31.15 CHOLINESTERASE INHIBITORS Kaplan & Sadock’s Comprehensive Textbook of Psychiatry CHAPTER 31. BIOLOGICAL THERAPIES 31.15 CHOLINESTERASE INHIBITORS STEVEN C. SAMUELS, M.D., AND KENNETH L. DAVIS, M.D. Tacrine Donepezil Investigational Drugs Future Directions Alzheimer's disease is a progressive neurodegenerative disease that gradually destroys brain function. Symptoms of the disease include cognitive deterioration involving memory, language, praxis, higher executive functioning and behavioral changes. In the United States, 4 million patients are afflicted with the disease, with direct and indirect costs for the disease approaching 100 billion dollars annually. The disease is age related with the prevalence of 3.0 percent at age 65, approaching 50 percent by age 85 years and leveling off at 40 percent by age 95. As the population ages, increased numbers of people will develop Alzheimer's disease. Cautious optimism stems from the recent availability of cholinesterase inhibitors that may slow down the progression of this terrible disease, but much more research is required before the disease can be arrested or reversed or those at risk for the disease can be reliably identified and prevented from developing it. Several lines of evidence suggest that cholinergic function has a substantial role in Alzheimer's disease. Cholinergic transmission is involved in learning and memory. Anticholinergic agents cause memory and attention deficits in animals and humans. Destruction of the basal forebrain in animals or cholinergic circuitry in humans results in cognitive deficits. In clinical trials, cholinergic agents have restored cognitive function and decreased decline in Alzheimer's disease patients. The correlation between cholinergic abnormalities and the degree of cognitive impairment in Alzheimer's disease is a consistent finding in a number of studies. The significance of the cholinergic changes in Alzheimer's disease was eloquently described in a comprehensive examination of neuropathological and neurochemical changes in brains of those afflicted. The strongest correlations between clinical measures of dementia severity and neurochemical changes involved choline acetyltransferase, the enzyme necessary for the formation of acetylcholine. The cholinergic hypothesis in Alzheimer's disease led to research and development of a number of potential therapeutic agents. These agents are in various stages of preclinical and clinical development in animals and humans. The agents currently approved by the Food and Drug Administration (FDA) for Alzheimer's disease are predominantly cholinesterase inhibitors. Attempts to alter cholinergic transmission have included increasing presynaptic precursors to acetylcholine, stimulating muscarinic receptors with selective muscarinic agonists and decreasing the enzymatic degradation of acetylcholine by blocking acetylcholinesterase or butylcholinesterase with cholinesterase inhibitors. Lecithin and choline, the precursors to acetylcholine, have been extensively studied and shown not to be beneficial in Alzheimer's disease. Muscarinic agonists have demonstrated benefit in preclinical studies, and some compounds are now in clinical trials. Although tonic stimulation may be relevant in arousal and attention, continuous stimulation of receptors by cholinergic agonists may result in receptor downregulation because the physiological stimulation is not pulsatile. This downregulation may limit the effectiveness of the muscarinic agonists. Advancing age and Alzheimer's disease progression are associated with a decrease in number and function of cholinergic neurons, possibly explaining the failure of precursors affect the disease. Moreover, this decline in cholinergic neuron number and function may also decrease the effectiveness of the muscarinic agonists and the cholinesterase inhibitors. TACRINE Tacrine (Cognex), the first FDA-approved cholinesterase inhibitor for the treatment of dementia of the Alzheimer's type, is a centrally acting, noncompetitive, reversible inhibitor of acetylcholinesterase and butyrylcholinesterase. Originally synthesized in 1945, tacrine was not recognized as a cholinesterase inhibitor until 1953. Tacrine was initially used to attenuate morphine withdrawal in patients with cancer and pain syndromes. Tacrine is effective in slowing the apparent progression of dementia in a subgroup of patients with Alzheimer's disease who can tolerate the medication for sufficient duration. Tacrine's use in Alzheimer's disease is limited by four-times-a-day dosing, gastrointestinal adverse effects, the potential for hepatic toxicity, and the need for frequent serum monitoring. Chemistry The molecular structure of tacrine (9-amino-1,2,3,4-tetrahydroacridine) is shown in Figure 31.15-1. Tacrine