Amiodarone Toxicity

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Slide 1 :

The Tale of Three Cases Mark Wiley University of Kansas

Slide 2 :

Atrial Fibrillation – Case I 76y/o WM with a known h/o coronary disease as well as recurrent atrial arrhythmias. The patient additionally has a history of moderate aortic stenosis. His rhythm is complicated by hypotension and congestive symptoms Emergent cardioversion results in NSR although hypotensive and requiring pressors and subsequently back to afib with RVR Repeat echocardiogram suggests severe aortic stenosis with a valve area of 0.9 Amiodarone was initiated on 1/27 to try to maintain sinus rhythm Thyroid studies subsequently revealed a free T4 of 5.1 (0.6-1.7) and suppressed TSH, total T3 was 153 (87-180) on 2/6

Slide 3 :

Torsade de Pointes –Case II 52y/o HF presents with atrial fibrillation and a rapid ventricular response rate as well as abdominal pain. She is admitted to initiate IV amiodarone. She converts to NSR with a bradycardic rate and the amiodarone is held She later develops sepsis secondary to ascending cholangitis and requires pressors. With the increased adrenergic tone she converts to atrial fibrillation and her ventricular response rate is in the 150’s. Amiodarone is restarted and about 5hours later she develops torsade de points in very frequent episodes associated with a long QT. Her potassium was noted to be 2.8 and magnesium 1.8

Slide 4 :

Optic Neuropathy – Case III 58y/o WM presents with atrial fibrillation with RVR and initiated on amiodarone. Subsequently develops bilateral eye pain and some blurred vision. Opthamology evaluates and determines him to have optic disc edema as well as corneal microdeposits.

Slide 5 :

Commonality? Medical complications associated with the use of amiodarone.

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Amiodarone Basics Pharmacoloy Amiodarone is considered to be predominantly a class III antiarrhythmic agent The principal effect on cardiac tissue is to delay repolarization by prolonging the action potential duration and effective refractory period. This affects all cardiac fibers and does not affect the resting membrane potential. Pharmacokinetics bioavailability of commercially available amiodarone is approximately 50%, but varies considerably, ranging from 22–86% Following oral administration, peak plasma amiodarone concentrations usually occur within 3–7 hours steady-state plasma amiodarone concentrations are not attained for at least 1 month and generally not for up to 5 months or longer Elimination is by hepatic excretion into the bile.

Slide 7 :

Amiodarone Basics Plasma concentrations of amiodarone appear to decline in a biphasic manner initial elimination half-life of about 2.5–10 days, which is followed by a terminal elimination half-life averaging 53 days

Slide 8 :

Case 1 - Amiodarone-Induced Thyrotoxicosis Occurs in 3% of US patients. Occurs in 10-20% of those living in iodine deficient countries. 50% of patients have “innocent” changes in thyroid hormone levels Type 1 – patients with underlying thyroid disorders Type 2 – patients with a previously normal thryoid

Slide 9 :

Amiodarone – a breakdown… 37% of amiodarone’s mass is organic iodine. (that is 444mg with a loading dose of amiodarone – 400mg PO TID) Of this amount 10% is free iodide (that is 44mg of free iodide daily) In the United States the recommended daily allowance (RDA) is infants 0-6 months is 110 mcg 1-8 years old, 90 mcg 9-13 years, 120 mcg 14 and older, 150 mcg The Food and Nutrition Board also sets the tolerable upper limits of the daily iodine intake as 1.1 mg (1100 mcg) for adults, with proportionately lower levels for younger age groups.

Slide 10 :

Amiodarone-Induced Thyrotoxicosis Amiodarone Inhibits 5’-deiodinase –decreasing conversion of T4 to T3 Decreases clearance of T4 and rT3 Can cause direct destructive effects on the thyroid gland

Slide 11 :

Effects on Thyroid Testing Clinically Euthyriod patients Slightly elevated FT4 Normal to low Total T3 Elevated reverse T3 Can be used to evaluate effectiveness of amiodarone Transient changes in TSH (increase or decrease) Innocent changes in thyroid testing occur in about 50% of patients Only need to monitor TSH

Slide 12 :

Amiodarone-Induced Thyrotoxicosis Type I – patients with latent thyroid disorders Caused by excessive, uncontrolled synthesis of thyroid hormone by autonomously functioning tissue in response to iodine. Type II – patients with previously normal thyroid glands Direct cytotoxic effect on thryoid follicles resulting in a destructive inflammatory thyroiditis

Slide 13 :

Diagnosis of Thyrotoxicosis Laboratory analysis Elevated Total and Free T4 Elevated Total and Free T3 Low TSH Color Flow Doppler Sonography for assisting diagnosis Pattern 0 – absent vascularity, gland destruction Pattern 1 – Uneven patchy parenchyma Pattern 2 – Diffuse, homogenous increased flow Pattern 3 – Markedly increased signal and diffuse homogenous distribution

Slide 14 :

Diagnosis of Thyrotoxicosis Clinical Findings Sinus Tachycardia Atrial Fibrillation Ventricular Tachycardia Heart Failure Cardiac manifestations may be limited given intrinsic inhibitory effects on the heart of amiodarone.

