Dimenhydrinate

Identification

Summary

Dimenhydrinate is a medication used to prevent and treat nausea, vomiting, vertigo, and motion sickness.

Brand Names
Dramamine, Driminate, Gravol
Generic Name
Dimenhydrinate
DrugBank Accession Number
DB00985
Background

Dimehydrinate was first described in the literature in 1949,5 and patented in 1950.11 Early research into dimenhydrinate focused on its role as an antihistamine for urticaria; the treatment of motion sickness was an accidental discovery.7

Dimenhydrinate, also known as B-dimethylaminoethyl benzohydrol ether 8-chlorotheophyllinate, is indicated to prevent nausea, vomiting, and dizziness caused by motion sickness.9,10,11 Dimenhydrinate is a combination of Diphenhydramine and 8-chlorotheophylline in a salt form, with 53%-55.5% dried diphenhydramine, and 44%-47% died 8-chlorotheophylline.10

The antiemetic properties of dimenhydrinate are primarily thought to be produced by diphenhydramine's antagonism of H1 histamine receptors in the vestibular system2 while the excitatory effects are thought to be produced by 8-chlorotheophylline's adenosine receptor blockade.3

When used in large doses, dimenhydrinate has been shown to cause a "high" characterized by hallucinations, excitement, incoordination, and disorientation.1

Dimenhydrinate was granted FDA approval on 31 May 1972.8

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 469.97
Monoisotopic: 469.1880675
Chemical Formula
C24H28ClN5O3
Synonyms
  • (O-benzhydryl(dimethylamino)ethanol) 8-chlorotheophyllinate
  • 8-chloro-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione - 2-(diphenylmethoxy)-N,N-dimethylethanamine (1:1)
  • Benzhydryl-β-dimethylaminoethylether 8-chlorotheophylline
  • Dimenhidrinato
  • Dimenhydrinate
  • Dimenhydrinatum
  • diphenhydramine 8-chlorotheophyllinate
  • diphenhydramine 8-chlorotheophylline
  • Diphenhydramine theoclate
  • N,N-dimethyl-2-diphenylmethoxyethylamine 8-chlorotheophyllinate
  • O-benzhydryldimethylaminoethanol 8-chlorotheophyllinate
  • β-dimethylaminoethyl benzhydryl ether 1,3-dimethyl-8-chloroxanthine

Pharmacology

Indication

Dimenhydrinate is indicated for the prevention and treatment of nausea, vomiting, or vertigo of motion sickness.9,10

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Dimenhydrinate is indicated for the prevention and treatment of nausea, vomiting, or vertigo of motion sickness.9,10 It has a short duration of action of 4-8 hours.4 Patients should be counselled regarding pronounced drowsiness, avoiding alcohol and other sedatives, and exercising caution when operating a motor vehicle or heavy machinery.9

Mechanism of action

Dimenhydrinate is a theoclate salt that separates into diphenhydramine and 8-chlorotheophylline.10,13 While the exact mechanism of action is unknown, diphenhydramine is theorized to reduce disturbances to equilibrium through antimuscarinic effects or histamine H1 antagonism.7 8-chlorotheophylline may produce excitation through blocking adenosine receptors, reducing the drowsiness produced by diphenhydramine.13

TargetActionsOrganism
AHistamine H1 receptor
antagonist
Humans
Absorption

A 50 mg oral film coated tablet reaches a Cmax of 72.6 ng/mL with a Tmax of 2.7 hours.12 A 100 mg suppository reaches a Cmax of 112.2 ng/mL with a Tmax of 5.3 hours.13

Volume of distribution

The volume of distribution of dimenhydrinate is 3-4 L/kg.12

Protein binding

Dimenhydrinate is 70-85% protein bound in plasma.12

Metabolism

Dimenhydrinate is a theoclate salt that separates into diphenhydramine and 8-chlorotheophylline.10 diphenhydramine can either be N-glucuronidated by UGTs to diphenhydramine N-glucuronide or N-demethylated by CYP2D6, CYP1A2, CYP2C9, and CYP2C19 to N-desmethyldiphenhydramine.6 N-desmethyldiphenhydramine can be N-demethylated again by the same enzymes to N,N-didesmethyldiphenhydramine, which undergoes oxidative deamination to form diphenylmethoxyacetic acid.6

