Tacrine adverse effects

The rate of dose escalation may be slowed if a patient is intolerant to the recommended titration schedule. However, it is not advisable to accelerate the dose incrementation plan. Following initiation of therapy, or any dosage increase, observe patients carefully for adverse effects. Take between meals whenever possible however, if minor Gl upset occurs, take with meals to improve tolerability. Taking tacrine with meals can be expected to reduce plasma levels approximately 30% to 40%. 

Adverse effects unrelated to inhibition of AChE can also occur. Tacrine presents a high risk of hepatotoxic-... 

Adverse effects produced by the drugs include nausea, diarrhea, vomiting, and insomnia. These symptoms are most frequent and severe with tacrine. Hepatotoxicity is associated with tacrine therapy. Because of these significant side effects, tacrine is not widely used. 

Authors evaluating the adverse effects of tacrine in Alzheimer s disease recommend regular monitoring for hepatotoxicity (SEDA-15,136). 

Of the acetylcholinesterase inhibitors, tacrine, methoxy-tacrine, metrifonate, donepezil hydrochloride, and rivastigmine are used in the treatment of Alzheimer s disease. In 12-30% of patients with Alzheimer s disease, tacrine causes an increase in hepatic transaminase activity. Abdominal adverse effects are very frequent, for example nausea, anorexia, diarrhea. The peripheral cholinomimetic effects of tacrine occur in a very high proportion of patients, probably the majority. The hepatic effects seem to be such that the use of these new (and in some cases still experimental) drugs would not be justified in... 

Fluvoxamine markedly increases the levels of tacrine, and increases its cholinei ic adverse effects, whereas fluoxetine, paroxetine, and sertraline are not expected to interact. Paroxetine and fluoxetine may increase donepezil and galantamine levels. Sertraline does not appear to have a pharmacokinetic interaction with donepezil, and concurrent use seems generally well tolerated however, one report describes hepatotoxicity, possibly as a result of their concurrent use. Rivastigmine and fluoxetine appear not to interact. 

Furthermore, there have been no drug withdrawals due to enzyme elevations in patients treated with SDZ ENA 713 while approximately 25% of patients treated with tacrine discontinue due to liver enzyme elevation. There appear to be no associated cardiac, renal or central nervous system adverse effects. The most commonly reported adverse effects are nausea, vomiting and diarrhoea of mild intensity. 

Tacrine is particularly damaging to the liver and can result in hepatotoxicity. Because tacrine is more likely to cause adverse reactions and drug interactions, it must be administered more frequently (4 times a day) and is rarely used in current therapy. Donepezil has fewer and milder side effects than tacrine It is considered the agent of first choice However, some patients may achieve a better response with one drug than another. Additional adverse reactions are listed in the Summary Drug Table Cholinesterase Inhibitors. 

Tacrine (tetrahydroaminoacridine) was one of the first drugs to be widely marketed for the loss of memory and intellectual decline in Alzheimer s disease. However, its efficacy is controversial. A Cochrane review of the use of tacrine in Alzheimer s disease produced results that were compatible with improvement, no change, or even harm (1). For measures of overall clinical improvement, the intention-to-treat analyses did not detect any difference between tacrine and placebo (OR = 0.87 95%CI = 0.61, 1.23). There was no effect on behavioral disturbance (SMD = 0.04 95% Cl = -0.52,0.43) or cognitive function (SMD = 0.14 95% Cl = -0.02, 0.30). The odds ratio for withdrawal due to an adverse event was significantly different from 1, the control group experiencing fewer events (OR = 0.7 95%CI = 4.1, 7.9). Raised serum liver cnzym cs caused the most withdrawals. 

In vitro studies with human and rat liver microsomes found that enoxaein, a specific inhibitor of the cytochrome P450 isoenzyme CYP1A2, significantly inhibited all known routes by which tacrine is metabolised. A reasonable conclusion to be drawn from this is that the effects of tacrine (both beneficial and adverse) would be increased by enoxacin, but this interaction does not appear to have been studied in patients or healthy subjects. The same study also suggested that enoxacin possibly inhibits the production of the hepatotoxic metabolites of tacrine. ... 

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