Amiodarone antiarrhythmic effects

Amiodarone (11), a benzofuran derivative, was initially developed as a coronary vasodilator in the early 1960 s [11,12]. Several years later, the efficacy of the compound as an antiarrhythmic agent began to be exploited. The first clinical trials with amiodarone were reported in 1974 [13]. Amiodarone was effective in controlling the tachyarrhythmias of eleven patients with Wolff-Parkinson-White syndrome. Since that time the compound has been studied extensively [14,15]. Recently, in the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT), amiodarone was shown to reduce mortality during a mean 18 month period following myocardial infarction (13.8% deaths in placebo group vs. 2.1 % deaths in the treatment group) [16]. 

Pharmacology Amiodarone possesses electrophysiologic characteristics of all 4 Vaughan Williams Classes but has predominantly Class III antiarrhythmic effects. The antiarrhythmic effect may be due to at least 2 major properties Prolongation of the myocardial cell-action potential duration and refractory period, and noncompetitive - and -adrenergic inhibition. 

Excretion - Following discontinuation of chronic oral therapy, amiodarone has a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 107 days. A much slower terminal plasma elimination phase shows a half-life of the parent compound of approximately 53 days. For the metabolite, mean plasma elimination half-life was approximately 61 days. Antiarrhythmic effects persist for weeks or months after the drug is discontinued. 

Somani P. Basic and clinical pharmacology of amiodarone relationship of antiarrhythmic effects, dose and drug concentrations to intracellular inclusion bodies. J Chn Pharmacol 1989 29(5) 405-12. 

Although nearly every type I or III antiarrhythmic drug has some published evidence of effectiveness in preventing recurrences of atrial fibrillation, amiodarone is clearly the most effective agent and now the most frequently chosen despite its impressive toxicity. Initially, uncontrolled studies indicated that low doses (100 to 200 mg/day) of amiodarone are effective. Later, in a comparative trial,amiodarone was shown to be superior to either sotalol or propafenone in maintaining sinus rhythm. Further, in a substudy of AFFIRM,amiodarone was demonstrated to be the most effective antiarrhythmic agent of those used in the study. 

Amiodarone, a special case Amiodarone is effective in most types of arrhythmias and is considered the most efficacious of all antiarrhythmic drugs. This may be because it has a broad spectrum it blocks sodium, calcium, and potassium channels and beta adrenoceptors. Because of its toxicities, however, amiodarone is usually reserved for use in arrhythmias that are resistant to other drugs. 

Initially developed as an antianginal (coronary vasodilator), amiodarone (Fig. 26.15) has antiarrhythmic effects that are somewhat similar to those of bretylium. It is approved by the U.S. FDA for the treatment of life-threatening ventricular arrhythmias that are refractory to other drugs. Its... 

Nearly 100% of amiodarone is eliminated by the liver (CL = 90 to 160 ml/h/kg). Desethyl-amiodarone is the main active metabolite and has EP activity similar to amiodarone (CL = 200 to 300 ml/h/kg).The mean elimination half-life after a single oral dose ranges from 4.6 to 36 h." During chronic therapy, elimination half-life is 40 to 55 days (range 26 to 107 days). The antiarrhythmic effect of amiodarone may last for 2 to 3 months after it is discontinued. ... 

It is not clear whether or not the amiodarone dosage should be inereased to accommodate this interaction because the metabolite of amiodarone (A-desethylamiodarone) also has important antiarrhythmic effects. ... 

The Vaughan-Williams classification of antiarrhythmic drugs has been criticized for a number of reasons. The classification is based on the effects of drugs on normal, rather than diseased, myocardium. In addition, many of the drugs may be placed into more than one class. For example, the class IA drugs prolong repolarization/refractoriness, either via the parent drug8,9 or an active metabolite,10 and therefore also maybe placed in class III. Sotalol is also a 3-blocker, and therefore fits into class II. Amiodarone inhibits sodium and potassium channels, is a non-competitive inhibitor of 3-receptors, and inhibits calcium... 

ICDs have been found to be significantly more effective than antiarrhythmic agents such as amiodarone or sotalol for reducing the risk of sudden cardiac death 45,46 therefore, ICDs are preferred therapy.44 However, many patients with ICDs receive concurrent antiarrhythmic drug therapy to reduce the frequency with which patients experience the discomfort of shocks and to prolong battery life of the devices. Combined pharmacotherapy with amiodarone and a 3-blocker is more effective than monotherapy with sotalol or (i-blockers for reduction in the frequency of ICD shocks.47... 

Amiodarone is the preferred antiarrhythmic during cardiac arrest according to the 2005 guidelines. Hypotension occurs frequently but can generally be reversed by decreasing the infusion rate. Other acute effects include fever, elevated liver function tests, confusion, nausea, and thrombocytopenia. 

Therapeutic uses. Because of their narrow therapeutic margin, these antiarrhythmics are only employed when rhythm disturbances are of such severity as to impair the pumping action of the heart, or when there is a threat of other compUcations. The choice of drug is empirical If the desired effect is not achieved, another drug is tried. Combinations of antiarrhythmics are not customary. Amiodarone is reserved for special cases. 

Amiodarone s antiarrhythmic action is connected to its ability to block K, Na, and Ca channels while noncompetitively blocking a- and j3-adrenergic receptors of the heart, thus prolonging the action potential and effective refractive period of atrial cells, atrioventricular junctions, and ventricles of the heart, which is accompanied by decreased automatism of sinus node and slowing of atrioventricular conductivity. 

Transfer to sotalol from other antiarrhythmic therapy- Before starting sotalol, generally withdraw previous antiarrhythmic therapy under careful monitoring for a minimum of 2 to 3 plasma half-lives if the patient s clinical condition permits. Treatment has been initiated in some patients receiving IV lidocaine without ill effect. After discontinuation of amiodarone, do not initiate sotalol until the QT interval is normalized. 

Uses Rapid conversion of AF/artmal fluto Action Class III antiarrhythmic Dose Adults >60 kg. 0.01 mg/kg (max 1 mg) IV inf over 10 min may repeat x 1 <60 kg Use 0.01 mg/kg (ECC 2005 D/C cardioversion preferred) Caution [C, -] Contra w/ class I/III antiarrhythmics (Table VI-7) QTc >440 ms Disp Inj SE Arrhythmias, HA Interactions t Refractory effects W7 amiodarone, disopyra-mide, procainamide, quinidine, sotalol t QT int val W7 antihistamines, antidepressants, erythromycin, phenothiazines, TCAs EMS Use antihistamines w/ caution, may T QT interval OD May cause increased repolarization leading to arrhythmias, bradycardia, hypotension leading to cardiac arrest symptomatic and supportive... 

On the basis of two large randomized trials aimed at suppressing premature ventricular complexes after MI, so-called warning arrhythmias, it was discovered that many common antiarrhythmic medications actually increase the risk of mortality [20, 21]. Amiodarone also has been shown to have no definitive effect on mortality in patients after an MI, including in the recent SCD-HeFT trial [22-24]. In fact, of all antiarrhythmic medications, only beta blockers have been clearly shown to prevent SCD after MI [25], particularly among those with depressed LV function [11]. 

Sotalol, as the racemate (a 1 1 mixture of the d- and 1-enantiomers), has a well-documented class Ill-antiarrhythmic activity, without showing the various side-effects of amiodarone. The -adrenoceptor blockade by this agent, however, limits its use in patients with heart failure. Dofetilide is an example of a newer, rather pure class in-antiarrhythmic, virtually devoid of other pharmacological properties. 

---