Amiodarone - Cordarone

Question 1

Antiarrhythmic class

Answer 1

Predominantly Class III

Question 2

Mechanism of action

Answer 2

• ↑ myocardial cell action potential duration and refractory period
• Alpha- and b-adrenergic inhibition

Question 3

Indications

Answer 3

Second-line therapy for:

• Recurrent VF
• Recurrent hemodynamically unstable VT AF

Guidelines recommend oral amiodarone as a possible 2nd-line therapy for rate control or rhythm control but warn about potential toxicities and drug interactions with long-term use

Question 4

Oral Dosing Strengths

Answer 4

200 mg

Question 5

Dosing

Answer 5

• Uniform, optimal dose not determined; titration suggested

— Lowest effective dose important to minimize AEs (monitor closely for extended period when adjusting dose)

• PI provides dosage for VA only:

— LD: 800–1600 mg for 1 to 3 weeks, then 600–800 mg for 1 month, then 400 mg maintenance dose

• AF guidelines recommendation for oral amiodarone: — For rate control: 100-200 mg QD (after an IV loading dose)

— For rhythm control: 400–600 mg daily in divided doses for 2-4 wk; maintenance typically 100-200 mg QD

No adjustment based on renal insufficiency or hepatic insufficiency

Question 6

Treatment setting

Answer 6

• Loading Dose in hospital facility with continuous ECG and electrophysiologic techniques available

Question 7

Monitoring requirements at initiation

Answer 7

• In-hospital cardiac monitoring during LD

Question 8

Pharmacokinetics

Answer 8

• ~Dose proportional

Question 9

Bioavailability/ absorption

Answer 9

• ~ 50% • Maximum plasma levels at 3–7 hours
• Food increases absorption
• In absence of LD, steady state between 130 and 535 days

Question 10

Half-life

Answer 10

58 Days

Question 11

Protein binding

Answer 11

~96%

Question 12

Metabolism

Answer 12

• Primarily hepatic and biliary: CYP3A4, CYP2C8

Question 13

Major active metabolite

Answer 13

• Desethylamiodarone (DEA)

— Accumulates in tissues

— Plasma terminal elimination half-life ~36 days

— Class III effects correlate with DEA levels more than with amiodarone levels

Question 14

Route of elimination

Answer 14

• Hepatic metabolism and biliary excretion

Question 15

Overdosage

Answer 15

• Fatal cases of amiodarone overdosage have occurred
• Monitor cardiac rhythm and BP
• Bradycardia (treat with b-adrenergic agent or pacemaker)
• Hypotension (treat with inotropic and/ or vasopressor agents)

Question 16

Contraindications

Answer 16

• Cardiogenic shock
• Severe sinus-node dysfunction causing sinus bradycardia
• 2nd- and 3rd-degree AV block
• Bradycardia causing syncope (except with pacemaker)
• Hypersensitivity to drug, iodine, or any components
• Surgery with most corneal laser surgery devices

Question 17

Boxed Warning

Answer 17

• Use only in life-threatening arrhythmias because of toxicity
• Fatal toxicities

— Pulmonary toxicity

— Liver injury

— Exacerbation of arrhythmia

• Life threatening in population at risk for sudden death • LD in hospital
• Switching to other AADs may be problematic due to prolonged amiodarone accumulation

Question 18

Warnings(except boxed warning—see above)

Answer 18

Warnings

• May cause pulmonary toxicity

— Hypersensitivity pneumonitis

— Interstitial/alveolar pneumonitis

• May cause worsened arrhythmia, TdP, bradycardia, or sinus arrest
• Use with implantable cardiac devices may affect pacing
• May cause thyrotoxicosis; some reports of death
• May cause liver injury
• May cause loss of vision
• May cause fetal harm; neonatal hypothyroidism or hyperthyroidism

Question 19

Precautions

Answer 19

• Amiodarone may cause Optic neuropathy or neuritis •Corneal microdeposits Peripheral neuropathy •Photosensitivity Thyroid abnormalities (may persist for months after discontinuation)

• Hypothyroidism
• Hyperthyroidism
• In surgery, amiodarone may cause General anesthesia sensitivity Hypotension post bypass Postoperative ARDS
• Contraindicated with most corneal refractive laser surgery devices
• Advise patient to read medication guide
• Monitor liver enzymes

Question 20

Drug interactions

Answer 20

• CYP3A4 inhibitors may ↑ serum amiodarone:
— Protease inhibitors (indinavir)

— Histamine antagonists (loratadine, cimetidine)

— Antidepressants (trazodone)

— Grapefruit juice

• Drugs that are substrates of CYP1A2, CYP2C9, CYP2D6, CYP3A4, or P-gP may be affected by amiodarone:

— Immunosuppressives (cyclosporine)

— HMG-CoA reductase inhibitors

— Digoxin

— Other antiarrhythmics (quinidine, procainamide, phenytoin)

— b-blockers (propranolol)

— CCBs (verapamil, diltiazem)

— Anticoagulants (warfarin, clopidogrel)

• CYP3A4 inducers may ↓ amiodarone serum levels:

— Rifampin

— Herbal preparations (St John’s wort)

• Other interactions:

— Fentanyl

— Lidocaine

— Dextromethorphan

— Cholestyramine

— Disopyramide

— Fluoroquinolones, macrolide antibiotics, azoles

— General anesthetic agents

— Drugs that induce hypokalemia or hypomagnesemia

• Drug–laboratory tests: — Alters thyroid-function test results

Question 21

Adverse Reactions

Answer 21

• Most serious AEs: pulmonary toxicity, exacerbation of arrhythmia, rare serious liver injury
• Common events: neurologic (20%– 40%), GI (25%), corneal microdeposits (virtually all after 6 months’ therapy), dermatologic (15%)
• Safety evaluated in 241 patients given amiodarone — AEs in 10% to 33%

■■ Nausea and vomiting

— AEs in 4% to 9%

■■ Solar dermatitis/photosensitivity

■■ Malaise and fatigue, tremor/ involuntary movements, lack of coordination, abnormal gait/ ataxia, dizziness, paresthesias

■■ Constipation, anorexia

■■ Visual disturbances

■■ Abnormal liver function tests

■■ Pulmonary inflammation or fibrosis — AEs in 1% to 3%

■■ Hypothyroidism, hyperthyroidism

■■ Decreased libido, insomnia, headache, sleep disturbances

■■ CHF, cardiac arrhythmias, SA node dysfunction

■■ Abdominal pain

■■ Hepatic disorders