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mirtazapine (Remeron)

Tradename: Remeron Indications: 1) treatment of major depression - may improve appetite in patients with major depression - especially good for anxiety, somatisation, sleep disturbance & in patients with Parkinson's disease 2) intractable pruritus 3) chronic tension headache [4] 4) anxiety associated with repetitive behaviors [5] 5) treatment of autism in the elderly (drug of choice) [6] * not useful for treatment of obstructive sleep apnea [5,6] Contraindications: - concurrent use of MAO inhibitor - separate by a 2 week washout Dosage: - Start 15 mg PO QHS - Average effective dose: 15-45 mg/day - Maximum: 45 mg/day Tabs: 7.5, 15 & 30 mg. Pharmacokinetics: 1) rapidly & completely absorbed following oral administration 2) absorption not affected by food 3) peak plasma levels reached 2 hours after oral dose 4) absolute bioavailability is about 50% 5) metabolized extensively by liver a) demethylation & hydroxylation b) glucuronide conjugation c) cyt P450 2D6 & 1A2 catalyze formation of 8-OH metabolite d) cyt P450 3A4 catalyzes formation of N-desmethyl & N-oxide metabolites 6) protein binding 85% 7) elimination 1/2life of 20-40 hours a) the (-) enantiomer has a 1/2life twice that of the (+) enantiomer b) mean t1/2 for females is 37 hours; 26 hours for males c) elimination 1/2life of 13-34 hours in younger adults [8] d) elimination 1/2life of 31-39 hours in older adults [8] 8) metabolites eliminated in the urine (75%) & feces (15%) Adverse effects: 1) common (> 10%) - increased appetite (15-20%) with weight gain - greatest weight gain among antidepressants [7] - somnolence (sedation) 2) less common (1-10%) - low anticholinergic effects - dry mouth - constipation - confusion - dizziness - abnormal thought & abnormal dreams - increased serum cholesterol & triglycerides 3) uncommon (< 2%) - agranulocytosis (0.1%, 3 cases, all reversible) - tremor - dyspnea - urinary frequency - increased alanine transaminase (ALT) > 3-fold (2%) - nausea 4) other - sedation at a lower dose of 7.5 mg/day is overcome at a higher dose of 15 mg/day - orthostatic hypotension - No sexual dysfunction - anxiety may occur upon discontinuation Overdose: No specific antidotes for overdose. Drug interactions: 1) drugs metabolized by or inhibiting cyt P450 2D6, 1A2, or 3A4 are expected to have some interaction 2) diazepam has minimal effect on mirtazapine plasma levels, but effects on motor skills were additive 3) alcohol had minimal effect on mirtazapine plasma levels, but effects on motor & cognitive skills were additive 4) increased CNS depression with clonidine Mechanism of action: 1) central alpha-2 adrenergic receptor antagonist 2) moderate peripheral alpha-1 adrenergic receptor antagonist 3) potent antagonist of 5HT2 & 5HT3 receptors -> no affinity for 5HT1a or 5HT1b receptors 4) antagonist of histamine H1 receptor 5) moderate antagonist of muscarinic receptors 6) increases norepinephrine activity 7) increases serotonin activity via alpha-1 heteroreceptors on serotoninergic neurons

Interactions

drug interactions drug adverse effects (more general classes)

Related

cytochrome p450 1A2 (cytochrome P3-450, phenacetin deethylase, cytochrome p450-4, CYP1A2) cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6) cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

General

alpha-2 adrenergic receptor antagonist atypical antidepressant

Properties

SIZE: MW = 265 GRAMS/MOLE INHIBITS: serotonin [5HT] receptor alpha adrenergic receptor MISC-INFO: elimination route LIVER KIDNEY 1/2life 20-40 HOURS protein-binding 85% pregnancy-category C safety in lactation ?

Database Correlations

PUBCHEM cid=4205

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Physician's Desk Reference (PDR) 54th edition, Medical Economics, 2000
  3. Bronstein J. In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  4. Journal Watch 24(14):116, 2004 Bendtsen L, Jensen R. Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology. 2004 May 25;62(10):1706-11. PMID: 15159466
  5. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010 - Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  6. Marshall NS, Yee BJ, Desai AV et al Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea. Sleep. 2008 Jun;31(6):824-31. PMID: 18548827
  7. Gafoor R, Booth HP, Gulliford MC. Antidepressant utilisation and incidence of weight gain during 10 years' follow-up: population based cohort study. BMJ 2018;361:k1951 PMID: 29793997 Free full text https://www.bmj.com/content/361/bmj.K1951
  8. Talebraza S et al Geriatrics Evaluation & Management Tools American Geriatrics Society. 2021 https://geriatricscareonline.org/ProductAbstract/geriatrics-evaluation-management-tools/B007/
  9. Department of Veterans Affairs, VA National Formulary