Amiodarone

بسم الله الرحمن الرحيم

Amiodarone Cordarone Class:Antiarrhythmic agent by the pharmacist Ayia nazum kamal

(100mg, 200mg, 300mg and 400mg) 50 mg / mL ( 3ml,6ml,9ml,18ml) Dosage forms available Tablet: Injection :

Class III agents block potassium channels and, thus, diminish the outward potassium current during repolarization of cardiac cells . These agents prolong the duration of the action potential without altering Phase 0 of depolarization or the resting membarane potential,instead they prolong the effective refractory period. Action of amiodarone contains iodine and is related structurally to thyroxine . It has complex effects, showing Class I, II, III, and IV actions . Its dominant effect is prolongation of the action potential duration and the refractory period . Amiodarone has antianginal as well as antiarrhythmic activity

During normal sinus rhythm (Panel A), myocardial activation is initiated in the sinus node, with a resulting coordinated wavefront of depolarization that spreads across both atria (arrows) to the atrioventricular node and specialized conduction system (green). Atrial fibrillation (Panel B) is triggered by atrial premature depolarizations arising in the region of the pulmonary veins (red asterisk) and propagates in an irregular and unsynchronized pattern (arrows). The resulting pattern of ventricularactivation is irregular (as shown on the electrocardiographic recording). Amiodarone (Panel C) has several electrophysiological effects.Chief among these in the control of atrial fibrillation is the effect on the potassium channel blockade, which slows repolarization, thus prolonging the action potential and the refractoriness of the myocardium. Waves of depolarization are more likely to encounter areas of myocardium that are unresponsive; thus, propagation is prevented. Although the prolongation of the action potential is most apparent on the electrocardiogram as an effect on the ventricular myocardium (prolonged QT interval), a similar effect occurs in the atria.

Amiodarone is used in the treatment of arrhythmias particularly when other drugs are ineffective or contra-indicated . * Amiodarone is used to suppress and treat cardiac arrhythmias, both ventricular and supraventricular. **Given intravenously it is effective in suppressing serious arrhythmias **Given over a long period of time by mouth, it effectively suppresses life-threatening ventricular arrhythmias, and also chronic atrial fibrillation. **Amiodarone is of particular value in patients who have severe arrhythmias due to accessory pathways (e.g. Wolff-Parkinson-White syndrome).

By mouth: 200 mg 3 times daily for 1 week reduced to 200 mg twice daily for a further week; maintenance , usually 200 mg daily or the minimum required to control the arrhythmia By intravenous infusion via central venous catheter, initially 5 mg/kg over 20–120 minutes with ECG monitoring; subsequent infusion given if necessary according to response up to max. 1.2 g in 24 hours Dose

Absorption Oral absorption is slow, variable and fair ( 20-55% ). Peak plasma concentrations after oral dosage occur after 3 to 7 hours Distribution The Vd is enormous, and variable ( about 5000 litres in a 70kg adult )! The drug is 96% protein bound . It accumulates in fat, skin, liver, lung, heart and muscle . A three - compartment model has been used to model its distribution : a small central compartment, a large deep compartment ( lymph nodes, liver, lung, fat ) and a peripheral compartment ( muscle and brain ). Amiodarone crosses the placenta , as does desethylamiodarone desethylamiodarone There is concern about potential fetal hypothyroidism

* Metabolism Metabolized by CYP3A4 to DEA ( active) * Elimination Eliminated primarily by hepatic excretion into bile ; some enterohepatic recirculation may occur negligible renal excretion. terminal t ½ is 26 to 107 days (mean, about 53 days) (oral) and 20 to 47 days ( IV). No dialyzable * Onset 2to 3 days but more commonly 1 to 3 wk * Special populations Elderly Cl is lower and t1/2 increased, monitor closely . Severe left ventricular dysfunction The t ½ of DEA is prolonged; monitor closely

* Cardiovascular effects include bradycardia , heart block and induction of ventricular arrhythmia …. * Other effects include nausea , vomiting , taste disturbance ….. * and the development of corneal microdiposits , which may rarely cause vasual haloes , night glare and photophobia;the latter are dose realated , resolve on discontinuation and do not threaten vison …. * Plasma transaminase level may rise ( required dose reduction or withdrawal if accompanied by acute liver disorder ) *Amiodarone cause both hypothyroidism (blocks conversion of T4 to T3,compensatory increase in TSH), hyperthyroidism (duo to iodine content of drug) …. are quite common. so (( liver-function and thyroid-function tests required before treatment and then every 6 months ))….. Adverse reactions

