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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
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
What kind of distribution does amiodarone have?
- Large Vd
- Highly lipophilic
- Widely distributes to the tissue
- Concentrates in tissue
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)
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
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
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
What is the primary route of amiodarone excretion/elimination?
- renal adjustments not necessary
What is the half-life of amiodarone?
- ~53 days (chronic oral dosing)
- 9-36 days (IV)
What factors alter clearance of amiodarone?
- cirrhosis (decreases formation of DEA, no change in amiodarone)
- elderly (decreased clearance)
Do renal failure, heart failure or dialysis have significan effects on clearance of amiodarone?
What is the onset of action ofamiodarone?
Oral: 1-3 weeks (minimum 2-3 days, max 3-6 weeks)
What is the duration of action of amiodarone after discontinuation?
What is the therapeutic range for amiodarone?
- 0.5 - 2 mg/L
- Peak concentration: 3-7 hours
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
How long is a patient on IV amiodarone before they can be switched directly to maintenance PO dose of amiodarone?
> 3 weeks
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
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
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
What drugs will prolong QT interval if taken with amiodarone?
- azole antifungals
- macrolide antibiotics (erythromycin, clarithromycin)
What drugs will delay AV node conduction if taken with amiodarone?
- non-dihydropyridine CCB
Amiodarone may increase the levels of what drugs?
- digoxin (decrease dose by 50%)
- warfarin (decrease dose by > 25%)
Amiodarone levels may be decreased by what drugs?
- st. johns wort
Amiodarone levels may be increased by what drugs?
- grapefruit juice (increase by 50%)
- protease inhibitors
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)
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
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 >
What is the MOA of pulmonary amiodarone toxicity (chronic therapy)?
abnormal phospholipid storage in lysosomal cells leading to membrane stiffness and cell damage
Does pre-existing pulmonary disease have any effect on amiodarone toxicity?
it may worsen prognosis, but does not increase the risk
What are the signs and symptoms of pulmonary amiodarone toxicity? How does it appear on chest x-ray?
- nonproductive cough
- pleuritic chest pain
- weight loss
- may also be asymptomatic
CXR = interstitial or alveolar infiltrates and/or extensive pulmonary fibrosis
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
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
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
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
What type of symptoms are associated with amiodarone neurotoxicity?
- peripheral neuropathy
- most common in elderly
What baseline labs should be obtained for a patient beginning amiodarone therapy?
- PFT (pulmonary)
- CXR (chest x-ray)
- LFT (liver function)
- TFT (thyroid function)
- Eye Examination
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