PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
verapamil

2D structure

Overview

Generic Names: Verapamil HCl; Verapamil [Usan:Ban:Inn]; Verapamilo [INN-Spanish]; Verapamilum [INN-Latin]
IUPAC Name: 2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-ylpentanenitrile
Trade Names: Apo-Verap; Arpamyl; Berkatens; Calan; Calan SR; Cardiagutt; Cardibeltin; Cordilox; Covera-HS; Dignover; Dilacoran; Drosteakard; Geangin; Iproveratril; Isoptimo; Isoptin; Isoptin SR; NU-Verap; Novo-Veramil; Quasar; Securon; Univer; Vasolan; Veracim; Veramex; Veraptin; Verelan; Verelan PM; Verexamil
Brand Mixtures: Tarka (trandolapril + verapamil hydrochloride)
PharmGKB Accession Id: PA451868

Description

A calcium channel blocker that is a class IV anti-arrhythmia agent. [PubChem]

Indication

For the treatment of hypertension and angina.

ATC Therapeutic Category

  • C08DA:Phenylalkylamine derivatives

Pharmacology and Interactions

Mechanism Of Action

Possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, verapamil, like diltiazem, inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to dilation of the coronary and systemic arteries,improved oxygen delivery to the myocardial tissue, and decreased total peripheral resistance, systemic blood pressure, and afterload.

Pharmacology

Verapamil, a class IV antiarrhythmic agent, is used as a calcium-channel blocking (CCB) agent for the treatment of angina, hypertension, and for supraventricular tachyarrhythmias.

Food Interactions

Avoid alcohol. Avoid excessive quantities of coffee or tea (Caffeine). Avoid natural licorice. Avoid taking with grapefruit juice. Take with food.

Absorption, Distribution, Metabolism, Elimination & Toxicity

Protein Binding

90%

Absorption

90%

Half Life

2.8-7.4 hours

Toxicity

LD50=8 mg/kg (i.v. in mice)

Chemical Properties

Chemical Formula:

C27H38N2O4

SMILES Code:

CC(C)C(CCCN(C)CCc1ccc(c(c1)OC)OC)(C#N)c2ccc(c(c2)O[CH2])OC

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

454.6016 / 454.2832

Curated Annotations (Curated Annotation)

