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

Tradename: Cordarone. Formerly Class III antiarrhythmic agent. Amiodarone hydrochloride. Indications: 1) supraventricular arrhythmias a) prevents recurrence of atrial fibrillation & flutter b) slows ventricular response to atrial fibrillation (onset of action is slow) 2) chemical cardioversion of atrial fibrillation 3) prevents recurrence of spontaneous ventricular tachycardia* & ventricular fibrillation (60% of patients) 4) shock-resistant ventricular fibrillation [4] * not effective for termination of acute ventricular tachycardia [15] Contraindications: hyperthyroidism Dose: 1) ACLS: ventricular tachycardia, ventricular fibrillation a) 150 mg IV over 10 minutes (stable) b) 300 mg IV push (unstable) 2) maintenance of sinus rhythm a) 800-1600 mg PO QD for 2 weeks, or b) 400 mg PO QD for 30 days c) maintenance dose to minimize toxicity generally 200 mg QD (rarely > 400 mg QD) Tabs: 200 mg. Pharmacokinetics: 1) metabolized by cyt P450 3A4 & cyt P450 2C8 [14] 2) 1/2life 40-50 days (variable) [5] Monitor: 1) liver function tests, thyroid function tests* baseline & every 6 months [11,18] 2) chest X-ray, EKG, eye exam baseline & yearly [14] * measure serum thyroid-stimulating immunoglobulin only if thyrotoxicosis or elevated fT4 & low serum TSH [30] Adverse effects: 1) of 75% of patients treated for 5 years, <20% require discontinuation of therapy 2) thyroid abnormalities a) 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 b) 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 [5] (type 2 toxicity) - treat with moderate to high-dose prednisone tapered over 1-3 months [5] - because distinguishing type 1 & type 2 is difficult, empiric treatment with prednisone is usually started (NEJM) [29] - consider salvage thyroidectomy with deterioration of cardiac function [24] - hypothyroidism due to destructive thyroiditis - women with pre-existing thyroid peroxidase antibodies at highest risk c) painless thyroiditis d) goiter [5] 3) pulmonary toxicity (1-15%) a) generally within 1st year of therapy b) risk factors: age, pre-existing lung disease, dose & duration of therapy c) signs/symptoms: cough, dyspnea, rales d) forms of pulmonary toxicity - chronic interstitial pneumonitis (most common) - pulmonary fibrosis - organizing pneumonia - acute respiratory distress syndrome - solitary pulmonary nodule e) pulmonary function testing f) chest X-ray every 3-6 months - pulmonary infiltrates - may not reveal pathology g) high-resolution computed tomography if pathology suggested by pulmonary function testing not revealed on chest X-ray [5,17] h) long 1/2life prolongs clearance from pulmonary parenchyma i) 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 [5] - consider addition of methimazole vs propylthiouracil (NEJM) [29] 4) hepatitis a) transient rise in serum transaminases (common) b) diminish or discontinue if serum transaminases exceed 3X baseline c) hepatotoxicity is rare [11] 5) corneal microdeposits (vortex keratopathy) [19] a) occur in all patients b) detectable with slit-lamp examination c) dose-dependent & reversible d) interfere with vision in 10% [11] 6) optic neuropathy, optic neuritis (2%) 7) cataracts [19] 8) photosensitivity - bluish skin 10% [11] ceruloderma [26] 9) cardiovascular a) ECG manifestations - QT prolongation - PR prolongation - QRS prolongation b) prolonged AV conduction time - AV block c) exacerbation of ventricular arrhythmias (2-5%) [11] (less commonly than with class I agents) d) torsades de pointes (rare) e) 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%) 10) gastrointestinal a) nausea b) anorexia c) constipation d) especially common during high-dose loading phase 11) lysosomal storage disorder a) binding to lysosomal phospholipid b) resistance of degradation 12) extrapyramidal effects including tremors. Drug interactions: 1) avoid with other agents that prolong the QT interval a) class Ia & class III agents b) phenothiazines, tricyclic antidepressants, erythromycin terfenadine, astemizole, moxifloxacin, ketoconazole c) see drug-induced QT-interval prolongation 2) amiodarone inhibits cyt P450 2C9, 2D6 & 3A4 a) may increase levels of drugs metabolized by cyt P450 2C9, cyt P450 2D6 & cyt P450 3A4 b) potentiates anticoagulant activity of warfarin & DOAC [27] c) digoxin - reduce digoxin dose by 1/2 when initiating amiodarone therapy d) flecainide, procainamide, quinidine e) cyclosporine f) phenytoin (dilantin) g) statins (simvastatin, lovastatin > atorvastatin) [16] 3) may potentiate effects of beta-blockers 4) may potentiate effects of calcium channel-blockers 5) drugs that inhibit cyt P450 3A4 or cyt P450 2C8 may increase amiodarone levels a) cimetidine, ritonavir, ciprofloxacin b) grapefruit juice 6) general anesthetics in combination may result in bradycardia, hypotension & heart block 7) inhibits P-glycoprotein membrane transporter - may affect drugs tranported by this mechanism 8) drugs that induce cyt P450 3A4 or cyt P450 2C8 may decrease amiodarone levels - rifampin, St John's wort Laboratory: 1) specimen: a) serum, plasma (EDTA), amiodarone in serum/plasma b) stable for at least 6 months at -20 degrees C 2) methods: HPLC 3) other amiodarone laboratory measurements - amiodarone in hair - amiodarone in blood - amiodarone in urine Mechanism of action: 1) prolongs action potential duration, repolarization & refractory period in atrial & ventricular tissue 2) slows sinus rate & prolongs AV conduction time 3) blocks peripheral conversion of T4 to T3 4) alpha & beta adrenergic receptor antagonism 5) anti-anginal agent 6) diminishes systemic vascular resistance & blood pressure generally without effects on left ventricular systolic function 7) therapeutic latency of 5-15 days with full suppression of arrhythmias delayed for up to 4-6 weeks

