Physostigmine Other names: Eserolein methylcarbamate Eserine Eserine sulfate Erserine

Physostigmine is a reversible inhibitor of acetylcholinesterase. As an inhibitor of acetyl-cholinesterase, physostigmine slows down the degradation of acetylcholine and acts like an indirect parasympathomimetic drug due to an increase of the acetylcholine concentration at the receptor. Unlike the quarternary amines, physostigmine is able to pass the blood-brain barrier and to act in the CNS. The main effect of physostigmine salicylate (also utilized therapeutically) is the inhibition of cholinesterase, limited in time, which causes increased formation of acetylcholine.

Like all medically used cholinesterase inhibitors, physostigmine is a carbamate, as far as its chemical structure is concerned. Its structure is similar to that of the substances neostigmine and pyridostigmine, however, unlike the latter, it has a tertiary nitrogen atom instead of a quaternary nitrogen atom.

In vitro, physostigmine inhibits the cholinesterase in the brain of rats up to a dilution of 1.2 × 10-7g (50%).

Physostigmine is well and quickly absorbed, both after intestinal and after subcutaneous and intramuscular administration. Absorption via the nasal mucosa after local use in the eye may also be clinically and systemically effective. The degradation of physostigmine is caused partly by hydrolysis, partly by enzymes. Hydrolysis produces metabolites, excretion is either in glucuronic or sulfactic form, predominantly via the urine (approx. 80%), to a lesser extent via the faeces (approx. 5%). Excretion of physostigmine is completed after 24 hours. Doses administered in intervals of 60 to 90 minutes do not cause accumulation.

Due to its structure as a tertiary amine, distribution is according to lipophilicity, i.e. with good passability of the blood-brain barrier. This is an important feature for the indications of physostigmine which is, therefore, used mainly in circumstances that require the inhibition of acetylcholinesterase in the CNS. Due to the lipophilicity and the increased affinity of physostigmine for the central nervous enzyme, doses are sufficient to obtain this effect which almost completely put the peripheral effects of physostigmine into the background.

Eseroline, the physostigmine metabolite, has analgesic effects which cannot be eliminated by naloxone or atropine. Eseroline causes cardiovascular stimulation due to a central effect on the peripheral release of adrenaline from the adrenal gland, which predominates over the peripheral vagal effect, so that a pulse increase is observed instead of bradycardia. After intravenous administration, the effect of physostigmine can be observed after only a few minutes. The antagonizing of anticholinergic effects requires a physostigmine-plasma concentration of 3 to 5 ng/l.

The pronounced effect lasts for approx. 20 minutes and wears off almost completely up to the 30th-40th minute.

In animals, the elimination half-life of physostigmine is between 20 and 30 minutes after intravenous administration, in human subjects it is between 18 and 30 minutes. This is in conformity with clinical experience in human subjects, with a pronounced effect for approx. 20 minutes and a wearing-off of the effect starting after the 30th to the 40th minute. In human subjects, clearance is between 1.5 and 5.7 l/min.

Toxicology

Toxicity studies with single administration have shown that the average lethal dose in rats is 1.28 mg/kg bodyweight after intramuscular administration, in rabbits it is 1.57 mg/kg bodyweight. An average lethal dose of 310 µg/kg bodyweight in mice and of 910 µg/kg bodyweight in rabbits has been determined after intravenous administration. Death occurred after unconsciousness and respiratory arrest.

Transient tremor, loss of body weight and decrease of body temperature and the death of 50% of the test animals have been observed after infusion of 0.24 mg/kg bodyweight/hour over 7 days in guinea pigs. Bacterial tests showed no evidence of mutagenic properties. Further studies with regard to mutagenic potential have not been done. No carcinogenicity studies have been performed.

No reproduction toxicology studies have been performed.