Amiodarone - WikiHQ

Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. It can be given by mouth, intravenously, or intraosseously.

Common side effects include feeling tired, tremor, nausea, and constipation. such as interstitial pneumonitis, liver problems, heart arrhythmias, vision problems, thyroid problems, and death. It was pulled from the market in 1967 due to side effects. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.

Medical uses

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.

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. A 2017 randomised study suggests that procainamide may be more effective than amiodarone in terminating ventricular tachycardia and may be associated with fewer short-term adverse effects. However, there is no strong evidence of improved survival, and data in patients requiring multiple shocks are limited, with amiodarone remaining the preferred treatment in this setting.

While early trial data showed that amiodarone plus beta-blockers significantly reduces ICD shocks, recent evidence suggests this combination lacks a consistent survival advantage and may not be more effective than beta-blocker monotherapy in general practice.

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.

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 randomized controlled trials, of which five included a placebo arm. The incidence of severe side effects in this group is low.

Amiodarone is an effective, antiarrhythmic-of-choice in achieving cardioversion to sinus rhythm in critical care populations with new onset atrial fibrillation (NOAF). However, other anti-arrhythmic agents may exert superior rhythm control, rate control and lower mortality rate which may be more favourable than amiodarone in specific cases.

Contraindications

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:

hypersensitivity to amiodarone or any of its components;

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.

Allergic reactions to amiodarone may occur. Most individuals administered amiodarone on a chronic basis will experience at least one side effect.

thyroid dysfunction (in approximately 15-20% of patients, amiodarone treatment results in thyroid dysfunction, either amiodarone-induced hypothyroidism or amiodarone-induced thyrotoxicosis; the drug can lead to both hypo- and hyperthyroidism); (lung problems such as pulmonary fibrosis or interstitial lung disease may occur rarely but have the potential for serious consequences if left untreated);

Lung

thumb|upright=1.3|A chest X-ray demonstrating [[pulmonary fibrosis due to amiodarone.]]

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. 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.

Thyroid function should be checked at least every six months.

Hypothyroidism (slowing of the thyroid) occurs frequently; in the SAFE trial, which compared amiodarone with other medications for the treatment of atrial fibrillation, biochemical hypothyroidism (as defined by a TSH level of 4.5–10 mU/L) occurred in 25.8% of the amiodarone-treated group as opposed to 6.6% of the control group (taking placebo or sotalol). Overt hypothyroidism (defined as TSH >10 mU/L) occurred at 5.0% compared to 0.3%; most of these (>90%) were detected within the first six months of amiodarone treatment.
Amiodarone induced thyrotoxicosis (AIT), can be caused due to the high iodine content in the drug via the Jod-Basedow effect. This is known as Type 1 AIT, and usually occurs in patients with an underlying predisposition to hyperthyroidism such as Graves' disease, within weeks to months after starting amiodarone. Type 1 AIT is usually treated with anti-thyroid drugs or thyroidectomy. Type 2 AIT is caused by a destructive thyroiditis due to a direct toxic effect of amiodarone on thyroid follicular epithelial cells. In practice, often the type of AIT is undetermined or presumed as mixed with both treatments combined. 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.

Loss of eyelashes has been linked to amiodarone use.

Liver

Abnormal liver enzyme results are common in people taking amiodarone.

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.

Amiodarone is sometimes responsible for epididymitis. Amiodarone accumulates in the head of the organ and can cause unilateral or bilateral inflammation. It tends to resolve if amiodarone is stopped.

Some cases of gynecomastia have been reported in men on amiodarone.

A retrospective cohort study found an increased risk of digestive, liver, head and neck and liver cancers amongst male patients exposed to amiodarone versus female participants in the same study and the general population. This study also identified that the Standardized Incidence Ratio of cancer occurrence increased significantly in males aged 20-59 and >80 years old who were exposed to a higher dose of Amiodarone in comparison to those exposed to a lower dose. This suggests that there is a dose-effect relationship.

Amiodarone has particularly important interactions with the following drugs:

class I antiarrhythmics (amiodarone should not be combined with other class I antiarrhythmic drugs, such as disopyramide, flecainide, procainamide, quinidine, etc., due to an increased risk of QTc prolongation and potential arrhythmias); Amiodarone potentiates the action of warfarin by inhibiting the clearance of both (S) and (R) warfarin. Individuals taking both of these medications should have their warfarin doses adjusted based on their dosing of amiodarone and have their anticoagulation status (measured as prothrombin time (PT) and international normalized ratio (INR)) measured more frequently. Dose reduction of warfarin is as follows: 40% reduction if the amiodarone dose is daily, 35% reduction if the amiodarone dose is daily, 30% reduction if the amiodarone dose is daily, and 25% reduction if amiodarone dose is daily.
anti-HIV medications (several HIV medications, such as ritonavir, indinavir, etc., interact with amiodarone by inhibiting CYP3A4 enzyme hence leading to decreased clearance of amiodarone, i.e., increasing the concentration of amiodarone in the organism).
rivaroxaban, an anticoagulant, develops significant increases in its blood levels in patients who are also treated with amiodarone; this may lead to serious but not life-threatening bleeding.

Amiodarone inhibits the action of the cytochrome P450 isozyme family; such inhibition reduces the clearance of many drugs, including the following:

ciclosporin,

Metabolism

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.

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:

phase I metabolism, when amiodarone undergoes oxidative processes mainly mediated by CYP3A4 and to a lesser extent by CYP2C8; these reactions result in the formation of several active metabolites, including desethylamiodarone (DEA) and di-desethylamiodarone (DDEA); DEA is the most abundant metabolite and exhibits similar pharmacological effects as amiodarone;
phase II metabolism, when both amiodarone and its major metabolite DEA can undergo conjugation reactions with glucuronic acid; this process increases water solubility of these compounds for their efficient elimination from the body.

Amiodarone has an exceptionally long half-life due to a combination of several factors:

Excretion

Excretion is primarily via the liver and the bile duct with almost no elimination via the kidney and it is not dialyzable.

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.

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.

Amiodarone chemically resembles thyroxine (thyroid hormone), and its binding to the nuclear thyroid receptor might contribute to some of its pharmacologic and toxic actions.

The mechanisms of action of amiodarone include blocking potassium ion channels (prolonging repolarization), blocking sodium ion channels, and antagonizing alpha- and beta-adrenergic receptors. 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. 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. 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.

Based on Singh's work, the Argentinian physician Mauricio Rosenbaum began using amiodarone to treat his patients who have supraventricular and ventricular arrhythmias, with impressive results. Based on papers written by Rosenbaum developing Singh's theories, physicians in the United States began prescribing amiodarone to their patients with potentially life-threatening arrhythmias in the late 1970s.

The US Food and Drug Administration (FDA) was reluctant to officially approve the use of amiodarone since initial reports had shown an 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 was not approved. In December 1985, amiodarone was approved by the FDA for the treatment of arrhythmias.

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.

Dosing

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).