Hover over products below to view reaction partners

Route of elimination

Dimenhydrinate is predominantly eliminated in the urine.12 1-3% of the dissociated diphenhydramine is eliminated in the urine unchanged, while 64% of diphenhydramine is eliminated in the urine as metabolites.13 The elimination of dimenhydrinate has not been fully studied.13

Half-life

The plasma elimination half life of dimenhydrinate is 5-8 hours.12

Clearance

Not Available

Adverse Effects
Medicalerrors
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Toxicity

Infants and children experiencing an overdose may lead to hallucinations, convulsions, or death.10 Adults experiencing an overdose may present with drowsiness, convulsions, coma, or respiratory depression.10 Treat overdoses with symptomatic and supportive measures including mechanically assisted ventilation.10

In mice the oral LD50 is 203 mg/kg, while in rats it is 1320 mg/kg.10 The intraperitoneal LD50 in mice is 149 mg/kg.10

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of adverse effects can be increased when Dimenhydrinate is combined with 1,2-Benzodiazepine.
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Dimenhydrinate.
AcetophenazineThe risk or severity of adverse effects can be increased when Dimenhydrinate is combined with Acetophenazine.
AclidiniumDimenhydrinate may increase the central nervous system depressant (CNS depressant) activities of Aclidinium.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Dimenhydrinate.
AdenosineThe risk or severity of QTc prolongation can be increased when Adenosine is combined with Dimenhydrinate.
AgomelatineThe risk or severity of adverse effects can be increased when Dimenhydrinate is combined with Agomelatine.
AjmalineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Dimenhydrinate.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Dimenhydrinate.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Dimenhydrinate.
Interactions
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Food Interactions
  • Avoid alcohol.

