CNS Drug Reviews

Physostigmine, as the salicylate salt, is being developed as a drug for the treatment of Alzheimer’s disease. The memory and learning enhancement capabilities as well as other pharmacological effects of physostigmine will be thoroughly reviewed in this paper. Physostigmine (Antilirium®, Isopto®, eserine), an alkaloid from the West African perennial shrub Physostigma venenosum, is the oldest known acetylcholinesterase (AChE) inhibitor. Naturally occurring physostigmine was initially used clinically for ophthalmic purposes in 1877. Physostigmine was first synthesized in 1935. The general and dominant pharmacology of physostigmine is due to a short-acting inhibition of the enzymes AChE and butyrylcholinesterase (BuChE). Physostigmine exerts a stereoselective inhibition by acting as a pseudosubstrate and transferring a carbamate residue to the enzyme’s active site. Spontaneous hydrolysis regenerates the native enzyme and function. This activity underlies physostigmine use in the treatment of glaucoma and atropine and organophosphate intoxication and its potential role in the amelioration of the symptoms of Alzheimer’s disease. The history of physostigmine has been reviewed by Holmstedt (120) and more recently by Somani and Dube (246). Physostigmine is extracted from the seeds of Physostigma venenosum. As “ordeal beans” these seeds were used in trials for witchcraft (80) and an early therapeutic use in ophthalmology was described in 1863 (12). The structure of physostigmine (1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethyl-pyrrolo[2,3b]indo-5-ol-methylcarbamate) was determined by Stedman and Barger in 1925 (251) and its effect in prolonging acetylcholine action, subsequently revealed as mediated through the inhibition of AChE (252), was discovered by Loewi and Navratil a year later (158). Physostigmine is a lipid soluble tertiary amine with a pKa value of 7.9 and is approximately 75% ionized at the pH of blood and brain (247). CNS Drug Reviews Vol. 4, No. 2, pp. 87–136 © 1998 Neva Press, Branford, Connecticut