Tacrine is Most Likely to Cause Hepatotoxicity
Among drugs used for Alzheimer's disease, tacrine (Cognex) is by far the most hepatotoxic, causing liver enzyme elevations in approximately 40-50% of treated patients, with serious hepatotoxicity requiring biweekly liver function monitoring during dose escalation and every three months thereafter. 1
Comparative Hepatotoxicity Profile
Tacrine - Highest Risk
- Tacrine causes elevation of liver enzyme levels in 40-49% of treated patients, making it a second-line agent with significant hepatotoxic potential 1, 2
- ALT levels greater than three times the upper limit of normal occur in approximately 25% of patients, with 2% experiencing ALT elevations greater than 20 times the upper limit of normal 2
- Mandatory biweekly liver function tests are required during the 16-week dose escalation period, followed by monitoring every three months thereafter 1
- The mean time to first significant ALT elevation (>3× ULN) is 50 days, with 90% of elevations occurring within the first 12 weeks of treatment 2
- Fatal hepatotoxicity has been reported, including cases occurring as late as 14 months after treatment initiation despite regular monitoring 3
Other Cholinesterase Inhibitors - Minimal to No Hepatotoxicity
Donepezil:
- Explicitly stated to be non-hepatotoxic with no laboratory monitoring required 1, 4
- Side effects are limited to mild gastrointestinal symptoms (nausea, vomiting, diarrhea) that can be reduced by taking with food 1
Rivastigmine:
- No hepatotoxicity reported and no laboratory monitoring is required 1
- Adverse effects include gastrointestinal symptoms, weight loss, and CNS effects, but not liver toxicity 1
Galantamine:
- While contraindicated in patients with pre-existing hepatic impairment, it does not cause hepatotoxicity in patients with normal liver function 1
- Most common side effects are gastrointestinal (nausea, vomiting, diarrhea) 1
Clinical Implications
Why Tacrine is Now Second-Line
The pharmacologic characteristics and hepatotoxic side effects of tacrine have relegated it to second-line status, unlike the newer cholinesterase inhibitors that lack hepatotoxicity 1. The requirement for four-times-daily dosing due to its short half-life further limits its clinical utility 1.
Monitoring Requirements Create Practical Barriers
The intensive monitoring schedule required for tacrine (biweekly for 16 weeks, then quarterly) represents a significant burden compared to donepezil, rivastigmine, and galantamine, which require no routine laboratory monitoring 1.
Reversibility Does Not Eliminate Risk
While tacrine-induced ALT elevations are generally reversible upon drug discontinuation, and 88% of patients can be successfully rechallenged 2, the occurrence of fatal hepatotoxicity cases 3 demonstrates that the risk is not merely theoretical.
Answer to Question
A. Tacrine is the correct answer - it is the only Alzheimer's medication among the options with clinically significant hepatotoxicity requiring mandatory liver function monitoring 1, 2.