Tacrine in the treatment of Alzheimer's disease

Summary
Tacrine is the first drug to be approved for the treatment of mild to moderate Alzheimer's disease. It is thought to increase concentrations of acetylcholine, one of the key neurotransmitters in Alzheimer's disease. The modest efficacy - helping some patients for some time - must be weighed up against tacrine's high rate of adverse effects and its cost. The medical practitioner's role is to make an accurate diagnosis and form a partnership with the patient and family for the long haul of management. The key elements of therapy remain assisting the patient and family to cope with the disease and maximising their quality of life. As the first drug treatment for Alzheimer's disease, tacrine represents an advance; the pros and cons of prescribing it should be discussed fully with the patient and family.

Introduction
Requests for treatment of Alzheimer's disease are sure to increase, given the ageing of our population, the rise of self -help groups such as the Alzheimer's Association, and the increasing number of drugs under trial for this condition. There is also considerable media interest, as evidenced when ex-President Ronald Reagan 'went public' about having Alzheimer's disease. Tacrine is the first drug to be approved for the treatment of mild to moderate Alzheimer's disease, and will be the benchmark for future medications.

Basis of tacrine therapy
Cerebral concentrations of most neurotransmitters and neuropeptides decrease with progression of Alzheimer's disease, particularly acetylcholine, the major neurotransmitter for memory. Drawing on the example of dopamine enhancement by levodopa in Parkinson's disease, several strategies have been tried to boost cerebral acetylcholine levels in Alzheimer's disease. The theoretical rationale for tacrine is that by blocking acetylcholinesterase, the enzyme that degrades acetylcholine, there will be more neurotransmitter available. As tacrine has multiple actions, its exact mechanism in Alzheimer's disease is uncertain.

History
Tacrine was first synthesised in Melbourne in 1949 and has been used after anaesthesia and in combination with morphine because of its analeptic properties. An influential study published in 1994 led to tacrine's approval in the U.S.A. for use in mild to moderate Alzheimer's disease.¹

Pharmacokinetics
Tacrine is rapidly absorbed from the gastrointestinal tract, with maximum plasma concentrations occurring 1-2 hours later. Mean peak plasma tacrine concentrations increase with increasing oral doses. The rate and extent of tacrine absorption are reduced by approximately 30% when it is taken with food. However, there is no significant food effect when tacrine is administered one hour before meals. In patients with Alzheimer's disease, steady state concentrations are attained within 24-36 hours of the first dose if doses are given every 6 hours. Tacrine has non-linear kinetics as the enzymes involved in first pass metabolism become saturated at higher doses. This means that a small increase in dose can produce a disproportionate rise in plasma concentrations.

Tacrine is metabolised in the liver with a plasma elimination half-life of 2.9-3.6 hours after repeated oral doses. Based on pooled pharmacokinetic studies, age has no clinically relevant influence on tacrine clearance. Renal dysfunction does not appear to affect clearance, while hepatic impairment theoretically should reduce the clearance of tacrine and its metabolites. Functional improvement in patients with Alzheimer's disease has been correlated with high tacrine concentrations, but, unfortunately, so have adverse effects such as increased concentrations of liver enzymes.

Therapeutic efficacy
There have been 9 cross-over, randomised, double-blind, placebo-controlled trials of tacrine therapy in patients with mild to moderate Alzheimer's disease, 7 of which have included concomitant lecithin, a choline precursor. Half the studies showed improvement on some tests of cognitive function but not others, and the other half showed no effect. In addition, there have been 6 parallel, randomised, double -blind, placebo-controlled trials of tacrine of which again half have found improvement on at least some sub-scale scores.² Given the evenness of the results, it is not surprising that the role of tacrine in the treatment of Alzheimer's disease has been controversial.

