Betahistine

Identification

Summary

Betahistine is an antivertigo agent used for the reduction of episodes of vertigo association with Ménière's disease.

Brand Names
Serc
Generic Name
Betahistine
DrugBank Accession Number
DB06698
Background

Ménière's disease is a progressive disease of the inner ear characterized by vertigo, tinnitus, and hearing loss. It has a significant impact on both the physical and social functioning of affected individuals.2,12

Betahistine is a histamine-like antivertigo drug used for treating symptoms associated with Ménière's disease. It is thought to reduce symptoms through its actions on histamine receptors.4,11 Betahistine was first approved by the FDA in the 1970s but withdrawn within approximately 5 years due to a lack of evidence supporting its efficacy. It is currently marketed in Canada by various companies, including Teva Pharmaceuticals.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 136.1943
Monoisotopic: 136.100048394
Chemical Formula
C8H12N2
Synonyms
  • [2-(2-pyridyl)ethyl]methylamine
  • 2-(β-methylaminoethyl)pyridine
  • 2-[2-(methylamino)ethyl]pyridine
  • Betahistina
  • Bétahistine
  • Betahistine
  • Betahistinum
  • N-methyl-2-(2-pyridinyl)ethanamine
  • N-methyl-2-pyridineethanamine

Pharmacology

Indication

Betahistine is indicated for the reduction of recurrent vertigo episodes associated with Ménière's disease in patients 18 years old and above.10

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Through its actions on the histamine receptors, betahistine provides relief from vertigo associated with Ménière's disease.3,5,10

Mechanism of action

Vertigo is a disturbing sensation of movement caused by dysfunction of the labyrinth (inner ear), vestibular nerve, cerebellum, brainstem, or Central Nervous System (CNS). Vestibular forms of vertigo are often accompanied by auditory dysfunctions such as hyperacusis, hearing loss, and tinnitus.3 In most cases, adaptive mechanisms of the CNS lead to functional recovery after episodes of vertigo, however, syndromes such as Ménière's disease tend to cause the recurrence of vertigo symptoms. This significantly impacts the quality of life and the ability to carry out daily activities.2

H1-receptor activity

The mechanism of action of betahistine is multifactorial. Ménière's disease is thought to result from a disruption of endolymphatic fluid homeostasis in the ear.6 Betahistine mainly acts as a histamine H1-receptor agonist. The stimulation of H1-receptors in the inner ear causes a vasodilatory effect leading to increased permeability of blood vessels and a reduction in endolymphatic pressure; this action prevents the rupture of the labyrinth, which can contribute to the hearing loss associated with Ménière's disease. Betahistine is also purported to act by reducing the asymmetrical functioning of sensory vestibular organs and increasing vestibulocochlear blood flow, relieving symptoms of vertigo.5

H3-receptor activity

In addition to the above mechanisms, betahistine also acts as a histamine H3-receptor antagonist, increasing the turnover of histamine from postsynaptic histaminergic nerve receptors, subsequently leading to an increase in H1-agonist activity. H3-receptor antagonism elevates levels of neurotransmitters including serotonin in the brainstem, inhibiting the activity of vestibular nuclei, thus restoring proper balance and decreasing vertigo symptoms.3

TargetActionsOrganism
AHistamine H1 receptor
agonist
Humans
AHistamine H3 receptor
antagonist
Humans
Absorption

When given orally, betahistine is rapidly and almost completely absorbed from the gastrointestinal tract.6,10 In the fasted state, Cmax is achieved within 1 hour of administration; in the fed state, Cmax is delayed, but the total drug absorption is similar. Food, therefore, has little effect on the absorption of betahistine.9

Volume of distribution

In a pharmacokinetic study of rats, betahistine was found to be distributed throughout the body.13 Human data for betahistine's volume of distribution is not readily available.6,9,10,13

