What are the pharmacokinetics and pharmacodynamics of Amiodarone (antiarrhythmic medication)?

From the Guidelines

Amiodarone's pharmacokinetics and pharmacodynamics are characterized by extensive tissue distribution, a long half-life, and a broad spectrum of antiarrhythmic activity, making it effective for both supraventricular and ventricular arrhythmias, but also requiring careful monitoring for adverse effects. The drug's pharmacokinetic properties include extensive tissue distribution, with an extremely long half-life averaging 40-55 days, and slow onset of action 1. Amiodarone is highly lipophilic, leading to extensive accumulation in adipose tissue, liver, lungs, and other organs, with oral bioavailability ranging from 30-80% and significant first-pass metabolism 1. The drug undergoes hepatic metabolism primarily via CYP3A4 and CYP2C8 to its active metabolite, desethylamiodarone, which possesses similar antiarrhythmic properties 1. Pharmacodynamically, amiodarone is classified as a Class III antiarrhythmic but exhibits properties of all four Vaughan Williams classes, primarily blocking potassium channels, prolonging action potential duration and effective refractory period, and also blocking sodium channels, calcium channels, and having noncompetitive beta-blocking effects 1. This broad spectrum of activity makes it effective for both supraventricular and ventricular arrhythmias, with loading doses typically ranging from 800-1600 mg daily for 1-2 weeks, followed by maintenance doses of 100-400 mg daily 1. Due to its long half-life, effects persist for weeks to months after discontinuation, requiring careful monitoring for adverse effects including pulmonary toxicity, thyroid dysfunction, liver abnormalities, and corneal deposits 1. Key considerations in the use of amiodarone include:

• Extensive tissue distribution and long half-life
• Broad spectrum of antiarrhythmic activity
• Potential for adverse effects, including pulmonary toxicity and thyroid dysfunction
• Need for careful monitoring and dose adjustment
• Importance of considering alternative treatments, such as beta blockers, in certain patient populations 1. Overall, amiodarone is a complex medication that requires careful use and monitoring to maximize its benefits and minimize its risks.

From the FDA Drug Label

In clinical trials, after 48 hours of continued infusions (125,500 or 1000 mg/day) plus supplemental (150 mg) infusions (for recurrent arrhythmias), amiodarone mean serum concentrations between 0.7 to 1.4 mg/L were observed (n=260). N-desethylamiodarone (DEA) is the major active metabolite of amiodarone in humans. DEA serum concentrations above 0. 05 mg/L are not usually seen until after several days of continuous infusion but with prolonged therapy reach approximately the same concentration as amiodarone. Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The highly variable systemic availability of oral amiodarone may be attributed potentially to large interindividual variability in CYP3A4 activity. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable Amiodarone and DEA cross the placenta and both appear in breast milk. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA’s precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain The development of maximal ventricular class III effects after oral amiodarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation. The systemic availability of oral amiodarone in healthy subjects ranges between 33% and 65%. From in vitro studies, the protein binding of amiodarone is >96%. In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 mL/h/kg Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of amiodarone HCl injection in cirrhotic patients, significantly lower C max and average concentration values are seen for DEA, but mean amiodarone levels are unchanged Normal subjects over 65 years of age show lower clearances (about 100 mL/h/kg) than younger subjects (about 150 mL/h/kg) and an increase in t½ from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t½ of DEA is prolonged Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with oral amiodarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction. There is no established relationship between drug concentration and therapeutic response for short-term intravenous use. Steady-state amiodarone concentrations of 1 to 2. 5 mg/L have been associated with antiarrhythmic effects and acceptable toxicity following chronic oral amiodarone therapy. Amiodarone HCl injection has been reported to produce negative inotropic and vasodilatory effects in animals and humans In clinical studies of patients with refractory VF or hemodynamically unstable VT, treatment-emergent, drug related hypotension occurred in 288 of 1836 patients (16%) treated with amiodarone HCl injection. No correlations were seen between the baseline ejection fraction and the occurrence of clinically significant hypotension during infusion of amiodarone HCl injection

The pharmacokinetics of amiodarone can be summarized as follows:

• Absorption: The systemic availability of oral amiodarone ranges between 33% and 65% 2.
• Distribution: Amiodarone is highly protein-bound (>96%) and has a large volume of distribution 2.
• Metabolism: Amiodarone is metabolized to desethylamiodarone (DEA) by the cytochrome P450 enzyme group, specifically CYP3A4 and CYP2C8 2.
• Elimination: Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion, with negligible excretion in urine 2. The pharmacodynamics of amiodarone can be summarized as follows:
• Mechanism of action: Amiodarone produces negative inotropic and vasodilatory effects in animals and humans 2.
• Antiarrhythmic effects: Steady-state amiodarone concentrations of 1 to 2.5 mg/L have been associated with antiarrhythmic effects and acceptable toxicity following chronic oral amiodarone therapy 2.
• Hypotension: Treatment-emergent, drug-related hypotension occurred in 16% of patients treated with amiodarone HCl injection 2. Key points to consider when using amiodarone include:
• Dose adjustment: No dosage adjustment is defined for patients with renal, hepatic, or cardiac abnormalities, but close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction 2.
• Monitoring: Close monitoring of patients is necessary due to the potential for hypotension and other adverse effects 2.

From the Research

Pharmacokinetics of Amiodarone

• Amiodarone is a highly lipophilic drug with unpredictable pharmacokinetics 3
• It has a very long plasma half-life 4
• The slow onset of its antiarrhythmic action requires a loading dose 3
• Amiodarone interacts with medications such as Warfarin, Digoxin, Macrolides, Floroquinolones etc., which share Cytochrome P450 metabolic pathway 5

Pharmacodynamics of Amiodarone

• Amiodarone is classified as a class III antiarrhythmic drug, but it also has class I, II, IV actions, making it a unique and effective anti-arrhythmic agent 5
• Its leading pharmacologic features are sodium and calcium channel block, nonselective β-adrenergic inhibition as well as high lipophilicity 4
• Amiodarone is a potent coronary and peripheral vasodilator and can be safely used in patients with left ventricular dysfunction after myocardial infarction or those with congestive heart failure or hypertrophic cardiomyopathy 3
• It is the most powerful pharmacological agent for long-term sinus rhythm maintenance in patients with atrial fibrillation 3

Clinical Indications and Efficacy

• Amiodarone is the most effective antiarrhythmic drug in maintaining sinus rhythm in patients with paroxysmal atrial fibrillation 4
• It prevents ventricular arrhythmias, such as frequent ventricular extrasystoles or nonsustained runs of ventricular tachycardia, as well as sustained ventricular tachycardia and ventricular fibrillation 4
• Amiodarone is a highly effective and safe antiarrhythmic drug in patients with increased risk for sudden cardiac death, e.g., with severely depressed left ventricular function 4
• It reduces the number of appropriate and inappropriate shocks in patients with an implantable cardioverter-defibrillator 4, 3

Side Effects and Toxicity

• Typical side effects of amiodarone include corneal microdeposits, blue-gray skin discoloration, photosensitivity, hypothyroidism, hyperthyroidism, peripheral neuropathy, optical neuritis and hepatotoxicity 4
• Irreversible, severe adverse effects, such as pulmonary toxicity, are very rare under the currently used maintenance dose of 200 mg/day 4
• Amiodarone has a high toxicity profile, and its use is associated with increased non-cardiovascular mortality in patients without structural heart disease 6
• Severe or even fatal outcomes due to amiodarone may occur years after treatment initiation and are often not acknowledged by the prescribing physician 6