An Australian study found no effect in 14 patients after 36 weeks of treatment with doses up to 80 mg/day compared with 18 patients taking placebo.³ The much larger U.S.A. multi centre trial1 enrolled 663 patients, of whom 263 (40%) had evaluable data at 30 weeks. There were 4 groups of patients; one took placebo, and the others took different doses of tacrine. The results showed significant dose-response trends. At the highest dose of tacrine, 40 mg 4 times daily, significantly more patients improved compared to those on placebo (on the intention-to-treat and evaluable patient analyses). Improvement was defined by tests of cognitive function and on clinician -rated global evaluation of change. However, only 28% (67/239) of patients allocated to the high dose of 40 mg 4 times daily of tacrine were able to tolerate this dose for 30 weeks. Clinical adverse effects and elevated liver enzyme concentrations were common.

In the trials, treatment was stopped if the concentrations of alanine transaminase (ALT) reached 3 times the upper limit of the normal range. However, many of these patients were able to resume long-term therapy with the drug on rechallenge.⁴ In all instances, discontinuing tacrine completely reversed ALT elevations and there were no deaths related to hepatotoxicity or evidence of permanent liver damage. However, while liver dysfunction seems reversible, there have been documented cases of hepatitic changes, liver cell necrosis and granuloma formation.

Further considerations

• In Alzheimer's disease, there is steady cognitive and functional decline. Thus, an effective drug may stabilise rather than improve cognitive and functional levels.
• Not all dementia is Alzheimer's disease and the clinical diagnosis, essentially one of exclusion of other causes, is likely to be correct in 80-90% of patients at best.
• There is no way of predicting which patients will respond to tacrine and, at lower dosages, its efficacy appears marginal.
• Tacrine neither replaces cholinergic neurones nor affects the underlying Alzheimer's disease pathology, and its duration of effect is unknown. When effective, tacrine appears to arrest cognitive decline for perhaps 6-24 months (91 weeks in one study⁵), after which patients will continue to decline.
• The trials have studied patients with Alzheimer's disease who have mild to moderate dementia but are otherwise healthy. Patients with concurrent systemic disease, behavioural problems or more severe dementia have been excluded, and so the results cannot be extrapolated to them.

Practical guidelines

Contraindications

• active liver disease
• previous tacrine-induced jaundice
• active untreated gastric or duodenal ulcer
• sensitivity or allergy to cholinomimetics
• pregnancy or possible pregnancy

Precautions

• Increased gastric ac id secretion due to cholinesterase inhibition may put patients at risk of peptic ulcers. Those with a history of ulcers or receiving concurrent non -steroidal anti-inflammatory drugs should be monitored closely for symptoms suggestive of ulceration.
• Tacrine may exert vagotonic effects e.g. bradycardia, conduction abnormalities, hypotension. Patients with 'sick sinus' syndrome or bradyarrhythmias require closer clinical monitoring.
• Care should be taken if prescribing tacrine to a patient with a history of liver disease, seizures, Parkinson's disease or severe asthma.

Drug interactions
No effects on the pharmacokinetics of digoxin, diazepam or warfarin have been demonstrated. Theophylline metabolism is inhibited by concurrent administration of tacrine. In the elderly, cimetidine inhibits the metabolism of tacrine and increases plasma tacrine concentrations.

Tacrine should be used with caution when administered with other cholinomimetics or anticholinergic drugs. As it is likely to prolong the effects of muscle relaxants such as suxamethonium, tacrine should, if possible, be stopped before anaesthesia.

Adverse reactions
Many patients are unable to tolerate tacrine. Elevated liver enzyme concentrations are common, usually occur in the first 12 weeks and may rise abruptly. The other main adverse effects are gastrointestinal. The frequencies of tacrine's adverse effects (compared to placebo) are:

nausea and/or vomiting 28% (9%)
diarrhoea 16% (5%)
dizziness 12% (11%)
anorexia 9% (3%)
myalgia 9% (5%)
dyspepsia 9% (6%)
rhinitis 8% (6%)
abdominal pain 8% (7%)
rash 7% (5%)

Less common adverse effects include:

weight loss
flatulence, constipation
fatigue, asthenia
ataxia, insomnia, somnolence, tremor
anxiety, hostility
blood dyscrasias (very rare)

Prescribing tacrine

Before prescribing
Diagnosing dementia does not in itself justify a trial of tacrine. The type of dementia must be established as Alzheimer's disease by a full history and physical examination, mental state testing, and usually, CT scan (without contrast) (see Table 1). In many cases, the patient's history will need to be confirmed by a reliable informant.

