Tacrine

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Abstract
Tacrine is a centrally acting cholinesterase inhibitor with additional pharmacological activity on monoamine levels and ion channels. It has been postulated that some or all of these additional properties may also be relevant to the mode of action of the drug. There are wide interindividual variations in pharmacological and clinical response to tacrine, possibly related to interindividual variation in bioavailability. Tacrine appears to improve cognitive function and behavioural deficits in a proportion of patients with Alzheimer’s disease, at dosages of 80 to 160 mg/day. In the best designed trials, 30 to 51% of evaluable patients showed an improvement of at least 4 points on the cognitive subscale of the Alzheimer’s Disease Assessment Scale, versus 16 to 25% of placebo recipients. A similar proportion of tacrine recipients were judged to have improved when global assessment scales were used. There was a significant dose-response relationship up to 160 mg/day. However, large numbers of patients were withdrawn during the trials, many because of tacrine-associated increases in transaminase levels. Elevated liver enzyme levels occurred in about 50% of tacrine recipients (reaching clinical significance in about 25%). Cholinergic symptoms also occurred more often in tacrine recipients than in those receiving placebo. A gradual increase in tacrine dosage, at 6-week intervals, is recommended when initiating therapy, and weekly serum transaminase monitoring is required for 6 weeks after each dosage increase. Despite the limitations implied by the low proportion of responders and high incidence of hepatic adverse effects associated with therapy, tacrine appears to make a measurable difference in both cognitive and behavioural function in a proportion of patients with Alzheimer’s disease — a welcome advance in an area previously devoid of acceptable treatment options. In patients with Alzheimer’s disease receiving tacrine, investigators have reported inhibition of acetylcholinesterase, increased release and synthesis of acetylcholine, increased levels of monoamine metabolites, increased numbers of nicotine brain receptors, stimulated glucose metabolism and improved neuropsychological performance. At in vitro concentrations of about 0.01 to 10 µmol/L, in preparations from animal and/or human brain or red blood cells (and in the plaques and tangles found in brain tissue of Alzheimer patients), tacrine inhibits acetylcholinesterase and butyrylcholinesterase. It also binds reversibly to brain muscarinic receptors, inhibits the uptake and increases the release of brain noradrenaline (norepinephrine), dopamine and serotonin (5-hydroxytryptamine), inhibits brain histamine-N-methyl-transferase (HNMT), blocks neuronal potassium and sodium ion channels and may inhibit monoamine oxidase activity. At higher tacrine concentrations, monoamine oxidase activity, cyclic AMP phosphodiesterase activity in the neuromuscular junction and potassium-evoked release of excitatory amino acids are inhibited, and neuronal calcium ion channels are blocked. Other postulated actions include increased acetylcholine release (in some animal models), increased acetylcholine synthesis under some conditions, potentiated neuromuscular transmission, changes in the neuronal membrane, and stimulation of insulin secretion and glucose metabolism. The mode of action of tacrine is assumed to depend mainly on the drug’s effects on cholinergic activity, but it has been postulated that some other pharmacological effects may also be relevant. In animal models of cognitive impairment, tacrine 0.3 to 10 mg/kg dose-dependently reversed deficits in memory and learning. In the range of 2 to 15 mg/kg in animal models, many of the other pharmacodynamic effects of tacrine seen in humans have been recorded, as well as suppression of electrophysiological changes in brain-lesioned or aged rats and inhibition of brain HNMT. The oral bioavailability of tacrine is about 17 to 24%, with peak plasma concentrations of 20 to 60 µg/L reached in 1 or 2 hours with dosages of 80 to 200 mg/day for 2 days to 2 weeks. The drug appears to be widely distributed, with high concentrations achieved in kidney, liver and brain tissue in animals. Individual patients show wide variations in pharmacokinetic values. A correlation between plasma tacrine concentrations and cognitive effects has been demonstrated. Tacrine is metabolised in the liver, principally by the cytochrome P450 IA2 isozyme, to a variety of monohydroxy metabolites. The plasma elimination half-life of tacrine was 2.9 to 3.6 hours in patients receiving 40 to 150 mg/day orally, and clearance was 144 to 168 L/h with intravenous doses of 15 to 30mg. Tacrine appears to alter the pharmacokinetic s of theophylline on coadministration, and mean plasma tacrine concentrations are increased when cimetidine is given concomitantly. Oral tacrine, in dosages of 80 to 160 mg/day, has been shown to improve cognitive function and behavioural deficits in a proportion of patients with Alzheimer’s disease in 2 double-blind placebo-controlled parallel design trials of 12 and 30 weeks’ duration. A significant dose-response relationship was demonstrated at dosages of up to 160 mg/day. Between 40 and 58% of patients entering the studies were withdrawn during treatment for various reasons (mainly adverse events). However, of the evaluable patients in these trials, 30 to 51 % achieved an improvement on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-C) of at least 4 points, compared with about 16 to 25% of those receiving placebo. The difference in ADAS-C scores between placebo and tacrine 80 and 160mg recipients remained statistically significant with intention-to-treat/last-observation-carried-forward analyses. Clinician-rated global outcome measures were judged to have improved in 25 to 42% of evaluable patients receiving tacrine 80 to 160 mg/day for 30 weeks, compared with 15 to 18% of placebo recipients. These results were substantiated by a third parallel-design trial using a dose titration phase, and by the results of some tests in 6 crossover-design trials, although several of these studies have been criticised for such aspects as the possible development of training and carry-over effects, low dosages, low patient numbers, and administration of confounding concomitant medication. Nonetheless, responding patients were observed in most trials. Tacrine-associated increases in alanine amino transferase (ALT) levels appear to correlate positively with tacrine bioavailability. Clinically significant increases (>3 times the normal upper limit) in ALT levels occurred in approximately 25% of 2446 patients with Alzheimer’s disease receiving tacrine therapy during clinical trials. Some increase above the normal upper limit occurred in about 50% of tacrine recipients. Most liver enzyme elevations are detected in the first 8 weeks of tacrine therapy, returning to normal levels (usually within 4 weeks) on withdrawal of tacrine. Patients who have not shown elevated ALT levels with tacrine 40 to 80 mg/day in the first 12 weeks of therapy appear unlikely to do so with further treatment at increased dosages. Rechallenge with tacrine, after drug withdrawal because of increased liver enzyme levels, has resulted in therapy being tolerated, sometimes at higher doses than those used initially, in many patients. The changes in liver function appear to involve direct injury to the liver cells in most patients. Among other adverse events occurring more often in tacrine recipients than in those receiving placebo, the most common are nausea and/or vomiting, diarrhoea, dyspepsia, myalgia, anorexia, rhinitis, rash and ataxia. The incidence of cholinergic symptoms appears to increase with increased tacrine dosage and may be higher in women than in men. It is recommended that the dosage of tacrine is gradually increased from 40 mg/day to 160 mg/day, at 6-week intervals, in increments of 40 mg/day, if tolerated by the patient. Weekly serum transaminase level monitoring is required for the first 18 weeks of therapy, and for 6 weeks following each further increase in dosage.