Verapamil

Last updated

Verapamil
Verapamil structure.svg
Verapamil-from-xtal-Mercury-3D-bs.png
Clinical data
Pronunciation /vɛˈræpəmɪl/
ve-RAP-ə-mil
Trade names Isoptin, Calan, others [1]
AHFS/Drugs.com Monograph
MedlinePlus a684030
License data
Pregnancy
category
Routes of
administration 		By mouth, intravenous
Drug class Calcium channel blocker
ATC code
Legal status
Legal status
  • UK: POM (Prescription only) [3]
  • US: ℞-only [4]
  • EU:Rx-only [5]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 35.1%
Metabolism Liver
Onset of action 1 to 2 hours (oral); 3 to 5 minutes (IV bolus) [6] [7]
Elimination half-life 2.8–7.4 hours [8]
Excretion Kidney: 11%
Identifiers
  • (RS)-2-(3,4-Dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.133 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C27H38N2O4
Molar mass 454.611 g·mol−1
3D model (JSmol)
Chirality Racemic 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,8,13-16H2,1-7H3 Yes check.svgY
  • Key:SGTNSNPWRIOYBX-UHFFFAOYSA-N Yes check.svgY
   (verify)

Verapamil, sold under various trade names, [1] is a calcium channel blocker medication used for the treatment of high blood pressure, angina (chest pain from not enough blood flow to the heart), and supraventricular tachycardia. [9] It may also be used for the prevention of migraines and cluster headaches. [10] [11] It is given by mouth or by injection into a vein. [9]

Contents

Common side effects include headache, low blood pressure, nausea, and constipation. [9] Other side effects include allergic reactions and muscle pains. [12] It is not recommended in people with a slow heart rate or heart failure. [12] It is believed to cause problems for the fetus if used during pregnancy. [2] It is in the non–dihydropyridine calcium channel blocker family of medications. [9]

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

Medical uses

Verapamil is used for controlling ventricular rate in supraventricular tachycardia (SVT) and migraine headache prevention. [17]

Verapamil is also used for the treatment of angina (chronic stable, vasospastic or Prinzmetal variant), unstable angina (crescendo, preinfarction), and for the prevention of paroxysmal supraventricular tachycardia (PSVT). [18]

Verapamil is a class-IV antiarrhythmic and more effective than digoxin in controlling ventricular rate. [19] Verapamil is not listed as a first line antihypertensive agent by the guidelines provided by JAMA in JNC-8. [20] However, it may be used to treat hypertension if patient has co-morbid atrial fibrillation or other types of arrhythmia. [17] [21]

Verapamil is used intra-arterially to treat cerebral vasospasm. [22] It is also used to treat cluster headaches. [23] Tentative evidence supports the use of verapamil topically to treat plantar fibromatosis. [24]

Use of verapamil in people with recent onset of type 1 diabetes may 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 higher C-peptide area 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 of mania and hypomania. [27] Addition of magnesium oxide to the verapamil treatment protocol enhances the antimanic effect. [28]

Contraindications

Use of verapamil is generally avoided in people with severe left ventricular dysfunction, hypotension (systolic blood pressure less than 90 mm Hg), cardiogenic shock, and hypersensitivity to verapamil. [4] It is also contraindicated in people with atrial flutter or fibrillation and an existing accessory tract such as in Wolff-Parkinson-White syndrome. [29] [4]

Side effects

The most common side effect of verapamil is constipation (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 study by The National Library of Medicine called "Effect of Verapamil on the Human Intestinal Transit" found that verapamil affects the colon but not the upper gastrointestinal tract. [30]

Other side effects include dizziness (3.3%), nausea (2.7%), low blood pressure (2.5%), and headache 2.2%. 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, rash and flushing. [4] Along with other calcium channel blockers, verapamil is known to induce gingival enlargement. [31]

Overdose

Acute overdose is often manifested by nausea, weakness, slow heart rate, dizziness, low blood pressure, and abnormal 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

Verapamil's mechanism in all cases is to block voltage-dependent calcium channels. [4] In cardiac pharmacology, calcium channel blockers are considered class-IV antiarrhythmic agents. Since calcium channels are especially concentrated in the sinoatrial and atrioventricular nodes, these agents can be used to decrease impulse conduction through the AV node, thus protecting the ventricles from atrial tachyarrhythmias. Specific conditions that fall under the definition of atrial tachyarrhythmias are atrial fibrillation, atrial flutter, multifocal atrial tachycardia, paroxysmal supraventricular tachycardia, and so on. [34] [35] [36]

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

Calcium channels are also present in the smooth muscle lining blood vessels. By relaxing the tone of this smooth muscle, calcium channel blockers dilate the blood vessels. This has led to their use in treating high blood pressure and angina pectoris. The pain of angina is caused by a deficit in oxygen supply to the heart.