Interactions

drug interactions

Related

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)

General

antiarrhythmic multichannel blocker

Properties

MISC-INFO: elimination route LIVER 1/2life 25 +/- 12 HOURS 50 HOURS therapeutic-range 0.5-2.5 UG/ML toxic-range >2.5 UG/ML protein-binding 96% elimination by hemodialysis - pregnancy-category D safety in lactation -

Database Correlations

PUBCHEM correlations

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. Medical Knowledge Self Assessment Program (MKSAP) 16, 17, 18. American College of Physicians, Philadelphia 2012, 2015, 2018.
  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#: 220233 (subscription needed) http://www.prescribersletter.com
  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#: 210207 (subscription needed) http://www.prescribersletter.com
  12. Dear Health Care Professional (Wyeth) concerning the Cordarone Medication Guide http://www.fda.gov/medwatch/SAFETY/2005/cordarone_DHCP.htm.
  13. Cordarone Medication Guide and Cordarone product information http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#Cordarone.
  14. Prescriber's Letter 12(12): 2005 Clinically significant Amiodarone interactions Detail-Document#: 211209 (subscription needed) http://www.prescribersletter.com
  15. Marill KA et al, Amiodarone is poorly effective for the acute termination of ventricular tachycardia Ann Emerg Med 2006; 47:217 PMID: 16492484 - 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: 18156531
  16. Prescriber's Letter 15(10): 2008 Rhabdomyolysis with Combined Use of Amiodarone and Simvastatin CHART: Clinically Significant Amiodarone Drug Interactions Detail-Document#: 241002 (subscription needed) http://www.prescribersletter.com
  17. Jackevicius CA et al Population-level incidence and risk factors for pulmonary toxicity associated with amiodarone. Am J Cardiol. 2011 Sep 1;108(5):705-10 PMID: 21704281
  18. Flaker G et al. Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: Insights from the ARISTOTLE trial. J Am Coll Cardiol 2014 Oct 14; 64:1541. PMID: 25301455 - Viles-Gonzalez JF and Halperin JL. Efficacy and safety of amiodarone in patients with atrial fibrillation in the era of target-specific anticoagulants. J Am Coll Cardiol 2014 Oct 14; 64:1551. PMID: 25301456
  19. Chan TC, Jhanji V. Images in clinical medicine. Amiodarone-induced vortex keratopathy. N Engl J Med. 2015 Apr 23;372(17):1656 PMID: 25901429 http://www.nejm.org/doi/full/10.1056/NEJMicm1406501
  20. Wyeth product information http://www.wyeth.com
  21. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  22. Goldschlager N, Epstein AE, Naccarelli G et al Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med. 2000 Jun 26;160(12):1741-8. PMID: 10871966
  23. Bogazzi F, Bartalena L, Martino E. Approach to the patient with amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab. 2010 Jun;95(6):2529-35. Review. PMID: 20525904
  24. Bartalena L, Bogazzi F, Chiovato L, et al. 2018 European Thyroid Association (ETA) Guidelines for the Management of Amiodarone-Associated Thyroid Dysfunction. Eur Thyroid J. 2018 Mr;7(2):55-66. PMID: 29594056 https://www.karger.com/Article/FullText/486957
  25. Danzi S, Klein I. Amiodarone-induced thyroid dysfunction. J Intensive Care Med. 2015 May;30(4):179-85. Review. PMID: 24067547
  26. Murphy RP, Canavan M Images in Clinical Medicine. Skin Discoloration from Amiodarone. N Engl J Med 2020; 382:e5. Jan 16 PMID: 31940702 https://www.nejm.org/doi/full/10.1056/NEJMicm1906774
  27. Paauw DS Drugs to Avoid in Patients on Direct Oral Anticoagulants. Medscape, July 23, 2020 https://www.medscape.com/viewarticle/934329
  28. Wolkove N, Baltzan M Amiodarone pulmonary toxicity. Can Respir J. 2009 Mar-Apr;16(2):43-8 PMID: 19399307 PMCID: PMC2687560 Free PMC article
  29. NEJM Knowledge+ Endocrinology
  30. NEJM Knowledge+ Complex Medical Care