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Identification
NameRivastigmine
Accession NumberDB00989  (APRD00321)
Typesmall molecule
Groupsapproved, investigational
Description

Rivastigmine is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type. Rivastigmine is a cholinesterase inhibitor that inhibits both butyrylcholinesterase and acetylcholinesterase.

Structure
Thumb
Synonyms
SynonymLanguageCode
Ena 713 Free BaseNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
ExelonNot Available
Exelon PatchNot Available
Brand mixturesNot Available
Categories
CAS number123441-03-2
WeightAverage: 250.3367
Monoisotopic: 250.168127958
Chemical FormulaC14H22N2O2
InChI KeyInChIKey=XSVMFMHYUFZWBK-NSHDSACASA-N
InChI
InChI=1S/C14H22N2O2/c1-6-16(5)14(17)18-13-9-7-8-12(10-13)11(2)15(3)4/h7-11H,6H2,1-5H3/t11-/m0/s1
IUPAC Name
3-[(1S)-1-(dimethylamino)ethyl]phenyl N-ethyl-N-methylcarbamate
SMILES
CCN(C)C(=O)OC1=CC=CC(=C1)[C@H](C)N(C)C
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenethylamines
Direct parentPhenethylamines
Alternative parentsPhenol Ethers; Tertiary Amines; Carbamic Acids and Derivatives; Ethers; Polyamines
Substituentsphenol ether; carbamic acid derivative; tertiary amine; polyamine; ether; amine; organonitrogen compound
Classification descriptionThis compound belongs to the phenethylamines. These are compounds containing a phenethylamine moiety, which consists of a phenyl group substituted at the second position by an ethan-1-amine.
Pharmacology
IndicationFor the treatment of mild to moderate dementia associated with Parkinson's disease or of the Alzheimer's type.
PharmacodynamicsRivastigmine is a parasympathomimetic and a reversible cholinesterase inhibitor. An early pathophysiological feature of Alzheimer's disease that is associated with memory loss and cognitive deficits is a deficiency of acetylcholine as a result of selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus. Tacrine is postulated to exert its therapeutic effect by enhancing cholinergic function. While the precise mechanism of rivastigmine's action is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. If this proposed mechanism is correct, rivastigmine's effect may lessen as the disease progresses and fewer cholinergic neurons remain functionally intact.
Mechanism of actionRivastigmine is a carbamate derivative that is structurally related to physostigmine, but not to donepezil and tacrine. The precise mechanism of rivastigmine has not been fully determined, but it is suggested that rivastigmine binds reversibly with and inactivates chlolinesterase (eg. acetylcholinesterase, butyrylcholinesterase), preventing the hydrolysis of acetycholine, and thus leading to an increased concentration of acetylcholine at cholinergic synapses. The anticholinesterase activity of rivastigmine is relatively specific for brain acetylcholinesterase and butyrylcholinesterase compared with those in peripheral tissues.
AbsorptionNot Available
Volume of distribution
  • 1.8 to 2.7 L/kg
Protein binding40%
Metabolism

Rivastigmine is rapidly metabolized by cholinesterase-mediated hydrolysis.

