PHARMACOLOGY AND THERAPETICS-INDIRECT ACTING CHOLINOMIMETICS
Introduction: The actions of acetylcholine released from autonomic and somatic motor nerves are terminated by enzymatic hydrolysis of the molecule. Hydrolysis is accomplished by the action of acetylcholinesterase, which is present in high concentrations in cholinergic synapses. The indirect-acting cholinomimetics have their primary effect at the active site of this enzyme, although some also have direct actions at nicotinic receptors.
Molecular structure and Pharmacokinetics: There are three chemical groups of cholinesterase inhibitors:
(1) simple alcohols bearing a quaternary ammonium group, eg, edrophonium;
(2) carbamic acid esters of alcohols having quaternary or tertiary ammonium groups (carbamates, eg, neostigmine); and
(3) organic derivatives of phosphoric acid (organophosphates, eg, echothiophate). Edrophonium, neostigmine, and pyridostigmine are synthetic quaternary ammonium agents used in medicine. Physostigmine (eserine) is a naturally occurring tertiary amine of greater lipid solubility that is also used in therapeutics. Carbaryl (carbaril) is typical of a large group of carbamate insecticides designed for very high lipid solubility, so that absorption into the insect and distribution to its central nervous system are very rapid. Many of the organophosphates (echothiophate is an exception) are highly lipid-soluble liquids. Echothiophate, a thiocholine derivative, is of clinical value because it retains the very long duration of action of other organophosphates but is more stable in aqueous solution. Soman is an extremely potent “nerve gas.” Parathion and malathion are thiophosphate (sulfur-containing phosphate) prodrugs that are inactive as such; they are converted to the phosphate derivatives in animals and plants and are used as insecticides.
