Tacrine Anticholinesterases

The only clinically available cholinergic therapy to date is an anticholinesterase (tacrine). Studies have shown short-term improvement in some aspects of memory and a delay in decline in some patients. It has been generally assumed that these effects are solely the result of enhancement of muscarinic mechanisms however, this assumption may be unwarranted. Direct muscarinic augmentation produces little measurable cognitive improvement and does not generally reproduce the memory-enhancing effects of anticholinesterases (Bruno et al. 1986 Tariot et al. 1988). 

The limited effectiveness of physostigmine did, however, encourage the development of longer-acting orally effective anticholinesterases such as tacrine (tetrahydroamino-acrydine), velnacrine and donepezil. 

The initial enthusiasm for tacrine and velnacrine, which are the anticholinesterases most studied clinically, has been tempered by the fact that not all patients respond. Most show the peripheral parasympathomimetic effects of cholinesterase inhibition, e.g. dyspepsia and diarrhoea, as well as nausea and vomiting, and about half of the patients develop hepatotoxicity with elevated levels of plasma alanine transaminase. While some peripheral effects can be attenuated with antimuscarinics that do not enter the brain, these add further side-effects and the drop-out rate from such trials is high (<75%) in most long-term studies. Donepezil appears to show less hepatotoxicity but its long-term value remains to be determined. 

A growing number of other diverse compounds have also been shown to bind to an allosteric site on the muscarinic receptors. Among them are pirenzepine (highly selective for Mi receptor), lidocaine and verapamil (ion channel blockers), tacrine (anticholinesterase compound), batrachotoxin, and strychnine (glycine receptor antagonist) [25,31-35],... 

Tacrine An anticholinesterase used in the treatment of Alzheimer s disease. 

Alcala MDM, Vivas NM, Hospital S, et ai. Characterisation of the anticholinesterase activity of two new tacrine-huperzine A hybrids, Neuropharmacol... 

Tacrine is a non-competitive, irreversible inhibitor of both acetyl and butyryl cholinesterase, with a greater potency for the latter enzyme. Based on the outcome of placebo-controlled, double-blind studies, tacrine was the first anticholinesterase to be licensed for the symptomatic treatment of AD in the United States. The main disadvantage of tacrine lies in its hepatotoxicity (approximately 50% of patients were found to develop elevated liver transaminases which reversed on discontinuation of the drug). Because of such side effects and limited efficacy, tacrine is no longer widely prescribed. 

Donepezil is primarily a reversible inhibitor of acetylcholinesterase with a long elimination half-life. It lacks the hepatotoxicity of tacrine but frequently causes nausea, vomiting and diarrhoea. These side effects, together with occasional bradycardia, sycope and changes in the sleep architecture, are directly associated with a central and peripheral enhancement of cholinergic function. At the present time, donepezil is the most widely prescribed anticholinesterase in the United States and Europe. 

Anticholinesterases E.g. physostigmine, tacrine, donepezil, metrifonate, huperzine A, eptastigmine, velnacrine, galantamine, rivastigmine Efficacy in early stages of AD... 

Eagger, S. A. Tacrine and older anticholinesterase drugs in dementia. Curr. Opin. Psychiat. 8 (1995) 264-270. 

Cholinomimetics that can increase central cholinergic activity have produced some improvements in Alzheimer s disease AChE inhibitors, particularly physostigmine, have been most studied. A study with an experimental potent, centrally acting anticholinesterase compound l,2,3,4-tetrahydro-9-aminoacridine (THA, Tacrine) involving Alzheimer s patients over a year-long period showed encouraging improvement without some side effects. 

Kirkby DL, Jones DN, Barnes JC, et al Effects of anticholinesterase drugs tacrine and E2020. the 5-... 

In 1993, tacrine amtnoacridinc, competitive unselective reversible inhibitor of cholinesterases) was the first anticholinesterase drug to receive FDA approval for the treatment of mild to moderate AD. The benefius of treatment were evident in end points that used ADAS as well as general clinical impressions, with 10-26% of recipients of high doses. showing measurable improvement over the course of 30 weeks (Knapp et ai, 1994). However, only a minority of patients were able to tolerate (he maximally effective dose... 

Tacrine, like other anticholinesterases, has been used intravenously in anaesthetic practice to reverse the effects of competitive (non-depolarising) blockers such as tubocurarine and to prolong the effects of depolarising... 

Memantine does not appear to attenuate the anticholinesterase effects of donepezil, galantamine, or tacrine, nor affect the pharmacokinetics of galantamine or donepezil. 

There is no pharmacokinetic interaction between digoxin and tacrine or donepezil. The bradycardic effects of anticholinesterases and digoxin may possibly be additive. 

Tacrine (THA, Cognex, 3), velnacrine (4) and SM 10888 (5) are members of the 9-amino-1,2,3,4-tetrahydroacridine family [1]. They have one common pharmacological property, that of selective inhibition of acetylcholinesterase in the central nervous system. Compared with classical anticholinesterases used in the treatment of myasthenia gravis, tacrine easily crosses the blood-brain barrier. 

In common with other anticholinesterase agents, tacrine induces a number of peripheral parasympathetic effects including nausea, vomiting, diarrhoea, abdominal cramps (9-40%), pollakiuria (6-25%), diaphoresis (3-17%) and ptyalism (3-10%), whilst agitation (5%), insomnia (6%) and confusion (3%) are rarely observed. 

---