  1. rs10918594 at chr1:160297312 in NOS1AP
    In a study of 112 patients taking verapamil, patients with genotype GG of this SNP showed significantly more QTc prolongation than users with the CC genotype. Genotype at this SNP was not significantly associated with QTc prolongation in the 44 patients studied who were taking isradipine.
    Related Drugs:
    isradipine, verapamil
    Evidence:
    PMID:19247217
  2. rs10494366 at chr1:160352309 in NOS1AP
    In a study of 112 patients taking verapamil, patients carrying genotype GG of this SNP showed significantly more QTc prolongation than users with the TT genotype. Genotype at this SNP was not significantly associated with QTc prolongation in the 44 patients studied who were taking isradipine.
    Related Drugs:
    isradipine, verapamil
    Evidence:
    PMID:19247217
  3. rs1042713 at chr5:148186633 in ADRB2
    None of the ADRB2 haplotypes tested that contained this SNP were associated with differential primary outcome (i.e., the first incidence of death, nonfatal myocardial infarction, or nonfatal stroke) in hypertensive patients with coronary artery disease.
    Variant Name:
    ADRB2:Gly16Arg (46G>A)
    Related Drugs:
    atenolol, verapamil
    Related Diseases:
    Death
    Evidence:
    PMID:18615004
  4. rs1042714 at chr5:148186666 in ADRB2
    None of the ADRB2 haplotypes tested that contained this SNP were associated with differential primary outcome (i.e., the first incidence of death, nonfatal myocardial infarction, or nonfatal stroke) in hypertensive patients with coronary artery disease.
    Variant Name:
    ADRB2:Gln27Glu; ADRB2:79C>G
    Related Drugs:
    atenolol, verapamil
    Related Diseases:
    Death, Myocardial Infarction, Stroke
    Evidence:
    PMID:18615004
  5. rs1042718 at chr5:148187110 in ADRB2
    None of the ADRB2 haplotypes tested that contained this SNP were associated with differential primary outcome (i.e., the first incidence of death, nonfatal myocardial infarction, or nonfatal stroke) in hypertensive patients with coronary artery disease.
    Variant Name:
    ADRB2:Arg175Arg (523C>A)
    Related Drugs:
    atenolol, verapamil
    Related Diseases:
    Death
    Evidence:
    PMID:18615004
  6. rs1045642 at chr7:86976581 in ABCB1
    rs1045642 is associated with altered inhibition by verapamil and cyclosporin A of substrate uptake in vitro.
    Variant Name:
    ABCB1:C3435T
    Related Drugs:
    cyclosporine, verapamil
    Evidence:
    PMID:17185560
  7. rs1045642 at chr7:86976581 in ABCB1
    Functional study of rs1045642 (3435C>T) and rs1128503 (2677G>T/A): in LLC-PK1 cells expressing wild-type (2677G/3435C) or polymorphic (2677G/3435T, 2677A/3435C, 2677A/3435T, 2677T/3435C, 2677T/3435T) constructs of ABCB1 in vitro, no significant differences were observed in transcellular efflux of structurally diverse P-gp substrates, verapamil, digoxin, vinblastine or cyclosporin A.
    Variant Name:
    ABCB1: c.3435C>T, mRNA 3853C>T
    Related Drugs:
    cyclosporine, digoxin, verapamil, vinblastine
    Evidence:
    PMID:12781336
  8. rs1045642 at chr7:86976581 in ABCB1
    Functional study of rs1045642 (3435C>T) and rs2032582 (2677G>T/A): in LLC-PK1 cells expressing wild-type (2677G/3435C) or polymorphic (2677G/3435T, 2677A/3435C, 2677A/3435T, 2677T/3435C, 2677T/3435T) constructs of ABCB1 in vitro, no significant differences were observed in transcellular efflux of structurally diverse P-gp substrates, verapamil, digoxin, vinblastine or cyclosporin A.
    Variant Name:
    ABCB1: c.3435C>T, mRNA 3853C>T, p.Ile1145Ile
    Related Drugs:
    cyclosporine, digoxin, verapamil, vinblastine
    Evidence:
    PMID:12781336
  9. rs1045642 at chr7:86976581 in ABCB1
    ABCB1 rs2032582 and rs1045642 genotype and peripheral blood lymphocyte efflux of P-gp substrate, rhodamine 123 (Rh123), in vitro, in healthy males: there was no significant difference in Rh123 efflux in CD56+ NK cells after 5, 10, 15, and 30 min efflux, or in CD4+ T-helper cells after 15, 30, 60, and 90 min between individuals with different genotypes. Rh123 efflux was not enhanced by a 10-day administration of P-gp inducer, rifampin, in vivo in 15 individuals before and after rifampin treatment. No genotypic effect was observed for inhibition of Rh123 efflux by P-pg inhibitor, verapamil, in vitro with CD56+ and CD4+.
    Variant Name:
    ABCB1:3435C>T, mRNA 3853C>T, Ile1145Ile
    Related Drugs:
    rifampin, verapamil
    Evidence:
    PMID:12914549
  10. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: None. Phenotype: Efflux of P-glycoprotein substrates (verapamil; digoxin; vinblastine; cyclosporin A) in vitro were not significantly affected by combined mutations for rs1128503 (2677G>T/A) and rs1045642 (3435C>T) in LLC-PK1 cell lines. Study size: Triplicate cell assays. Study population/ethnicity: N/A. Significance metric(s): Not significant, p > 0.05. Type of association: FA