Products

Products
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Active Moieties
NameKindUNIICASInChI Key
Diphenhydraminesalt8GTS82S83M58-73-1ZZVUWRFHKOJYTH-UHFFFAOYSA-N
8-chlorotheophyllinesaltGE2UA340FM85-18-7RYIGNEOBDRVTHA-UHFFFAOYSA-N
Product Images
International/Other Brands
Gravol (Church & Dwight) / Vertirosan (Astellas) / Vomex A (Astellas) / Xamamina (Adilna)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Dimenhydrinate Inj 10mgLiquid10 mg / mLIntravenousSandoz Canada Incorporated1973-12-31Not applicableCanada flag
Dimenhydrinate Inj 10mg/mlLiquid10 mg / mLIntravenousAstra Pharma Inc.1986-12-311999-07-29Canada flag
Dimenhydrinate Inj 50mg USPLiquid50 mg / mLIntramuscular; IntravenousSandoz Canada Incorporated1973-12-31Not applicableCanada flag
Dimenhydrinate Injection 50mg/mlSolution50 mg / mLIntramuscular; IntravenousAstra Zeneca1986-12-312005-05-31Canada flag
Dimenhydrinate Injection USPSolution50 mg / mLIntramuscular; IntravenousTeligent Ou2016-01-28Not applicableCanada flag
Dimenhydrinate Injection USP 250mg/5ml (50mg/ml)Solution50 mg / mLIntramuscular; IntravenousTeligent Ou2008-06-26Not applicableCanada flag
Dimenhydrinate Injection USP With PreservativeSolution50 mg / mLIntramuscular; IntravenousTeligent Ou2016-01-28Not applicableCanada flag
Dimenhydrinate Injection, USPSolution50 mg / mLIntramuscular; IntravenousMylan Pharmaceuticals1994-12-31Not applicableCanada flag
Gravol ImSolution50 mg / mLIntramuscularChurch & Dwight Canada Corp1953-12-31Not applicableCanada flag
Gravol IV AmpoulesSolution10 mg / mLIntravenousChurch & Dwight Canada Corp1953-12-312008-07-30Canada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DimenhydrinateInjection, solution50 mg/1mLIntramuscular; IntravenousFresenius Kabi USA, LLC2004-11-29Not applicableUS flag
Over the Counter Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Ag-dimenhydrinateTablet50 mgOralAngita Pharma Inc.Not applicableNot applicableCanada flag
Airmit AceTablet25 mg/1OralSato Pharmaceutical Co., Ltd.2005-03-11Not applicableUS flag
Anti-nauseantTablet50 mgOralApotex Corporation2013-07-02Not applicableCanada flag
Anti-nauseantTablet50 mgOralVita Health Products Inc2000-05-01Not applicableCanada flag
Anti-nauseantTablet50 mgOralTEVA Canada LimitedNot applicableNot applicableCanada flag
Anti-nauseantTablet50 mgOralPharmascience IncNot applicableNot applicableCanada flag
Anti-nauseantTablet50 mgOralPharmascience Inc2002-08-23Not applicableCanada flag
Anti-nauseant Liquid GelsCapsule50 mgOralVita Health Products Inc2020-08-04Not applicableCanada flag
Anti-nauseant TabletTablet50 mgOralStanley Pharmaceuticals, A Division Of Vita Health Products Inc.1998-05-262008-08-07Canada flag
Apo Dimenhydrinate Tab 50mgTablet50 mgOralApotex Corporation1977-12-31Not applicableCanada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Gravergol CapsulesDimenhydrinate (50 mg) + Caffeine (100 mg) + Ergotamine tartrate (1 mg)CapsuleOralCan Med Pharma Inc.1957-12-312011-12-07Canada flag
มาโนไดสิคDimenhydrinate (50 MG) + Pyridoxine (20 MG)Tabletบริษัท โรงงานเภสัชกรรมแหลมทองการแพทย์ จำกัด จำกัด1986-12-30Not applicableThailand flag
เวนซิกซ์Dimenhydrinate (50 MG) + Pyridoxine (10 MG)Capsuleบริษัท โมเดิร์น ฟาร์มา จำกัด2013-01-14Not applicableThailand flag
เวอร์ตามินDimenhydrinate (25 MG) + Pyridoxine (25 MG)Tablet, sugar coatedOralห้างหุ้นส่วนจำกัด โรงงานเลิศสิงห์เภสัชกรรม1985-04-02Not applicableThailand flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
JB937PER5C
CAS number
523-87-5
InChI Key
NFLLKCVHYJRNRH-UHFFFAOYSA-N
InChI
InChI=1S/C17H21NO.C7H7ClN4O2/c1-18(2)13-14-19-17(15-9-5-3-6-10-15)16-11-7-4-8-12-16;1-11-4-3(9-6(8)10-4)5(13)12(2)7(11)14/h3-12,17H,13-14H2,1-2H3;1-2H3,(H,9,10)
IUPAC Name
8-chloro-1,3-dimethyl-2,3,6,9-tetrahydro-1H-purine-2,6-dione; [2-(diphenylmethoxy)ethyl]dimethylamine
SMILES
CN1C2=C(N=C(Cl)N2)C(=O)N(C)C1=O.CN(C)CCOC(C1=CC=CC=C1)C1=CC=CC=C1

References

Synthesis Reference

Cusic, J.W.; U.S. Patent 2,499,058; February 28,1950; assigned to G.D. Searle & Co. Cusic, J.W.; U.S. Patent 2,534,813; December 19,1950; assigned to G.D. Searle & Co.