Slide 15 :

Discerning Type I vs. II Type I Antimicrosomal Ab Antithyroglobulin Ab Anti-receptor Ab Normal to slightly elevated IL-6 Color Flow Doppler reveals pattern 1, pattern 2 or pattern 3 Type II Elevated Thyroglobulin Elevated IL-6 Color flow Doppler reveals Pattern 0 (absent vascularity, gland destruction)

Slide 16 :

Medical Treatment Type I Treat with a thionamide – since it is associated with increased hormone synthesis (PTU or methimazole 30mg per day) Can use potassium perchlorate (200mg -1000mg per day) Type II Glucocorticoids are used for anti-inflammatory and membrane stabalizing properties (prednisone 30-40mg/day)

Slide 17 :

Pitfalls to Treatment Discontinue Amiodarone? Can lead to the loss of the inhibitory effect on 5’-monodeiodinase (inhibits conversion of tissue and pituitary T4 to T3) leading to a paradoxical worsening. Corticosteroids? Inhibits 5’-monodeiodinase and can worsen T4 thyrotoxicosis Potassium Perchlorate? Causes nephrotoxicity and bone marrow suppression Several reported cases of aplastic anemia.

Slide 18 :

Surgical Treatment Thyroidectomy – who should be considered? Severe cases that fail to respond Sick patients who need to continue with amiodarone Can be performed under local anesthetic for critically ill and can simplify care. Franzese C, Fan C, Stack B. Surgical Management of Amiodarone-Induced Thyrotoxicosis. Otolaryngology-Head and Neck Surgery 2003, Nov:565-570

Slide 19 :

Case 2 – Torsade de Pointes Occurs in 1% of patients taking Amiodarone Prolongs myocardial repolarization – particularly with predisposing conditions LVH Bradycardia Hypokalemia Hypomagnesemia

Slide 20 :

Ventricular Action Potential Ventricular Muscle Cell Action Potential

Slide 21 :

Patient Who Was Treated with Amiodarone for Atrial Fibrillation

Slide 22 :

Treatment Remove offending agent Temporary ventricular or atrial pacing Isoproterenol Increases rate and decreases QT interval Lidocaine Mexiletine Phenytoin Magnesium

Slide 23 :

Case 3 – Optic Neuropathy Ocular side effects Corneal microdeposits – 70-100% of patients Dry Eye Syndrome Anterior Lens opacities Optic Neuropathy – 1-2% of patients Results in optic disc swelling Associated with visual field defecit Can result in permanent visual loss

Slide 24 :

Optic Neuropathy Diagnosis Mild visual impairment Typically made as a diagnosis of exclusion Usually has bilateral optic disc swelling Insidious Onset Generally resolution of optic disc swelling with discontinuation of amiodarone

Slide 25 :

Ocular Side Effects Common Symptoms Colored rings around lights Blurred vision Glare Dryness of eyes Irritation of eyelid Findings Associated Corneal epithelial deposits Anterior lens opacity Retinopathy Keratitis sicca

Slide 26 :

Amiodarone Side Effect Profile Serious Side Effects Pulmonary 2-17% Hyperthyroid 2% Hypothyroid 6% Liver toxicity 1% Optic Neuropathy 1.8% Proarrhythmia <1% Minor Side Effects Nausea 30% Corneal Deposits >90% Photosensitivity 4-9% Blue Skin <9%

Slide 27 :

Guidelines for Monitoring Baseline Assessment Chest Radiograph Thyroid studies and liver transaminases Dig level, PT/INR when appropriate Pulmonary Function Studies, including DLco Ophthalmologic exam, if preexisting visual impairment

Slide 28 :

Guidelines for Monitoring Ongoing Surveillance Every 6months Thyroid studies and liver transaminases When clinical suspicion indicates Chest Radiograph with PFT’s/DLco Eye examination

Slide 29 :

Drug Interactions of Note Inhibits metabolism through cytochrome P450 CYP2CP –inhibits metabolization of warfarin CYP2D6 – inhibits metabolization of narcotics and several B-blockers CYP 3A4 - inhibits metabolization of sandimmune and calcium channel blockers Effects digoxin predictably – doubles dig level typically during coadministration Should reduce dig dose by 50% Avoid Grapefruit juice – can inhibit conversion of amiodarone to active metabolite (DEA)

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