Drugs acetylcholinesterase inhibitors

A systematic search of published literature identified 13 studies concerned with the value for money of acetylcholinesterase inhibitors. The majority were cost analyses of the potential savings in providing health and social care which may accrue from the introduction of these drugs. However, the available clinical evidence is not sufficient to support the assumption that acetylcholinesterase inhibitors are equivalent to other interventions in terms of clinical effect or side effects (Birks and Melzer, 1999 NICE, 2001). Furthermore, research to assess potential cost savings implicitly assumes that... 

To date, three of the four FDA-approved medications used in the treatment of the cognitive aspects of AD are acetylcholinesterase inhibitors, which increase overall levels of acetylcholine (the fourth reduces glutamate excitotoxicity via the NMD A receptor). The identification of compounds that reduce inflammation (and thus immune-mediated neuron loss) or increase the levels of acetylcholine are, therefore, also active areas of drug discovery. 

Another drug with a high incidence of hepatotoxicity is the acetylcholinesterase inhibitor tacrine. Binding of reactive metabolites to liver tissue correlated with the formation of a 7-hydroxy metabolite [13], highly suggestive of a quinone imine metabolite as the reactive species. Such a metabolite would be formed by further oxidation of 7-hydroxy tacrine (Figure 8.11). 

Acetylcholinesterase is a remarkably efficient enzyme turnover has been estimated as over 10 000 molecules per second at a single active site. This also makes it a key target for drug action, and acetylcholinesterase inhibitors are of considerable importance. Some natural and synthetic toxins also function by inhibiting this enzyme (see Box 7.26). 

Cummings JL, Ringman JM. Metrifonate (Trichlorfon) a review of the pharmacology, pharmacokinetics and clinical experience with a new acetylcholinesterase inhibitor for Alzheimer s disease. Expert Opin Investig Drugs 1999 8(4) 463-71. 

Mucke HAM. Metrifonate treatment of Alzheimer s disease, acetylcholinesterase-inhibitor. Drugs Future 1998 23 491-7. 

Rivastigmine (1) was the second drug after donepezil in a class of second-generation acetylcholinesterase inhibitors to become commercially available. It is now marketed in over 60 countries worldwide, including those in Europe and South America and the United Kingdom. It has central selectivity, suggesting fewer peripheral adverse effects. These include nausea, vomiting, abdominal pain, and anorexia (2,3). Daily doses up to 12 mg were tolerated and produced improvement in patients with Alzheimer s disease (4). 

Gottwald MD, Rozanski RI. Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer s disease review and current status. Expert Opin Invest Drugs 1999 8(10) 1673-82. 

Of the acetylcholinesterase inhibitors, tacrine, methoxy-tacrine, metrifonate, donepezil hydrochloride, and rivastigmine are used in the treatment of Alzheimer s disease. In 12-30% of patients with Alzheimer s disease, tacrine causes an increase in hepatic transaminase activity. Abdominal adverse effects are very frequent, for example nausea, anorexia, diarrhea. The peripheral cholinomimetic effects of tacrine occur in a very high proportion of patients, probably the majority. The hepatic effects seem to be such that the use of these new (and in some cases still experimental) drugs would not be justified in... 

The effect of acetylcholinesterase inhibitors can be reduced by drugs with anticholinergic effects, such as antihistamines or neuroleptic drugs (12). 

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