    Variant Name:
    ABCB1:3435C>T, mRNA 3853C>T, Ile1145Ile
    Related Drugs:
    cyclosporine, digoxin, verapamil, vinblastine
    Evidence:
    PMID:12781336
  11. rs72552784 at chr7:86983850 in ABCB1
    Drug efflux and cell surface expression (by MRK-16 and C219 probes) of P-gp was not different between wild-type and variant forms (single mutants: N21D, F103L, S400N, A893S, A998T, and double mutants: 21D-S400N, N21D-A893S, and S400N-A893S) in an in vitro vaccinia virus-based transient expression system. Fluroescent substrates included calcein AM, bodipy-FL-forskolin, bodipy-FL-verapamil, bodipy-FL-vinblastine, bodipy-FL-prazosin, bisantrene, and bodipy-FL-paclitaxel. There was a slight increase in wild-type P-gp efflux of bodipy-FL-paclitaxel over mutants.
    Variant Name:
    ABCB1: c.2995G>A, mRNA 3413G>A, p.Ala999Thr
    Related Drugs:
    bisantrene, calcein, forskolin, prazosin, verapamil, vinblastine
    Evidence:
    PMID:12065748
  12. rs2032582 at chr7:86998554 in ABCB1
    Drug efflux and cell surface expression (by MRK-16 and C219 probes) of P-gp was not different between wild-type and variant forms (single mutants: N21D, F103L, S400N, A893S, A998T, and double mutants: 21D-S400N, N21D-A893S, and S400N-A893S) in an in vitro vaccinia virus-based transient expression system. Fluroescent substrates included calcein AM, bodipy-FL-forskolin, bodipy-FL-verapamil, bodipy-FL-vinblastine, bodipy-FL-prazosin, bisantrene, and bodipy-FL-paclitaxel. There was a slight increase in wild-type P-gp efflux of bodipy-FL-paclitaxel over mutants.
    Variant Name:
    ABCB1: c.2677G>T/A, mRNA 3095G>T/A, p.Ala893Ser/Thr
    Related Drugs:
    bisantrene, calcein, forskolin, prazosin, verapamil, vinblastine
    Evidence:
    PMID:12065748
  13. rs2032582 at chr7:86998554 in ABCB1
    Functional study of rs1045642 (3435C>T) and rs2032582 (2677G>T/A): in LLC-PK1 cells expressing wild-type (2677G/3435C) or polymorphic (2677G/3435T, 2677A/3435C, 2677A/3435T, 2677T/3435C, 2677T/3435T) constructs of ABCB1 in vitro, no significant differences were observed in transcellular efflux of structurally diverse P-gp substrates, verapamil, digoxin, vinblastine or cyclosporin A.
    Variant Name:
    ABCB1: c.2677G>T/A, mRNA 3095G>T/A, p.Ala893Ser/Thr
    Related Drugs:
    cyclosporine, digoxin, verapamil, vinblastine
    Evidence:
    PMID:12781336
  14. rs2032582 at chr7:86998554 in ABCB1
    ABCB1 rs2032582 and rs1045642 genotype and peripheral blood lymphocyte efflux of P-gp substrate, rhodamine 123 (Rh123), in vitro, in healthy males: there was no significant difference in Rh123 efflux in CD56+ NK cells after 5, 10, 15, and 30 min efflux, or in CD4+ T-helper cells after 15, 30, 60, and 90 min between individuals with different genotypes. Rh123 efflux was not enhanced by a 10-day administration of P-gp inducer, rifampin, in vivo in 15 individuals before and after rifampin treatment. No genotypic effect was observed for inhibition of Rh123 efflux by P-pg inhibitor, verapamil, in vitro with CD56+ and CD4+.
    Variant Name:
    ABCB1:2677G>T/A, mRNA 3095G>T/A, Ala893Ser/Thr
    Related Drugs:
    rhodamine 123, rifampin, verapamil
    Evidence:
    PMID:12914549
  15. rs2032582 at chr7:86998554 in ABCB1
    Functional study of rs1045642 (3435C>T) and rs1128503 (2677G>T/A): in LLC-PK1 cells expressing wild-type (2677G/3435C) or polymorphic (2677G/3435T, 2677A/3435C, 2677A/3435T, 2677T/3435C, 2677T/3435T) constructs of ABCB1 in vitro, no significant differences were observed in transcellular efflux of structurally diverse P-gp substrates, verapamil, digoxin, vinblastine or cyclosporin A.
    Variant Name:
    ABCB1: c.2677G>T/A, mRNA 3095G>T/A, p.Ala893Ser/Thr
    Related Drugs:
    cyclosporine, digoxin, verapamil, vinblastine
    Evidence:
    PMID:12781336
  16. rs1128503 at chr7:87017537 in ABCB1
    Risk or phenotype-associated allele: None. Phenotype: Efflux of P-glycoprotein substrates (verapamil; digoxin; vinblastine; cyclosporin A) in vitro were not significantly affected by combined mutations for rs1128503 (2677G>T/A) and rs1045642 (3435C>T) in LLC-PK1 cell lines. Study size: Triplicate cell assays. Study population/ethnicity: N/A. Significance metric(s): Not significant, p > 0.05. Type of association: FA
    Variant Name:
    ABCB1:2677G>T/A, mRNA 3095G>T/A, Ala893Ser/Thr
    Related Drugs:
    cyclosporine, digoxin, verapamil, vinblastine
    Evidence:
    PMID:12781336
  17. rs2229109 at chr7:87017745 in ABCB1
