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Verapamil

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Verapamil
Clinical data
Trade namesvarious
License data
Routes of
administration		Oral, intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability35.1%
MetabolismHepatic
Elimination half-life2.8-7.4 hours
ExcretionRenal: 11%
Identifiers
  • (RS)-2-(3,4-Dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl]-(methyl)amino}-2-prop-2-ylpentanenitrile
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.133 Edit this at Wikidata
Chemical and physical data
FormulaC27H38N2O4
Molar mass454.602 g/mol g·mol−1
3D model (JSmol)
  • 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 checkY
  • Key:SGTNSNPWRIOYBX-UHFFFAOYSA-N checkY
  (verify)

Verapamil (INN) (/vɜːrˈæpəmɪl/) (sold under various trade names) is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine. Verapamil has also been used as a vasodilator during cryopreservation of blood vessels. It is a class-IV antiarrhythmic, more effective than digoxin in controlling ventricular rate[1] and was approved by the U.S. Food and Drug Administration (FDA) in March 1982.[2]

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[3]

Side effects

Some possible side effects of the drug are headaches, facial flushing, dizziness, lightheadedness, swelling, increased urination, fatigue, nausea, ecchymosis, galactorrhea, and constipation.[4][5]

Verelan 300-mg extended-release capsule

Along with other calcium channel blockers, verapamil is known to induce gingival hyperplasia. [6]

Overdose

Acute overdose is often manifested by nausea, asthenia, bradycardia, dizziness, hypotension, and cardiac arrhythmia. 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.[7][8]

Uses in cell biology

Verapamil is also used in cell biology as an inhibitor of drug efflux pump proteins such as P-glycoprotein.[9] 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.[10]

Mechanism and uses

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.

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 blood vessels, which increases the supply of blood and oxygen to the heart. This controls chest pain, but only when used regularly. It does not stop chest pain once it starts. A more powerful vasodilator such as nitroglycerin may be needed to control pain once it starts.

In animal trials, verapamil also inhibits thioredoxin-interacting protein, the protein that leads to the death of pancreatic beta cells that produce insulin, and thus causes diabetes. This may allow the reversal of types I and II diabetes.[11]

Verapamil is also used intra-arterially to treat cerebral vasospasm.[12] Verapamil has been used to treat cluster headaches,[13] but it can also cause headaches as a side effect.

Pharmacokinetic details

Given orally, 90–100% of verapamil is absorbed, 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 is metabolized in the liver to at least 12 inactive metabolites (though one metabolite, norverapamil, retains 20% of the vasodilating 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.

Verapamil has been reported to be effective in both short-term[14] and long-term treatment of mania and hypomania.[15] Addition of magnesium oxide to the verapamil treatment protocol enhances the antimanic effect.[16] It has on occasion been used to control mania in pregnant patients, especially in the first three months. It does not appear to be significantly teratogenic. For this reason, when one wants to avoid taking valproic acid (which is high in teratogenicity) or lithium (which has a small but significant incidence of causing cardiac malformation), verapamil is usable as an alternative, albeit presumably a less effective one.

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.[17][18][19] Such effect was not documented in another study with ponies.[20]

Potential use in the treatment of malaria

Recent resistance to the antimalarial drug chloroquine has hindered the treatment of malaria in Southeast Asia, South America, and Africa. Resistance to chloroquine is caused by the parasite cell's ability to expel the drug outside of its digestive vacuole. When used in combination with chloroquine, verapamil enhances the accumulation of chloroquine within a parasitic cell's digestive vacuole, rendering it incapable of detoxifying itself and making it more susceptible to death.[21][22]

Potential use in the treatment of Type 1 Diabetes

Recent research has shown verapamil to be an effective treatment for diabetes in animal models.[23][24] Verapamil helps treat diabetes by limiting TXNIP expression.[25] Human trials are expected to begin in 2015.

Trade names

Trade names for verapamil include Isoptin, Verelan, Verelan PM, Calan, Bosoptin, Calaptin, Verogalid ER and Covera-HS.