Dosage and administration
Issues of compliance and escalation of dosage make tacrine difficult to use in this patient group. It requires a supporter to ensure compliance with the 4 times daily schedule. Patients start at 10 mg 4 times daily and build up every 6 weeks to a higher dose capsule, to a maximum of 40 mg 4 times daily.

Tacrine is best taken between meals. If gastric irritation occurs, tacrine can be taken with meals, but this reduces the plasma concentration.

Liver function should be tested fortnightly for the first 12 we eks, monthly for the next 3 months and then quarterly thereafter. A blood count should be done every 6 weeks for 6 months, then quarterly.

If transaminase (ALT) concentrations reach 3 times the upper limit of normal, tacrine should be discontinued and ALT monitored weekly until normal, after which rechallenge with tacrine 10 mg 4 times daily is likely to be tolerated, but should be monitored with weekly ALT estimations. An exception is patients who have concomitant eosinophilia (>0.4 x 10⁹/L), fever (>37.8⁰C) and/or rash.⁶ If ALT levels reach 10 times the upper limit of normal, rechallenge is possible but must be very cautious, starting at 5 mg 4 times daily. Levels of ALT 20 times the upper limit of normal preclude further tacrine.

Individuals vary widely in their blood concentration. Serum assays, when available, may help to define patients in whom lack of response is due to low plasma concentrations.

After establishing the maximum tolerated maintenance dose, the drug may be continued until the decline of the patient has reached a point where further therapy is no longer worthwhile. Gradual discontinuation of tacrine should be considered when the patient's decline is obvious on two successive reviews (usually at 10-12 weekly intervals after the maximum maintenance dose of tacrine has been safely established) or when institutionalisation occurs. Proposed guidelines for withdrawing tacrine are to reduce the daily dose by 10 mg every two weeks and monitor the patient's function and cognitive performance fortnightly. If stepwise deterioration occurs, then the former dose should be re-instated; otherwise, reduction of tacrine should proceed. Over dosage is rare and will lead to a cholinergic syndrome that may be treated with a slow intravenous injection of atropine. A dose as high as 2-6 mg may be required.

Conclusions
Tacrine, the first drug to be approved for the treatment of mild to moderate Alzheimer's disease, represents an advance. Until better drugs are available, it will remain the only approved drug for this tragic disease. Ultimately, the decision whether or not to take tacrine rests with the patient and the family.

This decision to take tacrine should be based on these facts.

• Only one in 3 of all patients and one in 4 patients allocated to the highest and therefore the most effective dose (40 mg 4 times daily) were able to continue taking the drug for the full 30 weeks.¹
• Of the minority of patients who completed the trial, only 30-40% responded to therapy.
• Since the placebo response is about 20%1, the proportion of patients responding to tacrine at 40 mg 4 times daily could be estimated to be about 20%. The significant placebo response should be seen as encouraging the use of stimulation and behavioural strategies to complement any pharmacological treatment.
• The cost of tacrine ($200/month) should be considered against the possibility of deferring the costs of nursing home care by delaying admission.
• With the less rigid prescribing rules associated with 'real life' treatment, e.g. absence of forced titration, the proportion of patients able to tolerate the drug is likely to be greater than that observed in clinical trials.²

Expectations of patients and carers should not be raised unrealistically. They should appreciate that the small proportion of patients who appear to benefit from tacrine must be balanced against the relatively high incidence of adverse effects. Despite the drawbacks of modest efficacy linked with tolerability problems in many patients, tacrine may offer relief for some time to some patients with Alzheimer's disease and their carers.

While many patients and families will gladly try an imperfect therapy for Alzheimer's disease, educating the family, planning for the still inexorable decline of cognition, establishing support services for carers and linking them with community groups such as the Alzheimer's Association (see 'Patient Support Organisations' article) remain essential.