Amiodarone: Guidelines for Use and Monitoring

 

 

Introduction

Amiodarone is a complex class III antiarrhythmic agent with multiple electrophysiologic effects.  It prevents the recurrence of life-threatening ventricular arrhythmias and sudden death.  This drug is very potent with many possible toxicities associated with its use.  It also has many drug interactions that need to be monitored for, especially with warfarin and digoxin.  With all of this in mind, amiodarone is a very effective drug if it is used properly and continually monitored.

 

Pharmacokinetics

Amiodarone is an iodine-containing compound similar to thyroxine.  It’s bioavailability is poor; however, absorption is enhanced when the drug is taken with food.  Amiodarone is highly lipid soluble and therefore is stored in the fat, muscle, liver, lungs, and skin.  Desethylamiodarone (DEA) is the major metabolite.  Amiodarone has an elimination half-life average ~58 days.

 

Electrophysiologic Effects

Amiodarone prolongs QT interval, slows heart rate and atrioventricular nodal conduction (via beta receptor and calcium channel blockade).  It also prolongs refractoriness via the potassium and sodium blockade, and slows intracardiac conduction.

 

Indications

1.  FDA approved for emergency room treatment of ventricular tachyarrhythmias.

2.  FDA approved for long-term treatment of secondary prevention of life-threatening ventricular arrhythmias.                                                                                                               

3.  Not FDA approved but still used for the treatment of atrial fibrillation.

 

Dosing Guidelines

 

Life-Threatening Arrhythmia:       IV, inpatient treatment                  150mg IV bolus over 10 minutes, if needed bolus can be repeated after 10-30 minutes, then 1 mg/min for 6 hrs, then 0.5mg/min for 18 hrs, then reduce IV dose or convert to oral dosing if possible

 

Side Effects: hypotension, bradycardia, and atrioventricular block

 

Ventricular Arrhythmia:                     Oral, inpatient treatment                        800-1600 mg/day in divided doses, until a total of 10 g has been given; then 200-400 mg/day

 

Side Effects: bradycardia, QT prolongation, GI upset, constipation, and rarely Torsades de Pointes

 

Atrial Fibrillation:                     Oral, inpatient or outpatient treatment            600-800 mg/day in divided doses, until a total of 10 g has been given; then 200 mg/day

 

Side Effects: bradycardia, QT prolongation, GI upset, constipation, and rarely Torsades de Pointes

 

 

Toxicities

Amiodarone has been associate with toxicities involving the lungs, thyroid gland, liver, eyes, skin, and nerves.  The toxicities are associated with the dosage and duration of treatment with amiodarone.  It is important for physicians to dose below 300 mg/day and aim at 200 mg/day or less for maintenance therapy.

 

Pulmonary Toxicity: Is the most serious potential adverse effect.  The most common clinical presentation is cough and progressive dyspnea with patchy infiltrates on the chest radiograph and a decrease pulmonary function test.  If any of these signs/symptoms occur, amiodarone must be stopped and supportive care measures must be done.

 

Thyroid Toxicity: Is the most common complication that requires treatment.  Hypothyroidism is 2-4 x more common than hyperthyroidism.  If hypothyroidism occurs, amiodarone may be continued; however, thyroid supplementation must done.  If hyperthyroidism occurs, removal of amiodarone is warranted if possible, the addition of antithyroid medications or prednisone, and surgical thyroidectomy.

 

Liver Toxicity: This is seen in patients who are receiving long-term amiodarone therapy.  Patients are rarely symptomatic; however, if their liver enzymes are 3X higher than normal, amiodarone should be discontinued unless their risk for a recurrent life-threatening arrhythmia is high.

 

GI Toxicities: These include: nausea, vomiting, anorexia, and constipation which are often dose related and usually improve once the dose is reduced.

 

Neurologic Toxicities: Neurologic toxicities can include; ataxia, paresthesias, and tremor.  These conditions are often dose related.  Peripheral neuropathy occurs at a rate of 0.3% annually.

Ocular Toxicities: Corneal deposits are visible on examination in nearly all patients taking amiodarone.  Once these deposits are noted, it is important to discontinue the drug before progression of the toxicity occurs.  Optic neuropathy, optic neuritis, and total blindness have been noted, therefore, it is important to continue eye exams and discontinue the drug if any abnormalities are noted.

 

Dermatologic Toxicities: Skin discoloration is common in patients using amiodarone.  Patients should be cautioned to use sun block and avoid direct sun exposure for extended periods of time.  The blue-gray discoloration will resolve over several months after amiodarone is discontinued.

 

CV Toxicities: Possible cardiovascular adverse effects associated with amiodarone usage include; bradycardia, heart block, proarrhythmia, and hypotension.  Torsades de Pointes occurs rarely however, precautions must still be taken.  Amiodarone is contraindicated in patients with a 2-3 degree heart block who do not have a pacemaker.  If amiodarone is administered IV, and CV toxicities arise, it must be discontinued or the rate of the infusion should be reduced.

 

Monitoring Of These Toxicities

http://www.vapbm.org/monitoring/amiodaron.htm

 

Drug Interactions

Amiodarone is a potent inhibitor of hepatic and renal metabolism of several drugs.  It inhibits CYP2C9, CYP2D6, and CYP3A4.  Interactions with warfarin (increased bleeding) and digoxin (increase levels) are the most significant.  It can also interact with Simvastatin (increased myopathy), Sildenafil (increased levels), Cyclosporine (increased levels), other antiarrhythmic drugs, Quinolones, and antidepressants (increase amiodarone levels).  Also, it is important to counsel patients not to eat grapefruit, because it can inhibit the conversion of amiodarone to its active metabolite.

References

 

1.  Siddoway LA. MD, Amiodarone: Guidelines for use and monitoring.  American Family       Physician; Clinical Pharmacology.  December 2003.  Vol 68.  N11; Pg 2189-96.

 

2.  Stelfox HT.  MD,  Ahmed SB. MD, Fiskio J, Bates DW.  MD.  Pharmacoepidemiology and Drug Utilization; Monitoring amiodarone’s toxicities: Recommendations, evidence, and clinical practice.  Clinical Pharmacology and Therapeutics.  2004; 75;75:110-22.

 

3.  Hansten PD, Horn JR.  Drug Interactions analysis and management.  Vancouver: Applied Therapeutics;1998.

 

4.  Singh BN.  Amiodarone: The expanding antiarrhythmic role and how to follow a patient on chronic therapy.  Clin Cardiol 1997;20:608-18.

                                                                             

5.  Pollack PT.  Clinical organ toxicity of antiarrhythmic compounds: ocular and pulmonary manifestations.  Am J Cardiol 1999; 84:37R-45R.

 

6.  Cordarone (amiodarone) product information.  Wyeth Laboratories, Inc; 1998.

 

7.  Pacerone (amiodarone) product information.  Upsher-Smith Laboratories, Inc; 1998.