Cardiovascular Journal of Africa: Vol 32 No 6 (NOVEMBER/DECEMBER 2021)

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 32, No 6, November/December 2021 328 AFRICA of amiodarone after cardioversion we used: ‘atrial fibrillation’, ‘atrial flutter’, ‘amiodarone’, and ‘conversion’ or ‘cardioversion’. In order to compare amiodarone with other anti-arrhythmic drugs we added in our search strategy the following MeSH terms: ‘flecainide’, ‘propafenone’, ‘quinidine’, ‘disopyramide’, ‘sotalol’, ‘donedarone’, ‘betablockers’, ‘carvedilol’ ‘metoprolol’. ‘nebivolol’, ‘atenolol’, ‘bisoprolol’. To study the efficacy of amiodarone after catheter ablation, we used the same terms and we added: ‘catheter ablation’ or ‘pulmonary vein isolation’. We also reviewed the guidelines for AFmanagement published in 2010, 2012 and 2016 for additional references. The literature search resulted in 8 230 publications and we selected only articles published in English or if they had a summary available in English. To meet our inclusion criteria, studies had to have two groups: a study group and a control group. The study group must have received anti-arrhythmic treatment with amiodarone at an appropriate dosage to prevent episodes of AF and maintain SR. For the control group, either placebo or rate-control drugs (digoxin, calcium channel blockers, beta-blockers) could have been used or no treatment. For the secondary objective of assessing differences between two anti-arrhythmic drugs, the control group could have received any of the anti-arrhythmic drugs other than amiodarone that have shown efficacy on AF. Pharmacology of amiodarone Pharmacokinetics and pharmacodynamics of amiodarone Amiodarone is an iodine-richbenzofuranderivativewitha structure similar to the thyroid hormones. 8 Pharmacokinetic characteristics are summarised in Table 1. After oral administration, absorption is limited, the bioavailability ranging from 35 to 65% with extensive individual differences. 9 Due to its lipophilic nature, it has a large volume of distribution and high concentrations of amiodarone are found especially in adipose tissue but also in highly perfused organs such as the liver, lung, spleen or skin. 10,11 After oral administration, amiodarone onset of action is delayed, from two to three days, often one to three weeks and even longer . Its elimination half-life is multiphasic as follows: in the first three to 10 days after drug withdrawal, amiodarone plasma concentration initially decreases by 50%, followed by a terminal half-life of 26 to 107 days, with a mean of around 53 days. 9 Following repeated intake of amiodarone, administered more frequently than its half-life, initial accumulation in tissues is normal until steady state. 12 Without a loading dose, a steady- state concentration is achieved between 130 and 535 days. After long-term administration, amiodarone might accumulate in excess in tissues, which explains why some of the amiodarone adverse effects increase in frequency over time. 13 Amiodarone undergoes hepatic metabolism through the cytochrome p450 enzyme and is eliminated by biliary excretion, while < 1% is excreted unchanged via the renal route. 14 Amiodarone’s most prominent metabolite is desethylamiodarone (DEA). DEA is a pharmacologically active compound with properties similar to the parent drug, although with a much longer elimination half-life. 15 The normal therapeutic plasma amiodarone and DEA levels usually range between 1.0 and 2.5 µg/ml. 16 However, studies have shown that serum concentrations do not correlate well with amiodarone efficacy or side effects. 17-19 If administered intravenously, amiodarone has distinct phar- macokinetics compared to the oral formulation. Bioavailability becomes 100%, while the peak plasma concentration occurs 15 minutes after injection. 16 The distribution to tissues is rapid, within 30 to 45 minutes the decrease in concentration reaching 10% of the peak value. The metabolism is also different in terms of less DEA being produced. 16 Amiodarone has equally complex pharmacodynamics that are summarised in Table 2. 9 It has numerous effects and possesses class I, II, III and IV action. 14 The electrocardiographic and electrophysiological effects presented in Table 2 might vary according to the route of amiodarone administration, but these differences are further discussed below. Amiodarone effect on atrial remodelling Atrial remodelling has been proven to play a major role in the occurrence and maintenance of AF. 20,21 The main pathophysiological mechanisms contributing to AF are electrical remodelling, structural remodelling, autonomic nervous system changes, and Ca 2+ handling abnormalities. 22 Recognition of the mechanisms of remodelling in AF is important since they may lead to more specific therapies that target the underlying substrates. Electrical remodelling is the first mechanism that occurs at the onset of AF and promotes AF through a re-entry-prone substrate. Changes in atrial frequency are determined by changes in the physiology of ion channel activation. Studies have shown that the inward-rectifying K1 current (IK1) is a potential anti-arrhythmic target with an increased Table 1. Pharmacokinetics of amiodarone Pharmacokinetic parameters Bioavailability (%) 35–65 Binding to plasma proteins (%) 96 Vd (l/kg) 60 Onset of action after oral administration (weeks) 1–3 Onset of action after iv administration (hours) 1–2 Normal therapeutic plasma concentration (μg/ml) 1–2.5 Half-life after chronic therapy, mean (days) 56 Half-life after iv administration (hours) 4.2–34.5 Metabolism CYP3A4, CYP2C8 Excretion Bile, renal elimination is minimal Table 2. Pharmacodynamics of amiodarone Amiodarone mechanism of action In vitro electro- physiological character istics In vivo ECG measurements In vivo electro- physiological measurements Class III effect – blocks IK ↑ APD ↑ QT ↑ ERP AVN ↑ ERP ↑ ERP HPS ↑ ERPA ↑ ERPV Class I effect – blocks INa ↓ SN auto- maticity ↓ sinus rate ↑ AH Class II effect – anti-adrenergic ↓ CV ↑ PR ↑ HV Class IV effect – blocks ICa,L ↑ QRS ↑ = increase; ↓ = decrease; ECG = electrocardiographic; APD = action potential duration; ERP = effective refractory period; SN = sinus node; CV = conduc- tion velocity; AVN = AV node; HPS = His–Purkinje system; A = atrium; V = ventricle.