Identification

Name
Physostigmine
Accession Number
DB00981  (APRD00406)
Type
Small Molecule
Groups
Approved, Investigational
Description

A cholinesterase inhibitor that is rapidly absorbed through membranes. It can be applied topically to the conjunctiva. It also can cross the blood-brain barrier and is used when central nervous system effects are desired, as in the treatment of severe anticholinergic toxicity. [PubChem]

Structure
Thumb
Synonyms
  • Eserine
  • Physostigmine
  • Physostol
External IDs
MCV-4484
Product Ingredients
IngredientUNIICASInChI Key
Physostigmine salicylate2046ZRO9VU57-64-7HZOTZTANVBDFOF-PBCQUBLHSA-N
Physostigmine SulfateG63V2J2N7164-47-1YYBNDIVPHIWTPK-KYJQVDHRSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Antilirium Inj 1mg/mlLiquid1 mgIntramuscular; IntravenousForest Laboratories1975-12-311998-07-07Canada
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Physostigmine SalicylatePhysostigmine salicylate (1 mg/1mL)InjectionIntravenousAkorn2010-08-10Not applicableUs
Physostigmine SalicylatePhysostigmine salicylate (1 mg/1mL)InjectionIntravenousMedical Purchasing Solutions, Llc2010-08-10Not applicableUs
Physostigmine SalicylatePhysostigmine salicylate (1 mg/1mL)InjectionIntravenousCardinal Health2010-08-102018-11-30Us
International/Other Brands
Antilirium
Categories
UNII
9U1VM840SP
CAS number
57-47-6
Weight
Average: 275.3461
Monoisotopic: 275.163376931
Chemical Formula
C15H21N3O2
InChI Key
PIJVFDBKTWXHHD-HIFRSBDPSA-N
InChI
InChI=1S/C15H21N3O2/c1-15-7-8-17(3)13(15)18(4)12-6-5-10(9-11(12)15)20-14(19)16-2/h5-6,9,13H,7-8H2,1-4H3,(H,16,19)/t13-,15+/m1/s1
IUPAC Name
(3aS,8aR)-1,3a,8-trimethyl-1H,2H,3H,3aH,8H,8aH-pyrrolo[2,3-b]indol-5-yl N-methylcarbamate
SMILES
[H][C@]12N(C)CC[C@@]1(C)C1=C(C=CC(OC(=O)NC)=C1)N2C

Pharmacology

Indication

For the treatment of glaucoma, and in the treatment of severe anticholinergic toxicity.

Pharmacodynamics

Physostigmine is a parasympathomimetic, specifically, a reversible cholinesterase inhibitor which effectively increases the concentration of acetylcholine at the sites of cholinergic transmission. Physostigmine is used to treat glaucoma. Because it crosses the blood-brain barrier, it is also used to treat the central nervous system effects of atropine overdose and other anticholinergic drug overdoses. Physostigmine can reverse both central and peripheral anticholinergia.

Mechanism of action

Physostigmine inhibits acetylcholinesterase, the enzyme responsible for the breakdown of used acetylcholine. By interfering with the metabolism of acetylcholine, physostigmine indirectly stimulates both nicotinic and muscarinic receptors due to the consequential increase in available acetylcholine at the synapse.

TargetActionsOrganism
AAcetylcholinesterase
inhibitor
Human
UNeuronal acetylcholine receptor subunit alpha-4Not AvailableHuman
UNeuronal acetylcholine receptor subunit beta-2Not AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Quickly hydrolyzed by cholinesterases

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

Side effects include increased sweating, loss of bladder control, muscle weakness, nausea, vomiting, diarrhea, or stomach cramps or pain, shortness of breath, tightness in chest, or wheezing, slow or irregular heartbeat, unusual tiredness or weakness, watering of mouth, blurred vision or change in near or distant vision, and eye pain.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcebutololPhysostigmine may increase the bradycardic activities of Acebutolol.
AcetylcholineThe risk or severity of adverse effects can be increased when Physostigmine is combined with Acetylcholine.
AclidiniumThe therapeutic efficacy of Aclidinium can be decreased when used in combination with Physostigmine.
AgmatineThe therapeutic efficacy of Agmatine can be decreased when used in combination with Physostigmine.
AlcuroniumThe therapeutic efficacy of Alcuronium can be decreased when used in combination with Physostigmine.
AldosteroneThe therapeutic efficacy of Physostigmine can be decreased when used in combination with Aldosterone.
AlprenololPhysostigmine may increase the bradycardic activities of Alprenolol.
AmantadineThe therapeutic efficacy of Amantadine can be decreased when used in combination with Physostigmine.
AmikacinThe therapeutic efficacy of Physostigmine can be decreased when used in combination with Amikacin.
AmitriptylineThe therapeutic efficacy of Amitriptyline can be decreased when used in combination with Physostigmine.
Food Interactions
Not Available

