Physostigmine

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Physostigmine
Physostigmine structure.png
Systematic (IUPAC) name
(3aR,8aS)-1,3a,8-Trimethyl-1H,2H,3H,3aH,8H,8aH-pyrrolo[2,3-b]indol-5-yl N-methylcarbamate
Clinical data
Trade names Antilirium
AHFS/Drugs.com monograph
Pregnancy cat. C (AU) C (US)
Legal status -only (US)
Routes intravenous, intramuscular, ophthalmic
Pharmacokinetic data
Metabolism Major metabolite: Eseroline
Identifiers
CAS number 57-47-6 YesY
ATC code S01EB05 V03AB19
PubChem CID 5983
DrugBank DB00981
ChemSpider 5763 YesY
UNII 9U1VM840SP YesY
KEGG D00196 YesY
ChEBI CHEBI:27953 YesY
ChEMBL CHEMBL94 YesY
Chemical data
Formula C15H21N3O2 
Mol. mass 275.346 g/mol
 YesY (what is this?)  (verify)

Physostigmine (also known as eserine from éséré, West African name for the Calabar bean) is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean.

The chemical was synthesized for the first time in 1935 by the chemists Percy Lavon Julian and Josef Pikl. It is available in the U.S. under the trade names Antilirium, Eserine Salicylate, Isopto Eserine, and Eserine Sulfate.

Pharmacology[edit]

Physostigmine acts by interfering with the metabolism of acetylcholine. It is a covalent (reversible - bond hydrolyzed and released) inhibitor of acetylcholinesterase, the enzyme responsible for the breakdown of acetylcholine in the synaptic cleft of the neuromuscular junction.[1] It indirectly stimulates both nicotinic and muscarinic acetylcholine receptors.

Synthesis[edit]

Julian's synthesis of physostigmine

Physostigmine has two chiral carbon atoms. Therefore, attention needs to be paid to the synthesis of the correct diastereomers. There are 71 syntheses of physostigmine; 33 yield racemic mixtures, 38 yield product that is a single enantiomer. The first total synthesis of physostigmine was achieved by Julian and Piki in 1935.[2] The main goal of Julian’s physostigmine synthesis was to get the intermediate key compound, l-eseroline (compound 10 in the diagram to the left). Then, this compound would be easily converted to physostigmine. In one of his earlier works[3] Julian synthesized the ring of physostigmine from starting material 1-methyl-3-formyl oxindole, which was discovered by Friedlander. However, he faced the problems that the starting material was expensive, and the reduction of a nitrile to an amine (similar to the reaction of compound 6 to given compound 7 in the diagram) with sodium and alcohol did not result 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 chemical, the route had several drawbacks. First, the chemical resolution of compound 8 is unreliable, and the chemical resolution of d,l-eserethole gives optically pure enantiomers after eight recrystallizations of its tartrate salt. Second, the reaction of compound 8 to give compound 9 requires a large amount of Na. In the years since this initial work, many other groups have used a variety of approaches to overcome these problems.

Biosynthesis[edit]

Physostigmine biosynthesis is proposed from tryptamine methylation and post-heterocyclization catalyzed by an unknown enzyme:

Physostigmine proposed biosynthesis

Clinical uses[edit]

Physostigmine is used to treat glaucoma, Alzheimer's disease and delayed gastric emptying. It has been shown to improve short term memory (Krus et al. 1968). Recently, it has begun to be used in the treatment of orthostatic hypotension.

Because it is a tertiary amine, it can cross the blood–brain barrier, and physostigmine salicylate is used to treat the central nervous system effects of atropine, scopolamine and other anticholinergic drug overdoses.

Physostigmine is the antidote of choice for Datura stramonium poisoning. It is also an antidote for Atropa belladonna poisoning, the same as for atropine.[4] It has been also used as an antidote for poisoning with GHB as well,[5] but is poorly effective and often causes additional toxicity, so is not a recommended treatment.[6]

Bioactivity[edit]

Physostigmine functions as an acetylcholinesterase inhibitor. Its mechanism is to prevent the hydrolysis of acetylcholine by acetylcholinesterase at the transmitted sites of acetylcholine. 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.[medical citation needed] However, the drug form of physostigmine, physostigmine salicylate, has poor bioavailability.

Physostigmine also has a miotic function, causing pupillary constriction. It is useful in treating mydriasis. Physostigmine also increases outflow of the aqueous humor in the eye, making it useful in the treatment of glaucoma.

Recently, physostigmine has been proposed as antidote for intoxication with gamma hydroxybutyrate (GHB, a potent sedative-hypnotic agent that can cause loss of consciousness, loss of muscle control, and death). Physostigmine may treat GHB by producing a nonspecific state of arousal. However, there is not enough scientific evidence to prove physostigmine properly treats GHB toxicity. Furthermore, lower doses of GHB produce a stronger action at the GHB receptor than the GABAB-receptor, resulting in a stimulating effect which would act synergistically with physostigmine and producing hyperstimulation when the GHB blood levels begin to drop.

Physostigmine also has other proposed uses: it could reverse undesired side effects of benzodiazepines such as diazepam, alleviating anxiety and tension. Another proposed use of physostigmine is to reverse the effects of barbiturates (any of a group of barbituric acids derived for use as sedatives or hypnotics).

Side effects[edit]

An overdose can cause cholinergic syndrome.

Other side effects may include nausea, vomiting, diarrhea, anorexia, dizziness, headache, stomach pain, sweating, dyspepsia and seizures.[7]

See also[edit]

References[edit]

  1. ^ Katzung, B. G.; Masters, S.; Trever, A. (2009). Basic and Clinical Pharmacology. McGraw Hill. p. 110. ISBN 978-0-07-160405-5. 
  2. ^ Julian, P. L.; Pikl, J. (1935). "Studies in the Indole Series. III. On the Synthesis of Physostigmine". Journal of the American Chemical Society 57 (3): 539–544. doi:10.1021/ja01306a046. 
  3. ^ Julian, P. L.; Pikl, J.; Boggess, D. (1934). "Studies in the Indole Series. II. Alkylation of 1-Methyl-3-Formyloxindole and a Synthesis of the Basic Ring Structure of Physostigmine". Journal of the American Chemical Society 56 (8): 1797–1801. doi:10.1021/ja01323a046. 
  4. ^ Potter, S. O. L. (1893). A Handbook of Materia Medica, Pharmacy and Therapeutics. London: P. Blakiston's. p. 53. 
  5. ^ Traub, S. J.; Nelson, L. S.; Hoffman, R. S. (2002). "Physostigmine as a treatment for gamma-hydroxybutyrate toxicity: a review". Journal of Toxicology. Clinical Toxicology 40 (6): 781–787. doi:10.1081/CLT-120015839. PMID 12475191.  edit
  6. ^ Zvosec, D. L.; Smith, S. W.; Litonjua, R.; Westfal, R. E. (2007). "Physostigmine for gamma-hydroxybutyrate coma: inefficacy, adverse events, and review". Clinical Toxicology 45 (3): 261–265. doi:10.1080/15563650601072159. PMID 17453877.  edit
  7. ^ Alzheimer Research Forum