General References
  1. Halpert AG, Olmstead MC, Beninger RJ: Mechanisms and abuse liability of the anti-histamine dimenhydrinate. Neurosci Biobehav Rev. 2002 Jan;26(1):61-7. [Article]
  2. Jaju BP, Wang SC: Effects of diphenhydramine and dimenhydrinate on vestibular neuronal activity of cat: a search for the locus of their antimotion sickness action. J Pharmacol Exp Ther. 1971 Mar;176(3):718-24. [Article]
  3. Spealman RD: Psychomotor stimulant effects of methylxanthines in squirrel monkeys: relation to adenosine antagonism. Psychopharmacology (Berl). 1988;95(1):19-24. [Article]
  4. Koch A, Cascorbi I, Westhofen M, Dafotakis M, Klapa S, Kuhtz-Buschbeck JP: The Neurophysiology and Treatment of Motion Sickness. Dtsch Arztebl Int. 2018 Oct 12;115(41):687-696. doi: 10.3238/arztebl.2018.0687. [Article]
  5. FLEMING JF: New drug effective in motion sickness. Hosp Top. 1949 Mar;27(3):26. [Article]
  6. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]
  7. FERMIN H, van DEINSE JB, HAMMELBURG E: The effect of dimenhydrinate upon the labyrinth; (an experimental study). Acta Otolaryngol. 1950 Dec;38(6):543-9. doi: 10.3109/00016485009118417. [Article]
  8. FDA Approved Drug Products: Dimenhydrinate Oral Liquid (Discontinued) [Link]
  9. Dailymed: Dimenhydrinate Oral Tablet [Link]
  10. Dailymed: Dimenhydrinate Intramuscular and Intravenous Injection [Link]
  11. US Patent: US2499058A [Link]
  12. Sandoz Canada: Dimenhydrinate Intramuscular and Intravenous Injection [Link]
  13. Heads of Medicines Agencies Public Assessment Report: Dimenhydrinate Oral Lozenge [Link]
Human Metabolome Database
HMDB0015120
KEGG Drug
D00520
PubChem Compound
441281
PubChem Substance
46504881
ChemSpider
10210
RxNav
3444
ChEBI
94848
ChEMBL
CHEMBL1200406
Therapeutic Targets Database
DAP000333
PharmGKB
PA449338
Drugs.com
Drugs.com Drug Page
Wikipedia
Dimenhydrinate
AHFS Codes
  • 56:22.08 — Antihistamines
  • 04:04.04 — Ethanolamine Derivatives
MSDS
Download (72 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedPreventionPost Operative Nausea and Vomiting (PONV)1
4CompletedTreatmentDizziness / Nausea / Vomiting1
4CompletedTreatmentGastroenteritis1
4CompletedTreatmentPain / Postoperative pain1
4CompletedTreatmentVertigo, Peripheral1
3Unknown StatusTreatmentVertigo, Peripheral1
2CompletedTreatmentPost Operative Nausea and Vomiting (PONV)1
1CompletedTreatmentHealthy Volunteers1
Not AvailableCompletedTreatmentNausea / Vomiting1