Protein binding

The plasma protein binding of betahistine is reported to be less than 5%.9,10

Metabolism

Betahistine is metabolized primarily into the inactive metabolite 2-pyridylacetic acid. There is both clinical and in vitro evidence that monoamine oxidase enzymes are responsible for the metabolism of betahistine.8,10

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Route of elimination

Betahistine is mainly excreted in the urine; with approximately 85-91% being detected in urine samples within 24 hours of administration.6,9,10

Half-life

The half-life of betahistine is 3-4 hours.6,9,10

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Symptoms of an overdose with betahistine (< 640 mg) include dry mouth, nausea, dyspepsia, abdominal pain, and somnolence. Serious complications such as convulsions, pulmonary or cardiac effects may occur with higher doses (> 640 mg), especially during intentional overdoses and combination with other drugs. In the case of an overdose with betahistine, provide supportive therapy, and contact the local poison control center for further management.10

Pathways
PathwayCategory
Betahistine H1-Antihistamine ActionDrug action
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
AcrivastineThe therapeutic efficacy of Betahistine can be decreased when used in combination with Acrivastine.
AlimemazineThe therapeutic efficacy of Betahistine can be decreased when used in combination with Alimemazine.
AmitriptylineThe therapeutic efficacy of Betahistine can be decreased when used in combination with Amitriptyline.
AmoxapineThe therapeutic efficacy of Betahistine can be decreased when used in combination with Amoxapine.
AmphetamineAmphetamine may decrease the sedative and stimulatory activities of Betahistine.
AntazolineThe therapeutic efficacy of Betahistine can be decreased when used in combination with Antazoline.
ArbutamineThe therapeutic efficacy of Arbutamine can be decreased when used in combination with Betahistine.
ArformoterolThe therapeutic efficacy of Arformoterol can be decreased when used in combination with Betahistine.
AripiprazoleThe therapeutic efficacy of Betahistine can be decreased when used in combination with Aripiprazole.
Aripiprazole lauroxilThe therapeutic efficacy of Betahistine can be decreased when used in combination with Aripiprazole lauroxil.
Interactions
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Food Interactions
  • Take with food. This may reduce or prevent gastrointestinal upset.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Betahistine hydrochloride49K58SMZ7U5579-84-0XVDFMHARQUBJRE-UHFFFAOYSA-N
Betahistine maleateU5SU5350VT133206-34-5JLPICNMNXPSXMA-BTJKTKAUSA-N
Betahistine mesylateX1L0E3R43Y54856-23-4ZBJJDYGJCNTNTH-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Act BetahistineTablet24 mgOralActavis Pharma Company2011-10-132018-06-12Canada flag
Act BetahistineTablet16 mgOralActavis Pharma Company2011-10-132018-06-12Canada flag
BetahistineTablet8 mgOralSurax Healthcare IncNot applicableNot applicableCanada flag
BetahistineTablet24 mgOralSurax Healthcare IncNot applicableNot applicableCanada flag
BetahistineTablet24 mgOralSanis Health Inc2018-03-07Not applicableCanada flag
BetahistineTablet16 mgOralSurax Healthcare IncNot applicableNot applicableCanada flag
BetahistineTablet16 mgOralSanis Health Inc2018-03-07Not applicableCanada flag
M-betahistineTablet24 mgOralMantra Pharma IncNot applicableNot applicableCanada flag
M-betahistineTablet16 mgOralMantra Pharma IncNot applicableNot applicableCanada flag
M-betahistineTablet8 mgOralMantra Pharma IncNot applicableNot applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Apo-betahistineTablet16 mgOralApotex CorporationNot applicableNot applicableCanada flag
Apo-betahistineTablet8 mgOralApotex CorporationNot applicableNot applicableCanada flag
Apo-betahistineTablet24 mgOralApotex CorporationNot applicableNot applicableCanada flag
Auro-betahistineTablet16 mgOralAuro Pharma Inc2015-11-30Not applicableCanada flag
Auro-betahistineTablet8 mgOralAuro Pharma Inc2015-11-30Not applicableCanada flag
Auro-betahistineTablet24 mgOralAuro Pharma Inc2015-11-30Not applicableCanada flag
PMS-betahistineTablet16 mgOralPharmascience Inc2014-01-16Not applicableCanada flag
PMS-betahistineTablet24 mgOralPharmascience Inc2014-01-16Not applicableCanada flag
Teva-betahistineTablet8 mgOralTEVA Canada Limited2010-12-13Not applicableCanada flag
Teva-betahistineTablet24 mgOralTEVA Canada Limited2006-08-30Not applicableCanada flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
BETASERC 8 MG TABLET, 30 ADETBetahistine (8 mg)TabletOralABBOTT LABORATUARLARI İTHALAT İHRACAT VE TİC. LTD. ŞTİ.2020-08-14Not applicableTurkey flag

