DISTIGMINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H32N4O4
Molecular Weight	416.5139
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	2

SHOW SMILES / InChI

Structure Search

SMILES

CN(CCCCCCN(C)C(=O)OC1=CC=C[N+](C)=C1)C(=O)OC2=C[N+](C)=CC=C2

InChI

InChIKey=AHZBEVXBKNYXPU-UHFFFAOYSA-N

InChI=1S/C22H32N4O4/c1-23-13-9-11-19(17-23)29-21(27)25(3)15-7-5-6-8-16-26(4)22(28)30-20-12-10-14-24(2)18-20/h9-14,17-18H,5-8,15-16H2,1-4H3/q+2

HIDE SMILES / InChI

Description
Sources: http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=1755
Curator's Comment: description was created based on several sources, including: http://www.medicines.org.uk/emc/PIL.3897.latest.pdf | http://www.torii.co.jp/iyakuDB/data/if/if_ubr_t.pdf

Distigmine is an acetylcholinesterase (AChE) inhibitor. Distigmine shows direct binding to muscarinic receptors in the rat bladder, and repeated oral administration of distigmine causes downregulation of muscarinic receptors in the rat bladder. The observed direct interaction of distigmine with the bladder muscarinic receptors may partly contribute to the therapeutic and/or side effects seen in the treatment of detrusor underactivity. It is usually used to treat myasthenia gravis, dysuria due to hypotonic bladder such as neurogenic bladder or after surgery. Common side effects are: nausea/vomiting, abdominal pain, diarrhea, increased salivation, hypersecretion in respiratory tract, sweating, bradycardia, miosis, difficulty in breathing. Distigmine has a greater risk of causing cholinergic crisis because of accumulation of the drug being more likely than with neostigmine or pyridostigmine and so distigmine is rarely used as a treatment for myasthenia gravis, unlike pyridostigmine and neostigmine.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Acetylcholinesterase 209 Target ID: CHEMBL220 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20610884 \| https://www.ncbi.nlm.nih.gov/pubmed/8100221	Inhibitor 8504	45.0 nM [IC50]
Muscarinic receptors (rat) 2 Target ID: Muscarinic receptors (rat) Sources: https://www.ncbi.nlm.nih.gov/pubmed/20410601	Binding Agent 1076	0.36 µM [Ki]
Nicotinic receptors (rat) 2 Target ID: Nicotinic receptors (rat) Sources: https://www.ncbi.nlm.nih.gov/pubmed/20410601	Binding Agent 1076	22.9 µM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Neurogenic bladder 6 Sources: http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=1755	Primary	Approved 8583	Ubretid Approved Use It is usually used to treat myasthenia gravis, dysuria due to hypotonic bladder such as neurogenic bladder or after surgery.
Myasthenia gravis 21 Sources: http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=1755	Primary	Approved 8583	Ubretid Approved Use It is usually used to treat myasthenia gravis, dysuria due to hypotonic bladder such as neurogenic bladder or after surgery.
Dysuria due to hypotonic bladder after surgery 2 Sources: http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=1755	Primary	Approved 8583	Ubretid Approved Use It is usually used to treat myasthenia gravis, dysuria due to hypotonic bladder such as neurogenic bladder or after surgery.

C_max

Value	Dose	Co-administered	Analyte	Population
4.4 ng/mL OTHER GOV'T https://www.info.pmda.go.jp/go/interview/1/480306_1231014F1054_1_003_1F.pdf#page=19 \| https://pubmed.ncbi.nlm.nih.gov/10475142/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		DISTIGMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
228.4 μg × h/L OTHER GOV'T https://www.info.pmda.go.jp/go/interview/1/480306_1231014F1054_1_003_1F.pdf#page=19 \| https://pubmed.ncbi.nlm.nih.gov/10475142/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		DISTIGMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
69.5 h OTHER GOV'T https://www.info.pmda.go.jp/go/interview/1/480306_1231014F1054_1_003_1F.pdf#page=19 \| https://pubmed.ncbi.nlm.nih.gov/10475142/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		DISTIGMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
83.2% OTHER GOV'T https://www.info.pmda.go.jp/go/interview/1/480306_1231014F1054_1_003_1F.pdf#page=22			DISTIGMINE plasma	Homo sapiens

