Why ‘Amiodarone’ is a strange drug? Systematic (IUPAC) name (2-{4-[(2-butyl-1-benzofuran-3-yl)carbonyl]-2,6-diiodophenoxy}ethyl) diethylamine. Bioavailability    20 - 55% Metabolism          Liver Half-life                   58 days (range 15-142 days) Excretion               Primarily Hepatic and Biliary Formula                  C_25 H_29 I_2 NO_3 Mol. Mass             645,31 g/mol Cardiovascular risk during pregnancy Category A : Adequate studies - no risk of fetal abnormalities in any trimester Category B : Animal studies - no evidence of harm to the fetus, no adequate studies in pregnant women or Animal studies - adverse effect, adequate studies in pregnant women failed to demonstrate this risk. Category C : Animal studies - adverse effect no adequate studies in pregnant women or                       No adequate animal studies, no adequate studies in pregnant women. Category D : Adequate studies in pregnant women - risk to the fetus. However, the benefits of therapy may outweigh the potential risk. Category X: Adequate studies in animals or pregnant women - evidence of fetal abnormalities or risks. The use of the product is contraindicated in women who are or may become pregnant. History Developed in 1961 at the Labaz company, Belgium, by chemists Tondeur and Binon. It became popular in Europe as a treatment for angina pectoris. The Argentinian physician Dr. Mauricio Rosenbaum began using amiodarone to treat his patients who suffered from supraventricular and ventricular arrhythmias, with impressive results. Based on papers written by Dr. Rosenbaum developing Singh's theories, physicians in the US began prescribing amiodarone to their patients with potentially life-threatening arrhythmias in the late 1970s.   By 1980, amiodarone was commonly prescribed throughout Europe for the treatment of arrhythmias, but in the U.S. amiodarone remained unapproved by the FDA, and physicians were forced to directly obtain amiodarone from pharmaceutical companies in Canada and Europe. The FDA was reluctant to officially approve the use of amiodarone, since initial reports had shown increased incidence of serious pulmonary side-effects of the drug. In the mid 1980s, the European pharmaceutical companies began putting pressure on the FDA to approve amiodarone by threatening to cut the supply to American physicians if it were not approved. In December 1985, amiodarone was approved by the FDA for the treatment of arrhythmias. This makes amiodarone one of the few drugs approved by the FDA without rigorous randomized clinical trials. Why ‘amiodarone’ is a strange drug? 1) First, the drug takes weeks to achieve its maximum effectiveness. This is because amiodarone is stored in most of the tissues of the body, and to "load" the body with the drug, all the tissues need to be saturated. Therefore, needs to use very large doses for a week or two, then taper the dosage over the next month or so. It is not unusual to give patients 1200 or 1600 mg per day at first, and then maintain them on as little as 100 or 200 mg per day chronically. 2) Second, amiodarone leaves the body very, very slowly. It is not excreted (like most drugs) by the liver or the kidneys. It is lost when amiodarone-containing human cells are lost. Thus, if it is decided that one needs to stop amiodarone, the drug remains in the body in measurable quantities for months and months. The "half life" of the drug, in contrast to most other drugs, is measured in weeks instead of hours. 3) Third, because amiodarone is stored in many different kinds of tissues, it can produce side effects affecting many different organs.   Some of these side effects take months or years to develop, so it is never true that one can stop being vigilant. 4) Fourth, amiodarone works through many different mechanisms, unlike most drugs. It fits into two separate categories of antiarrhythmic drugs (Class I and Class III, previously being under unclassified); it acts as a beta blocker; it acts as a calcium blocker; it acts to dilate blood vessels; and it often acts to "block" the effect of thyroid horomone. Dosing Tab 100, 200, 400mg. It is also available in intravenous ampules and vials, typically in 150 mg. The dose of amiodarone administered is tailored to the individual and the dysarrhythmia that is being treated. When administered orally, better absorption when it is given with food. Amiodarone is fat-soluble, and tends to concentrate in tissues including fat, muscle, liver, lungs, and skin. Due to the long half-life of amiodarone, oral loading typically takes days to weeks. An oral loading dose is typically a total of 10 grams, divided over one to two weeks. Once an individual is loaded, a typical maintenance dose of amiodarone is 100 or 200 mg either once or twice daily. IV loading dose is typically 300 mg in 20-30 ml (D5W) for cardiac arrest. The loading infusion for dysrhythmias is typically 150 mg in a 100 ml bag of (D5W) given over 10 minutes . Both can be followed by a 360 mg infusion over 6 hours - a maintenance infusion of 540 mg over 18 hours. 360+540 = 900 mg (6 ampoules) in 500 ml G5W 500 - 900 ?       - 360       -   = 200 ml (200 ml must be given in 6 hours) 1 ml contains 15 drops so, 200 ml contain 3000 drops / 6 hours = 500 drops/hour,   /60 = 33.3 ml/hour (8.3 drops/min) for 6 hours, then The rest 300 ml contain 540 mg must be given in 18 hours 300 ml contain 4500 drops / 18 hours = 250 drops/hr    /60 = 16.6 ml/hour (4.1 drops/min) for 18 hours, till the end of the bag. Mechanism of action Amiodarone is categorized as a class III antiarrhythmic agent, and prolongs phase 3 of the cardiac action potential, the repolarization phase where there is normally decreased calcium permeability and increased potassium permeability. It has numerous other effects however, including actions that are similar to those of antiarrhythmic classes Ia, II, and IV. Amiodarone shows beta blocker-like and potassium channel blocker-like actions on the SA and AV nodes, increases the refractory period via sodium- and potassium-channel effects, and slows intra-cardiac conduction of the cardiac action potential, via sodium-channel effects. Amiodarone resembles thyroid hormone, and its binding to the nuclear thyroid receptor might contribute to some of its pharmacologic and toxic actions. Indications Because amiodarone has a low incidence of pro-arrhythmic effects (All the other antiarrhytmic agents being potent arrhythmogenics), it has been used both in the treatment of acute life-threatening arrhythmias as well as the chronic suppression of arrhythmias. It is useful both in supraventricular arrhythmias and ventricular arrhythmias. Ventricular fibrillation The treatment of choice for VF is electrical defibrillation. However, amiodarone can be useful in shock-refractory VF. In the ARREST trial, amiodarone was shown to improve survival to hospital admission (when compared to placebo) in individuals who suffer cardiac arrest with shock-refractory VF. It is on the basis of this study that the guidelines created by the AHA for the treatment of VF include amiodarone as a second line agent (after epinephrine or vasopressin). Ventricular tachycardia Amiodarone may be used in the treatment of ventricular tachycardia in certain instances. Individuals with hemodynamically unstable ventricular tachycardia should not initially receive amiodarone. These individuals should be cardioverted out of their unstable rhythm. Amiodarone can be used in individuals with hemodynamically stable ventricular tachycardia. In these cases, amiodarone can be used regardless of the individual's underlying heart function and the type of ventricular tachycardia; it can be used in individuals with monomorphic ventricular tachycardia, but is contraindicated in individuals with polymorphic ventricular tachycardia as it is associated with a prolong QT interval which will be made worse with anti-arrhythmic drugs. Atrial fibrillation In the ARCH trial, intravenous amiodarone (2 grams administered over 2 days) has been shown to reduce the incidence of atrial fibrillation after open heart surgery when compared to placebo. However, Clinical studies have failed to demonstrate long-term efficacy and have shown potentially fatal side effects. Amiodarone is not approved for AF by the FDA. So called 'acute onset atrial fibrillation', defined by the North American Society of Pacing and Electrophysiology (NASPE) in 2003, responds well to short duration treatment with amiodarone. This has been demonstrated in seventeen randomised controlled trials, of which five included a placebo arm. The incidence of severe side effects in this group is low. The benefit of amiodarone in the treatment of atrial fibrillation in the critical care population has yet to be determined but it may prove to be the agent of choice where the patient is haemodynamically unstable and unsuitable for DC cardioversion. It is recommended in such a role by the UK government's National Institute for Health and Clinical Excellence (NICE). Contraindications Individuals who are pregnant or may become pregnant are strongly advised to not take amiodarone. Since amiodarone can be expressed in breast milk, women taking amiodarone are advised to stop nursing. It is contraindicated in individuals with sinus bradycardia, AV block, and 2nd or 3rd degree HB who do not have an artificial pacemaker. Individuals with baseline depressed lung function should be monitored closely if amiodarone therapy is to be initiated. The injection should not be given to neonates, because the benzyl alcohol it contains may cause the fatal "gasping syndrome". Amiodarone can worsen the cardiac arrhythmia brought on by Digitalis toxicity. Not to be given with Lidocaine → increases risk of asystole Amiodarone is extensively metabolized in the liver by cytochrome P450 3A4, and can affect the metabolism of numerous other drugs. It interacts with digoxin, warfarin, phenytoin and others. The major metabolite of amiodarone is des-ethyl-amiodarone (DEA), which also has antiarrhythmic properties. The metabolism of amiodarone is inhibited by grapefruit juice, leading to elevated serum levels of amiodarone. On August 8, 2008 FDA issued a warning of the risk of rhabdomyolysis, which can lead to kidney failure or death, when simvastatin is used with amiodarone. This interaction is dose-dependent with simvastatin doses exceeding 20 mg. This drug combination especially with higher doses of simvastatin should be avoided. Interactions with other drugs Decreases digoxin excretion & potentiates the action of warfarin.   