Ventricular proarrhythmia

Adverse reactions occurring in at least 3% of patients include angina first-degree AV block CHF intraventricular conduction delay palpitations proarrhythmia ventricular tachycardia dizziness fatigue headache constipation dyspepsia nausea/vomiting unusual taste blurred vision dyspnea. About 20% of patients discontinued treatment due to adverse reactions. 

Proarrhythmia refers to development of a significant new arrhythmia (such as VT, ventricular fibrillation [VF], or TdP) or worsening of an existing arrhythmia. Proarrhythmia results from the same mechanisms that cause other arrhythmias or from an alteration in the underlying substrate due to the antiarrhythmic agent. TdP is a rapid form of polymorphic VT associated with evidence of delayed ventricular repolarization due to blockade of potassium conductance. TdP may be hereditary or acquired. Acquired forms are associated with many clinical conditions and drugs, especially type la and type III IKr blockers. 

Type Ic drugs profoundly slow conduction velocity while leaving refractoriness relatively unaltered. Although effective for both ventricular and supraventricular arrhythmias, their use for ventricular arrhythmias has been limited by the risk of proarrhythmia. 

Proarrhythmia Mexiletine can worsen arrhythmias it is uncommon in patients with less serious arrhythmias (freguent premature beats or nonsustained ventricular tachycardia) but is of greater concern in patients with life-threatening arrhythmias, such as sustained ventricular tachycardia. 

Proarrhythmia Like other antiarrhythmic agents, sotalol can provoke new or worsened ventricular arrhythmias in some patients, including sustained ventricular tachycardia or ventricular fibrillation, with potentially fatal consequences. Because of its effect on cardiac repolarization, is the most common form of proarrhythmia associated with sotalol, occurring in approximately 4% of high-risk patients. 

IC Flecainide Propafenone Markedly decrease V, of phase 0, profoundly decrease ventricular conduction velocity, markedly inhibit inward sodium current. High potential for proarrhythmia. 

III Amiodarone Bretylium Sotalol Prolong ventricular action potential, prolong refractoriness, inhibit potassium repolarization currents. Prolong QTc interval. Potential for proarrhythmia (torsades de pointes tachyarrhythmia). 

Quinidine Quinidex) was one of the first clinically used antiarrhythmic agents. Because of the high incidence of ventricular proarrhythmia associated with its use and numerous other equally efficacious agents, quinidine is now used sparingly. Quinidine shares all of the pharmacological properties of quinine, including an-timalarial, antipyretic, oxytocic, and skeletal muscle relaxant actions. 

Inhibitors of the renal cation secretion mechanism, eg, cimetidine, prolong the half-life of dofetilide. Since the QT-prolonging effects and risks of ventricular proarrhythmia are directly related to plasma concentration, dofetilide dosage must be based on the estimated creatinine clearance. Treatment with dofetilide should be initiated in hospital after baseline measurement of the rate-corrected QT interval (QTC) and serum electrolytes. A baseline QTC of > 450 ms (500 ms in the presence of an intraventricular conduction delay), bradycardia of < 50 bpm and hypokalemia are relative contraindications to its use. 

An initial increase in cardiac arrhythmias (proarrhythmic effect) may occur when class III drugs are instituted. The most important proarrhythmia is known as torsades de pointes, which is a form of ventricular tachycardia that can be fatal.11,40 Specific class III agents are associated with various other side effects. Amiodarone, for example, is associated with pulmonary toxicity and liver damage. Other class III drugs may have a more favorable side-effect profile but may not be as effective as amiodarone in controlling arrhythmias. Side effects of class HI drugs there-... 

Life-threatening proarrhythmia generally takes two forms sinusoidal or incessant monomorphic ventricular tachycardia (type Ic agents) and torsade de pointes (type la or III agents and others such as select antihistamines). 

The Cardiac Arrhythmia Suppression Trial (CAST) highlighted the importance and awareness of proarrhythmia. The main finding of CAST was that, despite elimination of complex ventricular ectopy after myocardial infarction, mortality was significantly higher in patients treated with encainide or flecainide. Others have reported that the overall risk of cardiac mortality is higher, presumably due to proarrhythmia, in patients treated with Type la antiarrhythmics for atrial fibrillation who have con-... 

The QT and QTc are monitored 2 to 3 h after each subsequent dose while the patient is in the hospital. If at any time the QT or QTc is >500 ms (550 in patients with ventricular conduction abnormalities), dofetilide should be discontinued. If this guide to dosing is followed, the incidence of torsades de pointes (proarrhythmia) is less than 1%. 

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