Doses

Dose	Population	Adverse events
10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14686764/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/14686764/	Disc. AE: Rhabdomyolysis... AEs leading to discontinuation/dose reduction: Rhabdomyolysis Sources: https://pubmed.ncbi.nlm.nih.gov/14686764/
10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11868380/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/11868380/	Other AEs: Cholinergic crisis... Other AEs: Cholinergic crisis (grade 5) Sources: https://pubmed.ncbi.nlm.nih.gov/11868380/
10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16180710/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/16180710/	Disc. AE: Parkinsonism... AEs leading to discontinuation/dose reduction: Parkinsonism Sources: https://pubmed.ncbi.nlm.nih.gov/16180710/
5 mg 1 times / day multiple, oral Recommended Dose: 5 mg, 1 times / day Route: oral Route: multiple Dose: 5 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14611928/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/14611928/	Disc. AE: Psychotic disorder... AEs leading to discontinuation/dose reduction: Psychotic disorder Sources: https://pubmed.ncbi.nlm.nih.gov/14611928/
0.5 mg 1 times / day multiple, intramuscular Studied dose Dose: 0.5 mg, 1 times / day Route: intramuscular Route: multiple Dose: 0.5 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6132645/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/6132645/	Disc. AE: Diarrhoea... AEs leading to discontinuation/dose reduction: Diarrhoea (6.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/6132645/

AEs

AE	Significance	Dose	Population
Rhabdomyolysis	Disc. AE	10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14686764/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/14686764/
Cholinergic crisis	grade 5	10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11868380/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/11868380/
Parkinsonism	Disc. AE	10 mg 2 times / day multiple, oral Recommended Dose: 10 mg, 2 times / day Route: oral Route: multiple Dose: 10 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16180710/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/16180710/
Psychotic disorder	Disc. AE	5 mg 1 times / day multiple, oral Recommended Dose: 5 mg, 1 times / day Route: oral Route: multiple Dose: 5 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14611928/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/14611928/
Diarrhoea	6.5% Disc. AE	0.5 mg 1 times / day multiple, intramuscular Studied dose Dose: 0.5 mg, 1 times / day Route: intramuscular Route: multiple Dose: 0.5 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6132645/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/6132645/

PubMed

Title	Date	PubMed
Symptomatic and urodynamic improvement by oral distigmine bromide in poor voiders after transurethral resection of the prostate.	2001 Feb	11182335
Effects of TAK-802, a novel acetylcholinesterase inhibitor, on distension-induced rhythmic bladder contractions in rats and guinea pigs.	2004 Feb 6	14757154
Effect of distigmine bromide on the central cholinergic system.	2009 Mar	18515453
Pharmacokinetic and pharmacodynamic analysis of acetylcholinesterase inhibition by distigmine bromide in rats.	2010	20610884
[Bizerine: new anticholinesterase drug with selective gastrointestinal action].	2010 Aug	20919551
[Establishing indicators for diagnosis of cholinergic crisis].	2010 Oct	21077286

Patents

Sample Use Guides

In Vivo Use Guide

For dysuria due to hypotonic bladder such as neurogenic bladder or after surgery, for adults, take 1 tablet (5 mg of the active ingredient) daily. For myasthenia gravis, for adults, take 1-4 tablet(s) (5-20 mg of the active ingredient) daily in 1-4 divided dose(s). Start with 1 tablet (5 mg) daily, and the dose should be adjusted according to symptoms.

Route of Administration: Oral

In Vitro Use Guide

Distigmine (30 nM—10 uM) inhibited specific [3H]oxotremorine-M binding in the bladder, submaxillary gland and cerebral cortex of rats in a concentration-dependent manner. The Ki values for distigmine did not differ significantly among tissues.

Name

Type

Language

DISTIGMINE

Common Name

English

DISTIGMINE CATION

Preferred Name

English

PYRIDINIUM, 3,3'-(1,6-HEXANEDIYLBIS((METHYLIMINO)CARBONYLOXY))BIS(1-METHYL-

Common Name

English

Distigmine [WHO-DD]

Common Name

English

DISTIGMINE ION

Common Name

English

Classification Tree Code System Code

WHO-VATC

QN07AA03