verapamil

Verapamil is used for controlling ventricular rate in supraventricular tachycardia (SVT) and migraine headache prevention.{{Cite book|title = Koda-Kimble and Young's Applied Therapeutics: The Clinical Use of Drugs | edition = 10th |publisher = USA: LWW|year = 2012|isbn = 978-1609137137|pages = 497, 1349}}

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).{{cite book | vauthors = Fahie S, Cassagnol M | pmid = 30860730 | date = 2023 | chapter = Verapamil | title = StatPearls [Internet]. | location = Treasure Island (FL) | publisher = StatPearls Publishing | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK538495/ | access-date = 6 November 2023 | archive-date = 10 April 2023 | archive-url = https://web.archive.org/web/20230410150723/https://www.ncbi.nlm.nih.gov/books/NBK538495/ | url-status = live }}

Verapamil is a class-IV antiarrhythmic and more effective than digoxin in controlling ventricular rate.{{cite journal | vauthors = Srinivasan V, Sivaramakrishnan H, Karthikeyan B | title = Detection, isolation and characterization of principal synthetic route indicative impurities in verapamil hydrochloride | journal = Scientia Pharmaceutica | volume = 79 | issue = 3 | pages = 555–568 | year = 2011 | pmid = 21886903 | pmc = 3163365 | doi = 10.3797/scipharm.1101-19 }} Verapamil is not listed as a first line antihypertensive agent by the guidelines provided by JAMA in JNC-8.{{cite journal | vauthors = 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 | title = 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) | journal = JAMA | volume = 311 | issue = 5 | pages = 507–520 | date = February 2014 | pmid = 24352797 | doi = 10.1001/jama.2013.284427 | doi-access = free }} However, it may be used to treat hypertension if patient has co-morbid atrial fibrillation or other types of arrhythmia.{{cite journal | vauthors = Beck E, Sieber WJ, Trejo R | title = Management of cluster headache | journal = American Family Physician | volume = 71 | issue = 4 | pages = 717–724 | date = February 2005 | pmid = 15742909 | url = http://www.aafp.org/afp/2005/0215/p717.html | access-date = 4 November 2015 | url-status = live | df = dmy-all | archive-url = https://web.archive.org/web/20151113055721/http://www.aafp.org/afp/2005/0215/p717.html | archive-date = 13 November 2015 }}

Verapamil is used intra-arterially to treat cerebral vasospasm.{{cite journal | vauthors = Jun P, Ko NU, English JD, Dowd CF, Halbach VV, Higashida RT, Lawton MT, Hetts SW | title = Endovascular treatment of medically refractory cerebral vasospasm following aneurysmal subarachnoid hemorrhage | journal = American Journal of Neuroradiology | volume = 31 | issue = 10 | pages = 1911–1916 | date = November 2010 | pmid = 20616179 | pmc = 4067264 | doi = 10.3174/ajnr.A2183 }} It is also used to treat cluster headaches.{{cite book | vauthors= Drislane F, Benatar M, Chang BS, Acosta J, Tarulli A |title=Blueprints Neurology | url=https://books.google.com/books?id=vj3td6GY0gcC&pg=PA71 |access-date=14 November 2010 |date=1 January 2009 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-9685-9 |pages= 71–|url-status=live |archive-url=https://web.archive.org/web/20130608025221/http://books.google.com/books?id=vj3td6GY0gcC&pg=PA71 |archive-date=8 June 2013 }} Tentative evidence supports the use of verapamil topically to treat plantar fibromatosis.{{cite journal | vauthors = Young JR, Sternbach S, Willinger M, Hutchinson ID, Rosenbaum AJ | title = The etiology, evaluation, and management of plantar fibromatosis | journal = Orthopedic Research and Reviews | volume = 11 | pages = 1–7 | date = 17 December 2018 | pmid = 30774465 | pmc = 6367723 | doi = 10.2147/ORR.S154289 | doi-access = free }}

Use of verapamil in people with recent onset of type 1 diabetes may improve pancreatic beta cell function. In a 2023 meta-analysis 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.{{cite journal | vauthors = Dutta D, Nagendra L, Raizada N, Bhattacharya S, Sharma M | title = Verapamil improves One-Year C-Peptide Levels in Recent Onset Type-1 Diabetes: A Meta-Analysis | journal = Indian J Endocrinol Metab | volume = 27 | issue = 3 | date = May–Jun 2023 | pages = 192–200 | pmid = 37583402 | doi = 10.4103/ijem.ijem_122_23 | pmc = 10424102 | doi-access = free }}