Categories

ATC Codes
N07CA01 — Betahistine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as aralkylamines. These are alkylamines in which the alkyl group is substituted at one carbon atom by an aromatic hydrocarbyl group.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
Amines
Direct Parent
Aralkylamines
Alternative Parents
Pyridines and derivatives / Heteroaromatic compounds / Dialkylamines / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Aralkylamine / Aromatic heteromonocyclic compound / Azacycle / Heteroaromatic compound / Hydrocarbon derivative / Organoheterocyclic compound / Organopnictogen compound / Pyridine / Secondary aliphatic amine / Secondary amine
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
secondary amino compound, aminoalkylpyridine (CHEBI:35677)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
X32KK4201D
CAS number
5638-76-6
InChI Key
UUQMNUMQCIQDMZ-UHFFFAOYSA-N
InChI
InChI=1S/C8H12N2/c1-9-7-5-8-4-2-3-6-10-8/h2-4,6,9H,5,7H2,1H3
IUPAC Name
methyl[2-(pyridin-2-yl)ethyl]amine
SMILES
CNCCC1=CC=CC=N1

References

Synthesis Reference

Jean S. Cherqui, Alain C. Djiane, "New galenical form of administration of betahistine and its derivatives and the preparation thereof." U.S. Patent US4264574, issued February, 1979.

