Verapamil Explained

Watchedfields:changed
Verifiedrevid:461939027
Width2:200
Chirality:Racemic mixture
Pronounce:
Tradename:Isoptin, Calan, others
Dailymedid:Verapamil
Pregnancy Au:C
Pregnancy Au Comment:[1]
Routes Of Administration:By mouth, intravenous
Class:Calcium channel blocker
Atc Prefix:C08
Atc Suffix:DA01
Legal Uk:POM
Legal Uk Comment:[2]
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[3]
Legal Status:Rx-only
Bioavailability:35.1%
Metabolism:Liver
Elimination Half-Life:2.8–7.4 hours[4]
Excretion:Kidney

11%

Index2 Label:as HCl
Cas Number:52-53-9
Pubchem:2520
Iuphar Ligand:2406
Drugbank:DB00661
Chemspiderid:2425
Unii:CJ0O37KU29
Kegg:D02356
Kegg2:D00619
Chebi:9948
Chembl:6966
Iupac Name:(RS)-2-(3,4-Dimethoxyphenyl)-5--2-(propan-2-yl)pentanenitrile
C:27
H:38
N:2
O:4
Smiles:N#CC(c1cc(OC)c(OC)cc1)(CCCN(CCc2ccc(OC)c(OC)c2)C)C(C)C
Stdinchi: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
Stdinchikey:SGTNSNPWRIOYBX-UHFFFAOYSA-N

Verapamil, sold under various trade names,[5] 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.[6] It may also be used for the prevention of migraines and cluster headaches.[7] [8] It is given by mouth or by injection into a vein.[6]

Common side effects include headache, low blood pressure, nausea, and constipation.[6] Other side effects include allergic reactions and muscle pains. It is not recommended in people with a slow heart rate or heart failure. It is believed to cause problems for the fetus if used during pregnancy. It is in the non–dihydropyridine calcium channel blocker family of medications.[6]

Verapamil was approved for medical use in the United States in 1981.[6] [9] It is on the World Health Organization's List of Essential Medicines.[10] [11] Verapamil is available as a generic medication.[6] Long acting formulations exist.[12] In 2021, it was the 196th most commonly prescribed medication in the United States, with more than 2million prescriptions.[13] [14]

Medical uses

Verapamil is used for controlling ventricular rate in supraventricular tachycardia (SVT) and migraine headache prevention.[15]

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).[16]

Verapamil is a class-IV antiarrhythmic and more effective than digoxin in controlling ventricular rate.[17] Verapamil is not listed as a first line antihypertensive agent by the guidelines provided by JAMA in JNC-8.[18] However, it may be used to treat hypertension if patient has co-morbid atrial fibrillation or other types of arrhythmia.[19] [20]

Verapamil is used intra-arterially to treat cerebral vasospasm.[21] It is also used to treat cluster headaches.[22] Tentative evidence supports the use of verapamil topically to treat plantar fibromatosis.[23]

Use of verapamil in people with recent onset of type 1 diabetes may improve pancreatic beta cell function. In a meta-analysis involving data from 2 randomized controlled trials (113 patients with recent onset type-1 diabetes), Dutta et al. demonstrated use of verapamil over 1 year was associated with significantly higher C-peptide area under the curve levels at 1-year [MD 0.27 nmol/L (95%CI: 0.19-0.35); P < 0.01]. Higher C-peptide levels means better pancreatic insulin production and beta cell function.[24]

Verapamil has been reported to be effective in both short-term[25] and long-term treatment of mania and hypomania.[26] Addition of magnesium oxide to the verapamil treatment protocol enhances the antimanic effect.[27]

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.[28] It is also contraindicated in people with atrial flutter or fibrillation and an existing accessory tract such as in Wolff-Parkinson-White syndrome.[29]

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. In a study conducted by The National Library of Medicine titled, "Effect of Verapamil on the Human Intestinal Transit", the study found that verapamil does not have an effect on upper GI transit but rather in the colon.[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. 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. 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. Verapamil is also a Kv voltage gated potassium channel blocker.[34]

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.

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.[35]

Pharmacokinetic details

More than 90% of verapamil is absorbed when given orally, 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. 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 1–2 hours after oral dosage. Half-life is 5–12 hours (with chronic dosages). It is not cleared by hemodialysis. It is excreted in human milk. Because of the potential for adverse reaction in nursing infants, nursing should be discontinued while verapamil is administered.

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.[36] [37] [38] Such effect was not documented in another study with ponies.[39]

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.[40]

Verapamil is also used in cell biology as an inhibitor of drug efflux pump proteins such as P-glycoprotein and other ABC transporter proteins.[41] 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.

