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      Drug-induced QT interval prolongation: mechanisms and clinical management

      1 , 1 , 2
      Therapeutic Advances in Drug Safety
      SAGE Publications

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          Abstract

          The prolonged QT interval is both widely seen and associated with the potentially deadly rhythm, Torsades de Pointes (TdP). While it can occur spontaneously in the congenital form, there is a wide array of drugs that have been implicated in the prolongation of the QT interval. Some of these drugs have either been restricted or withdrawn from the market due to the increased incidence of fatal polymorphic ventricular tachycardia. The list of drugs that cause QT prolongation continues to grow, and an updated list of specific drugs that prolong the QT interval can be found at www.qtdrugs.org. This review focuses on the mechanism of drug-induced QT prolongation, risk factors for TdP, culprit drugs, prevention and monitoring of prolonged drug-induced QT prolongation and treatment strategies.

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          Most cited references86

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          hERG potassium channels and cardiac arrhythmia.

          hERG potassium channels are essential for normal electrical activity in the heart. Inherited mutations in the HERG gene cause long QT syndrome, a disorder that predisposes individuals to life-threatening arrhythmias. Arrhythmia can also be induced by a blockage of hERG channels by a surprisingly diverse group of drugs. This side effect is a common reason for drug failure in preclinical safety trials. Insights gained from the crystal structures of other potassium channels have helped our understanding of the block of hERG channels and the mechanisms of gating.
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            Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation.

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              CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants.

              Over 40 cytochrome P450 (CYP) 2D6 allelic variants have been discovered thus far. The alleles may be classified on the basis of the level of activity for which they encode CYP2D6 enzymes, into functional, non-functional and reduced function groups. CYP2D6 allele frequency is known to vary amongst racial/ethnic groups. Generally, for European Caucasians and their descendants, the functional group of alleles are predominant, with a frequency of 71%. Non-functional alleles represent 26% of the variability, mainly CYP2D6*4. In Asians and their close descendants, functional alleles represent only ~ 50% of the frequency of CYP2D6 alleles. Asians and Pacific Islanders have a high frequency (median = 41%) of a reduced function allele, CYP2D6*10, contributing to the population shift to the right of metabolic rates indicating slower metabolism. Information concerning Amerindians from North (Canada), Central and South America indicate comparatively low frequencies of CYP2D6*10, perhaps a "founders" effect. The frequency of functional alleles in Africans and African Americans is also about 50%. Both Africans and African Americans have reduced function alleles representing 35% of allele variation, mainly CYP2D6*17. African Americans, however, have more than twice the median frequency of nonfunctional alleles compared with Africans (14.5% vs 6.3%). Non-functional and reduced function alleles represent about 50% of allele frequency in Black populations but a much greater variety than carried in Asians. Since alleles which encode for no or reduced functioning clearly affect metabolic activity of drugs mediated by CYP2D6, studies are needed in populations in which these alleles play a major role in order to assure optimal dosing recommendations are based on empirical pharmacogenetics.
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                Author and article information

                Journal
                Therapeutic Advances in Drug Safety
                Therapeutic Advances in Drug Safety
                SAGE Publications
                2042-0986
                2042-0994
                June 19 2012
                October 2012
                July 26 2012
                October 2012
                : 3
                : 5
                : 241-253
                Affiliations
                [1 ]Baylor University Medical Center, Jack and Jane Hamilton, Heart and Vascular Hospital Dallas, TX, USA
                [2 ]Baylor University Medical Center, Jack and Jane Hamilton, Heart and Vascular Hospital, 621 North Hall Street, Suite 500, Dallas, TX 75226, USA
                Article
                10.1177/2042098612454283
                4110870
                25083239
                14a084ef-cbf6-419e-98c1-41b5aad352a8
                © 2012

                http://journals.sagepub.com/page/policies/text-and-data-mining-license

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