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Acetylcholinesterase inhibitors
General information
Cholinesterase inhibitors increase parasympathetic nervous system (cholinergic) activity indirectly by inhibiting acetylcholinesterase, thereby preventing the breakdown of acetylcholine. They are only effective in the presence of acetylcholine. They are listed in Table 1 .
Table 1
Acetylcholinesterase inhibitors
| Ambenonium |
| Diisopropyl fluorophosphate (Diflos) |
| Distigmine |
| Donepezil |
| Ecothiopate |
| Edrophonium |
| Eserine |
| Methoxytacrine |
| Metrifonate |
| Neostigmine |
| Physostigmine |
| Prostigmine |
| Pyridostigmine |
| Rivastigmine |
| Tacrine and 7-methoxytacrine |
The cholinesterase inhibitors are used in the treatment of Alzheimer’s disease (tacrine, 7-methoxytacrine, donepezil, metrifonate, and rivastigmine), the treatment and diagnosis of myasthenia gravis (distigmine, edrophonium, neostigmine, physostigmine, prostigmine, and pyridostigmine), and the treatment of atony of the intestine or bladder. In the eye, they increase the flow rate of aqueous humor across the trabeculum, reduce resistance to its flow, and consequently lower the intraocular pressure.
Use of acetylcholinesterase inhibitors in Alzheimer’s disease
Of the acetylcholinesterase inhibitors, tacrine, methoxytacrine, 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experimental) drugs would not be justified in other-than-serious disease states, but they are reversible if the drug is withdrawn.
General adverse effects and adverse reactions
The acetylcholinesterase inhibitors have the effects that one would expect to result from their promoting nicotinic and muscarinic cholinergic activity, including unwanted effects such as bradycardia, miosis, colic, and hypersalivation. Adverse reactions have been stated to be relatively more common with neostigmine than with some other drugs such as pyridostigmine or ambenonium, but it is doubtful whether the benefit to harm balance indeed differs, since neostigmine also tends to be more effective in certain patients. Ambenonium is relatively likely to cause headache. When neostigmine and pyridostigmine are used as bromide salts, bromide rashes can occur.
Local adverse reactions
Acetylcholinesterase inhibitors as eye drops have more intense effects in myopic and young patients, causing aggravation of myopia, blurred vision, and periorbital pain, due to congestion of the iris and ciliary body. Anterior and posterior synechiae can develop. Allergic reactions have been reported as has epithelial toxicity. The acetylcholinesterase inhibitors can cause pseudopemphigoid reactions in the eyelids and occlusion of the lacrimal puncta [SED-12, 1198] [ ]. The danger that a miotic agent will produce retinal detachment is directly proportional to the capacity of the drug to produce spasm of the ciliary body. Retinal detachment has been reported after the use of cholinergic agents, but they can also be coincidental.
Systemic reactions
The commonest adverse reactions to the acetylcholinesterase inhibitors are headache and periorbital pain. Signs of vagal stimulation can occur, with nausea, vomiting, sweating, hypersalivation, lacrimation, hypotension, bradycardia, bronchial constriction, respiratory failure, and nightmares. These reactions essentially occur during intensive treatment for acute closed-angle glaucoma, requiring frequent instillations of pilocarpine. Elderly people and young children are at particular risk.
Organs and systems
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