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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Curr+Cardiol+Rev
2016 ; 12
(2
): 141-54
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Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis
of QT Abnormalities and Drug-induced Fatal Arrhythmias
#MMPMID26926294
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Curr Cardiol Rev
2016[]; 12
(2
): 141-54
PMID26926294
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Risk of severe and fatal ventricular arrhythmias, presenting as Torsade de
Pointes (TdP), is increased in congenital and acquired forms of long QT syndromes
(LQTS). Drug-induced inhibition of K+ currents, IKs, IKr, IK1, and/or Ito, delay
repolarization, prolong QT, and increase the risk of TdP. Drug-induced
interference with IKr is the most common cause of acquired LQTS/TdP. Multiple
drugs bind to KNCH2-hERG-K+ channels affecting IKr, including antiarrythmics,
antibiotics, antivirals, azole-antifungals, antimalarials, anticancer,
antiemetics, prokinetics, antipsychotics, and antidepressants. Azithromycin has
been recently added to this list. In addition to direct channel inhibition, some
drugs interfere with the traffic of channels from the endoplasmic reticulum to
the cell membrane, decreasing mature channel membrane density; e.g., pentamidine,
geldalamicin, arsenic trioxide, digoxin, and probucol. Other drugs, such as
ketoconazole, fluoxetine, norfluoxetine, citalopram, escitalopram, donepezil,
tamoxifen, endoxifen, atazanavir, and roxitromycin, induce both direct channel
inhibition and impaired channel trafficking. Although many drugs prolong the QT
interval, TdP is a rare event. The following conditions increase the risk of
drug-induced TdP: a) Disease states/electrolyte levels (heart failure, structural
cardiac disease, bradycardia, hypokalemia); b) Pharmacogenomic variables
(presence of congenital LQTS, subclinical ion-channel mutations, history of or
having a relative with history of drug-induced long QT/TdP); c) Pharmacodynamic
and kinetic factors (high doses, women, elderly, metabolism inhibitors, combining
two or more QT prolonging drugs, drugs that prolong the QT and increase QT
dispersion, and drugs with multiple actions on ion channels). Because most of
these conditions are preventable, careful evaluation of risk factors and
increased knowledge of drug use associated with repolarization abnormalities are
strongly recommended.