Amiodarone
Encyclopedia
Amiodarone is an antiarrhythmic agent
(medication used for irregular heart beat) used for various types of tachyarrhythmias (fast forms of irregular heart beat), both ventricular and supraventricular (atrial) arrhythmias. Discovered in 1961, it was not approved for use in the United States
until 1985. Despite relatively common side-effects, it is used in arrhythmias that are otherwise difficult to treat with medication. Related newer compounds, such as dronedarone
, have lower efficacy
but a reduced rate of side-effects.
, by chemists Tondeur and Binon. It became popular in Europe as a treatment for angina pectoris.
As a doctoral candidate at Oxford University, Dr. 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 remain unknown. It is thought to involve prolonging the action potential duration, prolonging the refractory period, or interacting with K+ channels.
Based on Singh's work, 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 United States
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 Food and Drug Administration
, 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.
Orally, it is available under the trade names Pacerone (produced by Upsher-Smith Laboratories, Inc.) and Cordarone (produced by Wyeth-Ayerst Laboratories) in 200 mg and 400 mg tablets; It is also available under the trade name Aratac (produced by Alphapharm Pty Ltd) in 100 mg and 200 mg tablets in Australia and New Zealand. Also Arycor in South Africa (Produced by Winthrop Pharmaceuticals.) in doses of 100 mg and 200 mg scored tablets. In South America, it is known as Atlansil and is produced by Roemmers.
It is also available in intravenous ampules and vials, typically in 150 mg increments.
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.
Amiodarone is fat-soluble, and tends to concentrate in tissues including fat, muscle, liver, lungs, and skin. This confers a high volume of distribution
(5000 liters in a 70 kg adult) and a long half-life. 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 but there are many other dosing regimens. Once an individual is loaded, a typical maintenance dose of amiodarone is 100 or 200 mg either once or twice daily.
An intravenous loading dose is typically 300 mg in 20-30cc D5W for cardiac arrest. The loading infusion for dysrhythmias is typically 150 mg in a 100cc bag of D5W given over 10 minutes. Both can be followed by a 360 mg slow infusion over 6 hours then a maintenance infusion of 540 mg over 18 hours.
. 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
(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 American Heart Association
for the treatment of VF include amiodarone as a second line agent (after epinephrine
or vasopressin
). ARREST was not adequately powered to demonstrate survival to hospital discharge.
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. The dose of amiodarone is 150 mg IV administered over 10 minutes.
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 gram
s 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 such as pulmonary toxicities. While Amiodarone is not approved for AF by the FDA, it is a commonly prescribed off-label treatment due to the lack of efficacious 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 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).
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.
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
. It interacts with digoxin, warfarin, phenytoin and others. The major metabolite of amiodarone is desethylamiodarone (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.
of numerous drugs
, including many that are commonly administered to individuals with heart
disease, are affected by amiodarone. Particularly, doses of digoxin
should be halved in individuals taking amiodarone.
Amiodarone potentiates the action of warfarin
. Individuals taking both of these medications should have their warfarin dose halved and their anticoagulation status (measured as prothrombin time
(PT) and international normalized ratio (INR)) measured more frequently. The effect of amiodarone in the warfarin concentration can be as early as a few days after initiation of treatment, or can be delayed a few weeks.
Amiodarone inhibits the action of the cytochrome P450 isozyme
family. This reduces the clearance of many drugs, including the following: -
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.
Due to the iodine content of the agent (37.3% by weight), abnormalities in thyroid
function are common. Amiodarone is structurally similar to thyroxine
(a thyroid hormone), 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.
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, the radioactive iodine uptake (nuclear thyroid uptake test) may still be helpful in the diagnosis and management of amiodarone-induced hyperthyroidism.
l micro-deposits (Corneal verticillata, also called 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 in 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.
, hepatomegaly
(liver enlargement), and hepatitis
(inflammation of the liver).
Low-dose amiodarone has been reported to cause pseudo-alcoholic cirrhosis.
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.
, a condition of the scrotum normally associated with bacterial infections but which can also occur as 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.
Antiarrhythmic agent
Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart , such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation....
(medication used for irregular heart beat) used for various types of tachyarrhythmias (fast forms of irregular heart beat), both ventricular and supraventricular (atrial) arrhythmias. Discovered in 1961, it was not approved for use in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
until 1985. Despite relatively common side-effects, it is used in arrhythmias that are otherwise difficult to treat with medication. Related newer compounds, such as dronedarone
Dronedarone
Dronedarone is a drug by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It is now available as 400 mg tablets in 20, 60 and 100 count packages...
