tingling in periphery. May also cause angina-like pain.
    Ergotism from chronic or acute overdosage. Symptoms include hallucinations, severe gastrointestinal upset, abortions, dry gangrene, and a painful burning sensation in the limbs and extremities commonly known as “St. Anthony’s Fire”. Ergotism was commonly seen in the middle ages as a fungal infestation of grains, especially rye grains.
    Contraindications: ischemic heart disease, myocardial infarction, uncontrolled hypertension, other heart disease and pregnancy.
    To reduce angina: do not give if risk factors: obesity, diabetes, hypercholesterolemia, smokers, men over 40, post-menopausal women.

    Drug therapy:
    Ergotamine + caffeine:
    Cafergot®: tablets: 1mg ergotamine + 100mg caffeine.
    Dosage: Take 2 tablets at onset. Then every 30 minutes as needed.
    • Maximum daily dose: 6 tablets per day.
    • Maximum weekly dose: 10 tablets per week
    Migranal® nasal spray 4mg/ml.
    Dosage: 1 spray (0.5mg) each nostril every 15 minutes for a maximum of 4 sprays.
    Don’t exceed 3mg/day (6 sprays)
    Don’t exceed 4mg/week (8 sprays)

    D.H.E.® injection: Dosage 1ml IM, IV or SC every 1 hour to a maximum of 3ml per 24 hours. (2ml if IV)
    • Maximum= 3ml per 24hr if SC or IM. 2ml max if IV. max =6ml per week.
    • Best to combine with metoclopramide (Reglan) for nausea
    Dr Robert Kaniecki: headache seminar:
    • Ergotamines are “hopelessly outdated”.
    • All ergots are pharmacologically non-selective.
    • Narrow window of opportunity
    • Enhances Nausea
    • Modest efficacy (little difference from NSAIDS)
    • Cardiovascular effects

    Side effects for opioids:
    Lightheadedness, dizziness, drowsiness, shortness of breath, nausea, vomiting, CONSTIPATION
    Contraindications for opioids:
    Alcoholics, heart failure, patients with opioid abuse potential
    Patient information for opioids:
    • Watch for drowsiness, caution driving. Avoid alcohol
    • Caution abuse potential, using and storage.
    • Do NOT adjust dose without consulting prescriber.
    • Caution if used in pregnancy
    REMEMBER: Patients treated with opioids as first-line therapy are significantly more likely to return to the emergency department with a headache within seven days of the original visit

    Dr Robert Kaniecki stated at the headache seminar:
    Use of opioids for migraine treatment:
    • Pro-inflammatory! (migraine is an inflammatory disorder)
    • Vasodilator
    • Increases nausea and vomiting
    • Sedating
    • Drug seeking behavior
    • (No contraindications with vascular disease: benefit)
    I was so frustrated when I saw a student pharmacist’s notes that had 29 pages of ergot alkaloids. Discussion of ergot alkaloids has a rich history that dates to known cases in the Middle Ages, that caused gangrene and hallucinations. The Salem witch trials were believed to be due to ergotism.

    It has been postulated that the 10th plague of the Egyptians was also due to wheat being infected by the ergot fungi (Claviceps purpurea) which caused ergotism, and then death of the first-born Egyptians. Yes, history is fun, but there is so much to learn about treatment of disease states with pharmacotherapies that are actually used.

    Dr Kaniecki with many years of headache management hit the nail on the head… “Ergots are hopelessly outdated.” I say they belong in the history books, and not occupy 29 pages in a student pharmacist’s lecture notes!

    Have a great day on the bench!!

    Micro-Learning CE Associated - Click Here For Details

    First Line Therapy for Tension and Migraine Headaches

    (tension or migraine)

    For mild to moderate migraine attacks not associated with vomiting or severe nausea, simple analgesics (NSAIDs, acetaminophen) or combination analgesics are first choice agents because they are effective, less expensive, and less likely to cause adverse effects than migraine-specific agents such as triptans or ergots.

    ACETAMINOPHEN: Mechanism: possibly decreases central prostaglandin synthesis (?). (mechanism unknown)

    Acetaminophen dosing:
    • max: 4000mg /day in healthy patient
    • max: 3000mg if drinking alcohol (social)
    • max: 2000mg if an alcoholic- best to limit acetaminophen use
    Drug interactions/Adverse Effects:
    Acetaminophen-induced hepatotoxicity is the most common cause of acute liver failure in the U.S. Around 30,000 patients are hospitalized each year in the U.S. to undergo treatment for this condition.

    Acetaminophen: warfarin- may result in significant elevations of international normalized ratio (INR), putting patients at increased risk for hemorrhage. If acetaminophen is necessary at doses near or greater than 2 g/day for more than 1 day, an extra INR measurement should be considered.

    Mechanism: NSAIDS inhibit cyclooxygenase (COX-1 & COX-2) which are enzymes that catalyzes the synthesis of prostaglandins, which are hormone-like substances that participate in a wide range of body functions such: as the contraction and relaxation of smooth muscle, the dilation and constriction of blood vessels, control of blood pressure, and modulation of inflammation. Prostaglandins are derived from a chemical called arachidonic acid.
    • Blocking COX-1 : causes blood thinning (good) and stomach ulcers (bad)
    • Blocking COX-2: causes coagulation (bad) and protects stomach (good)
    RX NSAIDS: Short-acting NSAIDS, with a duration of less than six hours include: ibuprofen (Motrin), diclofenac (Voltaren), etodolac (Lodine) and indomethacin (Indocin)

    Long-acting NSAIDS, with a duration of action over six hours including naproxen (Naprosyn), meloxicam (Mobic), celecoxib (Celebrex), nabumetone (Relafen)

