Common side effects include feeling tired, tremor, nausea, and constipation.[4] As amiodarone can have serious side effects, it is mainly recommended only for significant ventricular arrhythmias.[4] Serious side effects include lung toxicity[7] such as
interstitial pneumonitis,
liver problems, heart arrhythmias, vision problems,
thyroid problems, and death.[4] If taken during
pregnancy or
breastfeeding it can cause problems in the fetus or the infant.[4] It is a
class III antiarrhythmic medication.[4] It works partly by increasing the time before a heart cell can contract again.[4][6]
Amiodarone has been used both in the treatment of acute life-threatening arrhythmias as well as the long-term suppression of arrhythmias.[13] Amiodarone is commonly used to treat different types of abnormal heart rhythms, such as atrial arrhythmias (supraventricular arrhythmias) and ventricular arrhythmias.[13]
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 (PSVT). 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.[14]
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.[14]
Amiodarone can be effective in treating conditions like ventricular fibrillation (a rapid and irregular heartbeat), ventricular tachycardia (fast heartbeat originating from the lower chambers), and cardiac arrest due to shock-resistant ventricular fibrillation.[13]
In cases where a patient is experiencing stable ventricular tachycardia, amiodarone may be used to try to stop the episode. However, recent studies suggest that other antiarrhythmic medications like procainamide may be more effective for this purpose.[13][15]
Amiodarone is also commonly used as the first-line therapy for patients who receive implantable cardioverter defibrillator (ICD) shocks due to ventricular arrhythmias. Combining amiodarone with beta-blockers has been shown to reduce the likelihood of experiencing appropriate shocks from an ICD.[13]
Cardiac arrest
Defibrillation is the treatment of choice for
ventricular fibrillation and pulseless
ventricular tachycardia resulting in
cardiac arrest. While amiodarone has been used in shock-refractory cases, evidence of benefit is poor.[5] Amiodarone does not appear to improve survival or positive outcomes in those who had a cardiac arrest.[16]
Ventricular tachycardia
Amiodarone may be used in the treatment of ventricular tachycardia in certain instances.[17] 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.[18]
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.[13][19][20] 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.[21][22] 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.[15][23]
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.[15][24] 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.[25][26][27]
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 hemodynamically unstable and unsuitable for DC cardioversion.[15][28] It is recommended in such a role by the UK government's
National Institute for Health and Clinical Excellence (NICE).[28][29]
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.
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".[30]
Amiodarone can worsen the cardiac arrhythmia brought on by
digitalis toxicity.
Contraindications of amiodarone also include:
hypersensitivity to amiodarone or any of its components;[13]
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.[13]
Side effects
At oral doses of 400 mg per day or higher, amiodarone can have serious, varied
side effects, including
toxicity to the
thyroid gland,[31] liver, lung, and
retinal functions, requiring clinical surveillance and regular laboratory testing.[32][33]Allergic reactions to amiodarone may occur.[32] Most individuals administered amiodarone on a chronic basis will experience at least one side effect.[33] In some people, daily use of amiodarone at 100 mg oral doses can be effective for arrhythmia control with no or minimal side effects.[33]
taste disturbances (changes in taste perception, often described as a metallic or bitter taste in the mouth);[13]
photosensitivity of the skin, also known as
photodermatitis, where exposure to sunlight or ultraviolet radiation may lead to skin reactions such as rashes or sunburn-like symptoms;[13]
corneal microdeposits (deposits may accumulate on the
cornea over time, resulting in blurred vision or visual halos—bright circles or rings around a light source, such as headlights; still, these corneal deposits typically do not affect vision significantly);[13][34]
thyroid dysfunction[35] (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);[31]
pulmonary toxicity[36][37][38][39] (lung problems such as pulmonary fibrosis or interstitial lung disease may occur rarely but have the potential for serious consequences if left untreated);[7][13]
liver abnormalities (liver damage, including elevated liver enzymes (
AST/
ALT) and hepatotoxicity, although severe cases are rare);[13]
bradycardia and heart block (since it slows down heart rate by affecting the sinus node function and AV conduction system, it can increase the risk of heart block);[13]
Amiodarone can potentially cause renal toxicity, but solid studies on whether amiodarone may be toxic to the kidneys are lacking.[40]
