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| Trade names | Antilirium |
| AHFS/Drugs.com | Monograph |
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| Routes of administration | Intravenous,intramuscular,ophthalmic |
| Drug class | Cholinesterase inhibitor |
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| Metabolism | Major metabolite:Eseroline |
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| ECHA InfoCard | 100.000.302 |
| Chemical and physical data | |
| Formula | C15H21N3O2 |
| Molar mass | 275.352 g·mol−1 |
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Physostigmine (also known aseserine froméséré, the West African name for theCalabar bean) is a highlytoxicparasympathomimeticalkaloid, specifically, a reversiblecholinesterase inhibitor. It occurs naturally in theCalabar bean and the fruit of theManchineel tree.
The chemical was synthesized for the first time in 1935 byPercy Lavon Julian and Josef Pikl. It is available in the U.S. under the trade namesAntilirium andIsopto Eserine, and as eserine salicylate and eserine sulfate. Today, physostigmine is most commonly used for its medicinal value. However, before its discovery bySir Robert Christison in 1846, it was much more prevalent as anordeal poison. The positive medical applications of the drug were first suggested in the gold medal-winning final thesis ofThomas Richard Fraser at theUniversity of Edinburgh in 1862.[1]
Physostigmine, an acetylcholinesterase inhibitor, can be used to treatglaucoma anddelayed gastric emptying. Because it enhances the transmission of acetylcholine signals in the brain and can cross theblood–brain barrier, physostigmine salicylate is used to treatanticholinergic poisoning (that is, poisoning by substances that interfere with the transmission of acetylcholine signaling, such asatropine,scopolamine, and other anticholinergic drug overdoses).[2] It is also used to reverse neuromuscular blocking. Physostigmine is theantidote of choice forDatura stramonium poisoning. It is also an antidote forAtropa belladonna poisoning, the same as foratropine.[3] It has also been used as an antidote for poisoning withGHB,[4] but is poorly effective and often causes additional toxicity, so is not a recommended treatment.[5] It can also be used as an antidote fordimenhydrinate ordiphenhydramine poisoning.[6]
It has been shown to improve long-term memory,[7] and was once explored as a therapy forAlzheimer's disease, but inclinical trials it was not shown to confer convincing benefits, and it led to very common moderate to severe side-effects such asnausea,vomiting,diarrhea, loss of appetite, abdominal pain, andtremors, resulting in a high rate of withdrawal.[8] Physostigmine's poor tolerability led to it being abandoned in favor of later acetylcholinesterase inhibitors, three of which are currently in use:donepezil,galantamine, andrivastigmine.[9] Recently, it has begun to be used in the treatment oforthostatic hypotension.
Recently,[when?] physostigmine has been proposed as an antidote for intoxication withgamma hydroxybutyrate (GHB, a potent sedative-hypnotic agent that can cause loss of consciousness, loss of muscle control, and death).[citation needed] Physostigmine may counteract GHB by producing a nonspecific state of arousal. However, not enough scientific evidence shows physostigmine properly treats GHB toxicity. Furthermore, lower doses of GHB produce a stronger action at theGHB receptor than at theGABAB receptor, resulting in a stimulating effect which would act synergistically with physostigmine and produce hyperstimulation when the GHB blood levels begin to drop.
Physostigmine also has other proposed uses: it could reverse undesired side effects ofbenzodiazepines such asdiazepam, alleviating anxiety and tension.[10] Another proposed use[by whom?] of physostigmine is to reverse the effects ofbarbiturates (any of a group ofbarbituric acids derived for use as sedatives orhypnotics).
Physostigmine acts by interfering with the metabolism ofacetylcholine. It is a reversible inhibitor ofacetylcholinesterase, the enzyme responsible for the breakdown of acetylcholine in thesynaptic cleft of theneuromuscular junction.[11] It indirectlystimulates bothnicotinic andmuscarinic acetylcholine receptors. Physostigmine has anLD50 of 3 mg/kg in mice.
Physostigmine functions as an acetylcholinesterase inhibitor. Its mechanism is to prevent the hydrolysis of acetylcholine by acetylcholinesterase at the transmitted sites of acetylcholine.[12] This inhibition enhances the effect of acetylcholine, making it useful for the treatment of cholinergic disorders and myasthenia gravis. More recently, physostigmine has been used to improve the memory of Alzheimer's patients due to its potent anticholinesterase activity.[13] However, its drug form, physostigmine salicylate, has poor bioavailability.[14]
Physostigmine also has a miotic function, causing pupillary constriction. It is useful in treatingmydriasis. Physostigmine also increases outflow of the aqueous humor in the eye, making it useful in the treatment of glaucoma.[15]
An overdose can causecholinergic syndrome. Other side effects may includenausea,vomiting,diarrhea,anorexia, dizziness, headache, stomach pain, sweating,dyspepsia, and seizures.[16] The carbamatefunctional group readily hydrolyses in water, and in bodily conditions. The metabolite thus formed from physostigmine and some other alkaloids (e.g.cymserine) iseseroline, which research has suggested may be neurotoxic to humans.[17] Death can occur rapidly following overdose as a result ofrespiratory arrest andparalysis of the heart.
