**3. Mechanism of action**

Amiodarone is a Class III antiarrhythmic agent [7, 8] that prolongs the duration of action potential and hence increases the refractory period of atrial, nodal and ventricular tissues, thereby has a very broad spectrum of activity. An increase in the refractory period of the atrial cells is a major contributing factor for controlling the atrial tachyarrhythmia [5–7]. A reduc‐ tion in the permeability of the A-V node, both anterograde and retrograde, explains the efficacy of the medicine in nodal tachycardia caused by reentry through the A-V node [11–13]. Its action on ventricular arrhythmias is explained by a number of mechanisms, e.g. its effect on the atrium and A-V node results in a reduction in the frequency of stimuli reaching the ventricle, thus giving the ventricular cell mass enough time to repolarize in cases where there have been nonsynchro‐ nous refractory periods. Furthermore, prolonging the refractory period of the His-Purkinje system and ventricular contractile fibers reduces or prevents micro reentry [5–7]. Amiodar‐ one increases coronary blood flow, decreases cardiac oxygen requirements without produc‐ ing negative inotropic effects and also suppresses ectopic pacemakers, and this is particularly valuable in arrhythmias associated with ischemic damage or angina pectoris [10 –17].

#### **3.1. Metabolism**

Amiodarone is incompletely and erratically absorbed following oral administration. Absolute bioavailability ranges from 22 to 86% but there is extensive inter-subject variations [6, 7]. Its metabolism occurs in the gut wall and in the liver that could determine the availability of the medicine. The half-life of Amiodarone is long and with chronic oral dosing can be from 14 to 110 days but is usually in the range of 14–59 days. The principal metabolite of Amiodarone, which has been detected in the plasma and other tissues, is Desethylamiodarone [16, 18]. This metabolite has been reported to have a longer half-life than Amiodarone, i.e. 10 hours after a single dose of Amiodarone and 60– 90 days after chronic dosing with Amiodarone. The mechanism of action of this metabolite is not yet known. Amiodarone is highly protein bound and is thought to bind strongly to proteins at concentrations of 10μg/mL. It is believed that most of the medicine is excreted via the liver and gastrointestinal tract by biliary excretion [16, 8]. There may be some hepatic recirculation too. The apparent volume of distribution after oral administration (200–400mg) of Amiodarone is 6.31 ± 4.93L/kg. Amiodarone is highly lipid soluble and tends to accumulate in adipose tissues as well as in highly perfused organs, e.g. lung, bone marrow, adrenals, liver, pancreas, heart, spleen and kidney. The concentration of Amiodarone in packed red blood cells is approximately 60% of that in plasma [8, 9]. Amio‐ darone and its metabolite Desethylamiodarone (DEA) can cross the placenta and therefore it may be toxic to embryo [8, 9]. Amiodarone is metabolized in the liver by cytochrome P450 enzyme system [8] and excreted through biliary route with almost no elimination via renal route [11, 12].

#### **3.2. Chemistry**

Amiodarone is a benzofuran derivative with two atoms of iodine per molecule (Figure 1), with a molecular weight of 645.32 g/mol, It is highly lipophilic and is not water soluble [9, 12, 13].

**Figure 1.** Chemical structure of Amiodarone

#### **3.3. Interactions**

Amiodarone is subject to multiple interactions with oral anticoagulants (e.g. Warfarin) and any drugs that cause bradycardia, e.g. beta blockers and calcium channel blockers. Amiodar‐ one increases Digoxin level [8, 9]. Drugs that deplete potassium from the body (e.g. diuretics) should be avoided in the time of treatment with this drug. Amiodarone may increase Pheny‐ toin levels [8, 11].
