Identification

Name
Demecarium
Accession Number
DB00944  (APRD00905)
Type
Small Molecule
Groups
Approved
Description

Demecarium is an indirect-acting parasympathomimetic agent that is used to treat glaucoma. It is a cholinesterase inhibitor or an anticholinesterase. Cholinesterase inhibitors prolong the effect of acetylcholine, which is released at the neuroeffector junction of parasympathetic postganglion nerves, by inactivating the cholinesterases that break it down. Demecarium inactivates both pseudocholinesterase and acetylcholinesterase. In the eye, this causes constriction of the iris sphincter muscle (causing miosis) and the ciliary muscle. The outflow of the aqueous humor is facilitated, which leads to a reduction in intraocular pressure.

Structure
Thumb
Synonyms
  • Demecarium
Product Ingredients
IngredientUNIICASInChI Key
Demecarium bromide61D5V4OKTP56-94-0YHKBUDZECQDYBR-UHFFFAOYSA-L
International/Other Brands
Humorsol (MSD) / Tonilen / Tosmilen
Categories
UNII
ILP8XJ8R5K
CAS number
Not Available
Weight
Average: 556.7797
Monoisotopic: 556.398856172
Chemical Formula
C32H52N4O4
InChI Key
RWZVPVOZTJJMNU-UHFFFAOYSA-N
InChI
InChI=1S/C32H52N4O4/c1-33(31(37)39-29-21-17-19-27(25-29)35(3,4)5)23-15-13-11-9-10-12-14-16-24-34(2)32(38)40-30-22-18-20-28(26-30)36(6,7)8/h17-22,25-26H,9-16,23-24H2,1-8H3/q+2
IUPAC Name
N,N,N-trimethyl-3-{[methyl(10-{methyl[3-(trimethylazaniumyl)phenoxycarbonyl]amino}decyl)carbamoyl]oxy}anilinium
SMILES
CN(CCCCCCCCCCN(C)C(=O)OC1=CC=CC(=C1)[N+](C)(C)C)C(=O)OC1=CC=CC(=C1)[N+](C)(C)C

Pharmacology

Indication

For the topical treatment of chronic open-angle glaucoma.

Pharmacodynamics

Demecarium is a long-acting cholinesterase inhibitor and potent miotic. Because of its toxicity, it should be reserved for use in patients with open-angle glaucoma or other chronic glaucomas not satisfactorily controlled with the short-acting miotics and other agents. Application of demecarium to the eye produces intense miosis and ciliary muscle contraction due to inhibition of cholinesterase, allowing acetylcholine to accumulate at sites of cholinergic transmission. These effects are accompanied by increased capillary permeability of the ciliary body and iris, increased permeability of the blood-aqueous barrier, and vasodilation. Myopia may be induced or, if present, may be augmented by the increased refractive power of the lens that results from the accommodative effect of the drug.

Mechanism of action

Demecarium is an indirect-acting parasympathomimetic agent, also known as a cholinesterase inhibitor and anticholinesterase. Cholinesterase inhibitors prolong the effect of acetylcholine, which is released at the neuroeffector junction of parasympathetic postganglion nerves, by inactivating the cholinesterases that break it down. Demecarium inactivates both pseudocholinesterase and acetylcholinesterase. In the eye, this causes constriction of the iris sphincter muscle (causing miosis) and the ciliary muscle (affecting the accommodation reflex and causing a spasm of the focus to near vision). The outflow of the aqueous humor is facilitated, which leads to a reduction in intraocular pressure. Of the two actions, the effect on the accommodation reflex is the more transient and generally disappears before termination of the miosis.

TargetActionsOrganism
AAcetylcholinesterase
inhibitor
Human
UCholinesterase
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

The oral LD50 is 2.96 mg/kg in the mouse. Symptoms of overdose include nausea, vomiting, abdominal cramps, diarrhea, urinary incontinence, salivation, sweating, difficulty in breathing, bradycardia, or cardiac irregularities.

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

Interactions

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

References

Synthesis Reference

Schrnid, O.; US. Patent 2,789,981; April 23, 1957; assigned to Oesterreichische Stickstoffwerke AG, Austria.