    Drug efflux and cell surface expression (by MRK-16 and C219 probes) of P-gp was not different between wild-type and variant forms (single mutants: N21D, F103L, S400N, A893S, A998T, and double mutants: 21D-S400N, N21D-A893S, and S400N-A893S) in an in vitro vaccinia virus-based transient expression system. Fluroescent substrates included calcein AM, bodipy-FL-forskolin, bodipy-FL-verapamil, bodipy-FL-vinblastine, bodipy-FL-prazosin, bisantrene, and bodipy-FL-paclitaxel. There was a slight increase in wild-type P-gp efflux of bodipy-FL-paclitaxel over mutants.
    Variant Name:
    ABCB1: c.1199G>A, mRNA 1617G>A, p.Ser400Asn
    Related Drugs:
    bisantrene, calcein, forskolin, prazosin, verapamil, vinblastine
    Evidence:
    PMID:12065748
  18. rs9282564 at chr7:87067376 in ABCB1
    Drug efflux and cell surface expression (by MRK-16 and C219 probes) of P-gp was not different between wild-type and variant forms (single mutants: N21D, F103L, S400N, A893S, A998T, and double mutants: 21D-S400N, N21D-A893S, and S400N-A893S) in an in vitro vaccinia virus-based transient expression system. Fluroescent substrates included calcein AM, bodipy-FL-forskolin, bodipy-FL-verapamil, bodipy-FL-vinblastine, bodipy-FL-prazosin, bisantrene, and bodipy-FL-paclitaxel. There was a slight increase in wild-type P-gp efflux of bodipy-FL-paclitaxel over mutants.
    Variant Name:
    ABCB1: c.61A>G, mRNA 479A>G, p.Asn21Asp
    Related Drugs:
    bisantrene, calcein, forskolin, prazosin, verapamil, vinblastine
    Evidence:
    PMID:12065748
  19. rs1801252 at chr10:115794026 in ADRB1
    The haplotype defined by the A allele of this SNP and the C allele of rs1801253 is associated with increased mortality risk in hypertensive patients with documented coronary artery disease. This increased risk was observed in patients with one or two copies of the AC haplotype. Significant association of the AC haplotype with mortality risk manifested in patients who were treated with the Ca++ channel blocker verapamil, but not in patients treated with the beta-blocker atenolol. Thus, individuals with the AC haplotype may experience better outcomes from treatment with atenolol vs. treatment with verapamil. No association was observed for nonfatal myocardial infarction or nonfatal stroke.
    Variant Name:
    ADRB1:Ser49Gly (145A>G)
    Related Drugs:
    atenolol, verapamil
    Related Diseases:
    Death
    Evidence:
    PMID:18615004
  20. rs1801253 at chr10:115795046 in ADRB1
    The haplotype defined by the C allele of this SNP and the A allele of rs1801252 is associated with increased mortality risk in hypertensive patients with documented coronary artery disease. This increased risk was observed in patients with one or two copies of the AC haplotype. Significant association of the AC haplotype with mortality risk manifested in patients who were treated with the Ca++ channel blocker verapamil, but not in patients treated with the beta-blocker atenolol. Thus, individuals with the AC haplotype may experience better outcomes from treatment with atenolol vs. treatment with verapamil. No association was observed for nonfatal myocardial infarction or nonfatal stroke.
    Variant Name:
    ADRB1:Arg389Gly (1165C>G)
    Related Drugs:
    atenolol, verapamil
    Related Diseases:
    Death
    Evidence:
    PMID:18615004
  21. rs1051375 at chr12:2659140 in CACNA1C
    In a case-control study (258 cases; 774 controls) performed in patients residing in the mainland U.S. or Puerto Rico and who had hypertension and stable coronary artery disease, this SNP was found to be related to primary outcome of atenolol vs. verapamil SR - based treatment. AA genotype was associated with 46% reduction in primary outcome for patients on verapamil SR-based treatment compared to atenolol-based treatment (odds ratio 0.54; 95% CI 0.32 to 0.92), AG genotype showed no difference in primary outcome between the two strategies (odds ratio 1.47; 95% CI 0.86 to 2.53), and GG subjects had more than 4 fold increased risk of primary outcome on verapamil SR-based treatment as opposed to atenolol-based treatment (odds ratio 4.59; 95% CI 1.67 to 12.67). Study size: 258 cases; 774 controls. Study population/ethnicity: subjects residing in the mainland U.S. or Puerto Rico. Type of association: CO; GN; PD. Significance metric(s): P value: P=0.0001.
    Related Drugs:
    atenolol, Beta Blocking Agents, calcium channel blockers, verapamil
    Related Diseases:
    Coronary Artery Disease, Death, Death, Sudden, Cardiac, Hypertension, Myocardial Infarction, Stroke
    Evidence:
    PMID:20031608
Variant names are different names that have been used in the literature and other resources to refer to the same variant.