Verapamil has been reported to be effective in both short-term{{cite journal | vauthors = Giannini AJ, Houser WL, Loiselle RH, Giannini MC, Price WA | title = Antimanic effects of verapamil | journal = The American Journal of Psychiatry | volume = 141 | issue = 12 | pages = 1602–1603 | date = December 1984 | pmid = 6439057 | doi = 10.1176/ajp.141.12.1602 }} and long-term treatment of mania and hypomania.{{cite journal | vauthors = Giannini AJ, Taraszewski R, Loiselle RH | title = Verapamil and lithium in maintenance therapy of manic patients | journal = Journal of Clinical Pharmacology | volume = 27 | issue = 12 | pages = 980–982 | date = December 1987 | pmid = 3325531 | doi = 10.1002/j.1552-4604.1987.tb05600.x | s2cid = 34536914 }} Addition of magnesium oxide to the verapamil treatment protocol enhances the antimanic effect.{{cite journal | vauthors = Giannini AJ, Nakoneczie AM, Melemis SM, Ventresco J, Condon M | title = Magnesium oxide augmentation of verapamil maintenance therapy in mania | journal = Psychiatry Research | volume = 93 | issue = 1 | pages = 83–87 | date = February 2000 | pmid = 10699232 | doi = 10.1016/S0165-1781(99)00116-X | s2cid = 18216795 }}

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.{{cite web | title=Calan- verapamil hydrochloride tablet, film coated | website=DailyMed | date=17 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=55d5f933-42ff-4c80-a102-0ccb7f76b082 | access-date=26 March 2020 | archive-date=26 March 2020 | archive-url=https://web.archive.org/web/20200326004308/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=55d5f933-42ff-4c80-a102-0ccb7f76b082 | url-status=live }} It is also contraindicated in people with atrial flutter or fibrillation and an existing accessory tract such as in Wolff-Parkinson-White syndrome.{{cite web | title=Securon 2.5 mg/ml IV Intravenous Injection - Summary of Product Characteristics (SmPC) | website=(emc) | date=24 November 2016 | url=https://www.medicines.org.uk/emc/product/979/smpc | access-date=26 March 2020 | archive-date=26 March 2020 | archive-url=https://web.archive.org/web/20200326010715/https://www.medicines.org.uk/emc/product/979/smpc | url-status=live }}

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 1992 study found that verapamil causes a delay in colonic transit but does not affect upper gastrointestinal transit.{{cite journal | vauthors = Krevsky B, Maurer AH, Niewiarowski T, Cohen S | title = Effect of verapamil on human intestinal transit | journal = Digestive Diseases and Sciences | volume = 37 | issue = 6 | pages = 919–924 | date = June 1992 | pmid = 1587197 | doi = 10.1007/BF01300391 | s2cid = 1007332 }}

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.{{cite journal | vauthors = Steele RM, Schuna AA, Schreiber RT | title = Calcium antagonist-induced gingival hyperplasia | journal = Annals of Internal Medicine | volume = 120 | issue = 8 | pages = 663–664 | date = April 1994 | pmid = 8135450 | doi = 10.7326/0003-4819-120-8-199404150-00006 | s2cid = 41746099 }}

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.{{cite journal | vauthors = Wilimowska J, Piekoszewski W, Krzyanowska-Kierepka E, Florek E | title = Monitoring of verapamil enantiomers concentration in overdose | journal = Clinical Toxicology | volume = 44 | issue = 2 | pages = 169–171 | year = 2006 | pmid = 16615674 | doi = 10.1080/15563650500514541 | s2cid = 10351499 }}{{cite book | vauthors = Baselt R |title= Disposition of Toxic Drugs and Chemicals in Man |edition=8th |publisher=Biomedical Publications |location=Foster City, California |year=2008 |pages=1637–39}}

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. Specific conditions that fall under the definition of atrial tachyarrhythmias are atrial fibrillation, atrial flutter, multifocal atrial tachycardia, paroxysmal supraventricular tachycardia, and so on.{{cite journal |vauthors=Ahmad F, Abu Sneineh M, Patel RS, Rohit Reddy S, Llukmani A, Hashim A, Haddad DR, Gordon DK |title=In The Line of Treatment: A Systematic Review of Paroxysmal Supraventricular Tachycardia |journal=Cureus |volume=13 |issue=6 |pages=e15502 |date=June 2021 |pmid=34268033 |doi=10.7759/cureus.15502|doi-access=free |pmc=8261787 }}{{cite journal |vauthors=Delaney B, Loy J, Kelly AM |title=The relative efficacy of adenosine versus verapamil for the treatment of stable paroxysmal supraventricular tachycardia in adults: a meta-analysis |journal=Eur J Emerg Med |volume=18 |issue=3 |pages=148–52 |date=June 2011 |pmid=20926952 |doi=10.1097/MEJ.0b013e3283400ba2}}{{cite journal|doi=10.1007/s40746-021-00231-w |title=Management of Atrial Tachyarrhythmias in Adults with Single Ventricle Heart Disease |date=2021 |journal=Current Treatment Options in Pediatrics |volume=7 |issue=4 |pages=187–202 | vauthors = Soohoo MM, Stone ML, von Alvensleben J, Jacobsen R }}

Verapamil is also a Kv voltage gated potassium channel blocker.{{cite journal | vauthors = Wang SP, Wang JA, Luo RH, Cui WY, Wang H | title = Potassium channel currents in rat mesenchymal stem cells and their possible roles in cell proliferation | journal = Clinical and Experimental Pharmacology & Physiology | volume = 35 | issue = 9 | pages = 1077–1084 | date = September 2008 | pmid = 18505444 | doi = 10.1111/j.1440-1681.2008.04964.x | s2cid = 205457755 }}

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.

