Amiodarone
Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia, ventricular fibrillation, and wide complex tachycardia, atrial fibrillation, and paroxysmal supraventricular tachycardia. Evidence of benefit for cardiac arrest is poor. It can be given by mouth, intravenously, or intraosseously. When used by mouth, it can take a few weeks for effects to begin.
Amiodarone has been used both in the treatment of acute life-threatening arrhythmias as well as the long-term suppression of arrhythmias. Amiodarone is commonly used to treat different types of abnormal heart rhythms, such as atrial arrhythmias (supraventricular arrhythmias) and ventricular arrhythmias. Atrial arrhythmias and supraventricular arrhythmias are terms often used interchangeably to refer to abnormal heart rhythms originating from the upper chambers of the heart, known as the atria. These types of arrhythmias include conditions such as atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia. They are collectively referred to as supraventricular or atrial arrhythmias because they occur above (supra) the ventricles in the electrical conduction system of the heart. Ventricular arrhythmias are abnormal heart rhythms that originate in the ventricles, which are the lower chambers of the heart. These arrhythmias can be potentially life-threatening and may disrupt the heart's ability to pump blood effectively.
Cardiac arrest
Defibrillation is the treatment of choice for ventricular fibrillation and pulseless ventricular tachycardia resulting in cardiac arrest. Current evidence does not show a clear benefit of amiodarone on survival or neurological outcomes in cardiac arrest, and its effectiveness remains uncertain due to limitations in the available data. Although amiodarone does not appear to improve survival in those who had a cardiac arrest in-hospital, some studies suggested that early administration of amiodarone was associated with better survival and positive outcomes for people who had a cardiac arrest out-of-hospital.
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. 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 prolonged QT interval which will be made worse with anti-arrhythmic drugs.
Atrial fibrillation
Individuals who have undergone open heart surgery are at an increased risk of developing atrial fibrillation (or AF) in the first few days post-procedure. In the ARCH trial, intravenous amiodarone (2 g administered over 2 d) 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 such as pulmonary toxicities. While amiodarone is not approved for AF by the US Food and Drug Administration (FDA), it is a commonly prescribed off-label treatment due to the lack of equally effective treatment alternatives.
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Women who are pregnant or may become pregnant are strongly advised not to take amiodarone. Since amiodarone can be expressed in breast milk, women taking the drug are advised to stop nursing. It is contraindicated in individuals with sinus nodal bradycardia, atrioventricular block, and second or third-degree heart block who do not have an artificial pacemaker. Individuals with baseline depressed lung function should be monitored closely if amiodarone therapy is to be initiated. Formulations of amiodarone that contain benzyl alcohol should not be given to neonates, because the benzyl alcohol may cause the potentially fatal "gasping syndrome". Amiodarone can worsen the cardiac arrhythmia brought on by digitalis toxicity. Contraindications of amiodarone also include: There are no specific guidelines for endurance or high-intensity exercise while taking amiodarone. However, since amiodarone may cause bradycardia and QTc prolongation which can affect exercise capacity and increase the risk of arrhythmias during intense exercise, it would generally be advisable for patients taking this medication to consult their healthcare provider before engaging in high-intensity physical activities such as strenuous endurance exercises.
Amiodarone is a medication that takes time to build up in the body before it starts working properly. For this reason, patients are usually started on a higher and more frequent dosage for a short period (eg 1 to 2 weeks), followed by a lower daily maintenance dose. Adverse effects may not manifest until the maintenance stage is reached. At a lower daily dose (<400mg daily), especially with long-term use. Amiodarone may have adverse effect include thyroid problems, vision changes, nerve-related symptoms (such as tingling or unsteadiness), skin reactions, and a slow heart rate.Higher daily dose (>400mg daily) and longer duration of use is associated with more pulmonary toxicity. The overall exposure to amiodarone over time is an important factor in adverse effects. Therefore, regular blood tests and ongoing check-ups with a GP or Cardiologist are important to monitor for side effects while taking amiodarone.
Lung
Side effects of oral amiodarone at doses of 400 mg or higher include various pulmonary effects. The most serious reaction is interstitial lung disease. Risk factors include high cumulative dose, more than 400 milligrams per day, duration over two months, increased 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
Induced abnormalities in thyroid function are common. In approximately 15-20% of patients, amiodarone treatment results in thyroid dysfunction, either amiodarone-induced hypothyroidism or amiodarone-induced thyrotoxicosis. Both under- and overactivity of the thyroid may occur. Amiodarone is structurally similar to thyroxine and also contains iodine. Both of these factors contribute to the effects of amiodarone on thyroid function. Amiodarone also causes an anti-thyroid action, via Plummer and Wolff–Chaikoff effects, due its large amount of iodine in its molecule, which causes a particular "cardiac hypothyroidism" with bradycardia and arrhythmia.
Eye
Corneal micro-deposits (cornea verticillata, also called vortex or whorl keratopathy) are almost universally present (over 90%) in individuals taking amiodarone longer than 6 months, especially doses greater than 400 mg/day. These deposits typically do not cause any symptoms. About 1 in 10 individuals may complain of a bluish halo. Anterior subcapsular lens deposits are relatively common (50%) in higher doses (greater than 600 mg/day) after 6 months of treatment. Optic neuropathy, nonarteritic anterior ischemic optic neuropathy (N-AION), occurs in 1–2% of people and is not dosage dependent. Bilateral optic disc swelling and mild and reversible visual field defects can also occur.
