Torsade de pointe arrhythmia

A cell may produce early afterdepolarizations that are depolarization during incomplete repolarization. This is possible if the action potential is considerably prolonged. This is the typical mechanism for elicitation of Torsade de Pointes arrhythmia, a typical complication of class III antiarrhythmics and many other drugs. 

Newly developed class III drugs comprise dofetilide, a specific Ik, blocker, and ibutilide, which blocks IKl and activates the slow iNa- Both drugs lack hemodynamic side effects. These drugs are scheduled for the treatment of atrial fibrillation and atrial flutter. As with class HI drugs, they can induce torsade de pointes arrhythmia. 

Intravenous administration of magnesium sulfate (1-5 g) is used for the termination of torsade de pointes arrhythmia. The underlying electrophysiological mechanism is not well understood. It includes changes of the current-voltage relationship of Iki and Ca2+ channel blockade. 

Torsade de pointes arrhythmia can be terminated by intravenous (not oral) administration of large doses of magnesium. 

Thomsen, M.B., Matz, J., Volders, P.G. and Vos, M.A. (2006) Assessing the proarrhythmic potential of drugs current status of models and surrogate parameters of torsades de pointes arrhythmias. Pharmacology el Therapeutics, 112, 150-170. 

Procainamide s cardiotoxic effects include excessive action potential prolongation, QT interval prolongation, and induction of torsade de pointes arrhythmia and syncope. Excessive slowing of conduction can also occur. New arrhythmias can be precipitated. 

Quinidine has actions similar to those of procainamide it slows the upstroke of the action potential and conduction, and prolongs the QRS duration of the ECG, by blockade of sodium channels. The drug also prolongs the action potential duration by blockade of several potassium channels. Its toxic cardiac effects include excessive QT interval prolongation and induction of torsade de pointes arrhythmia. Toxic concentrations of quinidine also produce excessive sodium channel blockade with slowed conduction throughout the heart. 

Newer antidepressants (eg, fluoxetine, paroxetine, citalopram, venlafaxine) are mostly SSRIs and are generally safer than the tricyclic antidepressants and monoamine oxidase inhibitors, although they can cause seizures. Bupropion (not an SSRI) has caused seizures even in therapeutic doses. Some antidepressants have been associated with QT prolongation and torsade de pointes arrhythmia. SSRIs may interact with each other or especially with monoamine oxidase inhibitors to cause the serotonin syndrome, characterized by agitation, muscle hyperactivity, and hyperthermia (see Chapter 16). 

Schoenmakers M, Ramakers C, van Opstal JM et at. (2003) Asynchronous development of electrical remodeling and cardiac hypertrophy in the complete AV block dog. Cardiovascular Research 59 351-359 Van Opstal JM, Leunissen JDM, Wellens HJJ, Vos MA (2001) Azimilide and dofetilide produce similar electrophysiolog-ical and proarrhythmic effects in a canine model of Torsade de Pointes arrhythmias. European Journal of Pharmacology 412 67-76... 

Verduyn AC, Vos MA, van der Zande J et at. (1997) Further observations to elucidate the role of interventricular dispersion of repolarization and early afterdepolarizations in the genesis of acquired Torsade de Points arrhythmias. J Am Coll Cardiol 30 1575-1584... 

Vos MA, Verduyn SC, Gorgels APM et al. (1995) Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by d-sotalol and pacing in... 

Women also have a higher risk of developing drug-induced cardiac arrhythmia (Ebert et al., 1998) and life-threatening torsades de points arrhythmia may occur with drugs such as antihistamines, antibiotics or antipsychotics, making it important that Cardiac QT studies be conducted in volunteers of both genders (Woolsey, 2005). 

Possible use as antiarrhythmic agent in torsades. Note that most of the antiarrhythmic drugs that block K channels associated with the delayed rectifier current have been implicated in torsades de pointes arrhythmias. 

D. Magnesium Ion Magnesium has not been as well studied as potassium but appears to have similar depressant effects on digitalis-induced arrh5Thmias. Magnesium also appears to be effective in some cases of torsade de pointes arrhythmia. 

Class DI antiarrh3 thmic prototype blocks channels. Used for atrial and ventricular arrh3dhmias. Tox torsade de pointes arrhythmias. Others in group ibutilide, dofetilide. 

Procainamide causes a reversible syndrome similar to lupus erythematosus Pulmonary fibrosis and thyroid dysfunction are known adverse effects of amiodarone Torsade de pointes arrhythmias are often associated with drugs that prolong action potential duration... 

A 73-year-old woman taking amiodarone for atrial fibrillation was given loratadine and developed syncope and multiple episodes of torsade de pointes arrhythmia. ... 

Amiodarone alone is known to cause QT prolongation and torsade de pointes arrhythmia, but loratadine is not usually considered to have a clinically relevant effect on the QT interval, see Table 15.2 , (p.583). Amiodarone may have inhibited the metabolism of loratadine by the cytochrome P450 isoenzyme CYP3A4. 

Amiodarone is a class III antiarrhythmic and can prolong the QT interval. Disopyramide is a class la antiarrhythmic and also prolongs the QT interval. Their additive effects can result in the development of torsade de pointes arrhythmias. 

In general the concurrent use of two or more drugs that prolong the QT interval should be avoided, because this increases the risk of torsade de pointes arrhythmias (see also Drugs that prolong the QT interval + Other drugs that prolong the QT interval , p.257). The above quinolones should probably be avoided in patients on amiodarone. Ciprofloxacin appears to have less effect on the QT interval. ... 

On the basis of the above findings, the manufacturer contraindicates the use of dofetilide with hydrochlorothiazide alone or in combination with triamterene. Given the increase in QT interval, a risk factor for torsade de pointes arrhythmia, this appears a prudent precaution. Further study is needed. Any diuretic that depletes serum potassium (such as the loop diuretics) might be expected to increase the risk of QT prolongation and torsade de pointes with dofetilide, and serum potassium should be monitored. ... 

Cimetidine markedly increases plasma dofetilide levels, and hence increases dofetilide-induced QT prolongation and the risk of torsade de pointes arrhythmias. Its combined use with dofetilide should be avoided. Dofetilide appears not to interact with ranitidine. 

Ketoconazole markedly increases the plasma levels of dofetilide. This is likely to be associated with an increased risk of dofetilide-induced QT prolongation and torsade de pointes arrhythmias. 

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