Route of eliminationRivastigmine is extensively metabolized primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite NAP226-90. Renal excretion of the metabolites is the major route of elimination. Less than 1% of the administered dose is excreted in the feces.
Half life1.5 hours
Clearance
  • renal cl=2.1-2.8 L/hr
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9853
Caco-2 permeable + 0.7001
P-glycoprotein substrate Non-substrate 0.6571
P-glycoprotein inhibitor I Non-inhibitor 0.7919
P-glycoprotein inhibitor II Non-inhibitor 0.8756
Renal organic cation transporter Non-inhibitor 0.8406
CYP450 2C9 substrate Non-substrate 0.7993
CYP450 2D6 substrate Non-substrate 0.6659
CYP450 3A4 substrate Substrate 0.5932
CYP450 1A2 substrate Non-inhibitor 0.609
CYP450 2C9 substrate Non-inhibitor 0.8928
CYP450 2D6 substrate Non-inhibitor 0.8384
CYP450 2C19 substrate Non-inhibitor 0.8734
CYP450 3A4 substrate Non-inhibitor 0.9545
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8062
Ames test Non AMES toxic 0.5279
Carcinogenicity Non-carcinogens 0.5858
Biodegradation Not ready biodegradable 0.9463
Rat acute toxicity 3.4167 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9355
hERG inhibition (predictor II) Non-inhibitor 0.8986
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
  • Dr reddys laboratories inc
  • Sun pharmaceutical industries ltd
  • Watson laboratories inc
Packagers
Dosage forms
FormRouteStrength
CapsuleOral
SolutionOral
Prices
Unit descriptionCostUnit
Exelon 30 4.6 mg/24hr Patches Box252.18USDbox
Exelon 30 9.5 mg/24hr Patches Box252.18USDbox
Exelon 4.6 mg/24hr patch8.08USDpatch
Exelon 9.5 mg/24hr patch8.08USDpatch
Exelon 1.5 mg capsule4.81USDcapsule
Exelon 3 mg capsule4.81USDcapsule
Exelon 4.5 mg capsule4.81USDcapsule
Exelon 6 mg capsule4.81USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States63160231999-01-082019-01-08
United States49488071992-08-142012-08-14
Canada23157842006-06-272019-01-08
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP2.3Not Available
Predicted Properties
PropertyValueSource
water solubility2.04e+00 g/lALOGPS
logP2.45ALOGPS
logP2.41ChemAxon
logS-2.1ALOGPS
pKa (strongest basic)8.89ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count2ChemAxon
hydrogen donor count0ChemAxon
polar surface area32.78ChemAxon
rotatable bond count5ChemAxon
refractivity73.37ChemAxon
polarizability28.53ChemAxon
number of rings1ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Venkata Naga Brahmeswara Rao Mandava, Venkata Reddy Vajrala, Ganesh Varanasi, Vijay Kumar Adla, Mukund Reddy Jambula, Vijaypal Reddy Kanumathi Reddy, “PREPARATION OF RIVASTIGMINE AND ITS SALTS.” U.S. Patent US20080255383, issued October 16, 2008.