See also

References

  1. ^ Srinivasan, Viswanathan; Sivaramakrishnan, H; Karthikeyan, B (2011). "Detection, Isolation and Characterization of Principal Synthetic Route Indicative Impurities in Verapamil Hydrochloride". Scientia Pharmaceutica. 79 (3): 555–68. doi:10.3797/scipharm.1101-19. PMC 3163365. PMID 21886903.
  2. ^ "verapamil, Calan, Verelan, Verelan PM, Isoptin, Covera-HS". MedicineNet.com. Retrieved 6 October 2011.
  3. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  4. ^ "Verapamil". PubMed Health. Retrieved 10 January 2012.
  5. ^ ""verapamil, Calan, Verelan, Verelan PM, Isoptin, Covera-HS (cont.)". MedicineNet.com. Retrieved 10 January 2012.
  6. ^ Steele, RM; Schuna, AA; Schreiber, RT (1994). "Calcium antagonist-induced gingival hyperplasia". Annals of internal medicine. 120 (8): 663–4. doi:10.7326/0003-4819-120-8-199404150-00006. PMID 8135450.
  7. ^ Wilimowska, Jolanta; Piekoszewski, Wojciech; Krzyanowska-Kierepka, Ewa; Florek, Ewa (2006). "Monitoring of Verapamil Enantiomers Concentration in Overdose". Clinical Toxicology. 44 (2): 169–71. doi:10.1080/15563650500514541. PMID 16615674.
  8. ^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, California: Biomedical Publications. pp. 1637–9.
  9. ^ Bellamy, W T (1996). "P-Glycoproteins and Multidrug Resistance". Annual Review of Pharmacology and Toxicology. 36: 161–83. doi:10.1146/annurev.pa.36.040196.001113. PMID 8725386.
  10. ^ Luurtsema, Gert; Windhorst, Albert D.; Mooijer, Martien P.J.; Herscheid, Jacobus D.M.; Lammertsma, Adriaan A.; Franssen, Eric J.F. (2002). "Fully automated high yield synthesis of (R)- and (S)-[11C]verapamil for measuring P-glycoprotein function with positron emission tomography". Journal of Labelled Compounds and Radiopharmaceuticals. 45 (14): 1199–207. doi:10.1002/jlcr.632.
  11. ^ ""In human clinical trial, UAB to test drug shown to completely reverse diabetes in human islets, mice"". University of Alabama at Birmingham.
  12. ^ Jun, P.; Ko, N. U.; English, J. D.; Dowd, C. F.; Halbach, V. V.; Higashida, R. T.; Lawton, M. T.; Hetts, S. W. (2010). "Endovascular Treatment of Medically Refractory Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage". American Journal of Neuroradiology. 31 (10): 1911–6. doi:10.3174/ajnr.A2183. PMID 20616179.
  13. ^ Drislane, Frank; Benatar, Michael; Chang, Bernard S.; Acosta, Juan; Tarulli, Andrew (1 January 2009). Blueprints Neurology. Lippincott Williams & Wilkins. pp. 71–. ISBN 978-0-7817-9685-9. Retrieved 14 November 2010.
  14. ^ Giannini, AJ; Houser Jr, WL; Loiselle, RH; Giannini, MC; Price, WA (1984). "Antimanic effects of verapamil". The American Journal of Psychiatry. 141 (12): 1602–3. PMID 6439057.
  15. ^ Giannini, AJ; Taraszewski, R; Loiselle, RH (1987). "Verapamil and lithium in maintenance therapy of manic patients". Journal of clinical pharmacology. 27 (12): 980–2. doi:10.1002/j.1552-4604.1987.tb05600.x. PMID 3325531.
  16. ^ Giannini, A.James; Nakoneczie, Ann M.; Melemis, Stephen M.; Ventresco, James; Condon, Maggie (2000). "Magnesium oxide augmentation of verapamil maintenance therapy in mania". Psychiatry Research. 93 (1): 83–7. doi:10.1016/S0165-1781(99)00116-X. PMID 10699232.
  17. ^ Elferink, Jan G.R.; Deierkauf, Martha (1984). "The effect of verapamil and other calcium antagonists on chemotaxis of polymorphonuclear leukocytes". Biochemical Pharmacology. 33 (1): 35–9. doi:10.1016/0006-2952(84)90367-8. PMID 6704142.
  18. ^ Azzarone, Bruno; Krief, Patricia; Soria, Jeannette; Boucheix, Claude (1985). "Modulation of fibroblast-induced clot retraction by calcium channel blocking drugs and the monoclonal antibody ALB6". Journal of Cellular Physiology. 125 (3): 420–6. doi:10.1002/jcp.1041250309. PMID 3864783.
  19. ^ Steinleitner, Alex; Lambert, Hovey; Kazensky, Carol; Sanchez, Ignacio; Sueldo, Carlos (1990). "Reduction of primary postoperative adhesion formation under calcium channel blockade in the rabbit". Journal of Surgical Research. 48 (1): 42–5. doi:10.1016/0022-4804(90)90143-P. PMID 2296179.
  20. ^ Baxter, Gary M.; Jackman, Bradley R.; Eades, Susan C.; Tyler, David E. (1993). "Failure of Calcium Channel Blockade to Prevent Intra-abdominal Adhesions in Ponies". Veterinary Surgery. 22 (6): 496–500. doi:10.1111/j.1532-950X.1993.tb00427.x. PMID 8116206.
  21. ^ Martin, S.; Oduola, A.; Milhous, W. (1987). "Reversal of chloroquine resistance in Plasmodium falciparum by verapamil". Science. 235 (4791): 899–901. doi:10.1126/science.3544220. PMID 3544220.
  22. ^ Krogstad, D.; Gluzman, I.; Kyle, D.; Oduola, A.; Martin, S.; Milhous, W.; Schlesinger, P. (1987). "Efflux of chloroquine from Plasmodium falciparum: Mechanism of chloroquine resistance". Science. 238 (4831): 1283–5. doi:10.1126/science.3317830. PMID 3317830.
  23. ^ "UAB cures diabetes in lab mice, preparing for human trial".
  24. ^ "Human clinical trials to begin on drug that reverses diabetes in animal models".
  25. ^ "Preventing β-cell loss and diabetes with calcium channel blockers".

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