    Aspirin: 325mg tablets, 165mg & 81mg tablets (Ecotrin max strength 500mg & 650mg)
    • Dosage: 1 or 2 tablets every 4 hours as needed for pain
    • Monitor for increased bleeding with warfarin and aspirin
    • May cause tinnitus.
    Ibuprofen (Advil®, Motrin®) 200mg tablets OTC 400,600,800mg RX
    • Dosage 200 every 4-6 hours prn
    • OTC maximum is 1200mg; Rx maximum is 3200mg
    Naproxen sodium (Aleve®) 220mg OTC Anaprox® 275 &550mg RX
    • OTC Dosage: 220 every 8-12 hours. OTC maximum=440-660mg
    • Rx maximum dose: Anaprox® (1100-1650)
    • Rx maximum dose: 1000-1500mg (Naproxen-Naprosyn®)
    Side effects for NSAIDS: GI toxicity, bleeding, ulceration
    Contraindications for NSAID:
    • Caution if renal impaired, may cause nephrotoxicity
    • All are pregnancy Category –D in third trimester
    • active GI disease
    • Caution in liver impairment
    • GI bleeding
    • Photosensitivity
    • Avoid Aspirin & alcohol while taking NSAID
    • Watch for increased hypertension
    • Exacerbation of heart failure
    • Increased risk of myocardial infarction, stroke, CV death
    Patient information:
    • Know signs and symptoms of GI bleeding
    • Photosensitivity
    • Avoid Aspirin & alcohol while taking NSAID
    • Take with food to avoid GI upset
    • Asthmatics –caution with aspirin
    • Do not take OTC NSAIDS with prescription NSAIDS
    Drug interactions:
    • All OTC medications should be used with caution in Warfarin patients, including acetaminophen
    • Do not take with other NSAIDS
    Numerous combinations of OTC meds with aspirin & acetaminophen:
    • Percogesic® (acetaminophen + diphenhydramine)
      • Acetaminophen 325 mg/diphenhydramine 12.5 mg: 2 tablets orally every 4 to 6 hours as needed
      • Acetaminophen 500 mg/diphenhydramine 12.5 mg: 2 tablets every 6 hours as needed
    • Excedrin® (aspirin 250mg + acetaminophen 250mg + caffeine 65mg) 2 caplets as a single dose
    • Bufferin® (aspirin 325mg + calcium carb+ mag carb + mag oxide) 2 tablets every 4 hours as needed (maximum of 12 per day)
    • Vanquish® (acetaminophen 194mg + aspirin 227mg + caffeine 33mg) max=8 caplets/day
    Other techniques to recover from headaches:
    • Lie down and relax
    • Use warm/cold compresses (your choice)
    • Warm bath or massage
    • LIMIT number of pillows!
    Dr. Robert Kaniecki: Headache Seminar offered the following about NSAID use for Migraine Headache:
    • Relatively unlikely to cause drug induced headache.
    • Safe in the presence of vascular disease
    • No Sedation
    • No Increase in Nausea
    • Efficacy for mild to moderated headache
    • High doses are to be used.
    Migraine is an inflammatory disorder.

    Can you imagine a world without over the counter ibuprofen and naproxen sodium? Up until May 18,1984, ibuprofen was prescription only. It was not until ten years later in January 1994, did naproxen come over the counter.

    I'm glad as a pharmacist we can recommend over the counter therapies to help our patients get inexpensive, quick and immediate relief for their headaches. When I spend two days a week at the Empower-3 family practice office, I see the "dark side" of NSAIDS. All of the providers are in agreement that these drugs need to be prescribed with a lot of caution. One of the physicians "detests" NSAIDs given to anyone with cardiac issues, renal issues and even hypertension that is not well controlled.

    If we see patients on long term NSAIDs at the clinic, we always check renal function to see if these prostaglandin blockers are inhibiting renal perfusion, as they are notorious for blocking afferent vasodilatation to the glomerulus.

    If ever we need a third class of drugs for pharmacist dispensing only, NSAIDs would be the first class of drugs I'd bring behind the counter... right next to the pseudoephedrine!

    Have a great day on the bench!!

    Micro-Learning CE Associated - Click Here For Details

    Differentiating Between Types of Headaches: Tension, Migraine and Cluster


    Tension Headache definition: Also referred to as “chronic scalp muscle contraction headache”, tension headaches affect BOTH sides of the head and scalp with pain that may radiate to the jaw and shoulders. Due to blood vessel changes taking place from muscular components, causing a “band like vise” around the head. Chances are, that if an OTC recommendation can be made and is successful, it is probably a tension headache. Patients usually do not go to the physician to get treatment for tension headaches.

    Migraine headache definition: A migraine is a type of headache, usually occurring with symptoms such as nausea, vomiting, or sensitivity to light and sound. In many people, a throbbing pain is felt only on one side of the head. Migraines may last from 4-72 hours, patients will lay down for relief (turn out lights, have quiet). Migraine headaches tend to first appear between the ages of 10 and 45. Migraines may run in families. Source: Migraines start in the trigeminal nucleus caudalis.

    • Women are twice as likely to get migraines than men (17.5% women experience migraines as opposed to 8.6% of men). Some women, but not all, have fewer migraines when they are pregnant.
    • Women report a longer attack duration, increased risk of headache recurrence, greater disability, and a longer period of time required to recover.
    • Women are more sensitive to triggers of smell and are more likely to become nauseous.
    • Men are 35% more likely to report overexertion as a migraine trigger. Men are more sensitive to light.
    Classic migraine (migraine with aura): recurring headache that strikes after or at the same time as sensory disturbances called aura. These disturbances can include flashes of light, blind spots and other vision chang