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Pathway Description
Verapamil Drug Action Action Pathway (new) - finished
Homo sapiens
Drug Action Pathway
Verapamil is a cardioselective non-dihydropyridine calcium channel blocker that is typically administered orally or intravenously in a clinical setting to reduce angina (chest pain), lower hypertension (high blood pressure), and treat certain types of arrhythmias (also known as dysrhythmias: abnormal heartbeats). As a Class IV antiarrhythmic agent, it elongates the phase 3 (plateau) period of a cardiac action potential. Humans have at least five different types of calcium channels: L-, N-, P/Q-, R-, and T-type; verapamil targets the Cav1.2 portion of the alpha-1 subunit of L-type voltage-dependent calcium channels. As a phenylalkylamine, verapamil is thought to enter the pore subunit of the channel from the cytoplasmic side to block the channel intracellularly. Verapamil binds to these channels in a voltage- and frequency-dependent manner. These channels are highly expressed in vascular smooth muscle and myocardial tissue. Blocking L-type calcium channels decreases conduction and increases the refractory period, slowing conduction through the AV node to alter electrical activity mediating the heart rate such that there is an increase in the PR interval duration. Verapamil’s effects on pacemaker cells enable its use as a rate-controlling agent in atrial fibrillation. Verapamil decreases cardiac myocyte contractility by inhibiting the influx of calcium ions. Calcium ions entering the cell through L-type calcium channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of cardiac myocytes and results in an overall decreased force of contraction by the heart. Thus, there is a reduction in inotropy, chronotropy, and heart rate, making verapamil effective for supraventricular dysrhythmia (e.g. atrial fibrillation). Verapamil affects smooth muscle contraction and subsequent vasoconstriction in peripheral arterioles and coronary arteries by the same mechanism. Decreased cardiac contractility and vasodilation lower blood pressure as inhibition of calcium influx prevents the contraction of vascular smooth muscle, causing relaxation/dilation of blood vessels throughout the peripheral circulation, which lowers systemic vascular resistance (i.e. afterload) and thus blood pressure. This reduction in vascular resistance also reduces the force against which the heart must push, decreasing myocardial energy consumption and oxygen requirements and thus alleviating angina. 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, reducing angina. Due to potential interactions of verapamil with other calcium channels, potassium channels, and adrenergic receptors, it is used off-label for cluster headaches.
References
Verapamil Drug Action Pathway (new) - finished References
Tfelt-Hansen P, Tfelt-Hansen J: Verapamil for cluster headache. Clinical pharmacology and possible mode of action. Headache. 2009 Jan;49(1):117-25. doi: 10.1111/j.1526-4610.2008.01298.x.
Pubmed: 19125880
Striessnig J, Ortner NJ, Pinggera A: Pharmacology of L-type Calcium Channels: Novel Drugs for Old Targets? Curr Mol Pharmacol. 2015;8(2):110-22. doi: 10.2174/1874467208666150507105845.
Pubmed: 25966690
Perez-Reyes E, Van Deusen AL, Vitko I: Molecular pharmacology of human Cav3.2 T-type Ca2+ channels: block by antihypertensives, antiarrhythmics, and their analogs. J Pharmacol Exp Ther. 2009 Feb;328(2):621-7. doi: 10.1124/jpet.108.145672. Epub 2008 Oct 30.
Pubmed: 18974361
Bellamy WT: P-glycoproteins and multidrug resistance. Annu Rev Pharmacol Toxicol. 1996;36:161-83. doi: 10.1146/annurev.pa.36.040196.001113.
Pubmed: 8725386
Dilmac N, Hilliard N, Hockerman GH: Molecular determinants of frequency dependence and Ca2+ potentiation of verapamil block in the pore region of Cav1.2. Mol Pharmacol. 2004 Nov;66(5):1236-47. doi: 10.1124/mol.104.000893. Epub 2004 Jul 30.
Pubmed: 15286207
Dobrev D, Milde AS, Andreas K, Ravens U: The effects of verapamil and diltiazem on N-, P- and Q-type calcium channels mediating dopamine release in rat striatum. Br J Pharmacol. 1999 May;127(2):576-82. doi: 10.1038/sj.bjp.0702574.
Pubmed: 10385261
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
Ledwitch KV, Barnes RW, Roberts AG: Unravelling the complex drug-drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein. Biosci Rep. 2016 Jan 28;36(2). pii: BSR20150317. doi: 10.1042/BSR20150317.
Pubmed: 26823559
Nayler WG, Krikler D: Verapamil and the myocardium. Postgrad Med J. 1974 Jul;50(585):441-6. doi: 10.1136/pgmj.50.585.441.
Pubmed: 4619835
Ledwitch KV, Gibbs ME, Barnes RW, Roberts AG: Cooperativity between verapamil and ATP bound to the efflux transporter P-glycoprotein. Biochem Pharmacol. 2016 Oct 15;118:96-108. doi: 10.1016/j.bcp.2016.08.013. Epub 2016 Aug 13.
Pubmed: 27531061
Ding WG, Tano A, Mi X, Kojima A, Seto T, Matsuura H: Identification of Verapamil Binding Sites Within Human Kv1.5 Channel Using Mutagenesis and Docking Simulation. Cell Physiol Biochem. 2019;52(2):302-314. doi: 10.33594/000000022. Epub 2019 Feb 28.
Pubmed: 30816676
Chapy H, Saubamea B, Tournier N, Bourasset F, Behar-Cohen F, Decleves X, Scherrmann JM, Cisternino S: Blood-brain and retinal barriers show dissimilar ABC transporter impacts and concealed effect of P-glycoprotein on a novel verapamil influx carrier. Br J Pharmacol. 2016 Feb;173(3):497-510. doi: 10.1111/bph.13376. Epub 2016 Jan 15.
Pubmed: 26507673
Sheehy RM, Kuder CH, Bachman Z, Hohl RJ: Calcium and P-glycoprotein independent synergism between schweinfurthins and verapamil. Cancer Biol Ther. 2015;16(8):1259-68. doi: 10.1080/15384047.2015.1056420. Epub 2015 Jun 5.
Pubmed: 26046259
van Schalkwyk DA, Nash MN, Shafik SH, Summers RL, Lehane AM, Smith PJ, Martin RE: Verapamil-Sensitive Transport of Quinacrine and Methylene Blue via the Plasmodium falciparum Chloroquine Resistance Transporter Reduces the Parasite's Susceptibility to these Tricyclic Drugs. J Infect Dis. 2016 Mar 1;213(5):800-10. doi: 10.1093/infdis/jiv509. Epub 2015 Oct 26.
Pubmed: 26503982
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