Calcium channel blockers like verapamil dilate the coronary 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

Preventive therapy with verapamil is believed to work because it has an effect on the circadian rhythm and on CGRPs, as CGRP-release is controlled by voltage-gated calcium channels. [38]

Pharmacokinetic details

More than 90% of verapamil is absorbed when given orally, [4] but due to high first-pass metabolism, bioavailability is much lower (10–35%). It is 90% bound to plasma proteins and has a volume of distribution of 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

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

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 in cell biology as an inhibitor of drug efflux pump proteins such as P-glycoprotein and other ABC transporter proteins. [45] [44] This is useful, as many tumor cell lines overexpress drug efflux pumps, limiting the effectiveness of cytotoxic drugs or fluorescent tags. It is also used in fluorescent cell sorting for DNA content, as it blocks efflux of a variety of DNA-binding fluorophores such as Hoechst 33342. Radioactively labelled verapamil and positron emission tomography can be used with to measure P-glycoprotein function.[ medical citation needed ]

Related Research Articles

Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel blockers are also frequently used to alter heart rate, to prevent peripheral and cerebral vasospasm, and to reduce chest pain caused by angina pectoris.

<span class="mw-page-title-main">Sinus node dysfunction</span> Medical condition

Sinus node dysfunction (SND), also known as sick sinus syndrome (SSS), is a group of abnormal heart rhythms (arrhythmias) usually caused by a malfunction of the sinus node, the heart's primary pacemaker. Tachycardia-bradycardia syndrome is a variant of sick sinus syndrome in which the arrhythmia alternates between fast and slow heart rates.

<span class="mw-page-title-main">Antiarrhythmic agent</span> Heart rhythm medication

Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.

<span class="mw-page-title-main">Amlodipine</span> Medication against high blood pressure

Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat high blood pressure, coronary artery disease (CAD) and variant angina. It is taken orally.

<span class="mw-page-title-main">Amiodarone</span> Antiarrhythmic medication used for various types of irregular heartbeats

Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia, ventricular fibrillation, and wide complex tachycardia, atrial fibrillation, and paroxysmal supraventricular tachycardia. Evidence in cardiac arrest, however, is poor. It can be given by mouth, intravenously, or intraosseously. When used by mouth, it can take a few weeks for effects to begin.

<span class="mw-page-title-main">Ventricular tachycardia</span> Abnormally fast rhythm of the hearts ventricles

Ventricular tachycardia is a cardiovascular disorder in which fast heart rate occurs in the ventricles of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short period of time are referred to as an electrical storm. Short periods may occur without symptoms, or present with lightheadedness, palpitations, shortness of breath, chest pain, and decreased level of consciousness. Ventricular tachycardia may lead to coma and persistent vegetative state due to lack of blood and oxygen to the brain. Ventricular tachycardia may result in ventricular fibrillation (VF) and turn into cardiac arrest. This conversion of the VT into VF is called the degeneration of the VT. It is found initially in about 7% of people in cardiac arrest.

<span class="mw-page-title-main">Diltiazem</span> Calcium channel blocker medication

Diltiazem, sold under the brand name Cardizem among others, is a nondihydropyridine calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used. It is taken by mouth or given by injection into a vein. When given by injection, effects typically begin within a few minutes and last a few hours.

<span class="mw-page-title-main">Flecainide</span> Antiarrhythmic medication

Flecainide is a medication used to prevent and treat abnormally fast heart rates. This includes ventricular and supraventricular tachycardias. Its use is only recommended in those with dangerous arrhythmias or when significant symptoms cannot be managed with other treatments. Its use does not decrease a person's risk of death. It is taken by mouth or injection into a vein.

<span class="mw-page-title-main">Supraventricular tachycardia</span> Abnormally fast heart rhythm

Supraventricular tachycardia (SVT) is an umbrella term for fast heart rhythms arising from the upper part of the heart. This is in contrast to the other group of fast heart rhythms – ventricular tachycardia, which start within the lower chambers of the heart. There are four main types of SVT: atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia (PSVT), and Wolff–Parkinson–White syndrome. The symptoms of SVT include palpitations, feeling of faintness, sweating, shortness of breath, and/or chest pain.

