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tacrine; tetrahydroaminoacridine (Cognex, THA, Romotal)

Tradename: Cognex. 1,2,3,4-tetrahydro-5-aminoacridine, THA, Romotal, 1,2,3,4-tetrahydro-9-acridinamine. Indications: -> treatment of mild to moderate Alzheimer's disease (FDA approved in 1993) [7 {clinical trial}] Dosage: 1) 10 mg PO QID, titrate upwards every 6 weeks 2) 80 & 160 mg daily have been found to have modest beneficial effects in 30-50% of patients Tabs: 10, 20, 30, 40 mg. Pharmacokinetics: 1) rapidly absorbed after oral administration 2) absolute oral bioavailability is 17 +/- 13% [5] -> food diminishes bioavailability by 30-40% 3) maximal plasma levels reached 1-2 hours after oral administration 4) steady state levels attained within 24-36 hours following initiation of therapy 5) 55% bound to plasma proteins [5] 6) volume of distribution 329 +/- 193 L [5] 7) metabolized in the liver, principally by cyt P450 1A2 a) multiple metabolites, not all identified b) significant 1st pass metabolism 8) smoking may reduce tacrine plasma levels by 70% 9) elimination 1/2life is 2-4 hours 10) may accumulate in tissues -> after 14 days, only 75% of radiolabel recovered after administration of tacrine [5] Monitor: -> serum ALY every 2 weeks from week 4-16 after starting treatment, then every 3 monthsl repear sequence if therapy is interrupted for more than 4 weeks [9] Adverse effects: 1) common (> 10%) - hepatotoxicity (common, 70% at 160 mg/day) - nausea/vomiting (28%) - diarrhea (16%) 2) less common (1-10%) - myalgia - dyspepsia - anorexia - weight loss - constipation 3) uncommon (< 2%) - ataxia - rhinitis - facial flushing - rash - tremor Drug interactions: 1) tacrine may potentiate effects of drugs metabolized by cyt P450 1A2 -> a 2-fold increaase in plasma theophylline may be observed 3) antacids containing Mg+2 &/or Al+3 do NOT affect tacrine plasma levels 4) any drug which inhibits cyt P450 1A2 can increase tacrine levels -> fluvoxamine increases plasma levels of tacrine 5-8 fold 5) any drug which induces cyt P450 1A2 can diminish tacrine levels Mechanism of action: 1) reversible inhibition of acetylcholinesterase 2) reversible inhibition of butyrylcholinesterase [4] 3) respiratory stimulant 4) may slow, but does not arrest the progression of dementia 5) tacrine inhibits cyt P450 1A2 thus its own metabolism 6) mutagnenic in Ames test, but not in an in vitro mammalian mutagenic test

Interactions

drug interactions drug adverse effects of cholinesterase inhibitors

Related

cytochrome p450 1A2 (cytochrome P3-450, phenacetin deethylase, cytochrome p450-4, CYP1A2)

General

pharmaceutical agents for treatment of Alzheimer's disease (Alzheimer's agent) aminoacridine cholinesterase inhibitor

Properties

MISC-INFO: elimination route LIVER pregnancy-category C 1/2life 2-4 HOURS protein-binding 55% safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. Merck tenth ed. (1983)
  2. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
  4. Role of cholinergic therapy in treatment of Alzheimer's disease & other dementias, Farlow, M et al, 2001
  5. Physician's Desk Reference (PDR) 56th edition, Medical Economics, 2002
  6. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  7. Davis et al NEJM ?:1253, 1992 {clinical trial} (vol uncertain)
  8. Department of Veterans Affairs, VA National Formulary
  9. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com