Notes and References

  1. Web site: Verapamil Use During Pregnancy . Drugs.com . 18 November 2019 . 26 March 2020.
  2. Web site: Securon SR - Summary of Product Characteristics (SmPC) . (emc) . 17 May 2017 . 26 March 2020.
  3. Web site: Human Medicines Evaluation Division . Active substance(s): verapamil . List of nationally authorised medicinal products . European Medicines Agency . 14 October 2020 .
  4. Book: Schroeder JS, Frishman WH, Parker JD, Angiolillo DJ, Woods C, Scirica BM . Cardiovascular Therapeutics: A Companion to Braunwald's Heart Disease . Pharmacologic Options for Treatment of Ischemic Disease . Elsevier . 2013 . 978-1-4557-0101-8 . 10.1016/b978-1-4557-0101-8.00007-2 . 83–130 . The elimination half-life of standard verapamil tablets is usually 3 to 7 hours,... .
  5. Web site: Verapamil . www.drugs.com. 14 December 2016. live. https://web.archive.org/web/20170801162330/https://www.drugs.com/international/verapamil.html. 1 August 2017.
  6. Web site: Verapamil Hydrochloride. The American Society of Health-System Pharmacists. 8 December 2016. live. https://web.archive.org/web/20161221004213/https://www.drugs.com/monograph/verapamil-hydrochloride.html. 21 December 2016.
  7. Tfelt-Hansen PC, Jensen RH . Management of cluster headache . CNS Drugs . 26 . 7 . 571–580 . July 2012 . 22650381 . 10.2165/11632850-000000000-00000 . 22522914 .
  8. Merison K, Jacobs H . Diagnosis and Treatment of Childhood Migraine . Current Treatment Options in Neurology . 18 . 11 . 48 . November 2016 . 27704257 . 10.1007/s11940-016-0431-4 . 28302667 .
  9. Web site: Isoptin: FDA-Approved Drugs . U.S. Food and Drug Administration (FDA) . 26 March 2020.
  10. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 21st list 2019 . 2019 . 10665/325771 . World Health Organization . World Health Organization . Geneva . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO . free .
  11. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 22nd list (2021) . 2021 . 10665/345533 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2021.02 . free .
  12. Book: WHO Model Formulary 2008 . 2009 . 9789241547659 . ((World Health Organization)) . Stuart MC, Kouimtzi M, Hill SR . 10665/44053 . World Health Organization . World Health Organization . free .
  13. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  14. Web site: Verapamil - Drug Usage Statistics . ClinCalc . 14 January 2024.
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  16. Book: Fahie S, Cassagnol M . 30860730 . 2023 . Verapamil . StatPearls [Internet]. . Treasure Island (FL) . StatPearls Publishing . https://www.ncbi.nlm.nih.gov/books/NBK538495/ .
  17. Srinivasan V, Sivaramakrishnan H, Karthikeyan B . Detection, isolation and characterization of principal synthetic route indicative impurities in verapamil hydrochloride . Scientia Pharmaceutica . 79 . 3 . 555–568 . 2011 . 21886903 . 3163365 . 10.3797/scipharm.1101-19 .
  18. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC, Svetkey LP, Taler SJ, Townsend RR, Wright JT, Narva AS, Ortiz E . 6 . 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8) . JAMA . 311 . 5 . 507–520 . February 2014 . 24352797 . 10.1001/jama.2013.284427 . free .
  19. Book: Koda-Kimble and Young's Applied Therapeutics: The Clinical Use of Drugs. LWW . Tenth, North American . 2012. 978-1609137137. 320–22.
  20. Beck E, Sieber WJ, Trejo R . Management of cluster headache . American Family Physician . 71 . 4 . 717–724 . February 2005 . 15742909 . 4 November 2015 . live . dmy-all . https://web.archive.org/web/20151113055721/http://www.aafp.org/afp/2005/0215/p717.html . 13 November 2015 .
  21. Jun P, Ko NU, English JD, Dowd CF, Halbach VV, Higashida RT, Lawton MT, Hetts SW . 6 . Endovascular treatment of medically refractory cerebral vasospasm following aneurysmal subarachnoid hemorrhage . AJNR. American Journal of Neuroradiology . 31 . 10 . 1911–1916 . November 2010 . 20616179 . 4067264 . 10.3174/ajnr.A2183 .
