Color Atlas and Synopsis of Electrophysiology, 1st Ed.

32. AMIODARONE

Sunita J. Ferns, MD, MRCPCH, and Gerald V. Naccarelli, MD, FHRS

CASE PRESENTATION

A 65-year-old patient with diabetes, chronic kidney disease, hypertension, and known ischemic cardiomyopathy status postcoronary artery bypass grafting with an ejection fraction of 35% and no known arrhythmia history had a single chamber implantable cardioverter-defibrillator (ICD) placed for primary prevention. He presented 6 months later with two shocks within 48 hours. Interrogation of his ICD revealed a supraventricular tachycardia with rapid ventricular conduction. The best choice in the management of the above patient would be:

1. Upgrade to a dual chamber device.

2. Initiate treatment with a class IC antiarrhythmic medication.

3. Initiate treatment with tikosyn.

4. Initiate treatment with amiodarone.

5. Turn off ventricular tachytherapies as this is an atrial tachycardia.

COMMENT

Thirty to seventy percent of ICD patients require antiarrhythmic drug therapy for suppression of recurrent ventricular tachycardia (VT) or suppression of prophylaxis against atrial fibrillation (AF) with rapid ventricular rates. The majority of patients with ICDs have structural heart disease and left ventricular dysfunction that would preclude use of IC agents. In this patient with renal dysfunction, amiodarone would be the drug of choice.

HISTORY

Amiodarone was developed in Belgium in 1961 as a treatment for angina.1 Its antiarrhythmic properties were later confirmed by Mauricio Rosenbaum.2 Amiodarone has been widely used worldwide since the 1970s and in 1985 received FDA approval for the treatment of life-threatening ventricular tachyarrhythmias.3

MECHANISM OF ACTION

Amiodarone has a broad spectrum of antiarrhythmic actions across all four drug classes with effects on Na, K, and Ca channels via perturbation of the lipid environment in the membrane bilayer.4-8Additionally, it also has α- and β-blocking properties.9,10 Like other class III antiarrhythmic medications, amiodarone prolongs the cardiac action potential via inhibition of IKr with resultant lengthening of the repolarization phase (phase 3) of the action potential.5,11By prolongation of the action potential, it increases the wavelength of the wavefront within the reentrant circuit and thereby reduces the excitable gap. If the excitable gap is reduced sufficiently, the leading edge of activation encounters refractory tissue from the tail of the previous wave and cannot propagate further.12 A delay in repolarization manifests as an increase in the QT interval, which may be proarrhythmic.13,14 Due to its strong sodium channel blocking effects across all conduction tissue, it can also depress myocardial and His-Purkinje conduction.13,15 With acute administration, Na and Ca blocking effects predominate with AV node slowing, and with chronic administration, effects on the K channel predominate with predictable lengthening of refractory periods and repolarization.5,16,17

PHARMACOLOGY/METABOLISM

Chemically, amiodarone is a highly lipid soluble iodinated benzofuran derivative similar to thyroxine.18,19 The bioavailability ranges from 22% to 86% with about 50% absorbed from the gut. It has a large volume of distribution due to accumulation to varying degrees in different tissues, especially in fat, and may take many weeks to reach a steady state or be eliminated from the system. The half-life ranges from 30 to 110 days.3,20 With oral administration, peak plasma levels are reached in 6 to 8 hours, and with higher doses peak effects may be evident in 48 hours. In most cases with lower loading doses, however, effects may be seen only in 2 to 6 weeks. After discontinuation, plasma levels may be seen for 2 to 3 months but may continue to be detected up to 9 months later.21 Studies have shown that drug effects depend on tissue stores and not on plasma levels, and therefore plasma levels are not used to guide therapy. Because of its slow accumulation, a loading dose is usually prescribed with the aim of using the lowest possible maintenance dose to minimize toxicity. Amiodarone undergoes extensive hepatic metabolism to DEA (desethyl-amiodarone), an active metabolite very similar to amiodarone. It interacts with warfarin and other hepatically metabolized drugs due to interference with CYP2C9 hepatic metabolic pathway.22 As the kidney is not involved in its metabolism, there are no dose adjustments required in renal failure or dialysis.

INDICATIONS

Ventricular Arrhythmias

Oral Therapy

Due to its minimal arrhythmogenic and negative inotropic effects and its efficacy at preventing sustained VT/VF or death, amiodarone remains the drug of choice in patients with sustained ventricular tachyarrhythmias associated with structural heart disease, especially those with LV dysfunction ventricular dysfunction, who are not candidates for an implantable cardioverter-defibrillator (ICD).23-25 Its efficacy at 2 years in prevention of sustained VT/VF or death is approximately 60%, and in fact the efficacy of amiodarone is similar to ICD therapy in patients with left ventricular ejection fractions greater than 35%.26-28 However, in patients with NYHA III in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) trial, amiodarone adversely affected survival.29 Therefore, it is reserved for patients with nonsustained VT that is symptomatic, refractory to β-blocker therapy, and concerning enough to warrant treatment.25

Intravenous Therapy

The intravenous (IV) form is used for prophylaxis and treatment of recurrent VF and hemodynamically unstable VT in patients unresponsive to other antiarrhythmic therapy. The current ACLS guidelines suggest its use in persistent VF or pulseless VT when standard resuscitative measures fail.30,31