Lung
Side effects of oral amiodarone at doses of 400 mg or higher include various
pulmonary effects.[41] 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.[41] 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.[35][32] In approximately 15-20% of patients, amiodarone treatment results in thyroid dysfunction, either amiodarone-induced hypothyroidism or amiodarone-induced thyrotoxicosis.[42][43][31][17] Both under- and overactivity of the thyroid may occur.[32]
Amiodarone is structurally similar to
thyroxine and also contains
iodine. Both of these factors contribute to the effects of amiodarone on thyroid function.[17][42][44][45] 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.[46][47]
Thyroid function should be checked at least every six months.[48]
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.[49]
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.[42][50] Type 2 AIT can occur even years after starting amiodarone, is usually self-limited and responds to
anti-inflammatory treatment such as
corticosteroids.[50] In practice, often the type of AIT is undetermined or presumed as mixed with both treatments combined.[50] Thyroid uptake measurements (I-123 or I-131), which are used to differentiate causes of hyperthyroidism, are generally unreliable in patients who have been taking amiodarone. Because of the high iodine content of amiodarone, the thyroid gland is effectively saturated, thus preventing further uptake of isotopes of iodine. However, positive radioactive iodine can be used to rule in type 1AIT .[citation needed]
Corneal micro-deposits (
cornea verticillata,[51] 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.[52] Bilateral optic disc swelling and mild and reversible visual field defects can also occur.
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.[55][56] However, this extreme adverse event manifestation—pseudo-alcoholic cirrhosis caused by low dose amiodarone—is very rare.[33]
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.[57]
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.[58] Use during breastfeeding is generally not recommended though one dose may be okay.[58]
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.[60]
Some cases of
gynecomastia have been reported in men on amiodarone.[61]
There is a possible association between amiodarone and an increased risk of cancer, especially in males, with a
dose-dependent effect.[62]
beta blockers and
calcium channel blockers (combining amiodarone with beta-blockers or calcium channel blockers, such as
sotalol, can further slow down heart rate and cause bradycardia or heart block);[13]
digoxin (amiodarone inhibits a protein called P-glycoprotein (P-gp), which transports digoxin out of cells in the gut, liver, and kidneys, therefore, concurrent use of these medications increases
digoxin levels in the body, potentially leading to digoxin toxicity)[13]
statins (amiodarone can inhibit enzymes in the liver responsible for metabolizing certain statins, such as
simvastatin,
atorvastatin, etc., therefore interaction elevates plasma concentrations of these
statins, increasing the risk of
myopathy, that is muscle damage, or
rhabdomyolysis, that is severe muscle breakdown);[13]
warfarin (since the
anticoagulation effects of
warfarin depend on metabolism of warfarin by both cytochromes
CYP2C9 and
CYP3A4, coadministation leads to rise in
international normalized ratio (INR)—the amount of time taken for the blood to form a clot—placing patient at higher bleeding risks);[13] 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 400 mg daily, 35% reduction if the amiodarone dose is 300 mg;mg daily, 30% reduction if the amiodarone dose is 200 mg daily, and 25% reduction if amiodarone dose is 100 mg daily.[medical citation needed] The effect of amiodarone on the warfarin concentrations can be as early as a few days after initiation of treatment; however, the interaction may not peak for up to seven weeks;[medical citation needed]
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).[13][63]
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.[15][65][66][43]
The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties.[15]
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.[67]
Amiodarone is extensively metabolized in the liver. The primary metabolic pathway of amiodarone is by cytochrome P450 (CYP) enzymes, particularly CYP3A4 and CYP2C8.[63][43] 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;[medical citation needed]
phase II metabolism, when both amiodarone and its major metabolite DEA can undergo conjugation reactions with glucuronic acid;t his process increases water solubility of these compounds for their efficient elimination from the body.[medical citation needed]
Amiodarone has an exceptionally long half-life due to a combination of several factors:[13]
high lipid solubility, given that amiodarone has high lipid solubility, which allows it to distribute throughout various tissues in the body rapidly; the extensive tissue distribution of amiodarone contributes to a large volume of distribution that leads to slow clearance from plasma compartments;