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.{{cite journal | vauthors = Petersen AS, Barloese MC, Snoer A, Soerensen AM, Jensen RH | title = Verapamil and Cluster Headache: Still a Mystery. A Narrative Review of Efficacy, Mechanisms and Perspectives | journal = Headache | volume = 59 | issue = 8 | pages = 1198–1211 | date = September 2019 | pmid = 31339562 | doi = 10.1111/head.13603 | s2cid = 198193843 }}

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 to 2 hours after oral dosage, and 3 to 5 minutes after intravenous bolus dosage.{{cite web|url=https://www.medicine.com/drug/verapamil/hcp | archive-url = https://archive.today/20241030165120/https://www.medicine.com/drug/verapamil/hcp | archive-date = 30 October 2024 |title=Verapamil|quote=Onset of Action[...]Oral: Immediate release: 1 to 2 hours (Singh 1978); IV bolus: 3 to 5 minutes}}{{cite journal | vauthors = Singh BN, Ellrodt G, Peter CT | title = Verapamil: a review of its pharmacological properties and therapeutic use | journal = Drugs | volume = 15 | issue = 3 | pages = 169–197 | date = March 1978 | pmid = 346345 | doi = 10.2165/00003495-197815030-00001 }} Biphasic or triphasic following IV administration; terminal elimination half-life is 2–8 hours.{{cite journal |title=Verapamil Hydrochloride: AHFS 24:28.92 |date=2021-01-01 |journal=ASHP Injectable Drug Information |pages=1563–1568 |url=https://publications.ashp.org/display/book/9781585286850/ch396.xml |access-date=2024-12-01 |doi=10.37573/9781585286850.396 |isbn=978-1-58528-685-0 |url-access=subscription }} Plasma half-life of 2–8 or 4.5–12 hours after single oral dose or multiple oral doses, respectively.{{medical citation needed|date=October 2024}} It is not cleared by hemodialysis.{{medical citation needed|date=October 2024}} It is excreted in human milk.{{medical citation needed|date=October 2024}} Because of the potential for adverse reaction in nursing infants, nursing should be discontinued while verapamil is administered.{{medical citation needed|date=October 2024}}

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.{{cite journal | vauthors = Elferink JG, Deierkauf M | title = The effect of verapamil and other calcium antagonists on chemotaxis of polymorphonuclear leukocytes | journal = Biochemical Pharmacology | volume = 33 | issue = 1 | pages = 35–39 | date = January 1984 | pmid = 6704142 | doi = 10.1016/0006-2952(84)90367-8 }}{{cite journal | vauthors = Azzarone B, Krief P, Soria J, Boucheix C | title = Modulation of fibroblast-induced clot retraction by calcium channel blocking drugs and the monoclonal antibody ALB6 | journal = Journal of Cellular Physiology | volume = 125 | issue = 3 | pages = 420–426 | date = December 1985 | pmid = 3864783 | doi = 10.1002/jcp.1041250309 | s2cid = 10911875 }}{{cite journal | vauthors = Steinleitner A, Lambert H, Kazensky C, Sanchez I, Sueldo C | title = Reduction of primary postoperative adhesion formation under calcium channel blockade in the rabbit | journal = The Journal of Surgical Research | volume = 48 | issue = 1 | pages = 42–45 | date = January 1990 | pmid = 2296179 | doi = 10.1016/0022-4804(90)90143-P }} Such effect was not documented in another study with ponies.{{cite journal | vauthors = Baxter GM, Jackman BR, Eades SC, Tyler DE | title = Failure of calcium channel blockade to prevent intra-abdominal adhesions in ponies | journal = Veterinary Surgery | volume = 22 | issue = 6 | pages = 496–500 | year = 1993 | pmid = 8116206 | doi = 10.1111/j.1532-950X.1993.tb00427.x }}

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.{{cite journal | vauthors = Song J, Chang I, Chen Z, Kang M, Wang CY | title = Characterization of side populations in HNSCC: highly invasive, chemoresistant and abnormal Wnt signaling | journal = PLOS ONE | volume = 5 | issue = 7 | pages = e11456 | date = July 2010 | pmid = 20625515 | pmc = 2897893 | doi = 10.1371/journal.pone.0011456 | doi-access = free | bibcode = 2010PLoSO...511456S }}

Verapamil is also used in cell biology as an inhibitor of drug efflux pump proteins such as P-glycoprotein and other ABC transporter proteins.{{cite journal | vauthors = Bellamy WT | title = P-glycoproteins and multidrug resistance | journal = Annual Review of Pharmacology and Toxicology | volume = 36 | pages = 161–183 | year = 1996 | pmid = 8725386 | doi = 10.1146/annurev.pa.36.040196.001113 }} 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|date=March 2020}}

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