Amiodarone

From Anvita Health Wiki

Contents 1 Introduction 2 Indications 3 Contraindications 4 Dosage 5 Pharmacokinetics 6 Monitor 7 Adverse-effects 8 Drug-interactions 9 Laboratory 10 Mechanism-of-action 11 More General Terms 12 Additional Terms 13 Internet Database 14 References

Introduction

• Tradename: Cordarone. 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 [4]

• * not effective for termination of acute ventricular tachycardia [15]

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 [14]
• 1/2life 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 [11,18]
• chest X-ray, EKG, eye exam baseline & yearly [14]

Adverse-effects

• of 75% of patients treated for 5 years, <20% require discontinuation of therapy
• thyroid abnormalities (3%)

• hyperthyroidism (transient)

• iodide-induced
• thyroiditis

• hypothyroidism
• T4 is routinely elevated
• blocks peripheral conversion of T4 to T3

• pulmonary toxicity (1-15%)

• cough
• dyspnea
• pulmonary infiltrates
• rales
• pulmonary fibrosis
• chest X-ray every 3-6 months

• hepatitis

• transient rise in serum transaminases (common)
• diminish or discontinue if serum transaminases exceed 3X baseline
• hepatotoxicity is rare [11]

• corneal microdeposits

• occur in all patients
• detectable with slit-lamp examination
• dose-dependent & reversible
• interfere with vision in 10% [11]

• optic neuropathy, optic neuritis (2%)
• photosensitivity - bluish skin 10% [11]
• cardiovascular

• ECG manifestations

• QT prolongation
• PR prolongation
• QRS prolongation

• prolonged AV conduction time - AV block
• exacerbation of ventricular arrhythmias (2-5%) [11] (less commonly than with class I agents)
• torsades de pointes (rare)

• 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 adverse effects of antiarrhythmic agent, Group III

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
• digoxin - reduce digoxin dose by 1/2 when initiating amiodarone therapy
• flecainide, procainamide, quinidine
• cyclosporine
• phenytoin ( dilantin)
• statins (simvastatin, lovastatin > atorvastatin) [16]

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

Laboratory

• specimen:

• serum, plasma ( EDTA)
• stable for at least 6 months at -20 degrees C

• methods: HPLC

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 agent, Group III

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)

Internet Database

PubChem: 2157
PubChem: 2156
PubChem: 441325
PubChem: 29770

References

1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
2. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (ed), Companion Handbook, McGraw Hill, NY, 1994
3. Cotran et al Robbins Pathologic Basis of Disease, 5th ed. W.B. Saunders Co, Philadelphia, PA 1994 pg 22
4. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 159-60
5. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 124
6. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
7. Kaiser Permanente Northern California Regional Drug Formulary, 1998
8. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
9. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: [1] (subscription needed) [2]
10. Journal Watch 22(9):68, 2002 Dorian P et al, N Engl J Med 346:884, 2002
11. Prescriber's Letter 12(2): 2005 Medication Guide Required for Cordarone (Amiodarone) Detail-Document#: [3] (subscription needed) [4]
12. Dear Health Care Professional (Wyeth) concerning the Cordarone Medication Guide [5]
13. Cordarone Medication Guide and Cordarone product information [6]
14. Prescriber's Letter 12(12): 2005 Clinically significant Amiodarone interactions Detail-Document#: [7] (subscription needed) [8]
15. Marill KA et al, Amiodarone is poorly effective for the acute termination of ventricular tachycardia Ann Emerg Med 2006; 47:217 PMID: [9]
    - Tomlinson DR et al, Intravenous amiodarone for the pharmacological termination of haemodynamically-tolerated sustained ventricular tachycardia: Is bolus dose amiodarone an appropriate first-line treatment? Emerg Med J 2008, 25:15 PMID: [10]
16. Prescriber's Letter 15(10): 2008 Rhabdomyolysis with Combined Use of Amiodarone and Simvastatin CHART: Clinically Significant Amiodarone Drug Interactions Detail-Document#: [11] (subscription needed) [12]
17. Wyeth product information [13]
18. Anvita Health guideline :id 1640 Anvita Health guideline :id 1641
    - Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: [14] (subscription needed) [15]

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