  22. Book: Drislane F, Benatar M, Chang BS, Acosta J, Tarulli A . Blueprints Neurology . 14 November 2010 . 1 January 2009 . Lippincott Williams & Wilkins . 978-0-7817-9685-9 . 71–. live . https://web.archive.org/web/20130608025221/http://books.google.com/books?id=vj3td6GY0gcC&pg=PA71 . 8 June 2013 .
  23. Young JR, Sternbach S, Willinger M, Hutchinson ID, Rosenbaum AJ . The etiology, evaluation, and management of plantar fibromatosis . Orthopedic Research and Reviews . 11 . 1–7 . 17 December 2018 . 30774465 . 6367723 . 10.2147/ORR.S154289 . free .
  24. Dutta D, Nagendra L, Raizada N, Bhattacharya S, Sharma M . Verapamil improves One-Year C-Peptide Levels in Recent Onset Type-1 Diabetes: A Meta-Analysis. . Indian J Endocrinol Metab . 27 . 3 . May–Jun 2023 . 192–200 . 37583402 . 10.4103/ijem.ijem_122_23 . 10424102 . free .
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  26. Giannini AJ, Taraszewski R, Loiselle RH . Verapamil and lithium in maintenance therapy of manic patients . Journal of Clinical Pharmacology . 27 . 12 . 980–982 . December 1987 . 3325531 . 10.1002/j.1552-4604.1987.tb05600.x . 34536914 .
  27. Giannini AJ, Nakoneczie AM, Melemis SM, Ventresco J, Condon M . Magnesium oxide augmentation of verapamil maintenance therapy in mania . Psychiatry Research . 93 . 1 . 83–87 . February 2000 . 10699232 . 10.1016/S0165-1781(99)00116-X . 18216795 .
  28. Web site: Calan- verapamil hydrochloride tablet, film coated . DailyMed . 17 December 2019 . 26 March 2020.
  29. Web site: Securon 2.5 mg/ml IV Intravenous Injection - Summary of Product Characteristics (SmPC) . (emc) . 24 November 2016 . 26 March 2020.
  30. Krevsky B, Maurer AH, Niewiarowski T, Cohen S . Effect of verapamil on human intestinal transit . Digestive Diseases and Sciences . 37 . 6 . 919–924 . June 1992 . 1587197 . 10.1007/BF01300391 . 1007332 .
  31. Steele RM, Schuna AA, Schreiber RT . Calcium antagonist-induced gingival hyperplasia . Annals of Internal Medicine . 120 . 8 . 663–664 . April 1994 . 8135450 . 10.7326/0003-4819-120-8-199404150-00006 . 41746099 .
  32. Wilimowska J, Piekoszewski W, Krzyanowska-Kierepka E, Florek E . Monitoring of verapamil enantiomers concentration in overdose . Clinical Toxicology . 44 . 2 . 169–171 . 2006 . 16615674 . 10.1080/15563650500514541 . 10351499 .
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  36. Elferink JG, Deierkauf M . The effect of verapamil and other calcium antagonists on chemotaxis of polymorphonuclear leukocytes . Biochemical Pharmacology . 33 . 1 . 35–39 . January 1984 . 6704142 . 10.1016/0006-2952(84)90367-8 .
  37. Azzarone B, Krief P, Soria J, Boucheix C . Modulation of fibroblast-induced clot retraction by calcium channel blocking drugs and the monoclonal antibody ALB6 . Journal of Cellular Physiology . 125 . 3 . 420–426 . December 1985 . 3864783 . 10.1002/jcp.1041250309 . 10911875 .
  38. Steinleitner A, Lambert H, Kazensky C, Sanchez I, Sueldo C . Reduction of primary postoperative adhesion formation under calcium channel blockade in the rabbit . The Journal of Surgical Research . 48 . 1 . 42–45 . January 1990 . 2296179 . 10.1016/0022-4804(90)90143-P .
  39. Baxter GM, Jackman BR, Eades SC, Tyler DE . Failure of calcium channel blockade to prevent intra-abdominal adhesions in ponies . Veterinary Surgery . 22 . 6 . 496–500 . 1993 . 8116206 . 10.1111/j.1532-950X.1993.tb00427.x .
  40. Song J, Chang I, Chen Z, Kang M, Wang CY . Characterization of side populations in HNSCC: highly invasive, chemoresistant and abnormal Wnt signaling . PLOS ONE . 5 . 7 . e11456 . July 2010 . 20625515 . 2897893 . 10.1371/journal.pone.0011456 . free . 2010PLoSO...511456S .
  41. Bellamy WT . P-glycoproteins and multidrug resistance . Annual Review of Pharmacology and Toxicology . 36 . 161–183 . 1996 . 8725386 . 10.1146/annurev.pa.36.040196.001113 .

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