<span class="mw-page-title-main">Sotalol</span> Medication

Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or given by injection into a vein.

<span class="mw-page-title-main">AV nodal reentrant tachycardia</span> Medical condition

AV-nodal reentrant tachycardia (AVNRT) is a type of abnormal fast heart rhythm. It is a type of supraventricular tachycardia (SVT), meaning that it originates from a location within the heart above the bundle of His. AV nodal reentrant tachycardia is the most common regular supraventricular tachycardia. It is more common in women than men. The main symptom is palpitations. Treatment may be with specific physical maneuvers, medications, or, rarely, synchronized cardioversion. Frequent attacks may require radiofrequency ablation, in which the abnormally conducting tissue in the heart is destroyed.

<span class="mw-page-title-main">Paroxysmal supraventricular tachycardia</span> Episodes of abnormally fast heart rhythm

Paroxysmal supraventricular tachycardia (PSVT) is a type of supraventricular tachycardia, named for its intermittent episodes of abrupt onset and termination. Often people have no symptoms. Otherwise symptoms may include palpitations, feeling lightheaded, sweating, shortness of breath, and chest pain.

<span class="mw-page-title-main">Ivabradine</span> Heart medication

Ivabradine, sold under the brand name Procoralan among others, is a medication, which is a pacemaker current (If) inhibitor, used for the symptomatic management of heart-related chest pain and heart failure. Patients who qualify for use of ivabradine for coronary heart failure are patients who have symptomatic heart failure, with reduced ejection volume, and heart rate at least 70 bpm, and the condition not able to be fully managed by beta blockers.

<span class="mw-page-title-main">Lercanidipine</span> Antihypertensive drug of the calcium channel blocker class

Lercanidipine is an antihypertensive drug. It belongs to the dihydropyridine class of calcium channel blockers, which work by relaxing and opening the blood vessels allowing the blood to circulate more freely around the body. This lowers the blood pressure and allows the heart to work more efficiently.

<span class="mw-page-title-main">Prajmaline</span> Chemical compound

Prajmaline (Neo-gilurythmal) is a class Ia antiarrhythmic agent which has been available since the 1970s. Class Ia drugs increase the time one action potential lasts in the heart. Prajmaline is a semi-synthetic propyl derivative of ajmaline, with a higher bioavailability than its predecessor. It acts to stop arrhythmias of the heart through a frequency-dependent block of cardiac sodium channels.

<span class="mw-page-title-main">Ranolazine</span> Drug used to treat angina

Ranolazine, sold under the brand name Ranexa among others, is a medication used to treat heart related chest pain. Typically it is used together with other medications when those are insufficient. Therapeutic benefits appear smaller in females than males. It is taken by mouth.

Sodium channel blockers are drugs which impair the conduction of sodium ions (Na+) through sodium channels.

<span class="mw-page-title-main">Landiolol</span> Chemical compound

Landiolol, sold under the brand name Onoact among others, is a medication used for the treatment of tachycardia, atrial fibrillation, and atrial flutter. It is a beta-adrenergic blocker; an ultra short-acting, β1-superselective intravenous adrenergic antagonist, which decreases the heart rate effectively with less negative effect on blood pressure or myocardial contractility. In comparison to other beta blockers, landiolol has the shortest elimination half-life, ultra-rapid onset of effect, and predictable effectiveness with inactive metabolites. The pure S-enantiomer structure of landiolol is believed to develop less hypotensive side effects in comparison to other β-blockers. This has a positive impact on the treatment of patients when reduction of heart rate without decrease in arterial blood pressure is desired. It is used as landiolol hydrochloride.

<span class="mw-page-title-main">Tiapamil</span> Chemical compound

Tiapamil is a calcium antagonist or calcium channel blocker. It is an experimental drug that has never been marketed.

<span class="mw-page-title-main">Arrhythmia</span> Group of medical conditions characterized by irregular heartbeat

Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults – is called tachycardia, and a resting heart rate that is too slow – below 60 beats per minute – is called bradycardia. Some types of arrhythmias have no symptoms. Symptoms, when present, may include palpitations or feeling a pause between heartbeats. In more serious cases, there may be lightheadedness, passing out, shortness of breath, chest pain, or decreased level of consciousness. While most cases of arrhythmia are not serious, some predispose a person to complications such as stroke or heart failure. Others may result in sudden death.

References

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  6. 1 2 "Verapamil". Archived from the original on 30 October 2024. Onset of Action[...]Oral: Immediate release: 1 to 2 hours (Singh 1978); IV bolus: 3 to 5 minutes
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