Torsade de pointes Arrhythmias

Redfern et al. studied the occurrence of QT prolongation and the lethal arrhythmia torsades de pointes (see Chapter 16) in marketed drugs from the perspective of the therapeutic index [50]. This group proposed a therapeutic index of 30-fold, calculated from the free Cmax at the therapeutic dose and the in vitro potency in the manual hERG patch clamp assay. This level, or even higher, seems to be generally followed by the industry. 

Magnesium sulfate Sustained ventricular arrhythmias Torsades de pointes of magnesium depletion or glycoside toxicity... 

The newer drugs therefore represent a substantial improvement over original antihistamines. They are not, however, devoid of side effects. For example, certain nonsedating antihistamines such as astemizole and terfenadine may be cardiotoxic, and problems such as severe ventricular arrhythmias (torsades de pointes) have occurred when these drugs are taken in high doses or taken by individuals with preexisting cardiac and liver problems.70,71 These cardiac effects, however,... 

Kv7.x channels encompass a gene family consisting of 5 distinct members denoted Kv7.1-Kv7.5. Kv7.1, also known as KvLQTl, is expressed primarily in non-neuronal tissues, including cardiac tissue where it contributes to repolarization of the cardiac action potential. Kv7.1 loss-of-function mutations are associated with long QT syndrome that can lead to a rare ventricular arrhythmia, torsades de pointes (Wang et al. 1996). The other members of the Kv7 family encode related potassium channels that are widely expressed... 

The correct answer is C. Erythromycin and clarithromycin inhibit the metabolism of terfenadine giving rise to cardiac arrhythmias (torsade de pointe). 

Adverse reactions Sinus bradycardia, constipation, gingival hyperplasia Sinus bradycardia Facial flushing, peripheral edema, hypotension, headache, gingival hyperplasia, reflex tachycardia (palpitations, angina, myocardial infarct) Agranulocytosis, arrhythmias (torsade de pointes)... 

Henderson RA, Lane S, and Henry JA (1991) Life-threatening ventricular arrhythmia (torsade de pointes) after haloperidol overdose. Human and Experimental Toxicology 10 59-62. 

Potentially harmful drug interactions may not be identified during controlled clinical trials, due to the exclusion of patients taking concomitant medications, which are not allowed to be taken during a study. For example, terfenadine, a novel nonsedating antihistamine which was found to cause a serious and potentially fatal cardiac arrhythmia, torsades de pointes, when administered with keto-conazole or erythromycin, and this could not realistically have been expected to be identified in the clinical trial setting. The mechanism of this adverse drug interaction was found to be due to cumulation of unmetabolized terfenadine, due to inhibition of cytochrome P-450 (CYP) by ketoconazole or erythromycin the parent terfenadine molecule is usually cleared very rapidly when there is no concomitant CYP inhibitor. 

In the past decade there has been increased emphasis on drug safety, and more public visibility of safety problems. The volume of reports now exceeds 250 000 spontaneous reports per year, and adverse events have been highlighted in the medical sector and also in the media. In parallel, the FDA has focused more intently on this area in both NDA reviews and in the postmarketing period. This has accompanied withdrawals of a number of products, such as cisapride, phenylpropanolamine and terfenadine, and special scrutiny of products associated with particular adverse events, such as cardiac arrhythmias (torsades de Pointes ) and hepatic necrosis. The result has been an emphasis on the concept of risk management of a product. This concept, which is due to be described in forthcoming FDA recommendations, stresses the need to identify potential... 

Amiodarone CNS, corneal microdeposits/blurred vision, optic neuropathy/neuritis, Gl, aggravation of underlying ventricular arrhythmias, torsade de pointes, bradycardia or AV block, bruising without thrombocytopenia, pulmonary fibrosis, hepatitis, hypothyroidism, hyperthyroidism, photosensitivity, blue-gray skin discoloration, myopathy, hypotension and phlebitis (IV use)... 

The impairment of critical cellular functions can result in systemic toxicities such as those associated with the neuromuscular system (tremor, cardiac arrhythmia, and paralysis). renal (microtubule function), and vasculature (leaky blood vessels). A noteworthy example is the acquired long QT syndrome (LQTS) associated with blockade of cardiac ion channels (14-16). LQTS results in cardiac arrhythmias, torsade de pointes, ventricular fibrillation, and can lead to sudden death. One such ion channel is the HERG protein, respon-... 

Isoproterenol (ISUPREL, others) may be used in emergencies to stimulate heart rate in patients with bradycardia or heart block, particularly in anticipation of inserting ait artificial cardiac pacemaker or in patients with the ventricular arrhythmia torsades de pointes. In asthma and shock isoproterenol largely has been replaced by other sympathomimetic drugs (set below and Chapter 27). 

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