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What is the MOA of amiodarone?
- Class III antiarrhythmic
- Prolongs repolarization and the refractory period in atrial and ventricular tissue
- Inhibition of potassium channels
- Sodium blocker; Noncompetitive beta blocker; Calcium channel blocker
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What are the main uses for amiodarone?
- Supraventricular and ventricular tachycardia
- --> ventricular tachycardia, ventricular fibrillation, atrial fibrillation, atrial flutter
- Cardiac arrest
- Prevention of post-operative AF during cardio-thoracic surgery
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What kind of distribution does amiodarone have?
- Large Vd
- Highly lipophilic
- Widely distributes to the tissue
- Concentrates in tissue
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What kind of absorption does amiodarone have?
- Incomplete and slow absorption!
- F=50% (IV = 100%)
- Food enhances rate & extent of absorption
- Enterohepatic circulation (excreted by liver, reabsorbed, back to liver by portal vein)
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What kind of distribution does amiodarone have?
- Highly protein bound (96%)
- *bound to albumin and alpha-1-acid glycoprotein
- *free fractions of amiodarone are independent of total drug concentration and albumin levels
- Vd = ~60 L/kg
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What are the major sites of distribution of amiodarone?
- Fat, muscle, liver, spleen
- Tissue concentration 10-400 times greater than plasma concentrations
- Two compartment body model
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What is the major site of amiodarone metabolism?
- Liver CYP450-3A4
- Active metabolite: N-desethylamiodarone (DEA)
- Weak substrate of 1A2, 2C19 & 2D6
- Major inhibitor of CYP3A4 and P-glycoprotein
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What is the primary route of amiodarone excretion/elimination?
- BILE
- renal adjustments not necessary
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What is the half-life of amiodarone?
- ~53 days (chronic oral dosing)
- 9-36 days (IV)
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What factors alter clearance of amiodarone?
- cirrhosis (decreases formation of DEA, no change in amiodarone)
- elderly (decreased clearance)
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Do renal failure, heart failure or dialysis have significan effects on clearance of amiodarone?
No
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What is the onset of action ofamiodarone?
Oral: 1-3 weeks (minimum 2-3 days, max 3-6 weeks)
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What is the duration of action of amiodarone after discontinuation?
30-90 days
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What is the therapeutic range for amiodarone?
- 0.5 - 2 mg/L
- Peak concentration: 3-7 hours
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What is the LD and MD for amiodarone?
- Oral LD: 1.2-1.8 g/day in divided doses until 10 grams is reached
- IV LD: 5-7 mg/kg over 30-60 minutes, then 1.2-1.8 g/day CI until 10 grams is reached
- MD: 200-400 mg/day
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How long is a patient on IV amiodarone before they can be switched directly to maintenance PO dose of amiodarone?
> 3 weeks
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If a patient has been on IV amiodarone for < 1 week, what is the oral dose they should be converted to?
800-1600 mg/day for 1-2 weeks, then MD 200-400 mg/day
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If a patient has been on IV amiodarone for 1 to < 3 weeks, what is the oral dose they should be converted to?
600-800 md/day for 1-2 weeks, then MD 200-400 mg/day
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If a patient has been on IV amiodarone for > 3 weeks, what is the oral dose they should be converted to?
Start MD 200-400 mg/day
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What drugs will prolong QT interval if taken with amiodarone?
- azole antifungals
- macrolide antibiotics (erythromycin, clarithromycin)
- fluroquinolones
- haloperidol
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What drugs will delay AV node conduction if taken with amiodarone?
- non-dihydropyridine CCB
- beta-blockers
- digoxin
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Amiodarone may increase the levels of what drugs?
- digoxin (decrease dose by 50%)
- sildenafil
- cyclosporin
- tacrolimus
- theophylline
- warfarin (decrease dose by > 25%)
- atorvastatin
- simvastatin
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Amiodarone levels may be decreased by what drugs?
- phenytoin
- phenobarbital
- rifampin
- cholestyramine
- st. johns wort
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Amiodarone levels may be increased by what drugs?
- grapefruit juice (increase by 50%)
- protease inhibitors
- cimetidine
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What toxicity is associated with amiodarone use that is an extension of its MOA?
Arrythmias (sinus bradycardia, atrioventricular block, QT prolongation --> rarely Torsades de Pointes)
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What can occur if IV amiodarone is given too quickly or the concentration is too high?
- hypotension, bradycardia
- Phlebitis: concentrations > 2mg/nL should be administered via central line
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What are the proposed etiologies for amiodarone toxicity associated with chronic therapy?
What strength is this associated with?
- 1. long half-life due to accumulation of amiodarone and iodine
- 2. lipophilic distribution into adipose tissue of multiple organs
- 3. phospholipidosis (abnormal phospholipid storage)
- 4. free radical formation
Most common with doses > 400mg daily
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What is the MOA of pulmonary amiodarone toxicity (chronic therapy)?
abnormal phospholipid storage in lysosomal cells leading to membrane stiffness and cell damage
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Does pre-existing pulmonary disease have any effect on amiodarone toxicity?
it may worsen prognosis, but does not increase the risk
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What are the signs and symptoms of pulmonary amiodarone toxicity? How does it appear on chest x-ray?
- nonproductive cough
- dyspnea
- pleuritic chest pain
- weight loss
- malaise
- may also be asymptomatic
CXR = interstitial or alveolar infiltrates and/or extensive pulmonary fibrosis
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What hepatic toxicities are associated with amiodarone?
- transient elevations in LFT (15-30%)
- clinical hepatits and cirrhosis (<3%)
- s/sx: asymptomatic; typical signs of liver failure
- MOA: phopholipidosis & direct toxic effects
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What is the MOA of thyroid dysfunction due to amiodarone toxicity?
- structure and iodine content of amiodarone is structurally similar to endogenous thyroxine (T4)
- amiodarone blocks conversion of T4 to T3
- hypothyroidism (20%) hyperthyroidism (3%)
- independent of dose or duration of therapy
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What is the MOA of corneal microdeposits due to amiodarone toxicity?
- secretion of amiodarone by lacrimal glands and deposition on the surface of the cornea
- related to dose and duration of therapy
- may be asymptomatic or present with corneal cysts or abscesses
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What dermatologic conditions are associated with amiodarone toxicity and what is the MOA?
- photosensitivity (25-75%)
- blue-gray skin discoloration (dose-dependent)
MOA: photosensitive reaction resulting in lipofuscin deposits instead of melanin and pigment
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What type of symptoms are associated with amiodarone neurotoxicity?
- ataxia
- tremor
- peripheral neuropathy
- dose-related
- most common in elderly
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What baseline labs should be obtained for a patient beginning amiodarone therapy?
- EKG
- PFT (pulmonary)
- CXR (chest x-ray)
- LFT (liver function)
- TFT (thyroid function)
- Eye Examination
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What labs should be drawn at 6-months and annually?
- 6 months: LFT, TFT, Eye exam
- Annually: PFT (w/ symptoms only), CXR, EKG
- Also when clinical signs and symptoms warrant testing
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