is metabolized to a number of hydroxylated products, including 1-OH-tacrine (which itself was being developed for the treatment of dementia of the Alzheimer's type) as velnacrine. FIGURE 31.15-1 Molecular structure of tacrine. Pharmacological Actions Pharmacokinetics Tacrine is well absorbed from the gastrointestinal tract; however, intake with food reduces its bioavailability by 30 to 40 percent. Peak plasma concentration is reached 1 to 2 hours after oral dosing. Steady-state tacrine concentrations are reached after dosage initiation or change in 24 to 36 hours. The steady-state volume of distribution is about 300 L. The elimination half-life of tacrine is 2 to 3 hours. Tacrine is hepatically metabolized by the cytochrome P450 (CYP) is 0 enzymes 1A2 (CYP 1A) and CYP 2D6 and undergoes hydroxylation and conjugation. A small percentage of the drug is excreted in the urine, and dose adjustments are not necessary in patients with renal impairment. Pharmacodynamics Tacrine's mechanism of action in Alzheimer's disease appears related to acetylcholinesterase inhibition resulting in increased acetylcholine availability. The relation between plasma concentration and oral dosing is nonlinear. Plasma concentrations of tacrine in women are double those of men, possibly related to decreased CYP 1A2 activity in women. Cigarette smokers have up to one-third lower serum tacrine levels than nonsmokers, probably related to induction of CYP 1A2 in smokers. Age and tacrine clearance are not directly related. Design and Interpretation of Clinical Drug Studies Clinical trials using tacrine for Alzheimer's disease have variable methodological strength. Early studies demonstrating remarkable promise of tacrine for dementia were not well controlled. Additional studies in the 1980s had mixed results and continued methodological problems including inadequate dosing strength and duration of treatment. These concerns limited generalizations that could be made about effectiveness. Improved methodology in one 12-week study and 30-week study were pivotal in the ultimate FDA approval of tacrine. Tacrine and Functional Brain Studies Brain single photon emission computed tomography (SPECT) and xenon (Xe)-inhalation have been used to examine brain function in Alzheimer's disease patients who received tacrine. These studies revealed correlations between clinical response to tacrine and functional imaging changes. Tacrine may improve technetium-99 (99mTc)-labeled ethylene dicysteinate retention abnormalities (a measure of cerebral blood flow) in patients with mild-to-moderate dementia of the Alzheimer's type. The results were dose dependent; patients who received 75 mg of tacrine a day demonstrated improvement, while those receiving 25 mg of tacrine a day did not show functional change in brain SPECT. In an open-label 14-month trial of tacrine with maximum dosage of 125 mg a day, Xe-inhalation methodology was used to measure regional cerebral blood flow (rCBF) in probable Alzheimer's disease patients before and after tacrine treatment. Patients who responded favorably to tacrine showed improvement or stabilization in rCBF compared with those who did not receive tacrine. The results support a dosage-dependent response to tacrine. The possibility of using functional measures as predictors of clinical response to pharmaceuticals is intriguing, and further research is required in this area. Pharmacoeconomic Considerations Tacrine has been estimated to generate potential savings up to 17 percent of the current costs of Alzheimer's disease, or a total 3.6 billion dollars annually. These calculations were based upon an improvement of 1 point on the Mini-Mental State Examination (MMSE) by patients tolerating 80 to 160 mg a day and a 2 point increase in patients who tolerated 160 mg a day. Patients with 1 to 2 points of improvement on the MMSE are estimated to have 9.5 to 12.1 months of reduced community and institutional costs. Industry-sponsored studies examining the effects of various agents on the direct and indirect costs of Alzheimer's disease are ongoing, and justification for choosing one pharmacotherapeutic agent over another may become closely tied to a drug's pharmacoeconomic profile. Quality of Life In addition to pharmacoeconomic considerations, tacrine's effects on quality-of-life measures have been examined. The effect of tacrine on mortality and placement into a long-term care facility was examined in about 90 percent of the 663 patients from the 30-week clinical trial. Patients were followed for 2 years or until they died or were placed in a nursing home. Patients receiving more than 80 mg of tacrine daily were less likely to die or be placed in a nursing home than patients on a lower tacrine dose (odds ratio > 2.7). The absence of a control