References

Synthesis Reference

Edward J. Glamkowski, Barbara E. Kurys, "4- and 6-carbamates related to physostigmine and intermediates for the preparation thereof." U.S. Patent US5081117, issued September, 1978.

US5081117
General References
Not Available
External Links
Human Metabolome Database
HMDB0015116
KEGG Drug
D00196
KEGG Compound
C06535
PubChem Compound
5983
PubChem Substance
46506998
ChemSpider
5763
BindingDB
11023
ChEBI
27953
ChEMBL
CHEMBL94
Therapeutic Targets Database
DAP000561
PharmGKB
PA450957
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Physostigmine
ATC Codes
S01EB05 — PhysostigmineV03AB19 — Physostigmine
MSDS
Download (73.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedBasic ScienceInsulin Resistance1
3CompletedTreatmentPostoperative pain1
3RecruitingTreatmentCAM-ICU Diagnosed Delirium / Suspected Delirium After Elective or Emergency Heart Surgery1
4RecruitingTreatmentAnticholinergics Toxicity1
Not AvailableCompletedTreatmentPerioperative Period / Sepsis / Shock, Septic1
Not AvailableCompletedTreatmentUpper Airway Obstruction1
Not AvailableRecruitingOtherSchizophrenic Disorders / Smoking1
Not AvailableUnknown StatusPreventionCognitive Dysfunctions1
Not AvailableUnknown StatusTreatmentAnesthesia Recovery Period / Post-Operative Nausea and Vomiting (PONV)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Amend
  • Hope Pharmaceuticals
  • Hospira Inc.
  • Nycomed Inc.
  • Taylor Pharmaceuticals
Dosage forms
FormRouteStrength
LiquidIntramuscular; Intravenous1 mg
InjectionIntravenous1 mg/1mL
Prices
Unit descriptionCostUnit
Physostigmine salicyl cryst39.48USD g
Physostigmine 1 mg/ml ampul2.43USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)105.5 °CPhysProp
water solubility7760 mg/LNot Available
logP1.58HANSCH,C ET AL. (1995)
pKa6.12MERCK INDEX (1996)
Predicted Properties
PropertyValueSource
Water Solubility0.992 mg/mLALOGPS
logP1.8ALOGPS
logP2.23ChemAxon
logS-2.4ALOGPS
pKa (Strongest Acidic)14.77ChemAxon
pKa (Strongest Basic)6.59ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area44.81 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity78.4 m3·mol-1ChemAxon
Polarizability30.62 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9975
Caco-2 permeable+0.5804
P-glycoprotein substrateSubstrate0.6631
P-glycoprotein inhibitor INon-inhibitor0.5442
P-glycoprotein inhibitor IINon-inhibitor0.8382
Renal organic cation transporterNon-inhibitor0.7046
CYP450 2C9 substrateNon-substrate0.7838
CYP450 2D6 substrateNon-substrate0.6455
CYP450 3A4 substrateSubstrate0.7321
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8681
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.9232
BiodegradationNot ready biodegradable0.8652
Rat acute toxicity4.7557 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9066
hERG inhibition (predictor II)Non-inhibitor0.8397
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (9.24 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - GC-EI-TOFGC-MSsplash10-001j-1590000000-508da23acfe2c8a2f568
GC-MS Spectrum - GC-EI-TOFGC-MSsplash10-00ea-6790000000-c7dad12610a8d73fb915
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-00or-0090000000-1f322550abc600bd72a9
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-014i-0490000000-e4a06a93b3b18d738157
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-03di-0900000000-d9ddac609ada184032ac
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-03di-0900000000-ef8f7c2ddbdba70fe1d3
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-01ot-0900000000-daf3030c2c85de1db72e
LC-MS/MS Spectrum - LC-ESI-IT , positiveLC-MS/MSsplash10-014i-0090000000-8a9155530ad88f483e2e
MS/MS Spectrum - , positiveLC-MS/MSsplash10-03dj-2900000000-b9d164a9a3afaf8a17cf

