Physostigmine--an overview as pretreatment drug for organophosphate intoxication

Physostigmine (Phy) is one of the oldest drug isolated from Calabar beans and successfully used for the treatment of glaucoma in 1864. Since then, it has been widely employed for various therapeutic purposes. Recently, it has gained prominence because of its clinical trials in the treatment of Alzheimer's disease. Phy is also considered to be a potent prophylactic antidote for organophosphate poisoning. It is a reversible cholinesterase (ChE) inhibitor and has a short duration of action. It crosses the blood-brain barrier readily. Hence, it is a centrally acting carbamate. For the last 50 years, numerous authors have shown that pretreatment with Phy would rapidly improve the incapacitating effects of organophosphate intoxication in various animal species. Phy carbamylates to a portion of ChE enzyme and thus protects the enzyme from binding with organophosphate, which are irreversible ChE inhibitors. Organophosphates are metabolized very quickly in the body or bind to non-specific binding sites. The carbamylated ChE enzyme decarbamylates to free the enzyme for normal functioning. The rates of decarbamylation of butyrylcholinesterase (BuChE) in plasma and ChE in brain and muscle are different and are related to the half-life of Phy in these tissues. In addition to ChE inhibition, Phy has got a direct action on acetylcholine (ACh) receptor ionophore complex by interacting with the ACh-gated cation channels. Physostigmine has a half-life of 16, 23 and 30 min in rat, dog and man, respectively. The bioavailability of Phy is very low (about 2%) and it is extensively metabolized in the liver. Less than 4% of Phy is excreted unchanged in the urine and a portion is also eliminated in the bile. Physostigmine has a narrow margin of safety, and a slight increase in dose causes cholinergic symptoms, which can be counteracted by cholinolytic therapy. This review article deals with various aspects of physostigmine such as historical, therapeutic uses, mechanisms of action, methods for the determination, disposition and pharmacokinetics, toxicity and finally as an antidote against organophosphate intoxication.