* Photosensevity reactions are common ,may be very sever and patients should be warned explicity when withdrawal drugs … * A blue-gray discoloration of exposed skin may occur during long-term treatment. Risk may be increased in patients with fair complexion or those with excessive sun exposure caused by iodine accumulation in skin (occasionally reversible on discontinuing of drug) …. * less commonly,pneumonitis and pulmonary fibrosis occur ( chest x-ray required before treatment ) ….. * and hepatitis,some times rapidly during short term use of drug; these may be fatal,so vigilance should be high …. * Cirrhosis is reported …… * peripheral neuropathy and myopathy occur ( usually reversible on withdrawal )

This is the face of a 69 year old man who was noted to have marked facial pigmentation when he was admitted to hospital with chest pain. He had been given amiodarone (200 mg daily) at another hospital 10 years earlier for atrial tachyarrhythmia. Amiodarone is described as causing blue-grey pigmentation in 2-26% of patients, particularly at higher doses. The discolouration recedes or disappears some 12-18 months after the drug is discontinued. One-off topical treatment with Q-switched ruby laser therapy may also produce resolution within a few weeks and is useful in patients who must continue taking the drug Case presentation

(except in cardiac arrest) * S inus bradycardia …. * S ino - atrial heart block; unless pacemaker fitted avoid in severe conduction disturbances or sinus node disease … * T hyroid dysfunction … * I odine sensitivity …. * A void intravenous use in severe respiratory failure , circulatory collapse ,or severe arterial hypotension * Avoid bolus injection in CHF or cardiomyopathy .. * Pregnancy (category D) * Breast-feeding (excreted in breast milk) ……..

* hypokalaemia ( measure serum-potassium concentration before treatment ) ….. * heart failure …. * elderly ….. * severe bradycardia and conduction disturbances in excessive dosage . * intravenous use may cause moderate and transient fall in blood pressure ( circulatory collapse precipitated by rapid administration or overdosage ) or severe hepatocellular toxicity ( monitor transaminases closely ) …… * ECG monitoring and resuscitation facilities must be available during intravenous use …. * acute porphyria …… Caution

*Anticoagulants (eg, warfarin ) PT increased by 100% after 3 to 4 days; reduce dose of anticoagulant by one third to one half. *Antihypertensives Use with caution with beta blockers or calcium channel blockers because of the possible potentiation of bradycardia, sinus arrest, and AV block. *Azole antifungals/fluoroquinolones/macrolides Reports of QTc prolongation with or without torsades de pointes may occur when used concomitantly with amiodarone. *Cardiac glycosides (eg, digoxin) Digoxin levels are increased and may result in toxicity. Reduce digoxin dose by approximately 50% or discontinue. *Cholestyramine Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t ½ . Drug Interactions

Lidocaine Lidocaine plasma concentrations may be elevated, increasing the risk of seizures. Fentanyl In combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output. Grapefruit juice Amiodarone plasma concentrations may be elevated, increasing the risk of side effects. Patients taking oral amiodarone should avoid grapefruit juice Protease inhibitors (eg, ritonavir) Amiodarone plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions. CYP3A4 inducers (eg, rifampin) Amiodarone and the metabolite, desethylamiodarone, plasma levels may be reduced, decreasing the pharmacologic effect. CYP3A4 inhibitors (eg, cimetidine, ritonavir) Amiodarone plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions.

HMG-CoA reductase inhibitors (eg, simvastatin) This illustration depicts a postulated mechanism for the amiodarone-simvastatin interaction, including the subsequent impact of this interaction on skeletal muscle and the kidney. In the first column, amiodarone inhibits the enzyme CYP3A4, limiting simvastatin metabolism (depicted by dashed arrow). By limiting the metabolism of simvastatin, there is an increase in levels of circulating simvastatin in the blood. In the second column, high circulating simvastatin levels may result in myotoxicity in the skeletal muscles (rhabdomyolysis). The rapid breakdown of muscle protein produces excessive levels of myoglobin in the blood. In the third column, myoglobin, now at high circulating levels, reaches the kidneys where it can obstruct renal tubules and lead to acute renal failure. *Amiodarone's direct inhibition of CYP3A4 has been characterized as weak, suggesting that other factors may also contribute to how these two drugs interact

Symptoms Bradycardia , hypotension , life-threatening cardiac arrhythmias … Management of Toxicity * Massive overdose - Symptomatic treatment. If recent ingestion, consider emesis or lavage; appropriate management of hypotension or bradycardia ….. * Withdraw the drug ….. * Because of the long half-life, toxicity may continue for months after drug withdrawal, but side effects often resolve over a period of months ( for example, corneal infiltrates, and even lung toxicity )….. * Gallium scanning has been used to assess and follow-up pulmonary toxicity. Steroids have been used for lung toxicity Overdosage

Amiodarone

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