General References
  1. Ward DA, Abney K, Oliver JW: The effects of topical ocular application of 0.25% demecarium bromide on serum acetylcholinesterase levels in normal dogs. Vet Ophthalmol. 2003 Mar;6(1):23-5. [PubMed:12641839]
  2. Krohne SG: Effect of topically applied 2% pilocarpine and 0.25% demecarium bromide on blood-aqueous barrier permeability in dogs. Am J Vet Res. 1994 Dec;55(12):1729-33. [PubMed:7887518]
  3. Gum GG, Gelatt KN, Gelatt JK, Jones R: Effect of topically applied demecarium bromide and echothiophate iodide on intraocular pressure and pupil size in beagles with normotensive eyes and beagles with inherited glaucoma. Am J Vet Res. 1993 Feb;54(2):287-93. [PubMed:8430939]
External Links
Human Metabolome Database
HMDB0015079
KEGG Drug
D00667
PubChem Compound
5966
PubChem Substance
46507824
ChemSpider
5751
ChEBI
59719
ChEMBL
CHEMBL1201229
Therapeutic Targets Database
DAP000894
PharmGKB
PA164745610
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Demecarium_bromide
ATC Codes
S01EB04 — Demecarium

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Dispensing Solutions
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)164-170Schrnid, O.; US. Patent 2,789,981; April 23, 1957; assigned to Oesterreichische Stickstoffwerke AG, Austria.
logP-1.75Not Available
Predicted Properties
PropertyValueSource
Water Solubility1.69e-05 mg/mLALOGPS
logP0.65ALOGPS
logP-1.4ChemAxon
logS-7.6ALOGPS
Physiological Charge2ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area59.08 Å2ChemAxon
Rotatable Bond Count17ChemAxon
Refractivity185.71 m3·mol-1ChemAxon
Polarizability64.49 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.975
Blood Brain Barrier+0.8552
Caco-2 permeable+0.5237
P-glycoprotein substrateSubstrate0.6145
P-glycoprotein inhibitor INon-inhibitor0.778
P-glycoprotein inhibitor IIInhibitor0.6802
Renal organic cation transporterNon-inhibitor0.6822
CYP450 2C9 substrateNon-substrate0.7289
CYP450 2D6 substrateNon-substrate0.7984
CYP450 3A4 substrateSubstrate0.707
CYP450 1A2 substrateNon-inhibitor0.8801
CYP450 2C9 inhibitorNon-inhibitor0.8903
CYP450 2D6 inhibitorNon-inhibitor0.9166
CYP450 2C19 inhibitorNon-inhibitor0.8855
CYP450 3A4 inhibitorNon-inhibitor0.88
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8541
Ames testNon AMES toxic0.6225
CarcinogenicityNon-carcinogens0.684
BiodegradationNot ready biodegradable0.9618
Rat acute toxicity2.5848 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7692
hERG inhibition (predictor II)Inhibitor0.5084
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenoxy compounds. These are aromatic compounds contaning a phenoxy group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Phenoxy compounds
Direct Parent
Phenoxy compounds
Alternative Parents
Aniline and substituted anilines / Quaternary ammonium salts / Carbamate esters / Organic carbonic acids and derivatives / Organopnictogen compounds / Organic salts / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds / Amines
show 1 more
Substituents
Phenoxy compound / Aniline or substituted anilines / Quaternary ammonium salt / Carbamic acid ester / Carbonic acid derivative / Amine / Carbonyl group / Hydrocarbon derivative / Organic oxide / Organic salt
show 7 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
carbamate ester, quaternary ammonium ion (CHEBI:59719)

Targets

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. Ward DA, Abney K, Oliver JW: The effects of topical ocular application of 0.25% demecarium bromide on serum acetylcholinesterase levels in normal dogs. Vet Ophthalmol. 2003 Mar;6(1):23-5. [PubMed:12641839]
  2. 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
Actions
Inhibitor
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da
References
  1. Meiniel R: Neuromuscular blocking agents and axial teratogenesis in the avian embryo. Can axial morphogenetic disorders by explained by pharmacological action upon muscle tissue? Teratology. 1981 Apr;23(2):259-71. [PubMed:7196602]
  2. Gum GG, Gelatt KN, Gelatt JK, Jones R: Effect of topically applied demecarium bromide and echothiophate iodide on intraocular pressure and pupil size in beagles with normotensive eyes and beagles with inherited glaucoma. Am J Vet Res. 1993 Feb;54(2):287-93. [PubMed:8430939]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 08:40