Pharmacology and clinical efficacy of cholinesterase inhibitors.

The pharmacology and clinical efficacy of cholinesterase inhibitors (ChEIs) in patients with Alzheimer's disease (AD) are discussed. ChEIs can be classified pharmacologically on the basis of the duration of cholinesterase inhibition. The duration of inhibition is short for tacrine and donepezil, intermediate for rivastigmine, and long for metrifonate. Pharmacokinetic differences also distinguish ChEIs. The two instruments that are most accepted for use in evaluating the efficacy of drugs for AD are the Alzheimer's Disease Assessment Scale-Cognitive Portion (ADAS-Cog) and the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus). In clinical trials, all ChEIs have produced improvements in the cognitive deficits seen in patients with AD, and some have also improved behavioral problems and increased patients' ability to perform activities of daily living. Only donepezil and metrifonate are administered once daily. Except for metrifonate, the dosage of each drug should be adjusted upward over several weeks to minimize adverse effects. Hepatotoxicity, the most important adverse effect of tacrine, has not been observed with other ChEIs. Tacrine and donepezil have the potential to interact with other drugs that depend on the same metabolic pathways. Although ChEIs generally improve cognition in patients with AD, differences among these medications are substantial in some cases and should be thoroughly considered by clinicians.