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Pathway Description
Verapamil Calcium Channel Cardiac Muscle Relaxation Action Pathway
Homo sapiens
Drug Action Pathway
Verapamil, known as the brand names Calan, Isoptin, Tarka, and Verelan, is a non-dihydropyridine calcium channel blocker used in the treatment of angina, arrhythmia, and hypertension. It is used for the treament of vasopastic angina, unstable angina, chronic stable angina, treat hypertension, for the prophylaxis of repetitive paroxysmal supraventricular tachycardia,and atrial fibrillation or atrial flutter in combination with digoxin. It is normally given intravenously, so it has a rapid release with a short duration of action. Verapamil acts on smooth muscles and cardiac muscles.
Excitation of cardiac muscle involves the activation of a slow calcium inward current that is induced by L-type slow calcium channels, which are voltage-sensitive, ion-selective channels associated with a high activation threshold and slow inactivation profile. L-type calcium channels are the main current responsible for the late phase of the pacemaker potential. Activation of L-type calcium channels allows the influx of calcium ions into the muscles upon depolarization and excitation of the channel. This is essential for the propogation of action potentials in the myocytes necessary for the contraction of the muscle tissue and the heart's electrical pacemaker activity. It is proposed that this cation influx may also trigger the release of additional calcium ions from intracellular storage sites.
Electrical activity through the AV node is responsible for determining heart rate. This activity is dependent on calcium influx through L-type calcium channels. Therefore, the inhibition of L-type calcium channels, by verapamil, decreases the influx of calcium, which prolongs the refractory period of the AV node and slows conduction. This slows and controls the heart rate.
Verapamil's mechanism of action in the treatment of cluster headaches is unclear, but is thought to be involved with its effect on calcium channels.
References
Verapamil Calcium Channel Cardiac Muscle Relaxation Pathway References
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
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
Morel N, Buryi V, Feron O, Gomez JP, Christen MO, Godfraind T: The action of calcium channel blockers on recombinant L-type calcium channel alpha1-subunits. Br J Pharmacol. 1998 Nov;125(5):1005-12. doi: 10.1038/sj.bjp.0702162.
Pubmed: 9846638
Patel MK, Clunn GF, Lymn JS, Austin O, Hughes AD: Effect of serum withdrawal on the contribution of L-type calcium channels (CaV1.2) to intracellular Ca2+ responses and chemotaxis in cultured human vascular smooth muscle cells. Br J Pharmacol. 2005 Jul;145(6):811-7. doi: 10.1038/sj.bjp.0706237.
Pubmed: 15880143
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
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018817s033lbl.pdf
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
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