Atrial Arrhythmias

Oral Therapy

Despite not being FDA approved for atrial fibrillation (AF), amiodarone is frequently used for the management of AF as it has a greater than 60% efficacy rates for maintaining sinus rhythm.32 The current American College of Cardiology (ACC) guidelines suggest its use for AF in patients postmyocardial infarction or with congestive heart failure, LV dysfunction, or hypertrophy who are not candidates for sotalol or dofetilide; patients who are antiarrhythmic drug-refractory; or symptomatic patients as a medical alternative to catheter ablation.33 It is not routinely recommended for preoperative prophylaxis.25

Intravenous Therapy

The IV form is used to treat various supraventricular arrhythmias especially in the acute and postoperative setting.34 It can also be used as a rate controlling agent in acute onset AF, and though ineffective in AF conversion in the acute setting, it can help maintain sinus rhythm 1 to 2 days after cardioversion.25,35

DOSING

Loading may be initiated on an outpatient basis depending on the situation; however, for high loading doses hospital admission with monitoring of rhythm and the QT interval is advisable.

Oral

A loading dose of up to 1600 mg a day may be started with reduction in maintenance dose to as low as 100 mg a day.36

Intravenous

IV boluses may be up to 150 mg followed by a continuous infusion of 1 to 2 mg/min. An IV infusion is administered through a central line as it can cause local phlebitis.12

Adverse Effects

Adverse effects that are dose-related are usually seen in the initial phases of therapy and may decrease with down titration of the dose. Close monitoring of these patients is necessary to assess efficacy, adjust dose, and evaluate for toxic effects. Due to the long half-life of the drug, initial visits should be every 3 to 6 months. The diagnosis and management of adverse effects are summarized in Table 32-1.

TABLE 32-1 Diagnosis and Management of Adverse Effects

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Cardiac

Cardiac adverse effects are related to amiodarone’s effects on the action potential and include bradyarrhythmias, worsening of conduction defects, and ventricular arrhythmias.37,38 In patients with an ICD, ventricular tachycardias may occur at a lower rate than the detection rate, and arrhythmias may go unrecognized. The defibrillation threshold may be increased, and ICD treatments may be ineffective. Hypotension may be a side effect especially with the IV form and is thought to be related to its α-blocking properties.

Extracardiac

Amiodarone has significant extracardiac effects on multiple organ systems. Because of its high iodine content and close structural association to thyroxine and effects on thyroid metabolism, hypothyroidism may be seen in up to a third of patients.39 Thyroid screening is indicated at baseline and 6 months after starting therapy as it usually takes a few months for hormonal levels to equilibrate.25 Hypothyroidism is diagnosed with a high TSH level that reverses after discontinuation of the drug. If hypothyroidism persists, possibly due to intrinsic defects in thyroid synthesis, thyroid supplements are required. Hyperthyroidism is a much less frequent problem but may occur any time during therapy. The typical clinical symptoms of hyperthyroidism may be masked due to the β-blocking effect of the drug. Treatment with antithyroid agents may be needed in addition to discontinuation of the drug.40

Pulmonary toxicity can occur in up to 5% to 20% of patients on chronic doses and can manifest as pulmonary fibrosis, chronic interstitial pneumonitis, organizing pneumonia, bronchiolitis obliterans, or ARDS.41-44 Toxicity involving the lung is usually related to the cumulative dose but may occur any time during the course of therapy, and data supports involvement at both low and higher dose ranges.45 The usual presentation is an initial cough, followed by progressive dyspnea. A high index of suspicion is required as these may be confused with heart failure symptoms. Pulmonary function tests show restrictive lung disease and a decreased diffusion capacity. Though this is a sensitive test, the specificity is limited and therefore not suggested as a routine monitoring tool.25 Management includes discontinuing the drug and initiation of steroids. Gastrointestinal symptoms are usually dose-related, though long-term effects on the liver may be seen with chronic accumulation. An increase in transaminase levels may be seen in 10% to 20% of patients, though hepatitis is relatively rare. Corneal microdeposits may be seen in 50% to 100% of patients with prolonged therapy. Although these do not affect vision, the deposits can cause cysts and abscesses, but usually reverse with drug discontinuation. Another reversible side effect, with long term use, is blue gray discoloration of the skin seen in up to 10% of patients.46 Skin photosensitivity with exposure to sunlight may be seen as an acute or chronic effect. Other side effects include gastrointestinal upset and neurological problems such as headache, proximal muscle weakness, peripheral neuropathy, and ataxia.24 Due to these numerous side effects, under two-thirds of patients remain on therapy 5 years after treatment.47

DRUG INTERACTIONS

Amiodarone has multiple drug interactions especially with drugs that are metabolized in the liver or highly protein bound.48 The interactions are summarized in Table 32-2.

TABLE 32-2 Drug Interactions with Amiodarone

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PREGNANCY AND PEDIATRIC PATIENTS

Amiodarone can cross the placental barrier due to its high lipid solubility and can affect the developing fetus. It should therefore be avoided in pregnancy.49,50 Despite not being adequately studied in children, the IV form is frequently used in atrial and ventricular tachyarrhythmias after congenital heart surgery. Due to its side effects, it is less commonly used for long-term maintenance therapy.

SUMMARY

In summary, amiodarone is the most effective antiarrhythmic agent for the treatment of AF and ventricular tachycardias. Amiodarone has a low propensity for proarrhythmia and can be initiated as an outpatient drug and safely used in most patients with structural heart disease. Due to its potential to cause serious end-organ toxicity, amiodarone should be reserved to treat patients who have not been successfully treated with other antiarrhythmic agents. Close monitoring is essential as side effects can manifest at any time during the course of therapy.

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