Chapter: Modern Pharmacology with Clinical Applications: Pharmacological Management of Chronic Heart Failure

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Amiodarone (Cordarone) is an iodine-containing benzo-furan derivative identified as a class III agent because it predominantly prolongs action potentials.


Amiodarone (Cordarone) is an iodine-containing benzo-furan derivative identified as a class III agent because it predominantly prolongs action potentials. Amiodarone also blocks sodium and calcium channels and is a non-competitive β-receptor blocker. Amiodarone is effective for the treatment of most arrhythmias. Toxicity associ-ated with amiodarone has led the U. S. Food and Drug Administration (FDA) to recommend that it be reserved for use in patients with life-threatening arrhythmias.

Electrophysiological Actions

The most notable electrophysiological effect of amio-darone after long-term administration is prolongation of repolarization and refractoriness in all cardiac tis-sues, an action that is characteristic of class III antiar-rhythmic agents.

Sinoatrial Node

Amiodarone decreases the slope of phase 4 depolar-ization. The rate of spontaneous discharge of the sino-atrial node is increased by amiodarone as well as by its metabolite, desethylamiodarone. The depressant action of amiodarone on sinoatrial pacemaker function is, in addition to β-receptor blockade, related to an inhibition of the slow inward current carried by the calcium ion.

Amiodarone prolongs the action potential in atrial muscle and increases the absolute and effective refrac-tory periods.

Amiodarone, like its major metabolite desethyl-amiodarone, increases A-V nodal conduction time and refractory period.

His-Purkinje System and Ventricular Muscle

The dominant effect on ventricular myocardium that has been chronically exposed to either amiodarone or desethylamiodarone is a prolongation in the action potential with an associated increase in the refractory period and a modest decrease in Vmax as a function of stimulus frequency. Amiodarone inhibits the delayed outward potassium current, a finding consistent with the observation of a prolonged action potential. Both amio-darone and its metabolite significantly decrease the ac- tion potential duration and shorten the ERP in Purkinje fibers, at the same time prolonging action potential in ventricular muscle.

Electrocardiographic Changes

Amiodarone’s predominant electrocardiographic changes include prolongation of the PR and QT inter-vals, development of U waves, and changes in T-wave contour.

Hemodynamic Effects

Amiodarone relaxes vascular smooth muscle; one of its most prominent effects is on the coronary circulation, reducing coronary vascular resistance and improving regional myocardial blood flow. In addition, its effects on the peripheral vascular bed lead to a decrease in left ventricular stroke work and myocardial oxygen con-sumption. Therefore, amiodarone improves the rela-tionship between myocardial oxygen demand and oxy-gen supply. IV administration may be associated with profound hypotension requiring volume expansion therapy.


The pharmacokinetic characteristics of amiodarone are extremely complex:

Oral bioavailability : 35–65%

Onset of action : 2–3 days, up to 2–3 months

Peak response : 3–7 hours after IV adminis tration

Duration of action : Variable, weeks to months

Plasma half-life : 2–10 days; 26–107 days with chronic administration

Primary route of metabolism: Hepatic, active metabolites

Primary route of excretion : Biliary

Therapeutic serum concentration: 0.5–2 μg /mL

Clinical Uses

Amiodarone is regarded as one of the most efficacious antiarrhythmic agents because of its usefulness in the management of a variety of cardiac rhythm disorders with minimal tendency for induction of torsades de pointes tachyarrhythmia. Its use, however, is limited by the multiple and severe noncardiac side effects that it produces.

Amiodarone is available as an IV formulation as well as an oral preparation. IV amiodarone is indicated for initiating treatment and for prophylaxis of fre-quently recurring ventricular fibrillation and hemody- namically unstable ventricular tachycardia in patients refractory to other therapy. IV administration also can be used to treat patients with ventricular tachycardia or ventricular fibrillation for whom oral amiodarone is in-dicated, but who are unable to take oral medication.

Amiodarone may elicit life-threatening side effects in addition to presenting substantial management diffi-culties associated with its use. The oral formulation of amiodarone is indicated only for the treatment of life-threatening recurrent ventricular arrhythmias (e.g., re-current ventricular fibrillation and/or recurrent hemo-dynamically unstable ventricular tachycardia) that have not responded to other potentially effective antiar-rhythmic drugs or when alternative interventions could not be tolerated. Despite its efficacy as an antiarrhyth-mic agent, there is no evidence from clinical trials that the use of amiodarone favorably affects survival.

Initiation of treatment with amiodarone should be done in the hospital setting and only by physicians familiar with the management of patients with life-threatening arrhythmias; this is because of the life-threatening nature of the arrhythmias and the possi-bility of interactions with previous therapy and of exacerbation of the arrhythmia.

Amiodarone is effective in maintaining sinus rhythm in most patients with paroxysmal atrial fibrilla-tion and in many patients with persistent atrial fibrilla-tion. It is also effective in preventing recurrences of A-V nodal reentry and atrial tachyarrhythmias and in the prevention of reentrant rhythms and atrial fibrilla-tion in patients with Wolff-Parkinson-White syndrome. Also, it is the most efficacious therapy for postoperative junctional ectopic tachycardia.

Adverse Effects

Amiodarone’s most significant adverse effects include hepatitis, exacerbation of arrhythmias, worsening of con-gestive heart failure, thyroid dysfunction, and pulmonary fibrosis. Pulmonary fibrosis is frequently fatal and may not be reversed with discontinuation of the drug. Interestingly, despite significant prolongation of the QT interval, the risk of torsades de pointes is relatively low.

Patients with underlying sinus node dysfunction tend to have significant worsening of nodal function, frequently requiring pacemaker implantation. Corneal microdeposits develop in most adults receiving amio-darone. As many as 10% of patients complain of halos or blurred vision. The corneal microdeposits are re-versible with stoppage of the drug.

Photosensitization occurs in 10% of patients. With continued treatment, the skin assumes a blue-gray col-oration. The risk is increased in patients of fair com-plexion. The discoloration of the skin regresses slowly, if at all, after discontinuation of amiodarone.

Amiodarone inhibits the peripheral and possibly in-trapituitary conversion of thyroxine (T4) to triiodothy-ronine (T3) by inhibiting 5 -deiodination. The serum concentration of T4 is increased by a decrease in its clearance, and thyroid synthesis is increased by a re-duced suppression of the pituitary thyrotropin T3. The concentration of T3 in the serum decreases, and reverse T3 appears in increased amounts. Despite these changes, most patients appear to be maintained in an euthyroid state. Manifestations of both hypothyroidism and hy-perthyroidism have been reported.

Tremors of the hands and sleep disturbances in the form of vivid dreams, nightmares, and insomnia have been reported in association with the use of amio-darone. Ataxia, staggering, and impaired walking have been noted. Peripheral sensory and motor neuropathy or severe proximal muscle weakness develops infre-quently. Both neuropathic and myopathic changes are observed on biopsy. Neurological symptoms resolve or improve within several weeks of dosage reduction.


Amiodarone is contraindicated in patients with sick sinus syndrome and may cause severe bradycardia and second-and third-degree atrioventricular block. Amiodarone crosses the placenta and will affect the fetus, as evi-denced by bradycardia and thyroid abnormalities. The drug is secreted in breast milk.

Drug Interactions

Amiodarone increases the hypoprothrombinemic re-sponse to warfarin (an oral anticoagulant) by reducing its metabolism. Patients receiving digoxin may undergo an increase in serum digoxin concentrations when amiodarone is added to the treatment regimen. Amiodarone interferes with hepatic and renal elimina-tion of flecainide, phenytoin, and quinidine.

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