US20080255383
General Reference
  1. Camps P, Munoz-Torrero D: Cholinergic drugs in pharmacotherapy of Alzheimer’s disease. Mini Rev Med Chem. 2002 Feb;2(1):11-25. Pubmed
  2. Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stahelin HB, Hartman R, Gharabawi M: Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ. 1999 Mar 6;318(7184):633-8. Pubmed
  3. Finkel SI: Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer’s disease. Clin Ther. 2004 Jul;26(7):980-90. Pubmed
  4. Rosler M, Retz W, Retz-Junginger P, Dennler HJ: Effects of two-year treatment with the cholinesterase inhibitor rivastigmine on behavioural symptoms in Alzheimer’s disease. Behav Neurol. 1998;11(4):211-216. Pubmed
  5. Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, De Deyn PP, Durif F, Kulisevsky J, van Laar T, Lees A, Poewe W, Robillard A, Rosa MM, Wolters E, Quarg P, Tekin S, Lane R: Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med. 2004 Dec 9;351(24):2509-18. Pubmed
  6. Birks J, Grimley Evans J, Iakovidou V, Tsolaki M, Holt FE: Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD001191. Pubmed# Naik RS, Hartmann J, Kiewert C, Duysen EG, Lockridge O, Klein J: Effects of rivastigmine and donepezil on brain acetylcholine levels in acetylcholinesterase-deficient mice. J Pharm Pharm Sci. 2009;12(1):79-85. Pubmed
  7. Farlow MR: Update on rivastigmine. Neurologist. 2003 Sep;9(5):230-4. Pubmed
External Links
ResourceLink
KEGG DrugD03822
KEGG CompoundC11766
PubChem Compound77991
PubChem Substance46507452
ChemSpider70377
BindingDB10620
Therapeutic Targets DatabaseDAP000149
PharmGKBPA451262
Drug Product Database2242118
RxListhttp://www.rxlist.com/cgi/generic2/rivastig.htm
Drugs.comhttp://www.drugs.com/cdi/rivastigmine.html
WikipediaRivastigmine
ATC CodesN06DA03
AHFS Codes
  • 12:04.00
PDB Entries
FDA labelshow(74 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AmantadinePossible antagonism of action
AmitriptylinePossible antagonism of action
AmoxapinePossible antagonism of action
AzatadinePossible antagonism of action
BenzatropinePossible antagonism of action
BiperidenPossible antagonism of action
BrompheniraminePossible antagonism of action
ChlorphenaminePossible antagonism of action
ChlorpromazinePossible antagonism of action
ChlorprothixenePossible antagonism of action
CimetidinePossible antagonism of action
ClemastinePossible antagonism of action
ClomipraminePossible antagonism of action
ClozapinePossible antagonism of action
CyclizinePossible antagonism of action
CyclobenzaprinePossible antagonism of action
CyproheptadinePossible antagonism of action
DarifenacinPossible antagonism of action
DesipraminePossible antagonism of action
DicyclominePossible antagonism of action
DimenhydrinatePossible antagonism of action
DiphenhydraminePossible antagonism of action
DisopyramidePossible antagonism of action
DoxepinPossible antagonism of action
FlavoxatePossible antagonism of action
FlupentixolPossible antagonism of action
GlutethimidePossible antagonism of action
GlycopyrrolatePossible antagonism of action
HydroxyzinePossible antagonism of action
HyoscyaminePossible antagonism of action
ImipraminePossible antagonism of action
IsocarboxazidPossible antagonism of action
LoxapinePossible antagonism of action
MaprotilinePossible antagonism of action
MeclizinePossible antagonism of action
MesoridazinePossible antagonism of action
MethotrimeprazinePossible antagonism of action
MirtazapinePossible antagonism of action
MoclobemidePossible antagonism of action
NortriptylinePossible antagonism of action
OlanzapinePossible antagonism of action
OrphenadrinePossible antagonism of action
OxybutyninPossible antagonism of action
PerphenazinePossible antagonism of action
PethidinePossible antagonism of action
PhenelzinePossible antagonism of action
PimozidePossible antagonism of action
ProcainamidePossible antagonism of action
ProchlorperazinePossible antagonism of action
PromethazinePossible antagonism of action
PropericiazinePossible antagonism of action
QuetiapinePossible antagonism of action
QuinidinePossible antagonism of action
ThioproperazinePossible antagonism of action
ThioridazinePossible antagonism of action
TizanidinePossible antagonism of action
TrazodonePossible antagonism of action
TrifluoperazinePossible antagonism of action
TrihexyphenidylPossible antagonism of action
TrimethobenzamideThe therapeutic effects of the anticholinergic, Trimethobenzamide, and/or the acetylcholinesterase inhibitor (central), Rivastigmine, may be reduced due to antagonism. Monitor therapeutic effects of both agents.
TrospiumThe therapeutic effects of the anticholinergic, Trospium, and/or the acetylcholinesterase inhibitor (central), Rivastigmine, may be reduced due to antagonism. Monitor therapeutic effects of both agents.
Food InteractionsNot Available

1. Acetylcholinesterase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Acetylcholinesterase P22303 Details

References:

  1. Kennedy JS, Polinsky RJ, Johnson B, Loosen P, Enz A, Laplanche R, Schmidt D, Mancione LC, Parris WC, Ebert MH: Preferential cerebrospinal fluid acetylcholinesterase inhibition by rivastigmine in humans. J Clin Psychopharmacol. 1999 Dec;19(6):513-21. Pubmed
  2. Goldblum D, Garweg JG, Bohnke M: Topical rivastigmine, a selective acetylcholinesterase inhibitor, lowers intraocular pressure in rabbits. J Ocul Pharmacol Ther. 2000 Feb;16(1):29-35. Pubmed
  3. Grossberg GT, Stahelin HB, Messina JC, Anand R, Veach J: Lack of adverse pharmacodynamic drug interactions with rivastigmine and twenty-two classes of medications. Int J Geriatr Psychiatry. 2000 Mar;15(3):242-7. Pubmed
  4. Stahl SM: The new cholinesterase inhibitors for Alzheimer’s disease, Part 1: their similarities are different. J Clin Psychiatry. 2000 Oct;61(10):710-1. Pubmed
  5. Gottwald MD, Rozanski RI: Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer’s disease: review and current status. Expert Opin Investig Drugs. 1999 Oct;8(10):1673-1682. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Birks J, Grimley Evans J, Iakovidou V, Tsolaki M, Holt FE: Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD001191. Pubmed# Naik RS, Hartmann J, Kiewert C, Duysen EG, Lockridge O, Klein J: Effects of rivastigmine and donepezil on brain acetylcholine levels in acetylcholinesterase-deficient mice. J Pharm Pharm Sci. 2009;12(1):79-85. Pubmed
  8. Lalli S, Albanese A: Rivastigmine in Parkinson’s disease dementia. Expert Rev Neurother. 2008 Aug;8(8):1181-8. Pubmed
  9. Onor ML, Trevisiol M, Aguglia E: Rivastigmine in the treatment of Alzheimer’s disease: an update. Clin Interv Aging. 2007;2(1):17-32. Pubmed
  10. Farlow MR: Update on rivastigmine. Neurologist. 2003 Sep;9(5):230-4. Pubmed
  11. Greig NH, Lahiri DK, Sambamurti K: Butyrylcholinesterase: an important new target in Alzheimer’s disease therapy. Int Psychogeriatr. 2002;14 Suppl 1:77-91. Pubmed

2. Cholinesterase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Cholinesterase P06276 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Stahl SM: The new cholinesterase inhibitors for Alzheimer’s disease, Part 1: their similarities are different. J Clin Psychiatry. 2000 Oct;61(10):710-1. Pubmed
  3. Gottwald MD, Rozanski RI: Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer’s disease: review and current status. Expert Opin Investig Drugs. 1999 Oct;8(10):1673-1682. Pubmed
  4. Birks J, Grimley Evans J, Iakovidou V, Tsolaki M, Holt FE: Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD001191. Pubmed# Birks J: Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005593. Pubmed# Naik RS, Hartmann J, Kiewert C, Duysen EG, Lockridge O, Klein J: Effects of rivastigmine and donepezil on brain acetylcholine levels in acetylcholinesterase-deficient mice. J Pharm Pharm Sci. 2009;12(1):79-85. Pubmed
  5. Smith DA: Treatment of Alzheimer’s disease in the long-term-care setting. Am J Health Syst Pharm. 2009 May 15;66(10):899-907. Pubmed
  6. Bassil N, Grossberg GT: Novel regimens and delivery systems in the pharmacological treatment of Alzheimer’s disease. CNS Drugs. 2009;23(4):293-307. Pubmed# Lalli S, Albanese A: Rivastigmine in Parkinson’s disease dement
    ia. Expert Rev Neurother. 2008 Aug;8(8):1181-8. Pubmed
  7. Onor ML, Trevisiol M, Aguglia E: Rivastigmine in the treatment of Alzheimer’s disease: an update. Clin Interv Aging. 2007;2(1):17-32. Pubmed
  8. Farlow MR: Update on rivastigmine. Neurologist. 2003 Sep;9(5):230-4. Pubmed
  9. Greig NH, Lahiri DK, Sambamurti K: Butyrylcholinesterase: an important new target in Alzheimer’s disease therapy. Int Psychogeriatr. 2002;14 Suppl 1:77-91. Pubmed

1. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Comments
Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12