Liver
Abnormal liver enzyme results are common in people taking amiodarone. Much rarer are jaundice, hepatomegaly (liver enlargement), and hepatitis (inflammation of the liver). In clinical observations, it has been noted that the administration of amiodarone, even at lower therapeutic doses, has been associated with the development of a condition mimicking alcoholic cirrhosis. This condition, often referred to as pseudo-alcoholic cirrhosis, presents with similar histopathological features to those observed in patients with alcoholic cirrhosis. However, this extreme adverse event manifestation—pseudo-alcoholic cirrhosis caused by low dose amiodarone—is very rare.
Skin
Long-term administration of amiodarone (usually more than eighteen months) is associated with a light-sensitive blue-grey discoloration of the skin, sometimes called ceruloderma; such patients should avoid exposure to the sun and use sunscreen that protects against ultraviolet-A and -B. The discoloration will slowly improve upon cessation of the medication, however, the skin color may not return completely.
Pregnancy and breastfeeding
Use during pregnancy may result in a number of problems in the infant including thyroid problems, heart problems, neurological problems, and preterm birth. Use during breastfeeding is generally not recommended though one dose may be okay.
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The pharmacokinetics of numerous drugs, including many that are commonly administered to individuals with heart disease, are affected by amiodarone. Amiodarone has particularly important interactions with the following drugs: Amiodarone inhibits the action of the cytochrome P450 isozyme family; such inhibition reduces the clearance of many drugs, including the following: In 2015, Gilead Sciences warned healthcare providers about people who began taking the hepatitis C drugs ledipasvir/sofosbuvir or sofosbuvir along with amiodarone, who developed abnormally slow heartbeats or died of cardiac arrest.
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Amiodarone is extensively metabolized in the liver by CYP3A4, a member of the cytochrome P450 superfamily of enzymes, therefore, amiodarone and can affect the metabolism of numerous other drugs that depend on cytochrome P450, such as digoxin, phenytoin, warfarin, etc. The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties. The metabolism of amiodarone is inhibited by grapefruit, leading to elevated serum levels of amiodarone. On 8 August 2008, the US Food and Drug Administration (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. Amiodarone is extensively metabolized in the liver. The primary metabolic pathway of amiodarone is by cytochrome P450 (CYP) enzymes, particularly CYP3A4 and CYP2C8. The metabolism of amiodaron can be characterized by two phases:
Excretion
Excretion is primarily via the liver and the bile duct with almost no elimination via the kidney and it is not dialyzable. Elimination half-life average of 58 days (ranging from 25 to 100 days [Remington: The Science and Practice of Pharmacy 21st edition]) for amiodarone and 36 days for the active metabolite, desethylamiodarone (DEA). There is 10-50% transfer of amiodarone and DEA in the placenta as well as a 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.
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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.[medical citation needed] Amiodarone is a blocker of voltage gated potassium (KCNH2) and voltage gated calcium channels (CACNA2D2). Amiodarone slows the conduction rate and prolongs the refractory period of the SA and AV nodes. It also prolongs the refractory periods of the ventricles, bundles of His, and the Purkinje fibers without exhibiting any effects on the conduction rate. Amiodarone has been shown to prolong the myocardial cell action potential duration and refractory period and is a non-competitive β-adrenergic inhibitor. It also shows beta blocker-like and calcium 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. It is suggested that amiodarone may also exacerbate the phenotype associated with Long QT-3 syndrome causing mutations such as ∆KPQ. This effect is due to a combination of blocking the peak sodium current, but also contributing to an increased persistent sodium current.
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The original observation that amiodarone's progenitor molecule, khellin, had cardioactive properties, was made by the Russian physiologist Gleb von Anrep while working in Cairo in 1946. Khellin is obtained from a plant extract of Khella or Ammi visnaga, a common plant in north Africa. Anrep noticed that one of his technicians had been cured of anginal symptoms after taking khellin, then used for various, non-cardiac ailments. This led to efforts by European pharmaceutical industries to isolate an active compound.[citation needed] Amiodarone was initially developed in 1961 at the Labaz company, Belgium, by chemists Tondeur and Binon, who were working on preparations derived from khellin. It became popular in Europe as a treatment for angina pectoris. As a doctoral candidate at Oxford University, Bramah Singh determined that amiodarone and sotalol had antiarrhythmic properties and belonged to a new class of antiarrhythmic agents (what would become the class III antiarrhythmic agents). Today the mechanisms of action of amiodarone and sotalol have been investigated in more detail.[citation needed] Both drugs have been demonstrated to prolong the duration of the action potential, prolonging the refractory period, by interacting among other cellular functions with K+ channels.[citation needed]
Name
Amiodarone may be an acronym for its IUPAC name (2-butyl-1-benzofuran-3-yl)-[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone, where ar is a placeholder for phenyl. This is partially supported by dronedarone which is noniodinated benzofuran derivative of amiodarone, where the arylmethanone is conserved.
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Amiodarone is available in oral and intravenous formulations. Orally, it is available under the brand names Pacerone (produced by Upsher-Smith Laboratories, Inc.) and Cordarone (produced by Wyeth-Ayerst Laboratories). It is also available under the brand name Aratac (produced by Alphapharm Pty Ltd) in Australia and New Zealand, and in Australia alone under the brand names Cardinorm and Rithmik, as well as a number of generic brands. It is also produced by Winthrop Pharmaceuticals in South Africa under the brand name Arycor. In South America, it is known as Atlansil and is produced by Roemmers. In India, amiodarone is marketed (produced by Cipla Pharmaceutical) under the brand name Tachyra. It is also available in intravenous ampules and vials. The dose of amiodarone administered is tailored to the individual and the dysrhythmia that is being treated. When administered orally, the bioavailability of amiodarone is quite variable. Absorption ranges from 22 to 95%, with better absorption when it is given with food.