extensive tissue binding, so that amiodarone extensively binds to different tissues, including fat deposits, muscles, heart tissue, and other organs; this binding creates reservoirs where drug release can occur slowly over time, resulting in an extended duration of action even after stopping the therapy;
enterohepatic recycling, meaning that amiodarone undergoes enterohepatic recycling, where it is reabsorbed from the intestines after being excreted into bile, which contributes to its prolonged presence.[68]
Excretion
Excretion is primarily via the liver and the bile duct with almost no elimination via the kidney and it is not dialyzable.[1] 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).[1] There is 10-50% transfer of amiodarone and DEA in the placenta as well as a presence in breast milk.[1] Accumulation of amiodarone and DEA occurs in adipose tissue and highly perfused organs (i.e. liver, lungs),[1] 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.[1]
Whereas amiodarone is primarily eliminated from the body through hepatic metabolism and biliary excretion, a very small portion of amiodarone and its metabolites are excreted unchanged in urine or feces.[63][43]
The liver plays a significant role in the elimination of amiodarone. After being extensively metabolized by cytochrome P450 enzymes, particularly
CYP3A4 and
CYP2C8, amiodarone is transported into bile via multidrug-resistant protein 2 (MRP2) transporter. Bile containing amiodarone and its metabolites is then released into the gastrointestinal tract.[medical citation needed]
Some of these compounds can be reabsorbed back into systemic circulation through enterohepatic recirculation, where they may undergo additional rounds of metabolism before eventually being excreted again into bile.[medical citation needed]
Although renal excretion contributes only minimally to the elimination of amiodarone, dose adjustment based on kidney function is generally not necessary. This is because most patients with normal renal function can adequately clear the drug through hepatic metabolism and biliary elimination pathways.[13]
Pharmacology
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 slows the conduction rate and prolongs the refractory period of the SA and AV nodes.[70] It also prolongs the refractory periods of the ventricles, bundles of His, and the Purkinje fibers without exhibiting any effects on the conduction rate.[70] Amiodarone has been shown to prolong the myocardial cell action potential duration and refractory period and is a non-competitive β-adrenergic inhibitor.[71]
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.[72]
Amiodarone chemically resembles
thyroxine (thyroid hormone), and its binding to the nuclear thyroid receptor might contribute to some of its pharmacologic and toxic actions.[73]
The mechanisms of action of amiodarone include blocking potassium ion channels (prolonging repolarization), blocking sodium ion channels, and antagonizing alpha- and beta-adrenergic receptors.[13]
The action of amiodarone can be characterized by the following effects:[13]
potassium channel blockade, since amiodarone blocks potassium channels involved in cardiac repolarization during phase 3 of the action potential, so that this blockade prolongs the duration of cardiac action potentials, resulting in an increased refractory period and decreased excitability;[13]
sodium channel blockade, characterized by inhibiting sodium ion influx through voltage-gated sodium channels, so that amiodarone reduces the conduction velocity of electrical impulses in cardiac tissue that leads to a slowed heart rate and improved rhythm control;[13]
calcium channel blockade, by inhibiting L-type calcium channels in myocardial cells, decreasing intracellular calcium concentration during ventricular contraction;[13]
noncompetitive adrenergic receptor antagonism, meaning that amiodarone has both alpha- and beta-adrenergic receptor antagonistic effects, which help reduce sympathetic stimulation on the heart.[13]
History
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.[74] 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.[75][76][77]
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).[78] 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.[77]
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.[79][80]
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.[2][81]
Name
Amiodarone may be an acronym[citation needed] for its IUPAC name (2-butyl-1-benzofuran-3-yl)-[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone,[82] 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.[citation needed]
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).[1][2] It is also available under the brand name Aratac (produced by Alphapharm Pty Ltd) in Australia and New Zealand, and further in Australia under the brands Cardinorm and Rithmik as well as a number of generic brands. Also Arycor in South Africa (Produced by Winthrop Pharmaceuticals.). 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.[15]
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