Ion channels cardiac

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Anantharam, A., Markowitz, S.M. and Abbott, G.W. (2003) Pharmacogenetic considerations in diseases of cardiac ion channels. The Journal of Pharmacology and Experimental Therapeutics, 307, 831-838. 

Napolitano, C., Schwartz, P.J., Brown, A.M., Ronchetti, E., Bianchi, L., Pinnavaia, A., Acquaro, G. and Priori, S.G. (2000) Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. Journal of Cardiovascular Electrophysiology, 11, 691-696. 

Netzer, R., Bischoff, U., and Ebneth, A., HTS techniques to investigate the potential effects of compounds on cardiac ion channels at early-stages of drug discovery, Curr. Opin. Drug Discov. Dev., 6, 462-469, 2003. 

Among all the cardiac ion channels, hERG seems to generate the biggest impact because its blockade by small molecules causes serious clinical consequences and therefore it is the main focus of subsequent sections. 

Dofetilide s mechanism of action involves blockade of the cardiac ion channel that carries the rapid component of the delayed rectifier potassium current, IKr. Dofetilide inhibits IKr with no significant effects on other repolarizing potassium currents (e.g., IKs, IKl) over a wide range of concentrations. At plasma concentrations within the therapeutic range, dofetilide has no effect on sodium channels or on either i- or p-adreno-ceptors. 

Carmeliet E and Mubagwa K. Antiarrhythmic drugs and cardiac ion channels mechanisms of action. Prog Biophys Molec Biol 1998 70 1-72. 

Roden DM and George AL Jr. The cardiac ion channels Relevance to management of arrhythmias. Annu Rev Med 1996 47 135-148. 

For example, studies on liver cytochrome P450 enzymes would be performed to determine whether the drug of interest is likely to be a substrate or inhibitor of these enzymes or to interfere with the metabolism of other drugs. Effects on cardiac ion channels such as the hERG potassium channel, possibly predictive of life-threatening arrhythmias, are considered. 

Flarvey RD, Belevych AE Muscarinic regulation of cardiac ion channels. Br J Pharmacol 2003 139 1074. [PMID 12871825]... 

Important differences between the available calcium channel blockers arise from the details of their interactions with cardiac ion channels and, as noted above, differences in their relative smooth muscle versus cardiac effects. Sodium channel block is modest with verapamil, and still less marked with diltiazem. It is negligible with nifedipine and other dihydropyridines. Verapamil and diltiazem interact kinetically with the calcium channel receptor in a different manner than the dihydropyridines they block tachycardias in calcium-dependent cells, eg, the atrioventricular node, more selectively than do the dihydropyridines. (See Chapter 14 for additional details.) On the other hand, the dihydropyridines appear to block smooth muscle calcium channels at concentrations below those required for significant cardiac effects they are therefore less depressant on the heart than verapamil or diltiazem. 

Hartzell, H. C. 1988. Regulation of cardiac ion channels by catecholamines, acetylcholine and second messenger systems. Prog. Biophys. Mol. Biol. 52 165-247. 

Hool, L. C., Middleton, L. M., and Harvey, R. D. 1998. Genistein increases the sensitivity of cardiac ion channels to p-adrenergic receptor stimulation. Circ. Res. 83 33—42. 

Tikosyn Dofetilide 125, 250, 500 (jig Capsule Maintenance of normal sinus rhythm and conversion of atrial fibrillation/ flutter Cardiac ion channel blocker/ antiarrhythmic drug MCC, corn starch, silicon dioxide, magnesium stearate Pfizer... 

Carmeliet A, Mubagawa K (1998) Antiarrhythmic drugs and cardiac ion channels mechanism of action. Progr Biophys Mol Biol 70 1-71... 

Taglialatela M, Castaldo P, Pannaccione A, Giorgio G, Genovese A, Marone G, Annunziato L. Cardiac ion channels and antihistamines possible mechanisms of cardio-toxicity. Clin Exp Allergy 1999 29(Suppl 3) 182-9. 

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