US4264574
General References
  1. Murdin L, Hussain K, Schilder AG: Betahistine for symptoms of vertigo. Cochrane Database Syst Rev. 2016 Jun 21;(6):CD010696. doi: 10.1002/14651858.CD010696.pub2. [Article]
  2. Orji F: The Influence of Psychological Factors in Meniere's Disease. Ann Med Health Sci Res. 2014 Jan;4(1):3-7. doi: 10.4103/2141-9248.126601. [Article]
  3. Della Pepa C, Guidetti G, Eandi M: Betahistine in the treatment of vertiginous syndromes: a meta-analysis. Acta Otorhinolaryngol Ital. 2006 Aug;26(4):208-15. [Article]
  4. Parfenov VA, Golyk VA, Matsnev EI, Morozova SV, Melnikov OA, Antonenko LM, Sigaleva EE, Situkho MI, Asaulenko OI, Popovych VI, Zamergrad MV: Effectiveness of betahistine (48 mg/day) in patients with vestibular vertigo during routine practice: The VIRTUOSO study. PLoS One. 2017 Mar 30;12(3):e0174114. doi: 10.1371/journal.pone.0174114. eCollection 2017. [Article]
  5. Lacour M, van de Heyning PH, Novotny M, Tighilet B: Betahistine in the treatment of Meniere's disease. Neuropsychiatr Dis Treat. 2007 Aug;3(4):429-40. [Article]
  6. Duaa J. Al-Tamimi, Afaq M. Ammoo , Mays E. Alani, Jaafar J. Ibraheem, Duaa J. Al-Tamimi , Afaq M. Ammoo , Mays E. Alani and Jaafar J. Ibraheem: Pharmacokinetics and dose proportionality of betahistine in healthy individuals Scientia Pharmaceutica. [Article]
  7. Strupp M, Kraus L, Schautzer F, Rujescu D: Meniere's disease: combined pharmacotherapy with betahistine and the MAO-B inhibitor selegiline-an observational study. J Neurol. 2018 Mar 12. pii: 10.1007/s00415-018-8809-8. doi: 10.1007/s00415-018-8809-8. [Article]
  8. Sternson LA, Tobia AJ, Walsh GM, Sternson AW: The metabolism of betahistine in the rat. Drug Metab Dispos. 1974 Mar-Apr;2(2):123-8. [Article]
  9. Ramos Alcocer R, Ledezma Rodriguez JG, Navas Romero A, Cardenas Nunez JL, Rodriguez Montoya V, Deschamps JJ, Liviac Ticse JA: Use of betahistine in the treatment of peripheral vertigo. Acta Otolaryngol. 2015;135(12):1205-11. doi: 10.3109/00016489.2015.1072873. Epub 2015 Aug 6. [Article]
  10. Product Monograph: SERC (betahistine hydrochloride) oral tablets [Link]
  11. Medicines UK: Betahistine Dihydrochloride 16mg Tablets [Link]
  12. NIH StatPearls: Meniere's disease [Link]
  13. Product monograph: SERC † (Betahistine dihydrochloride) 8 mg, 16 mg, and 24 mg oral tablets [Link]
Human Metabolome Database
HMDB0015644
KEGG Drug
D07522
PubChem Compound
2366
PubChem Substance
99443252
ChemSpider
2276
BindingDB
96589
RxNav
1511
ChEBI
35677
ChEMBL
CHEMBL24441
ZINC
ZINC000001675415
PharmGKB
PA165958372
Wikipedia
Betahistine
MSDS
Download (24.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentGait or Balance Disorder Problems1
4CompletedTreatmentMenière's Disease1
4WithdrawnTreatmentVertigo1
2CompletedTreatmentAutism Spectrum Conditions/Disorders / Bipolar 1 Disorder / Bipolar Disorder, Type II / Bipolar NOS(Not Otherwise Specified) / Psychotic Disorder Not Otherwise Specified (NOS) / Schizoaffective Disorders / Schizophrenia / Schizophreniform Disorders1
2CompletedTreatmentObesity (Disorder)2
2TerminatedPreventionWeight Gain1
2TerminatedTreatmentHigh Cholesterol1
2TerminatedTreatmentRecurrent Major Depressive Disorder With Atypical Features1
1CompletedNot AvailableHealthy Subjects (HS)2
1CompletedTreatmentAttention Deficit Hyperactivity Disorder (ADHD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SolutionOral
TabletOral
TabletOral5 mg/1
TabletOral2.5 mg/1
TabletOral15.6 mg/1
TabletOral24 mg
Tablet, orally disintegratingOral24 mg
Tablet, extended releaseOral
Solution / dropsOral
Tablet, orally disintegratingOral
TabletOral4 mg / tab
TabletOral8 mg / tab
Tablet, film coatedOral8 mg
SolutionOral8 mg
Tablet, coatedOral8 mg
Tablet, coatedOral24 mg
SolutionOral12.5 mg
Tablet, film coatedOral16 mg
TabletOral8 mg
TabletOral16 mg
Tablet, film coatedOral24 mg
