Alzheimer’s disease is a degenerative disorder characterised by marked atrophy of cerebral cortex resulting in progressive impairment of cognitive abilities with a relentless course to death in 6 to 10 years.
Various drugs have been tried, to halt or slow the progress of the disease including choline chloride, phosphatidyl choline (lecithin), and physostigmine. But the most promising is tacrine hydrochloride.
Tacrine and related drugs are centrally-acting, non-competitive reversible cholinesterase inhibitors, currently approved for treatment of Alzheimer’s disease. They also act as partial agonists at muscarinic receptors, block reuptake of dopamine, serotonin and noradrenaline, inhibit monoamine oxidase activity, and may block sodium and potassium channels. Tacrine is an acridine derivative (1,2,3,4-tetrahydro-9-aminoacridine), and is a potent centrally acting inhibitor of acetylcholinesterase. It can be combined with lecithin.
Apart from Alzheimer’s disease, tacrine has also been tried in the treatment of acute antidepressant drug overdose, myasthenia gravis, and tardive dyskinesia.
Echothiophate is a long-acting, irreversible cholinesteraseinhibitor used in the treatment of glaucoma. Metrifonate is the prodrug of dichlorvos (DDVP), an organophosphate insecticide, and has itself been used as an insecticide. Worldwide research and development of velnacrine for Alzheimer’s disease was halted by Hoechst-Roussel in 1994.
Tacrine was actually developed originally as a partial antagonist of morphine, and has been used along with it in the treatment of terminal cancer pain.
When tacrine is taken concurrently with food, bioavail-ability is reduced by 30 to 40%. Administration of tacrine at least 1 hour before meals has no effect on absorption. Tacrine is well absorbed following an oral dose due to its lipid solubility. The oral bioavailability of tacrine ranged from 2.4% to 36% in patients with either Alzheimer’s disease or amyotrophic lateral sclerosis. Absolute bioavailability is approximately 17%. Tacrine readily penetrates the blood-brain barrier. Protein binding is approximately 55%. Metabolism is extensive and occurs primarily in liver; the aromatic ring is hydroxylated at one or more positions primarily by cytochrome P-450 IA2 isozymes. At least 3 hydroxylated metabolites of tacrine have been identified in the urine, which may be biologically active. Up to 80% of a systemic dose is eliminated via the urine.
Chronic use of tacrine is associated with vomiting, diar-rhoea, headache, myalgia, and ataxia. Gastroenteritis appears to be a dose-dependant effect. Patients receiving metrifonate (15 mg/kg) experienced adverse effects of nausea, vomiting and diarrhoea, which were not seen at lower doses. Significant dose-related elevations in liver function tests, primarily SGPT (ALT), have been observed in 20 to 40% of Alzheimer’s patients within 6 to 8 weeks after beginning oral tacrine. This appears to be a reversible effect. Liver biopsies in several patients with elevated hepatic function tests have demonstrated granulomatous hepa-titis and liver cell necrosis. An immunologic mechanism has been suggested. Urinary frequency, stimulation of ureters and urinary bladder may occur, with resultant involuntary urination as a result of cholinergic effects of tacrine, especially at higher doses or overdoses.
Tacrine may be carcinogenic since it belongs to the chemical class, acridines, of which some members are animal carcinogens.
Drugs that may interact with tacrine include bethane-chol, cimetidine, succinylcholine, and theophylline. Because bethanechol is a cholinergic agonist and tacrine is a cholinest-erase inhibitor, additive or possibly synergistic cholinergic adverse effects (such as diarrhoea or vomiting) may result with concurrent use. Concurrent administration of tacrine with cimetidine may result in an increase in the AUC of tacrine of 64% and an increase in peak tacrine levels of 54%. Concomitant tacrine and succinylcholine therapy can result in prolongation of the action of succinylcholine. This is due to inhibition of plasma pseudocholinesterase, the enzyme responsible for metabolism of succinylcholine. Concurrent administration of tacrine with theophylline has doubled the half-life of theophylline and doubled the average plasma theophylline levels.
Overdose results in a cholinergic crisis characterised by muscarinic effects such as severe vomiting, salivation, sweating, bradycardia, hypotension, miosis, flushing, bronchos-pasm, increased bronchial secretions, involuntary urination and/ or defaecation, lacrimation, and convulsions. Decreased cardiac contractility, shock, cardiac arrest, atrial fibrillation, and heart block may occur as a result of cholinergic crisis. In severe cases, nicotinic effects such as muscle weakness and fasciculations might develop. Death may result from respiratory failure.
It is estimated that the human lethal dose of tacrine is approximately 30 mg/kg when unopposed by anticholinergic agents. This is based on LD50 studies in animals and prelethal toxicity. Therapeutic serum concentrations range from 7 to 16 ng/ml.
Treatment of overdose involves mainly symptomatic and supportive measures. Liver function tests should be closely monitored in any patient presenting with overdose. Monitor arterial blood gases and/or pulse oximetry, pulmonary function tests, and chest X-ray in patients with significant exposure. Depression of blood cholinesterase may occur following overdoses with these drugs. Decreases seen in plasma cholinesterase are immediate, while there is a gradual decline in erythrocyte cholinesterase levels. Atropine can be used as an antidote (initial dose of 1 to 2 mg IV, repeated every 3 to 60 minutes as needed to control muscarinic symptoms, then as needed for 24 to 48 hours). Glycopyrrolate and methscopola- mine bromide have been suggested as alternatives to atropine in treating the peripheral cholinergic symptoms induced by cholinergic, muscarinic agonists. However, controversy exists on the effectiveness of glycopyrrolate to reverse the cholin- ergic effects of tacrine.
For bronchospasm, administer beta2 adrenergic agonists. Consider the use of inhaled ipratropium and systemic corti- costeroids. Monitor peak expiratory flow rate; monitor for hypoxia and respiratory failure, and administer oxygen as necessary. For seizures, administer benzodiazepines or barbiturates.
Pralidoxime should be considered in patients with severe nicotinic effects after large, acute, recent exposures. The WHO currently recommends an initial bolus of at least 30 mg/kg, followed by an infusion of more than 8 mg/kg/hr. It is estimated that a plasma concentration of at least 4 mg/L may be necessary for pralidoxime to be effective. An alternative dose for adults is 1 to 2 grams diluted in 100 ml of normal saline infused over 15 to 30 minutes.
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