Curated Information

The following genes are in curated knowledge about this drug.

  Gene Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ABCB1
  •   
  • PD
  • PK
  • FA
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ADRB1
  • CO
  •   
  •   
  •   
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ADRB2
  • CO
  •   
  •   
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
CACNA1C
  • CO
  • PD
  •   
  •   
  • GN
Publications, Variants
No phenotype data Genotype Data Available Literature annotations available Not annotated
CYP1A2
  •   
  •   
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
CYP2C8
  •   
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C9
  •   
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
CYP3A
  •   
  •   
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A4
  •   
  • PD
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A5
  •   
  • PD
  • PK
  •   
  • GN
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
CYP3A7
  •   
  •   
  • PK
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
NOS1AP
  • CO
  •   
  •   
  •   
  • GN
Publications, Variants
No phenotype data Genotype Data Available Literature annotations available Not annotated
SLC22A5
  •   
  •   
  •   
  • FA
  •   
Publications
No phenotype data Genotype Data Available Literature annotations available Has annotations
SLCO1B1
  •   
  • PD
  • PK
  •   
  •   
Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other genes is available.

Metabolizing Enzymes

Drug Targets

Non-Curated Information

A list of non-curated publications that mention this drug along with other drugs is available.

Curated Information

The following diseases are in curated knowledge about this drug.

  Disease Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
Cardiomyopathies
  •   
  • PD
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Carotid Artery Diseases
  •   
  • PD
  • PK
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Coronary Artery Disease
  • CO
  • PD
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Death
  • CO
  • PD
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Death, Sudden, Cardiac
  • CO
  • PD
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Diabetes Mellitus
  •   
  • PD
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Epilepsy
  •   
  •   
  • PK
  • FA
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Heart Failure
  • CO
  •   
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Hypertension
  • CO
  • PD
  •   
  •   
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Myocardial Infarction
  • CO
  • PD
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Rhabdomyolysis
  •   
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
Stroke
  • CO
  • PD
  •   
  •   
  • GN
Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB00661
KEGG Compound ID:
C07188
KEGG Drug ID:
D02356
PubChem Compound ID:
2520
PubChem Substance ID:
7849415

Common Searches

Search PubMed
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Non-Curated Publications

A list of non-curated publications that mention this drug is available.

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