Donepezil Anticholinesterases

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. 

Shintani EY, Uchida KM. (1997). Donepezil an anticholinesterase inhibitor for Alzheimer s disease. 

Figure 5. Cartoon of a cholinergic synapse showing major steps in the synthesis of acetylcholine. The two major receptor types, the ionotropic nicotinic receptor and the metabotropic muscarinic receptor, are shown (see also Chapter 1). Presynaptic muscarinic (M2) and nicotinic receptors are also depicted. Drugs which have been widely used to manipulate the cholinergic systems, and which are mentioned in the text, include the muscarinic receptor antagonists scopolamine and atropine and the nicotinic receptor agonist nicotine. Anticholinesterases (discussed elsewhere in this volume) include drugs such as physostigmine, rivastigmine, donepezil, and galanthamine.

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... 

A more recent use of anticholinesterase drugs has been to improve cognitive function in patients with Alzheimer s disease, where both the degree of dementia and amyloid plaque density correlate with the impairment of brain cholinergic function. Donepezil and rivastigmine are licensed in the UK for this indication. Both are orally active and cross the blood-brain barrier readily (see p. 408). 

Design, synthesis, and assessment of anticholinesterase activity of 2-(2-(4-Renzylpiperazin-l-yl)ethyl)isoindoline-l,3-dione derivatives showed that some of these compounds can function as potential acetylcholinesterase inhibitors with a potency comparable to that of donepezil [170]. 

Janowsky, D.S., Davis, J.M. and Overstreet, D.H. Anticholinesterase (DFP) toxicity antagonism by chronic donepezil a potential nerve agent treatment, Pharmacol Biochem. Behav., 81, 917, 2005. 

Funding/implementation issues led to variable availability in the UK. Subject of national guideline from National Institute for Clinical Excellence (NICE) requiring availability of licensed anticholinesterases (donepezil, rivastigmine, galantamine) subject to specific requirements ... 

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

An in vitro study in rats suggested that memantine does not attenuate the anticholinesterase effects of donepezil at therapeutic concentrations. In a later study 19 healthy subjects were given memantine 10 mg before and on the last day of taking donepezil (5 mg daily for 7 days then 10 mg daily for 22 days). The pharmacokinetics of both drugs were not significantly affected by concurrent use, and the effects of donepezil on anticholinesterase were also unaffected. Furthermore, an efficacy and safety study of one year s duration has reported that the combination is well tolerated and beneficial. ... 

Parkinsonism is due to an imbalance between two neurotransmitters, dopamine and acetylcholine, in the basal ganglia of the brain. Centrally acting anticholinesterases increase the amount of acetylcholine in the brain, which could lead to an exacerbation of parkinsonian symptoms. Levodopa improves the situation by increasing the levels of dopamine. It is not known why donepezil modestly increased the levels of levodopa. 

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

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