TabletOral12 mg
TabletOral6 mg
Tablet, coatedOral16 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)150-144https://www.chembk.com/en/chem/Betahistine%20Hydrochloride
boiling point (°C)210.9±15.0 °Chttps://www.chemsrc.com/en/cas/5638-76-6_951490.html
logP0.10https://www.chemsrc.com/en/cas/5638-76-6_951490.html
pKa3.5, 9.7https://www.mylan.ca/-/media/mylanca/documents/english/product-pdf/pdfs-dec-2015/serc-pm-2016.01.08.pdf?la=en-ca
Predicted Properties
PropertyValueSource
Water Solubility49.3 mg/mLALOGPS
logP0.59ALOGPS
logP0.63ChemAxon
logS-0.44ALOGPS
pKa (Strongest Basic)9.77ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area24.92 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity41.33 m3·mol-1ChemAxon
Polarizability15.85 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9949
Blood Brain Barrier+0.9485
Caco-2 permeable+0.7747
P-glycoprotein substrateSubstrate0.5736
P-glycoprotein inhibitor INon-inhibitor0.9568
P-glycoprotein inhibitor IINon-inhibitor0.9843
Renal organic cation transporterInhibitor0.5858
CYP450 2C9 substrateNon-substrate0.7936
CYP450 2D6 substrateSubstrate0.7703
CYP450 3A4 substrateNon-substrate0.71
CYP450 1A2 substrateNon-inhibitor0.6919
CYP450 2C9 inhibitorNon-inhibitor0.9339
CYP450 2D6 inhibitorNon-inhibitor0.9345
CYP450 2C19 inhibitorNon-inhibitor0.9253
CYP450 3A4 inhibitorNon-inhibitor0.8961
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9759
Ames testNon AMES toxic0.8219
CarcinogenicityNon-carcinogens0.9557
BiodegradationNot ready biodegradable0.8351
Rat acute toxicity1.3795 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8518
hERG inhibition (predictor II)Non-inhibitor0.8184
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
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. Barak N: Betahistine: what's new on the agenda? Expert Opin Investig Drugs. 2008 May;17(5):795-804. doi: 10.1517/13543784.17.5.795 . [Article]
  2. Lacour M, Sterkers O: Histamine and betahistine in the treatment of vertigo: elucidation of mechanisms of action. CNS Drugs. 2001;15(11):853-70. [Article]
  3. Lacour M, van de Heyning PH, Novotny M, Tighilet B: Betahistine in the treatment of Meniere's disease. Neuropsychiatr Dis Treat. 2007 Aug;3(4):429-40. [Article]
  4. Product Monograph: SERC (betahistine hydrochloride) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Histamine receptor activity
Specific Function
The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive a...
Gene Name
HRH3
Uniprot ID
Q9Y5N1
Uniprot Name
Histamine H3 receptor
Molecular Weight
48670.81 Da
References
  1. Barak N: Betahistine: what's new on the agenda? Expert Opin Investig Drugs. 2008 May;17(5):795-804. doi: 10.1517/13543784.17.5.795 . [Article]
  2. Lacour M, Sterkers O: Histamine and betahistine in the treatment of vertigo: elucidation of mechanisms of action. CNS Drugs. 2001;15(11):853-70. [Article]
  3. Gbahou F, Davenas E, Morisset S, Arrang JM: Effects of betahistine at histamine H3 receptors: mixed inverse agonism/agonism in vitro and partial inverse agonism in vivo. J Pharmacol Exp Ther. 2010 Sep 1;334(3):945-54. doi: 10.1124/jpet.110.168633. Epub 2010 Jun 8. [Article]
  4. Lacour M, van de Heyning PH, Novotny M, Tighilet B: Betahistine in the treatment of Meniere's disease. Neuropsychiatr Dis Treat. 2007 Aug;3(4):429-40. [Article]
  5. Product Monograph: SERC (betahistine hydrochloride) oral tablets [Link]

Enzymes

Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Serotonin binding
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...

Components:
References
  1. Sternson LA, Tobia AJ, Walsh GM, Sternson AW: The metabolism of betahistine in the rat. Drug Metab Dispos. 1974 Mar-Apr;2(2):123-8. [Article]
  2. Medicines UK: Betahistine Dihydrochloride 16mg Tablets [Link]

Drug created on May 06, 2010 16:01 / Updated on October 22, 2021 23:18