Physostigmine has twostereocenters—the two carbons where the five-membered rings join—so any attempt at thetotal synthesis must pay attention to obtaining the correctstereoisomer. The 71 syntheses of physostigmine yield 33racemic mixtures and 38 products of a singleenantiomer. The first total synthesis of physostigmine was achieved by Julian and Pikl in 1935.[18] The main goal of Julian's formal physostigmine synthesis was to prepare the key compound (L)-eseroline (compound10 in the adjacent diagram), the conversion of which to physostigmine would be straightforward. In one of his earlier works[19] Julian synthesized the ring of physostigmine from 1-methyl-3-formyl-oxindole as starting material, which was discovered byPaul Friedländer. However, the starting material was expensive, and the reduction of a nitrile to an amine (similar to the reaction of compound6 to give compound7 in the diagram) with sodium and alcohol did not proceed in good yield. In his second work "Studies in the Indole Series III," he had improved the yield of amine from nitrile significantly by using palladium and hydrogen. Although he succeeded in the synthesis of the target compound, the route had several drawbacks. First, the chemical resolution of compound8 is unreliable, and the chemical resolution of''rac''-eserethole gives optically pure product only after eight recrystallizations of its tartrate salt. Second, the reductive amination going from compound8 to compound9 requires a large amount of Na. In the years since this initial work, many other groups have used a variety of approaches to construct the ring system and showcase new synthetic methods.
Physostigmine biosynthesis is proposed fromtryptamine methylation and post-heterocyclization catalyzed by an unknown enzyme:[20]
TheEfik people, living inCross River State and theIbibio people inAkwa Ibom State, in what is now the south-south ofNigeria, were the first to come in contact with physostigmine, the active ingredient in the Calabar bean.[21] The Calabar bean, or chopping nut, was very prevalent in Efik culture as anordeal poison. Individuals accused of witchcraft would drink the white, milky extract of the bean, made by crushing the bean in a mortar and soaking the remains in water. If the accused died, it was considered proof of their use of witchcraft. If they lived, usually due to vomiting up the poison, then they were declared innocent and sent free.[22]
In 1846, European missionaries arrived in what was referred to as Old Calabar, now part of Nigeria. These missionaries wrote about the use of the Calabar bean as a test for witchcraft. These beans eventually made their way back to Scotland, the home of these particular missionaries, where in 1855Robert Christison, atoxicologist, tested the toxicity of the poison on himself by eating one. He survived to document the experience. The bean was studied throughout the 1860s by a few differentEdinburgh scientists, includingDouglas Argyll Robertson who wrote a paper on the use of Calabar bean extract on the eye and was the first to use it medicinally, and Thomas Richard Fraser, who researched how to best extract the active principle, which was later determined to be physostigmine. Fraser also studied theantagonism between physostigmine andatropine extremely rigorously, at a time when the concept of antagonism had little if any experimental support. Fraser's research is still the basis of today's knowledge about the interactions between atropine and physostigmine at many different and specific doses.[23] Physostigmine's first use as a treatment forglaucoma was byLudwig Laqueur in 1876. Laqueur himself had glaucoma so, like Christison, he experimented on himself, although Laqueur was much more scientific and methodical in his self-treatment.
In the 1920s,Otto Loewi determined thebiomechanical mechanism for the effects of physostigmine on the body. Loewi was studying how actions that we now consider to be controlled by theparasympathetic nervous system, were directed by chemicals. During his studies, Loewi discoveredacetylcholine and that physostigmine acted by preventing acetylcholine inhibition. In 1936, Loewi was awarded the Nobel Prize for his work on discovering acetylcholine and biological chemical transmitters.
Other important discoveries surrounding physostigmine were made at theUniversity of Edinburgh in 1925. Edgar Stedman and George Barger determined the structure of physostigmine using a method called chemical degradation. In 1935Percy Lavon Julian was later the first to synthesize physostigmine. English scientistRobert Robinson was also working on the synthesis of physostigmine, but surprisingly Julian, a relatively unknown scientist at the time, was the successful one.[22]
In 1934, while working atSt Alfege's Hospital in London,Dr Mary Walker discovered that asubcutaneous injection of physostigmine could temporarily reverse the muscle weakness found in patients withmyasthenia gravis. She had noted that the symptoms and signs of myasthenia were similar to those found incurare poisoning, and physostigmine was used as anantidote to curare poisoning at that time.[24] Her article explaining the first case of myasthenia gravis being successfully treated with physostigmine was published inThe Lancet in June 1934.[25]
This database provides a catalog of the therapeutics currently or previously tested as treatment for Alzheimer's disease and related disorders, focusing on those that have progressed to Phase 2 or beyond in U.S. clinical trials.
