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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

Antihistamines
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 Antihistamines	Generation	Recommended Adult Dose (≥12 years)	Recommended Pediatric Dose (6≥11 years)
Chlorpheniramine	1	4mg every 4-6 hours	2mg every 4-6 hours
Clemastine fumarate	1	1.34mg BID, or 2.68mg daily	0.67mg BID, or 1.34mg daily
Diphenhydramine	1	25mg every 4-6 hours	Not recommended3
Hydroxyzine	1	10-25mg at bedtime	12.5-25mg at bedtime
Triprolidine	1	2.5mg every 4-6 hours	1.25mg every 4-6 hours
Cetirizine (Zyrtec®)	2	10mg daily	5-10mg daily
Desloratadine (Clarinex®)	2	5mg daily	2.5mg daily
Fexofenadine (Allegra®)	2	60mg BID, or 180mg daily	30mg BID, or 60mg daily
Levocetirizine (Xyzal®)	2	5mg daily	2.5mg daily
Loratadine (Claritin®)	2	5mg BID, or 10mg daily	5-10mg 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.

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

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 Agents	OTC/Rx	Typical Dose and Frequency
Ipratropium (Atrovent Nasal®)	Rx	2 sprays in each nostril 2-3 times daily
Cromolyn (NasalCrom®)	OTC	1 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.

Summary
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.

References

• 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

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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

ICS	Daily ICS Dose in Micrograms
	Low	Medium	High
Beclomethasone diprop. DPI	100-200	>200-400	>400
Budesonide MDI or DPI	200-400	>400-800	>800
Ciclesonide MDI	80-160	>160-320	>320
Fluticasone fur. DPI	100	100	200
Fluticasone prop. MDI or DPI	100-250	>250-500	>500
Mometasone fur. MDI	200-400	200-400	>400

**Adapted from GINA 2021, Box 3-6A⁶

Children Ages 6-11 Years

ICS	Daily ICS Dose in Micrograms
	Low	Medium	High
Beclomethasone diprop. DPI	50-100	>100-200	>200
Budesonide MDI or DPI	100-200	>200-400	>400
Budesonide nebules	250-500	>500-1000	>1000
Ciclesonide MDI	80	>80-160	>160
Fluticasone fur. DPI	50	50	n/a
Fluticasone prop. MDI or DPI	40-100	>100-200	>200
Mometasone fur. MDI	100	100	200

*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

Summary

• 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

References

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

Cardiovascular

• 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

Neurologic

• Muscle weakness and lethargy, tremor

Hematologic

• Leukocytosis reported (generally benign)

Dermatologic
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!!