So, doses of digoxin & warfarin   should be halved in individuals taking amiodarone. Amiodarone inhibits the action of the cytochrome P450 isozyme family. This reduces the clearance of many drugs, including the following: Cyclosporine, Digoxin, Flecainide, Procainamide, Quinidine, Sildenafil, Simvastatin, Theophylline, & Warfarin. + QT & proarrhythmia with (Fluoroquinolones) - HR & AV conduction with (BB – CCB) Excretion Excretion is primarily hepatic and biliary with almost no elimination via the renal route and it is not dialyzable. Elimination half-life average of 58 days (ranging from 25–100 days for amiodarone and 36 days for the active metabolite, des-ethyl-amiodarone (DEA). There is 10-50% transfer of amiodarone and DEA in the placenta as well as presence in breast milk. Accumulation of amiodarone and DEA occurs in adipose tissue and highly perfused organs (i.e. liver, lungs), therefore, if an individual was taking amiodarone on a chronic basis, if it is stopped it will remain in the system for weeks to months. Side effects Amiodarone has numerous side effects. Most individuals administered amiodarone on a chronic basis will experience at least one side effect. Lung (pneumonitis – pulmonary fibrosis) - This can occur in 5% of patients who receive amiodarone. It is fatal in 5% of cases. A chest X-ray demonstrating pulmonary fibrosis secondary to amiodarone. The most serious reaction that is due to amiodarone is interstitial lung disease. Risk factors include high cumulative dose, more than 400 milligrams per day, duration over two months, older age, and preexisting pulmonary disease. Some individuals were noted to develop pulmonary fibrosis after a week of treatment, while others did not develop it after years of continuous use. Common practice is to avoid the agent if possible in individuals with decreased lung function. The most specific test of pulmonary toxicity due to amiodarone is a dramatically decreased DLCO noted on pulmonary function testing. Thyroid (hypo-hyperthyroidism) - Thyroxine and amiodarone have similar structures. Due to the iodine content of the agent (37.3% by weight), abnormalities in thyroid function are common. Amiodarone is structurally similar to thyroxine, which contributes to the effects of amiodarone on thyroid function. Both under- and overactivity of the thyroid may occur on amiodarone treatment. Measurement of free thyroxine (FT4) alone may be unreliable in detecting these problems and thyroid-stimulating hormone (TSH) should therefore also be checked every 6 months. Hypothyroidism (Wolff-Chaikoff effect) occurs frequently; in the SAFE trial, which compared amiodarone with other medications for the treatment of AF, biochemical hypothyroidism occurred in 25.8% of the amiodarone-treated group as opposed to 6.6% of the control group (taking placebo or sotalol). Overt hypothyroidism occurred at 5.0% compared to 0.3%; most of these ( />90%) were detected within the first six months of amiodarone treatment. Hyperthyroidism (Jod-Basedow Effect) can also occur. However, in the SAFE trial, the increased rate of hyperthyroidism (5.3% compared to 2.4%) was not statistically significant. Most hyperthyroid patients were asymptomatic.                                                                  Eye (optic neuritis-corneal deposits) Corneal micro-deposits (Corneal verticillata-or- Vortex keratopathy) are almost universally present (over 90%) in individuals taking amiodarone for at least 6 months. These deposits typically do not cause any symptoms. About 1 of 10 individuals may complain of a bluish halo. Optic neuropathy occurs in 1-2% of people and is not dosage dependent. Bilateral optic disk swelling and mild and reversible visual field defects can also occur. Amiodarone: Keratopathy - whorl-like opacities in the corneal epithelium. They appear in nearly 100% of patients treated for more than six months with amiodarone. Gastrointestinal system and liver Abnormal liver enzyme results are common in patients on amiodarone. Much rarer are jaundice, hepatomegaly (liver enlargement), and hepatitis. Low-dose amiodarone has been reported to cause pseudo-alcoholic cirrhosis. Constipation. Skin Long-term administration of amiodarone is associated with a blue-grey discoloration of the skin. This is more commonly seen in individuals with lighter skin tones. The discoloration may revert upon cessation of the drug. However, the skin color may not return completely to normal. Individuals taking amiodarone may become more sensitive to the harmful effects of UV-A light. Using sunblock that also blocks UV-A rays appears to prevent this side effect. Amiodarone induced skin necrosis - A 61-year-old man was admitted with an acute inferior NSTEMI. On day 3, he was noted to be pulseless and in ventricular fibrillation. He was electrically defibrillated to sinus rhythm and administered a 300 mg bolus of IV amiodarone. Cardiovascular Pro-arrhythmia - CHF exacerbation – HB – Bradycardia – Hypotension. Thrombophlebitis of peripheral vein is a well- recognised complication of intravenous amiodarone use in high doses (300–1200 mg) or prolonged infusion. Even smaller doses of amiodarone can cause significant thrombophlebitis. Neurological Long-term administration of amiodarone has been associated with peripheral neuropathies. Parasthesia, Tremor, Ataxia, & Headache. Gynecomastia Some cases of gynecomastia have been reported with men on amiodarone. Epididymis Amiodarone is sometimes responsible for epididymitis,   a non-bacterial inflammatory condition. Amiodarone accumulates in the head of the organ and can cause unilateral or bilateral inflammation. It tends to resolve if amiodarone is stopped.                                   
Posted by Dr. K. Ashutosh