Wikipedia

Verapamil

Verapamil,sold under various trade names,[1]is acalcium channel blockermedication used for the treatment ofhigh blood pressure,angina(chest pain from not enough blood flow to the heart), andsupraventricular tachycardia.[9]It may also be used for the prevention ofmigrainesandcluster headaches.[10][11]It is given by mouth or byinjection into a vein.[9]

Verapamil
Clinical data
Pronunciation/vɛˈræpəmɪl/
ve-RAP-ə-mil
Trade namesIsoptin, Calan, others[1]
AHFS/DrugsMonograph
MedlinePlusa684030
License data
Pregnancy
category
Routes of
administration		By mouth,intravenous
Drug classCalcium channel blocker
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability35.1%
MetabolismLiver
Onset of action1 to 2 hours (oral); 3 to 5 minutes (IV bolus)[6][7]
Eliminationhalf-life2.8–7.4 hours[8]
ExcretionKidney:11%
Identifiers
  • (RS)-2-(3,4-Dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.000.133Edit this at Wikidata
Chemical and physical data
FormulaC27H38N2O4
Molar mass454.611g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • N#CC(c1cc(OC)c(OC)cc1)(CCCN(CCc2ccc(OC)c(OC)c2)C)C(C)C
  • InChI=1S/C27H38N2O4/c1-20(2)27(19-28,22-10-12-24(31-5)26(18-22)33-7)14-8-15-29(3)16-13-21-9-11-23(30-4)25(17-21)32-6/h9-12,17-18,20H,8,13-16H2,1-7H3checkY
  • Key:SGTNSNPWRIOYBX-UHFFFAOYSA-NcheckY
(verify)

Common side effects include headache,low blood pressure,nausea,andconstipation.[9]Other side effects includeallergic reactionsandmuscle pains.[12]It is not recommended in people with aslow heart rateorheart failure.[12]It is believed to cause problems for the fetus if used duringpregnancy.[2]It is in thenon–dihydropyridine calcium channel blockerfamily of medications.[9]

Verapamil was approved for medical use in the United States in 1981.[9][13]It is on theWorld Health Organization's List of Essential Medicines.[14]Verapamil is available as ageneric medication.[9]Long acting formulations exist.[12]In 2022, it was the 188th most commonly prescribed medication in the United States, with more than 2million prescriptions.[15][16]

Medical uses

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Verapamil is used for controllingventricular rateinsupraventricular tachycardia(SVT) andmigraine headacheprevention.[17]

Verapamil is also used for the treatment ofangina(chronic stable, vasospastic orPrinzmetal variant),unstable angina(crescendo, preinfarction), and for the prevention ofparoxysmal supraventricular tachycardia(PSVT).[18]

Verapamil is aclass-IV antiarrhythmicand more effective thandigoxinin controlling ventricular rate.[19]Verapamil is not listed as a first line antihypertensive agent by the guidelines provided byJAMAin JNC-8.[20]However, it may be used to treat hypertension if patient has co-morbidatrial fibrillationor other types ofarrhythmia.[17][21]

Verapamil is used intra-arterially to treat cerebralvasospasm.[22]It is also used to treatcluster headaches.[23]Tentative evidence supports the use of verapamil topically to treatplantar fibromatosis.[24]

Use of verapamil in people with recent onset oftype 1 diabetesmay improve pancreatic beta cell function. In a 2023 meta-analysis[25]involving data from two randomized controlled trials (113 patients with recent onset type-1 diabetes), it was demonstrated that the use of verapamil over one year was associated with significantly higherC-peptidearea under the curve levels. Higher C-peptide levels means better pancreatic insulin production and beta cell function.[25]

Verapamil has been reported to be effective in both short-term[26]and long-term treatment ofmaniaandhypomania.[27]Addition ofmagnesium oxideto the verapamil treatment protocol enhances the antimanic effect.[28]

Contraindications

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Use of verapamil is generally avoided in people with severe left ventricular dysfunction,hypotension(systolicblood pressureless than 90 mm Hg),cardiogenic shock,and hypersensitivity to verapamil.[4]It is also contraindicated in people withatrial flutterorfibrillationand an existing accessory tract such as in Wolff-Parkinson-White syndrome.[29][4]

Side effects

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The most common side effect of verapamil isconstipation(7.3%). While the definite mechanism by which verapamil causes constipation has not been studied, studies have been conducted to rule out mechanisms of actions that might yield this adverse effect. A 1992 study found that verapamil causes a delay incolonictransit but does not affectupper gastrointestinaltransit.[30]