Pharmacoeconomics

Manufacturers
  • App pharmaceuticals llc
  • Baxter healthcare corp anesthesia and critical care
  • Watson laboratories inc
  • Wyeth ayerst laboratories
  • Alra laboratories inc
  • Heather drug co inc
  • Nexgen pharma inc
Packagers
  • APP Pharmaceuticals
  • C.O. Truxton Inc.
  • Consolidated Midland Corp.
  • Dispensing Solutions
  • Hospira Inc.
  • Ivax Pharmaceuticals
  • Major Pharmaceuticals
  • Martin Surgical Supply
  • Medisca Inc.
  • Nexgen Pharma Inc.
  • Pfizer Inc.
  • Pharmacia Inc.
  • Prescript Pharmaceuticals
  • Southwood Pharmaceuticals
Dosage Forms
FormRouteStrength
TabletOral25 mg/1
Suspension
TabletOral
Tablet, coatedOral50 mg
SolutionOral15 mg / 5 mL
SuppositoryRectal50 mg
Injection, solutionIntramuscular; Intravenous50 mg/1mL
TabletOral
TabletOral50 mg/1
Tablet, film coatedOral50 mg/1
LiquidIntravenous10 mg / mL
LiquidIntramuscular; Intravenous50 mg / mL
SolutionIntramuscular; Intravenous50 mg / mL
LiquidOral15 mg / 5 mL
TabletOral50.0 mg
Tablet, chewableOral50 mg/1
Tablet, chewableOral25 mg/1
CapsuleOral
Capsule, extended releaseOral75 mg
Tablet, chewableOral50 mg
TabletOral15 mg
SolutionIntramuscular50 mg / mL
Tablet, multilayerOral100 mg
SolutionIntravenous10 mg / mL
CapsuleOral50 mg
Tablet, extended releaseOral75 mg
SuppositoryRectal100 mg
TabletOral25 mg
Tablet, chewableOral15 mg
SyrupOral15 mg / 5 mL
SuppositoryRectal25 mg
TabletOral0.05 g
Tablet, sugar coatedOral
SyrupOral
Tablet, coatedOral50 mg/1
SyrupOral3 mg / mL
Gum, chewingOral20 MG
Gum, chewingOral
Tablet, sugar coatedOral
Tablet, coatedOral
SuppositoryRectal
Injection, solutionIntramuscular; Intravenous
Solution / dropsOral
Tablet, coatedOral
SuppositoryRectal
Tablet, orally disintegratingSublingual
SuppositoryRectal150 MG
SuppositoryRectal70 MG
SuppositoryRectal40 MG
Tablet, orally disintegratingSublingual50 MG
InjectionIntramuscular; Intravenous
CapsuleOral
Tablet, film coatedOral50 mg
Tablet
Capsule
Solution50 mg/1ml
TabletOral50 mg
Tablet, sugar coatedOral50 mg
SyrupOral15 mg/5ml
Prices
Unit descriptionCostUnit
Dimenhydrinate 50 mg/ml vial5.7USD ml
Dimenhydrinate I.M. 50 mg/ml1.17USD ml
Meclizine 12.5 mg tablet0.62USD tablet
Dramamine less drowsy tablet0.42USD tablet
Dimenhydrinate I.V. 10 mg/ml0.32USD ml
Dramamine 50 mg tablet0.28USD tablet
Novamine 15% iv solution0.09USD ml
Dimenhydrinate 100% powder0.07USD g
Driminate 50 mg tablet0.05USD tablet
Dimenhydrinate 50 mg tablet0.03USD tablet
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)103-104Cusic, J.W.; U.S. Patent 2,499,058; February 28,1950; assigned to G.D. Searle & Co. Cusic, J.W.; U.S. Patent 2,534,813; December 19,1950; assigned to G.D. Searle & Co.
water solubility3000 mg/LMERCK INDEX (1996); approx.
Predicted Properties
PropertyValueSource
Water Solubility9.86 mg/mLALOGPS
logP0.44ALOGPS
logP3.65ChemAxon
logS-1.3ALOGPS
pKa (Strongest Basic)8.87ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area12.47 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity79.93 m3·mol-1ChemAxon
Polarizability30.02 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9975
Blood Brain Barrier+0.8551
Caco-2 permeable+0.5198
P-glycoprotein substrateSubstrate0.7863
P-glycoprotein inhibitor INon-inhibitor0.6923
P-glycoprotein inhibitor IIInhibitor0.6502
Renal organic cation transporterNon-inhibitor0.6507
CYP450 2C9 substrateNon-substrate0.7536
CYP450 2D6 substrateNon-substrate0.8181
CYP450 3A4 substrateSubstrate0.7086
CYP450 1A2 substrateInhibitor0.5287
CYP450 2C9 inhibitorNon-inhibitor0.6308
CYP450 2D6 inhibitorNon-inhibitor0.8589
CYP450 2C19 inhibitorNon-inhibitor0.5817
CYP450 3A4 inhibitorNon-inhibitor0.9028
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5738
Ames testNon AMES toxic0.5629
CarcinogenicityNon-carcinogens0.7548
BiodegradationNot ready biodegradable0.8211
Rat acute toxicity2.4087 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.5364
hERG inhibition (predictor II)Inhibitor0.5405
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Histamine receptor activity
Specific Function
In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamin...
Gene Name
HRH1
Uniprot ID
P35367
Uniprot Name
Histamine H1 receptor
Molecular Weight
55783.61 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  2. Halpert AG, Olmstead MC, Beninger RJ: Mechanisms and abuse liability of the anti-histamine dimenhydrinate. Neurosci Biobehav Rev. 2002 Jan;26(1):61-7. [Article]

Drug created on June 13, 2005 13:24 / Updated on June 21, 2021 12:15