amiodarone (Cordarone, Pacerone, Ritmocardyl, Rhythmarone, Ancaron)

Introduction

Tradename: Cordarone. Formerly Class III antiarrhythmic agent. Amiodarone hydrochloride.

Indications

• supraventricular arrhythmias
  • prevents recurrence of atrial fibrillation & flutter
  • slows ventricular response to atrial fibrillation (onset of action is slow)
• chemical cardioversion of atrial fibrillation
• prevents recurrence of spontaneous ventricular tachycardia* & ventricular fibrillation (60% of patients)
• shock-resistant ventricular fibrillation

* not effective for termination of acute ventricular tachycardia

Contraindications

hyperthyroidism

pregnancy category = d

safety in lactation = -

Dosage

• ACLS: ventricular tachycardia, ventricular fibrillation
  • 150 mg IV over 10 minutes (stable)
  • 300 mg IV push (unstable)
• maintenance of sinus rhythm
  • 800-1600 mg PO QD for 2 weeks, or
  • 400 mg PO QD for 30 days
  • maintenance dose to minimize toxicity generally 200 mg QD (rarely > 400 mg QD)

Tabs: 200 mg.

Pharmacokinetics

• metabolized by cyt P450 3A4 & cyt P450 2C8
• 1/2life 40-50 days (variable)

elimination via liver

1/2life = 50 hours chronic PO therapy

protein binding = 96 %

elimination by hemodialysis = -

Monitor

• liver function tests, thyroid function tests* baseline & every 6 months
• chest X-ray, EKG, eye exam baseline & yearly

* measure serum thyroid-stimulating immunoglobulin only if thyrotoxicosis or elevated fT4 & low serum TSH

Adverse effects

• of 75% of patients treated for 5 years, <20% require discontinuation of therapy
• thyroid abnormalities
  • blocks peripheral conversion of T4 to T3
    • temporary decrease in serum T3 & serum T4
    • minor increase in serum TSH
    • thyroid function tests generally normalize within 3 months
  • 15-25% of patients develop hyperthyroidism or hypothyroidism
    • type 1 toxicity in patients with multinodular goiter or latent Grave's disease (see Monitor: above)
      • discontinue amiodarone
    • transient/iodide-induced thyrotoxicosis (type 2 toxicity)
      • treat with moderate to high-dose prednisone tapered over 1-3 months
      • because distinguishing type 1 & type 2 is difficult, empiric treatment with prednisone is usually started (NEJM)
      • consider salvage thyroidectomy with deterioration of cardiac function
    • hypothyroidism due to destructive thyroiditis
      • women with pre-existing thyroid peroxidase antibodies at highest risk
  • painless thyroiditis
  • goiter
• pulmonary toxicity (1-15%)
  • generally within 1st year of therapy
  • risk factors: age, pre-existing lung disease, dose & duration of therapy
  • signs/symptoms: cough, dyspnea, rales
  • forms of pulmonary toxicity
    • chronic interstitial pneumonitis (most common)
      • pulmonary fibrosis
    • organizing pneumonia
    • acute respiratory distress syndrome
    • solitary pulmonary nodule
  • pulmonary function testing
  • chest X-ray every 3-6 months
    • pulmonary infiltrates
    • may not reveal pathology
  • high-resolution computed tomography if pathology suggested by pulmonary function testing not revealed on chest X-ray
  • long 1/2life prolongs clearance from pulmonary parenchyma
  • management:
    • rare improvement with discontinuation of amiodarone alone
    • glucocorticoids;
      • treat with moderate to high-dose oral prednisone tapered over 1-3 months - add another antiarhythmic agent - high risk of recurrence with glucocorticoid taper
      • consider addition of methimazole vs propylthiouracil (NEJM)
• hepatitis
  • transient rise in serum transaminases (common)
  • diminish or discontinue if serum transaminases exceed 3X baseline
  • hepatotoxicity is rare
• corneal microdeposits (vortex keratopathy)
  • occur in all patients
  • detectable with slit-lamp examination
  • dose-dependent & reversible
  • interfere with vision in 10%
• optic neuropathy, optic neuritis (2%)
• cataracts
• photosensitivity - bluish skin 10% ceruloderma
• cardiovascular
  • ECG manifestations
    • QT prolongation
    • PR prolongation
    • QRS prolongation
  • prolonged AV conduction time - AV block
  • exacerbation of ventricular arrhythmias (2-5%) (less commonly than with class I agents)
  • torsades de pointes (rare)
  • increased risk of embolic stroke in patients with atrial fibrillation
    • annual risk 1.6% vs 1.2% year (RR = 1.47)
    • risk higher for patients on warfarin than apixaban (1.8% vs 1.2%)
• gastrointestinal
  • nausea
  • anorexia
  • constipation
  • especially common during high-dose loading phase
• lysosomal storage disorder
  • binding to lysosomal phospholipid
  • resistance of degradation
• extrapyramidal effects including tremors.

Drug interactions

• avoid with other agents that prolong the QT interval
  • class Ia & class III agents
  • phenothiazines, tricyclic antidepressants, erythromycin terfenadine, astemizole, moxifloxacin, ketoconazole
  • see drug-induced QT-interval prolongation
• amiodarone inhibits cyt P450 2C9, 2D6 & 3A4
  • may increase levels of drugs metabolized by cyt P450 2C9, cyt P450 2D6 & cyt P450 3A4
  • potentiates anticoagulant activity of warfarin & DOAC
  • digoxin - reduce digoxin dose by 1/2 when initiating amiodarone therapy
  • flecainide, procainamide, quinidine
  • cyclosporine
  • phenytoin (dilantin)
  • statins (simvastatin, lovastatin > atorvastatin)
• may potentiate effects of beta-blockers
• may potentiate effects of calcium channel-blockers
• drugs that inhibit cyt P450 3A4 or cyt P450 2C8 may increase amiodarone levels
  • cimetidine, ritonavir, ciprofloxacin
  • grapefruit juice
• general anesthetics in combination may result in bradycardia, hypotension & heart block
• inhibits P-glycoprotein membrane transporter
  • may affect drugs tranported by this mechanism
• drugs that induce cyt P450 3A4 or cyt P450 2C8 may decrease amiodarone levels
  • rifampin, St John's wort

• drug interaction(s) of sofosbuvir with amiodarone
• drug interaction(s) of antiarrhythmic agents in combination with diuretics
• drug interaction(s) of simvastatin with amiodarone
• drug interaction(s) of fluroquinolones with amiodarone

Laboratory

• specimen:
  • serum, plasma (EDTA), amiodarone in serum/plasma
  • stable for at least 6 months at -20 degrees C
• methods: HPLC
• other amiodarone laboratory measurements
  • amiodarone in hair
  • amiodarone in blood
  • amiodarone in urine

Mechanism of action

• prolongs action potential duration, repolarization & refractory period in atrial & ventricular tissue
• slows sinus rate & prolongs AV conduction time
• blocks peripheral conversion of T4 to T3
• alpha & beta adrenergic receptor antagonism
• anti-anginal agent
• diminishes systemic vascular resistance & blood pressure generally without effects on left ventricular systolic function
• therapeutic latency of 5-15 days with full suppression of arrhythmias delayed for up to 4-6 weeks

More general terms

• antiarrhythmic multichannel blocker

Additional terms

• cytochrome P450 2C9; cytochrome P450 BP-1; cytochrome P450 MP-4; S-mephenytoin-4-hydroxylase; limonene 6-monooxygenase; limonene 7-monooxygenase (CYP2C9, CYP2C10)
• cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6)
• cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2157
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2156
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=441325
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=29770