, have lower efficacy
Efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...
but a reduced rate of side-effects.
History
Amiodarone was initially developed in 1961 at the Labaz company, BelgiumBelgium
Belgium , officially the Kingdom of Belgium, is a federal state in Western Europe. It is a founding member of the European Union and hosts the EU's headquarters, and those of several other major international organisations such as NATO.Belgium is also a member of, or affiliated to, many...
, by chemists Tondeur and Binon. It became popular in Europe as a treatment for angina pectoris.
As a doctoral candidate at Oxford University, Dr. Bramah Singh determined that amiodarone and sotalol
Sotalol
Sotalol is a drug used in individuals with rhythm disturbances of the heart, and to treat hypertension in some individuals. It is a non-selective competitive β-adrenergic receptor blocker that also exhibits Class III antiarrhythmic properties by its inhibition of potassium channels...
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 remain unknown. It is thought to involve prolonging the action potential duration, prolonging the refractory period, or interacting with K+ channels.
Based on Singh's work, the Argentinian
Argentina
Argentina , officially the Argentine Republic , is the second largest country in South America by land area, after Brazil. It is constituted as a federation of 23 provinces and an autonomous city, Buenos Aires...
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 United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
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 Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
, and physicians were forced to directly obtain amiodarone from pharmaceutical companies in Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
and Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
.
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.
Dosing
Amiodarone is available in oral and intravenous formulations.Orally, it is available under the trade names Pacerone (produced by Upsher-Smith Laboratories, Inc.) and Cordarone (produced by Wyeth-Ayerst Laboratories) in 200 mg and 400 mg tablets; It is also available under the trade name Aratac (produced by Alphapharm Pty Ltd) in 100 mg and 200 mg tablets in Australia and New Zealand. Also Arycor in South Africa (Produced by Winthrop Pharmaceuticals.) in doses of 100 mg and 200 mg scored tablets. In South America, it is known as Atlansil and is produced by Roemmers.
It is also available in intravenous ampules and vials, typically in 150 mg increments.
The dose of amiodarone administered is tailored to the individual and the dysrhythmia that is being treated. When administered orally, the bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
of amiodarone is quite variable. Absorption ranges from 22 to 95%, with 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. This confers a high volume of distribution
Volume of distribution
The volume of distribution , also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing...
(5000 liters in a 70 kg adult) and a long half-life. 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 but there are many other dosing regimens. Once an individual is loaded, a typical maintenance dose of amiodarone is 100 or 200 mg either once or twice daily.
An intravenous loading dose is typically 300 mg in 20-30cc D5W for cardiac arrest. The loading infusion for dysrhythmias is typically 150 mg in a 100cc bag of D5W given over 10 minutes. Both can be followed by a 360 mg slow infusion over 6 hours then a maintenance infusion of 540 mg over 18 hours.
Mechanism of action
Amiodarone is categorized as a class III antiarrhythmic agent, and prolongs phase 3 of the cardiac action potentialCardiac action potential
In electrocardiography, the cardiac action potential is a specialized action potential in the heart, necessary for the electrical conduction system of the heart....
. It has numerous other effects however, including actions that are similar to those of antiarrhythmic classes Ia, II, and IV.
Amiodarone shows beta blocker
Beta blocker
Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...
-like and potassium channel blocker
Potassium channel blocker
Potassium channel blockers are agents which interfere with conduction through potassium channels.-Arrhythmia:Potassium channel blockers used in the treatment of cardiac arrhythmia are classified as class III antiarrhythmic agents.-Mechanism:...
-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
Cardiac action potential
In electrocardiography, the cardiac action potential is a specialized action potential in the heart, necessary for the electrical conduction system of the heart....
, 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 for use
Because amiodarone has a low incidence of pro-arrhythmic effects, 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 ventricular fibrillationVentricular fibrillation
Ventricular fibrillation is a condition in which there is uncoordinated contraction of the cardiac muscle of the ventricles in the heart, making them quiver rather than contract properly. Ventricular fibrillation is a medical emergency and most commonly identified arrythmia in cardiac arrest...
(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
Hospital
A hospital is a health care institution providing patient treatment by specialized staff and equipment. Hospitals often, but not always, provide for inpatient care or longer-term patient stays....
admission (when compared to placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
) in individuals who suffer cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
with shock-refractory VF. It is on the basis of this study that the guidelines created by the American Heart Association
American Heart Association
The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...
for the treatment of VF include amiodarone as a second line agent (after epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
or vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
). ARREST was not adequately powered to demonstrate survival to hospital discharge.
