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Pyridostigmine

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Pyridostigmine.svg
ChemSpider 2D Image | Pyridostigmine | C9H13N2O2

Pyridostigmine 

  • Molecular FormulaC9H13N2O2
  • Average mass181.211 Da

155-97-5[RN]3-[(Dimethylcarbamoyl)oxy]-1-methylpyridinium
3-Dimethylcarbamoyloxy-1-methyl-pyridinium5-21-02-00078 (Beilstein Handbook Reference)[Beilstein]

Pyridostigmine Bromide

 Pyridostigmine BromideCAS Registry Number: 101-26-8CAS Name: 3-[[(Dimethylamino)carbonyl]oxy]-1-methylpyridinium bromideAdditional Names: 3-hydroxy-1-methylpyridinium bromide dimethylcarbamate; 1-methyl-3-hydroxypyridinium bromide dimethylcarbamate; 3-(dimethylcarbamyloxy)-1-methylpyridinium bromideManufacturers’ Codes: Ro-1-5130Trademarks: Kalymin (Temmler); Mestinon (Roche); Regonol (Organon)Molecular Formula: C9H13BrN2O2Molecular Weight: 261.12Percent Composition: C 41.40%, H 5.02%, Br 30.60%, N 10.73%, O 12.25%Literature References: Reversible inhibitor of acetylcholinesterase. 
Prepn: Urban, US2572579 (1951 to Hoffmann-La Roche). Mechanism of protective effect in soman poisoning: X. Deyi et al.,Fundam. Appl. Toxicol.1, 217 (1981). Evaluation of effect on neuromuscular function: M. Glikson et al.,ibid.16, 288 (1991). Evaluation of side effects profile under desert conditions: J. E. Cook et al.,Mil. Med.157, 250 (1992). Review of prophylactic effect in nerve agent poisoning: R. M. Dawson, J. Appl. Toxicol.14, 317 (1994).Properties: Shiny, hygroscopic crystals from abs ethanol, mp 152-154°. Freely sol in water, alcohol. Practically insol in ether, acetone, benzene. Aq solns may be sterilized by autoclaving with steam.Melting point: mp 152-154°Therap-Cat: Cholinergic; in treatment of myasthenia gravis. Pre-exposure antidote to chemical warfare agents.Keywords: Cholinergic.

Pyridostigmine is a medication used to treat myasthenia gravis.[1] It is also used together with atropine to end the effects of neuromuscular blocking medication of the non-depolarizing type.[2] It is typically given by mouth but can also be used by injection.[2] The effects generally begin within 45 minutes and last up to 6 hours.[2]

Common side effects include nausea, diarrhea, frequent urination, and abdominal pain.[2] More severe side effects include low blood pressure, weakness, and allergic reactions.[2] It is unclear if use in pregnancy is safe for the fetus.[2] Pyridostigmine is an acetylcholinesterase inhibitor in the cholinergic family of medications.[2] It works by blocking the action of acetylcholinesterase and therefore increases the levels of acetylcholine.[2]

Pyridostigmine was patented in 1945 and came into medical use in 1955.[3] It is on the World Health Organization’s List of Essential Medicines.[4] Pyridostigmine is available as a generic medication.[2]

Medical uses

Pyridostigmine is used to treat muscle weakness in people with myasthenia gravis or forms of congenital myasthenic syndrome and to combat the effects of curariform drug toxicity. Pyridostigmine bromide has been FDA approved for military use during combat situations as an agent to be given prior to exposure to the nerve agent Soman in order to increase survival. Used in particular during the first Gulf War, pyridostigmine bromide has been implicated as a causal factor in Gulf War syndrome.[5]

Pyridostigmine sometimes is used to treat orthostatic hypotension.[6] It may also be of benefit in chronic axonal polyneuropathy.[7]

It is also being prescribed ‘off-label’ for the postural tachycardia syndrome as well as complications resulting from Ehlers–Danlos syndrome.[7][8]

Contraindications

Pyridostigmine bromide is contraindicated in cases of mechanical intestinal or urinary obstruction and should be used with caution in patients with bronchial asthma.[9][10]

Side effects

Common side effects include:[9]

  • Sweating
  • Diarrhea
  • Nausea
  • Vomiting
  • Abdominal cramps
  • Increased salivation
  • Tearing
  • Increased bronchial secretions
  • Constricted pupils
  • Facial flushing due to vasodilation
  • Erectile dysfunction

Additional side effects include:[9]

  • Muscle twitching
  • Muscle cramps and weakness

Mechanism of action

Pyridostigmine inhibits acetylcholinesterase in the synaptic cleft, thus slowing down the hydrolysis of acetylcholine. It is a quaternary carbamate inhibitor of cholinesterase that does not cross the blood–brain barrier which carbamylates about 30% of peripheral cholinesterase enzyme. The carbamylated enzyme eventually regenerates by natural hydrolysis and excess ACh levels revert to normal.

