Drug Induced Ventricular Arrhythmias

Supraventricular tachyarrhythmias are often treated with class III anti-arrhythmic drugs (Vaughan Williams 1984). These K+ channel blockers act by increasing the action potential duration and the effective refractory period in order to prevent premature re-excitation (Coumel et al. 1978). While these interventions can be useful in targeting tachyarrhythmias, they may predispose some patients to the development of other types of arrhythmia (Priori 2000). It has become apparent that drug-induced IKr block and QT prolongation are the likely molecular targets responsible for the cardiac toxicity of a wide range of pharmaceutical agents (Roden 2000; Sanguinetti and Jurkiewicz 1990b).

More than 50 commercially available agents (see www.torsades.org) or in-vestigational drugs, often for the purpose of treating syndromes unrelated to cardiac disease, have been implicated with the drug-induced LQTS (Clancy et al. 2003). A number of these drugs have been withdrawn from the market in recent years (e.g., prenylamine, terodiline, and in some countries, terfenadine, astemizole, and cisapride) because their risk for triggering lethal arrhythmias was believed to outweigh therapeutic benefits (Walker et al. 1999). A number of histamine receptor-blocking drugs, including astemizole and terfenadine and more recently loratadine, have been shown to block IKr as an adverse side effect and prolong the Q-T interval of the electrocardiogram (Crumb 2000). Cisapride (Propulsid), a widely used gastrointestinal prokinetic agent in the treatment of gastroesophageal reflux disease and gastroparesis, also blocks KCNH2 K+ channels and is associated with acquired LQTS and ventricular arrhythmias (Wysowski and Bacsanyi 1996). Cisapride produces a preferential prolongation of the APD of M cells, leading to the development of a large dispersion of APD between the M cell and epi/endocardium (Di Diego et al. 2003; Fig. 4). Changes in the morphology of the T wave were observed in more than 85% of patients treated for psychosis when the plasma concentration of the anti-psychotic drug thioridazine was greater than 1 |M (Axelsson and Aspenstrom 1982) due to blockade of iKr (IC50, 1.25 |M) and Iks (IC50, 14 |M). Since inadvertent side effects of drugs on cardiac K+ channels are plentiful, the issue of Q-T interval prolongation has also become a major concern in the development of new pharmacological therapies (Shah 2004).

It is important to consider that in the majority of patients, drugs that block repolarizing currents may not produce an overt baseline Q-T interval prolongation, due to "repolarization reserve" (Roden 1998). However, a subclinical vulnerability stemming from genetic defects or polymorphisms, gender, hy-pokalemia, concurrent use of other medications, or structural heart abnormal-

A Control B dl-Sotalol (100 |iM)

A Control B dl-Sotalol (100 |iM)

200 msec 200 msec

Fig. 4a,b Drug-induced prolongation of the Q-T interval and increased dispersion of repolarization. Each panel shows action potentials recorded from epicardial (Epi), M region (M), and endocardial (Endo) sites (top), and a transmural electrogram simulating an ECG (bottom). The traces were simultaneously recorded from an isolated arterially perfused canine wedge under control condition (a) and in the presence of the IKr blocker d,l-sotalol (100 mM, 30 min; b). Sotalol produced a preferential prolongation of the M cell action potential leading to the appearance of a long Q-T interval in the electrogram and the development of a large transmural dispersion of repolarization. (Reproduced with permission from Haverkamp et al. 2000)

200 msec 200 msec

Fig. 4a,b Drug-induced prolongation of the Q-T interval and increased dispersion of repolarization. Each panel shows action potentials recorded from epicardial (Epi), M region (M), and endocardial (Endo) sites (top), and a transmural electrogram simulating an ECG (bottom). The traces were simultaneously recorded from an isolated arterially perfused canine wedge under control condition (a) and in the presence of the IKr blocker d,l-sotalol (100 mM, 30 min; b). Sotalol produced a preferential prolongation of the M cell action potential leading to the appearance of a long Q-T interval in the electrogram and the development of a large transmural dispersion of repolarization. (Reproduced with permission from Haverkamp et al. 2000)

ities may provide a substrate allowing for the initiation of arrhythmic triggers (De Ponti et al. 2002; Ebert et al. 1998). Many such arrhythmic events are heart rate-dependent and may be linked to sudden changes in heart rate due to exercise or auditory stimulation that may trigger life-threatening arrhythmias (Splawski et al. 2000). On the other hand, not all drugs that significantly prolong the Q-T interval are associated with arrhythmias. Amiodarone clearly prolongs the Q-T interval but rarely causes TdP arrhythmias (Zabel et al. 1997), although it may in the presence of polymorphisms in cardiac ion channels (Splawski et al. 2002). These findings have led to the belief that Q-T interval prolongation may not be an ideal predictor of proarrhythmia, and other parameters such as the Q-T interval dispersion, T wave vector loop, and T-U wave morphology analysis are currently being evaluated as screening tools in drug development (Anderson et al. 2002).

Recent experimental studies by Hondeghem et al. (2001a,b) have also suggested that prolongation of the APD is not inherently proarrhythmic. The cardiac electrophysiological effects of drugs known to block IKr were studied in rabbit Langendorff-perfused hearts. Beat-to-beat variability of APD, reverse frequency dependence of AP prolongation, and triangulation of AP repolarization were found to correlate with the induction of polymorphic VT. In contrast, agents that prolonged APD without instability (i.e., APD alternans) were an-tiarrhythmic. These data suggest that block of IKr may not be proarrhythmic per se, but that the specific mechanism of ion channel modulation and effects on other channels are critical.

Herbal Remedies For Acid Reflux

Herbal Remedies For Acid Reflux

Gastroesophageal reflux disease is the medical term for what we know as acid reflux. Acid reflux occurs when the stomach releases its liquid back into the esophagus, causing inflammation and damage to the esophageal lining. The regurgitated acid most often consists of a few compoundsbr acid, bile, and pepsin.

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