Taxonomy

Description
This compound belongs to the class of organic compounds known as pyrroloindoles. These are compounds containing a pyrroloindole moiety, which is a tricyclic heterocycle which consists of a pyrrole ring fused to an indole. Pyrrole is 5-membered ring consisting of four carbon atoms and one nitrogen atom. Indole is a bicyclic compound consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Pyrroloindoles
Direct Parent
Pyrroloindoles
Alternative Parents
Indoles / Dialkylarylamines / N-alkylpyrrolidines / Benzenoids / Pyrroles / Carbamate esters / Organic carbonic acids and derivatives / Azacyclic compounds / Organopnictogen compounds / Organic oxides
show 2 more
Substituents
Pyrroloindole / Indole / Dialkylarylamine / Benzenoid / N-alkylpyrrolidine / Pyrrole / Pyrrolidine / Carbamic acid ester / Carbonic acid derivative / Azacycle
show 9 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
carbamate ester, indole alkaloid (CHEBI:27953) / Alkaloids, Pyrroloindole alkaloids (C06535)

Targets

Details
1. Acetylcholinesterase
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine hydrolase activity
Specific Function
Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.
Gene Name
ACHE
Uniprot ID
P22303
Uniprot Name
Acetylcholinesterase
Molecular Weight
67795.525 Da
References
  1. Nguyen PV, Aniksztejn L, Catarsi S, Drapeau P: Maturation of neuromuscular transmission during early development in zebrafish. J Neurophysiol. 1999 Jun;81(6):2852-61. [PubMed:10368402]
  2. Tuovinen K, Kaliste-Korhonen E, Raushel FM, Hanninen O: Success of pyridostigmine, physostigmine, eptastigmine and phosphotriesterase treatments in acute sarin intoxication. Toxicology. 1999 Jun 15;134(2-3):169-78. [PubMed:10403635]
  3. Blasina MF, Faria AC, Gardino PF, Hokoc JN, Almeida OM, de Mello FG, Arruti C, Dajas F: Evidence for a noncholinergic function of acetylcholinesterase during development of chicken retina as shown by fasciculin. Cell Tissue Res. 2000 Feb;299(2):173-84. [PubMed:10741458]
  4. Monnet-Tschudi F, Zurich MG, Schilter B, Costa LG, Honegger P: Maturation-dependent effects of chlorpyrifos and parathion and their oxygen analogs on acetylcholinesterase and neuronal and glial markers in aggregating brain cell cultures. Toxicol Appl Pharmacol. 2000 Jun 15;165(3):175-83. [PubMed:10873710]
  5. Bolognesi ML, Andrisano V, Bartolini M, Minarini A, Rosini M, Tumiatti V, Melchiorre C: Hexahydrochromeno[4,3-b]pyrrole derivatives as acetylcholinesterase inhibitors. J Med Chem. 2001 Jan 4;44(1):105-9. [PubMed:11141093]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Curator comments
noncompetitive antagonist
General Function
Ligand-gated ion channel activity
Specific Function
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeabl...
Gene Name
CHRNA4
Uniprot ID
P43681
Uniprot Name
Neuronal acetylcholine receptor subunit alpha-4
Molecular Weight
69956.47 Da
References
  1. Eaton JB, Peng JH, Schroeder KM, George AA, Fryer JD, Krishnan C, Buhlman L, Kuo YP, Steinlein O, Lukas RJ: Characterization of human alpha 4 beta 2-nicotinic acetylcholine receptors stably and heterologously expressed in native nicotinic receptor-null SH-EP1 human epithelial cells. Mol Pharmacol. 2003 Dec;64(6):1283-94. [PubMed:14645658]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Curator comments
noncompetitive antagonist
General Function
Ligand-gated ion channel activity
Specific Function
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeabl...
Gene Name
CHRNB2
Uniprot ID
P17787
Uniprot Name
Neuronal acetylcholine receptor subunit beta-2
Molecular Weight
57018.575 Da
References
  1. Eaton JB, Peng JH, Schroeder KM, George AA, Fryer JD, Krishnan C, Buhlman L, Kuo YP, Steinlein O, Lukas RJ: Characterization of human alpha 4 beta 2-nicotinic acetylcholine receptors stably and heterologously expressed in native nicotinic receptor-null SH-EP1 human epithelial cells. Mol Pharmacol. 2003 Dec;64(6):1283-94. [PubMed:14645658]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 08:53