The ACh diffuses across the synaptic cleft and binds to receptors on the post synaptic membrane, causing an influx of Na+, resulting in depolarization. If large enough, this depolarization results in an action potential. To prevent constant stimulation once the ACh is released, an enzyme called acetylcholinesterase is present in the endplate membrane close to the receptors on the post synaptic membrane, and quickly hydrolyses ACh.

Names

Pyridostigmine bromide is available under the trade names Mestinon (Valeant Pharmaceuticals), Regonol and Gravitor (SUN Pharma).

Chemistry

Pyridostigmine, 3-[(dimethylaminocarbonyl)oxy]-1-methyl pyridinium bromide, is synthesized from 3-hydroxypyridine, which is reacted with dimethylaminocarbamoyl chloride, which gives 3-(dimethylaminocarbamoyl)pyridine. The last is reacted with methylbromide, giving pyridostigmine.

Syn

youtube

SYN

Method of synthesis

i. 3-hydroxypiridine is reacted with dimethylaminocarbamoyl chloride to give 3-(dimethylaminocarbamoyl)pyridine.

ii. The above formed compound is reacted with methylbromide to produce pyridostigmine. [2]

File:Synthese von Pyridostigmin.svg - Wikimedia Commons

CLIP

Paper

Journal of Biological Chemistry (1961), 236, 1498-500.

 Zeitschrift fuer Klinische Medizin (1985) (1986), 41(7), 495-8

Zhonghua Yaoxue Zazhi (1993), 45(6), 601-14.

Trends in Organic Chemistry (2011), 15, 25-31.

PATENT

WO 9822458

PATENT

WO 2008074816

https://patents.google.com/patent/WO2008074816A1/en

References

  1. ^ World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 429. hdl:10665/44053ISBN 9789241547659.
  2. Jump up to:a b c d e f g h i “Neostigmine Bromide”. The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  3. ^ Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 540. ISBN 9783527607495Archived from the original on 2016-12-20.
  4. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. ^ Golomb BA (March 2008). “Acetylcholinesterase inhibitors and Gulf War illnesses”Proceedings of the National Academy of Sciences of the United States of America105 (11): 4295–300. Bibcode:2008PNAS..105.4295Gdoi:10.1073/pnas.0711986105JSTOR 25461411PMC 2393741PMID 18332428Lay summary – Reuters (March 10, 2008).
  6. ^ Gales BJ, Gales MA (2007). “Pyridostigmine in the treatment of orthostatic intolerance”. Annals of Pharmacotherapy41 (2): 314–8. doi:10.1345/aph.1H458PMID 17284509S2CID 22855759.
  7. Jump up to:a b Gales BJ, Gales MA (February 2007). “Pyridostigmine in the treatment of orthostatic intolerance”. The Annals of Pharmacotherapy41 (2): 314–8. doi:10.1345/aph.1H458PMID 17284509S2CID 22855759.
  8. ^ Kanjwal K, Karabin B, Sheikh M, et al. (June 2011). “Pyridostigmine in the treatment of postural orthostatic tachycardia: a single-center experience”. Pacing and Clinical Electrophysiology34 (6): 750–5. doi:10.1111/j.1540-8159.2011.03047.xPMID 21410722S2CID 20405336.
  9. Jump up to:a b c Mestinon | Home Archived 2008-05-13 at the Wayback Machine
  10. ^ Mestinon Official FDA information, side effects and uses Archived 2008-05-24 at the Wayback Machine

External links[

Clinical data
Trade namesMestinon, others
AHFS/Drugs.comMonograph
MedlinePlusa682229
Pregnancy
category
AU: C
Routes of
administration
by mouth, intravenous
ATC codeN07AA02 (WHO)
Legal status
Legal statusUK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
Bioavailability7.6 +/- 2.4%
Elimination half-life1.78 +/- 0.24hrs
Excretionkidney
Identifiers
showIUPAC name
CAS Number155-97-5 
PubChem CID4991
DrugBankDB00545 
ChemSpider4817 
UNII19QM69HH21
KEGGD00487 
ChEMBLChEMBL1115 
CompTox Dashboard (EPA)DTXSID20165786 
Chemical and physical data
FormulaC9H13N2O2
Molar mass181.215 g·mol−1
3D model (JSmol)Interactive image
hideSMILESO=C(Oc1ccc[n+](c1)C)N(C)C
hideInChIInChI=1S/C9H13N2O2/c1-10(2)9(12)13-8-5-4-6-11(3)7-8/h4-7H,1-3H3/q+1 Key:RVOLLAQWKVFTGE-UHFFFAOYSA-N 

/////////////Pyridostigmine,


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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