Abstract
Humans vary widely in their response to drug therapy. This may reflect variability in the relationship between a drug dose and the concentrations of drug and metabolite(s) at relevant target sites; this is termed pharmacokinetic variability. Another mechanism is that individuals vary in their response to identical exposures to drug (pharmacodynamic variability). In this case, there may be variability in the target molecule(s) with which a drug interacts, or more generally in the broad biologic context in which the drug-target interaction occurs; for example, ischemia, electrolyte disturbances, or hypertrophy can all modulate drug effects. Variants in the genes encoding proteins important for pharmacokinetics or for pharmacodynamics have now been described as important contributors to variable drug actions, including proarrhythmia, and are described here. These increasingly well-recognized examples have two important implications; first, it may be possible to develop drugs devoid of heretofore-unexplained adverse effects and, second, it may become possible to preselect drug for individual patients based on specific genetic factors.
Similar content being viewed by others
References
Roden DM, Kim RB. Pharmacokinetics, pharmacodynamics, pharmacogenetics, and drug interactions. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: W.B. Saunders, 2000:882–890.
Kalow W. Pharmacogenetics—Heredity and Responses to Drugs. Philadelphia: W.B. Saunders, 1962.
Hill MR, Gotz VP, Harman E, McLeod I, Hendeles L. Evaluation of the asthmogenicity of propafenone, a new antiarrhythmic drug: Comparison of spirometry with methacholine challenge. Chest 1986;90:698–702.
Lee JT, Kroemer HK, Silberstein DJ, Funck-Brentano C, Lineberry MD, Wood AJ, Roden DM, Woosley RL. The role of genetically determined polymorphic drug metabolism in the beta-blockade produced by propafenone. N Engl J Med 1990;322:1764–1768.
Meyer UA, Zanger UM. Molecular mechanisms of genetic polymorphisms of drug metabolism. Annual Review of Pharmacology & Toxicology 1997;37:269–296.
Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001;27:383–391.
Priori SG. Exploring the hidden danger of noncardiac drugs. J Cardiovasc Electrophysiol 1998;9:1114–1116.
Roden DM. Point of view: Acquired long QT syndromes and the risk of proarrhythmia. J Cardiovasc Electrophysiol 2000;11:938–940.
Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 2001;104:569–580.
Marx SO, Kurokawa J, Reiken S, Motoike H, D'Armiento J, Marks AR, Kass RS. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science 2002;295:496–499.
Sesti F, Abbott GW, Wei J, Murray KT, Saksena S, Schwartz PJ, Priori SG, Roden DM, George AL, Jr., Goldstein SA. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci USA 2000;97:10613–10618.
Kupershmidt S, Yang IC, Sutherland M, Wells KS, Yang T, Yang P, Balser JR, Roden DM. The cardiac-enriched LIM domain protein FHL2 is required to generate I Ks in a heterolgous system. FASEB J, accepted for publication.
Yang IC, Kupershmidt S, Wei J, Petersen CI, Johns DC, George AL, Jr., Roden DM, Balser JR. A molecular toggle for drug block of HERG potassium channels. Circulation 2000;102:260.
Wang SM, Morales MJ, Liu SG, Strauss HC, Rasmusson RL. Time, voltage, and ionic concentration dependence of rectification of h-erg expressed in Xenopus oocytes. FEBS Lett 1996;389:167–173.
Yang T, Snyders DJ, Roden DM. Rapid inactivation determines the rectification and [K+]o dependence of the rapid component of the delayed rectifier K+ current in cardiac cells. Circ Res 1997;80:782–789.
Numaguchi H, Johnson JP, Jr., Petersen CI, Balser JR. A sensitive mechanism for cation modulation of potassium current. Nat Neurosci 2000;3:429–430.
Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC.A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci USA 2000;97:12329–12333.
Roden DM. Taking the idio out of idiosyncratic—Predicting torsades de pointes. PACE 1998;21:1029–1034.
Donger C, Denjoy I, Berthet M, Neyroud N, Cruaud C, Bennaceur M, Chivoret G, Schwartz K, Coumel P, Guicheney P. KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation 1997;96:2778–2781.
Napolitano C, Schwartz PJ, Brown AM, Ronchetti E, Bianchi L, Pinnavaia A, Acquaro G, Priori SG. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J Cardiovasc Electrophysiol 2000;11:691–696.
Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH, Shimizu W, Schwartz PJ, Stanton MS, Murray KT, Norris K, George ALJ, Roden DM. Allelic variants in Long QT disease genes in patients with drug-associated Torsades de Pointes. Circulation 2002;105: 1943–1948.
Wei J, Yang IC, Tapper AR, Murray KT, Viswanathan P, Rudy Y, Bennett PB, Norris K, Balser JR, Roden DM, George AL. KCNE1 polymorphism confers risk of drug-induced long QT syndrome by altering kinetic properties of IKs potassium channels. Circulation 1999;I-495.
Splawski I, Timothy KW, Tateyama M, Clancy CE, Malhotra A, Beggs AH, Cappuccio FP, Sagnella GA, Kass RS, Keating MT. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 2002;297: 1333–1336.
Alings M, Wilde A. “Brugada” syndrome: Clinical data and suggested pathophysiological mechanism. Circulation 1999;99:666–673.
Chen QY, Kirsch GE, Zhang DM, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortizlopez R, Wang Z, Antzelevitch C, Obrien RE, Schulzebahr E, Keating MT, Towbin JA, Wang.Genetic basis and molecular mechanism for idiopathic—ventricular fibrillation. Nature 1998;392:293–296.
Roden DM. The problem, challenge, and opportunity of genetic heterogeneity in monogenic diseases predisposing to sudden death. J Am Coll Cardiol 2002;40:359.
Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet 2000;356:1667–1671.
Roden DM, George AL, Jr. The genetic basis of variability in drug responses. Nature Reviews Drug Discovery 2002;1:37–44.
Roses AD. Pharmacogenetics and the practice of medicine. Nature 2000;405:857–865.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Roden, D.M. Genetic Polymorphisms, Drugs, and Proarrhythmia. J Interv Card Electrophysiol 9, 131–135 (2003). https://doi.org/10.1023/A:1026267903800
Issue Date:
DOI: https://doi.org/10.1023/A:1026267903800