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 cardiovertedCardioversion
Cardioversion is a medical procedure by which an abnormally fast heart rate or cardiac arrhythmia is converted to a normal rhythm, using electricity or drugs. Synchronized electrical cardioversion uses a therapeutic dose of electric current to the heart, at a specific moment in the cardiac cycle...
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. The dose of amiodarone is 150 mg IV administered over 10 minutes.
Atrial fibrillation
Individuals who have undergone open heart surgeryCoronary artery bypass surgery
Coronary artery bypass surgery, also coronary artery bypass graft surgery, and colloquially heart bypass or bypass surgery is a surgical procedure performed to relieve angina and reduce the risk of death from coronary artery disease...
are at an increased risk of developing atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
(or AF) in the first few days post-procedure. In the ARCH trial, intravenous amiodarone (2 gram
Gram
The gram is a metric system unit of mass....
s 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 such as pulmonary toxicities. While Amiodarone is not approved for AF by the FDA, it is a commonly prescribed off-label treatment due to the lack of efficacious 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 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
National Institute for Health and Clinical Excellence
The National Institute for Health and Clinical Excellence is a special health authority of the English National Health Service , serving both English NHS and the Welsh NHS...
(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 nodal bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
, atrioventricular
Atrioventricular node
The atrioventricular node is a part of the electrical control system of the heart that coordinates heart rate. It electrically connects atrial and ventricular chambers...
block, and second or third degree heart block who do not have an artificial pacemaker
Artificial pacemaker
A pacemaker is a medical device that uses electrical impulses, delivered by electrodes contacting the heart muscles, to regulate the beating of the heart...
.
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
Digitalis
Digitalis is a genus of about 20 species of herbaceous perennials, shrubs, and biennials that are commonly called foxgloves. This genus was traditionally placed in the figwort family Scrophulariaceae, but recent reviews of phylogenetic research have placed it in the much enlarged family...
toxicity.
Not to be given with Lidocaine
Lidocaine
Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...
→ increases risk of asystole
Metabolism
Amiodarone is extensively metabolized in the liver by cytochrome P450 3A4, and can affect the metabolism of numerous other drugsMedication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
. It interacts with digoxin, warfarin, phenytoin and others. The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties. The metabolism of amiodarone is inhibited by grapefruit
Grapefruit
The grapefruit , is a subtropical citrus tree known for its sour fruit, an 18th-century hybrid first bred in Barbados. When found, it was named the "forbidden fruit"; it has also been misidentified with the pomelo or shaddock , one of the parents of this hybrid, the other being sweet orange The...
juice, leading to elevated serum
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
levels of amiodarone.
On August 8, 2008 FDA issued a warning of the risk of rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
, which can lead to kidney failure or death, when simvastatin
Simvastatin
Simvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the...
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
The pharmacokineticsPharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
of numerous drugs
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
, including many that are commonly administered to individuals with heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
disease, are affected by amiodarone. Particularly, doses of digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
should be halved in individuals taking amiodarone.
Amiodarone potentiates the action of warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
. Individuals taking both of these medications should have their warfarin dose halved and their anticoagulation status (measured as prothrombin time
Prothrombin time
The prothrombin time and its derived measures of prothrombin ratio and international normalized ratio are measures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin...
(PT) and international normalized ratio (INR)) measured more frequently. The effect of amiodarone in the warfarin concentration can be as early as a few days after initiation of treatment, or can be delayed a few weeks.
Amiodarone inhibits the action of the cytochrome P450 isozyme
Isozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...
family. This reduces the clearance of many drugs, including the following: -
- Cyclosporine
- DigoxinDigoxinDigoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
- FlecainideFlecainideFlecainide acetate is a class Ic antiarrhythmic agent used to prevent and treat tachyarrhythmias . It is used to treat a variety of cardiac arrhythmias including paroxysmal atrial fibrillation , paroxysmal supraventricular tachycardia Flecainide acetate is a class Ic antiarrhythmic agent used to...
- ProcainamideProcainamideProcainamide INN is a pharmaceutical antiarrhythmic agent used for the medical treatment of cardiac arrhythmias, classified by the Vaughan Williams classification system as class Ia.-History:...
- QuinidineQuinidineQuinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...
- SildenafilSildenafilSildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
- SimvastatinSimvastatinSimvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the...
- TheophyllineTheophyllineTheophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
- WarfarinWarfarinWarfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
Excretion
Excretion is primarily hepatic and biliary with almost no elimination via the renal route and it is not dialyzable [Package Insert- Pacerone(R)]. Elimination half-life average of 58 days (ranging from 25–100 days [Remington: The Science and Practice of Pharmacy 21st edition]) for amiodarone and 36 days for the active metabolite, desethylamiodarone (DEA) [Package Insert- Pacerone(R)]. There is 10-50% transfer of amiodarone and DEA in the placenta as well as presence in breast milk [Package Insert- Pacerone(R)]. Accumulation of amiodarone and DEA occurs in adipose tissue and highly perfused organs (i.e. liver, lungs) [Package Insert- Pacerone(R)], 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
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, increased age, and preexisting pulmonary disease. Some individuals were noted to develop pulmonary fibrosisPulmonary fibrosis
Pulmonary fibrosis is the formation or development of excess fibrous connective tissue in the lungs. It is also described as "scarring of the lung".-Symptoms:Symptoms of pulmonary fibrosis are mainly:...
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
DLCO
DLCO is the extent to which oxygen passes from the air sacs of the lungs into the blood. Commonly, it refers to the test used to determine this parameter. It was introduced in 1909....
noted on pulmonary function testing.
Thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
function are common. Amiodarone is structurally similar to thyroxine
Thyroxine
Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
(a thyroid hormone), 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
Thyroxine
Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
(FT4) alone may be unreliable in detecting these problems and thyroid-stimulating hormone
Thyroid-stimulating hormone
Thyrotrophin-stimulating hormone is a peptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid gland.- Physiology :...
(TSH) should therefore also be checked every 6 months.
- HypothyroidismHypothyroidismHypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
(slowing of the thyroid, due to the Wolff-Chaikoff effectWolff-Chaikoff effectThe Wolff–Chaikoff effect is a reduction in thyroid hormone levels caused by ingestion of a large amount of iodine.It is an autoregulatory phenomenon that inhibits organification in the thyroid gland, the formation of thyroid hormones inside the thyroid follicle, and the release of 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 sotalolSotalolSotalol is a drug used in individuals with rhythm disturbances of the heart, and to treat hypertension in some individuals. It is a non-selective competitive β-adrenergic receptor blocker that also exhibits Class III antiarrhythmic properties by its inhibition of potassium channels...
). 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.
- HyperthyroidismHyperthyroidismHyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
(an overactive thyroid, due to the 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 (defined as TSH <0.35 mU/l) were asymptomatic.
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, the radioactive iodine uptake (nuclear thyroid uptake test) may still be helpful in the diagnosis and management of amiodarone-induced hyperthyroidism.
Eye
CorneaCornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
l micro-deposits (Corneal verticillata, also called 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 in 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.
Gastrointestinal system and liver
Abnormal liver enzyme results are common in patients on amiodarone. Much rarer are jaundiceJaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
, hepatomegaly
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
(liver enlargement), and hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
(inflammation of the liver).
Low-dose amiodarone has been reported to cause pseudo-alcoholic cirrhosis.
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
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
light. Using sunblock that also blocks UV-A rays appears to prevent this side effect.
Neurological
Long-term administration of amiodarone has been associated with peripheral neuropathies.Epididymis
Amiodarone is sometimes responsible for epididymitisEpididymitis
Epididymitis is a medical condition in which there is inflammation of the epididymis . This condition comprises gradual onset of testicular pain that can vary from mild to severe, and the scrotum may become red, warm and swollen...
, a condition of the scrotum normally associated with bacterial infections but which can also occur as 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.
See also
- Advanced cardiac life supportAdvanced cardiac life supportAdvanced cardiac life support or Advanced Cardiovascular Life Support refers to a set of clinical interventions for the urgent treatment of cardiac arrest and other life threatening medical emergencies, as well as the knowledge and skills to deploy those interventions.Extensive medical knowledge...
(ACLS) - Antiarrhythmic agents
- Atrial fibrillationAtrial fibrillationAtrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
- Cardiac action potentialCardiac action potentialIn electrocardiography, the cardiac action potential is a specialized action potential in the heart, necessary for the electrical conduction system of the heart....
- DronedaroneDronedaroneDronedarone is a drug by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It is now available as 400 mg tablets in 20, 60 and 100 count packages...
(similar drug under investigation) - Ventricular tachycardiaVentricular tachycardiaVentricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...