Other side effects includedizziness(3.3%),nausea(2.7%),low blood pressure(2.5%), andheadache2.2%. Other side effects seen in less than 2% of the population include:edema,congestive heart failure,pulmonary edema,diarrhea,fatigue,elevated liver enzymes,shortness of breath,low heart rate,atrioventricular block,rashandflushing.[4]Along with other calcium channel blockers, verapamil is known to inducegingival enlargement.[31]

Overdose

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Acute overdose is often manifested by nausea,weakness,slow heart rate,dizziness, low blood pressure, andabnormal heart rhythms.Plasma,serum,or blood concentrations of verapamil and norverapamil, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities. Blood or plasma verapamil concentrations are usually in a range of 50–500 μg/L in persons on therapy with the drug, but may rise to 1–4 mg/L in acute overdose patients and are often at levels of 5–10 mg/L in fatal poisonings.[32][33]

Mechanism of action

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Verapamil'smechanismin all cases is to blockvoltage-dependent calcium channels.[4]In cardiac pharmacology, calcium channel blockers are considered class-IVantiarrhythmic agents.Since calcium channels are especially concentrated in thesinoatrialandatrioventricular nodes,these agents can be used to decrease impulse conduction through the AV node, thus protecting theventriclesfromatrial tachyarrhythmias.Specific conditions that fall under the definition of atrial tachyarrhythmias areatrial fibrillation,atrial flutter,multifocal atrial tachycardia,paroxysmal supraventricular tachycardia,and so on.[34][35][36]

Verapamil is also a Kv voltage gatedpotassium channel blocker.[37]

Calcium channels are also present in thesmooth musclelining blood vessels. By rela xing the tone of this smooth muscle, calcium channel blockers dilate the blood vessels. This has led to their use in treatinghigh blood pressureandangina pectoris.The pain of angina is caused by a deficit in oxygen supply to the heart.

Calcium channel blockers like verapamil dilate thecoronary blood vessels,which increases the supply of blood and oxygen to the heart. They also cause dilatation of systemic peripheral vessels as well, causing a reduction in the workload of the heart. Thereby reducing myocardial oxygen consumption.[4]

Cluster headaches

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Preventive therapy with verapamil is believed to work because it has an effect on thecircadian rhythmand onCGRPs,as CGRP-release is controlled by voltage-gated calcium channels.[38]

Pharmacokinetic details

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More than 90% of verapamil is absorbed when given orally,[4]but due to highfirst-pass metabolism,bioavailabilityis much lower (10–35%). It is 90%bound to plasma proteinsand has avolume of distributionof 3–5 L/kg. It takes 1 to 2 hours to reach peak plasma concentration after oral administration.[4]It is metabolized in the liver to at least 12 inactive metabolites (though one metabolite, norverapamil, retains 20% of the vasodilatory activity of the parent drug). As its metabolites, 70% is excreted in the urine and 16% in feces; 3–4% is excreted unchanged in urine. This is a nonlinear dependence between plasma concentration and dosage. Onset of action is 1 to 2 hours after oral dosage, and 3 to 5 minutes after intravenous bolus dosage.[6][7]Biphasic or triphasic following IV administration; terminal elimination half-life is 2–8 hours.[39]Plasma half-life of 2–8 or 4.5–12 hours after single oral dose or multiple oral doses, respectively.[medical citation needed]It is not cleared by hemodialysis.[medical citation needed]It is excreted in human milk.[medical citation needed]Because of the potential for adverse reaction in nursing infants, nursing should be discontinued while verapamil is administered.[medical citation needed]

Veterinary use

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Intra-abdominal adhesions are common in rabbits following surgery. Verapamil can be given postoperatively in rabbits which have suffered trauma to abdominal organs to prevent formation of these adhesions.[40][41][42]Such effect was not documented in another study with ponies.[43]

Uses in cell biology

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Verapamil inhibits the ATP-binding cassette (ABC) transporter family of proteins found in stem cells and has been used to study cancer stem cells (CSC) within head and neck squamous cell carcinomas.[44]

Verapamil is also used incell biologyas aninhibitorof drug efflux pump proteins such asP-glycoproteinand other ABC transporter proteins.[45][44]This is useful, as manytumorcell lines overexpress drug efflux pumps, limiting the effectiveness ofcytotoxic drugsorfluorescent tags.It is also used in fluorescent cell sorting forDNAcontent, as it blocks efflux of a variety of DNA-bindingfluorophoressuch asHoechst 33342.Radioactively labelledverapamil andpositron emission tomographycan be used with to measure P-glycoprotein function.[medical citation needed]

References

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