tacrine; tetrahydroaminoacridine (Cognex, THA, Romotal)
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Introduction
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
- 10 mg PO QID, titrate upwards every 6 weeks
- 80 & 160 mg daily have been found to have modest beneficial effects in 30-50% of patients
Tabs: 10, 20, 30, 40 mg.
Pharmacokinetics
- rapidly absorbed after oral administration
- absolute oral bioavailability is 17 +/- 13%[5]
- food diminishes bioavailability by 30-40%
- maximal plasma levels reached 1-2 hours after oral administration
- steady state levels attained within 24-36 hours following initiation of therapy
- 55% bound to plasma proteins[5]
- volume of distribution 329 +/- 193 L[5]
- metabolized in the liver, principally by cyt P450 1A2
- multiple metabolites, not all identified
- significant 1st pass metabolism
- smoking may reduce tacrine plasma levels by 70%
- elimination 1/2life is 2-4 hours
- may accumulate in tissues
- after 14 days, only 75% of radiolabel recovered after administration of tacrine[5]
elimination via liver
1/2life = 2-4 hours
protein binding = 55 %
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
- common (> 10%)
- hepatotoxicity (common, 70% at 160 mg/day)
- nausea/vomiting (28%)
- diarrhea (16%)
- less common (1-10%)
- uncommon (< 2%)
Drug interactions
- tacrine may potentiate effects of drugs metabolized by cyt P450 1A2
- a 2-fold increaase in plasma theophylline may be observed
- antacids containing Mg+2 &/or Al+3 do NOT affect tacrine plasma levels
- any drug which inhibits cyt P450 1A2 can increase tacrine levels
- fluvoxamine increases plasma levels of tacrine 5-8 fold
- any drug which induces cyt P450 1A2 can diminish tacrine levels
- drug interaction(s) of cholinesterase inhibitors with NSAIDs
- drug interaction(s) of parasympatholytic with parasympathomimetic
Mechanism of action
- reversible inhibition of acetylcholinesterase
- reversible inhibition of butyrylcholinesterase[4]
- respiratory stimulant
- may slow, but does not arrest the progression of dementia
- tacrine inhibits cyt P450 1A2 thus its own metabolism
- mutagnenic in Ames test, but not in an in vitro mammalian mutagenic test
More general terms
Additional terms
References
- ↑ Merck tenth ed. (1983)
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
- ↑ 4.0 4.1 Role of cholinergic therapy in treatment of Alzheimer's disease & other dementias, Farlow, M et al, 2001
- ↑ 5.0 5.1 5.2 5.3 5.4 Physician's Desk Reference (PDR) 56th edition, Medical Economics, 2002
- ↑ Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220233&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Davis et al NEJM ?:1253, 1992 {clinical trial} (vol uncertain)
- ↑ Department of Veterans Affairs, VA National Formulary
- ↑ 9.0 9.1 Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260704&pb=PRL (subscription needed) http://www.prescribersletter.com