Amiodarone

Amiodarone is an antiarrhythmic Class III agent belonging to a multi-channel blocker.

Amiodarone is used in the treatment of life-threatening ventricular arrhythmias. It is also used to treat supraventricular tachyarrhythmias such as atrial fibrillation.

Amiodarone is Variably and slowly absorbed from the gastrointestinal tract. Bioavailability: Oral: Approx 50% (range: 35-65%).It is extensively distributed and accumulates in fat, skeletal muscles, and highly perfused tissues (e.g. liver, lung, spleen) Crosses the placenta, and enters breast milk. The volume of distribution for Oral is 66 L/kg (range: 18-148 L/kg); IV: 40-84 L/kg. Plasma protein binding: >96%.It gets metabolized in the liver primarily by CYP3A4 and CYP2C8 to N-desethylamiodarone (active metabolite), and may undergo enterohepatic recirculation. It gets excreted mainly via feces, and urine (<1% as unchanged drug) with an elimination half-life of Amiodarone of 58 days (range: 15-142 days); N-desethylamiodarone: 36 days (range: 14-75 days).

The common side effects are Nausea, vomiting, dry mouth, dysgeusia, constipation, diarrhea, abdominal pain, flatulence, etc.

Amiodarone is available in the form of a dosage form such as tablets and injections.

Amiodarone is available in Italy, Europe, India, U.S.A.

Amiodarone is considered a class III antiarrhythmic drug. It blocks potassium currents that cause repolarization of the heart muscle during the third phase of the cardiac action potential as a result amiodarone increases the duration of the action potential as well as the effective refractory period for cardiac cells (myocytes). Therefore, cardiac muscle cell excitability is reduced, preventing and treating abnormal heart rhythms.

Amiodarone also interferes with the functioning of beta-adrenergic receptors, sodium channels, and calcium channels. These actions, at times, can lead to undesirable effects, such as hypotension, bradycardia, and Torsades de pointes (TdP). In addition to the above, Amiodarone may increase the activity of peroxisome proliferator-activated receptors, leading to steatogenic changes in the liver or other organs.

The onset of Action of Amiodarone was within 1 and 30 minutes

The Duration of Action of Amiodarone was 1-3 hours.

The Tmax was about 3 to 7 hours. and Cmax was about 0.4 to 11.99 μg/ml

Amiodarone is available in the form of a dosage form such as tablets and injection.

Amiodarone is used in the treatment of life-threatening ventricular arrhythmias. It is also used to treat supraventricular tachyarrhythmias such as atrial fibrillation.

The electrophysiological effect of Amiodarone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, Amiodarone reduces the fast inward current carried by sodium ions, which is responsible for the drug's antiarrhythmic actions.

Amiodarone is used in the treatment of life-threatening ventricular arrhythmias. It is also used to treat supraventricular tachyarrhythmia such as atrial fibrillation.

• Supraventricular arrhythmias, Ventricular arrhythmias

Adult: Initially, 5 mg/kg via infusion over a period of 20-120 minutes, may repeat infusion up to 1,200 mg (approx 15 mg/kg) per 24 hours, with a rate of infusion adjusted based on clinical response. For emergency cases: 150-300 mg via slow inj over ≥3 minutes, may be repeated at least 15 minutes after the first dose.

Elderly: Use the minimum effective dose.

• Although not approved there have been certain off label use documented for Amiodarone which includes:-

Intravenous

• Pulseless ventricular tachycardia, Ventricular fibrillation

Adult: For cardiopulmonary resuscitation in cases that are resistant to defibrillation: Initially, 300 mg (or 5 mg/kg) via rapid inj. Additional 150 mg (or 2.5 mg/kg) may be given if ventricular fibrillation or pulseless ventricular tachycardia persists.

Oral

• Supraventricular arrhythmias, Ventricular arrhythmias

Adult: Initially, 200 mg tid for 1 week then reduced to 200 mg bid for another week. Maintenance: ≤200 mg daily based on patient response.

Elderly: Use minimum effective dose.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Amiodarone is available in various dosage strengths :

• Tablets: 100mg,200mg and 400mg
• Injection: 50mg/mL,150mg/100mL,360mg/200mL

Amiodarone is available in the form of a dosage form such as tablets and injection.

Amiodarone is used in the treatment of life-threatening ventricular arrhythmias. It is also used to treat supraventricular tachyarrhythmias such as atrial fibrillation.

Ventricular arrhythmias: Diets high in processed foods, such as fast food, and items high in added sugar, like soda and sugary baked goods, have been linked to increased heart disease risk.

Drinking too much alcohol can increase the risk of developing AFib.It may also trigger AFib episodes in people who already have AFib, especially if patients have existing cardiovascular disease or diabetes.

The dietary restriction should be individualized as per the patient's requirements.

Amiodarone may be contraindicated in the following

• Sinus bradycardia, sino-atrial heart block, severe conduction disturbances (e.g. high-grade AV block, bifascicular or trifascicular block) without a presence of pacemaker, cardiogenic shock, severe hypotension, severe respiratory failure, known or history of thyroid dysfunction, known hypersensitivity to iodine, corneal refractive laser surgery. IV (bolus inj): Hypotension, heart failure, cardiomyopathy. Lactation. Concomitant use with drugs which may induce QT prolongation or torsades de pointes.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

Precautions:

US BOXED WARNINGS (TABLET): These effects may also be seen with IV administration.

● Fatal toxicity: This drug is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity. Even in patients at high risk of arrhythmic death, in whom the toxicity of this drug is an acceptable risk, this drug poses significant management problems that could be life-threatening in a population at risk of sudden death, so every effort should be made to utilize alternative agents first. The difficulty of using this drug safely and effectively itself poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose is given, and a response generally requires at least one week, usually two or more. Because absorption and elimination are variable, the maintenance-dose selection is difficult, and it is not unusual to require a dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15% to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when this drug must be stopped will be made difficult by the gradually, but unpredictably, changing body burden of this drug. A similar problem exists when this drug is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.

● Hepatotoxicity: Liver injury is common with this drug, but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Obtain baseline and periodic liver transaminases and discontinue or reduce dose if the increase exceeds three times normal, or doubles in a patient with an elevated baseline. Discontinue this drug if the patient experiences signs or symptoms of clinical liver injury.

● Proarrhythmic effects: Like other antiarrhythmics, this drug can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2% to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2% to 5%. All of these events should be manageable in the proper clinical setting in most cases. Although the frequency of such proarrhythmic events does not appear greater with this drug than with many other agents used in this population, the effects are prolonged when they occur. Initiate this drug in a clinical setting where continuous ECGs and cardiac resuscitation are available.

● Pulmonary toxicity: This drug has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10% to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal about 10% of the time. Obtain a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, when treatment with this drug is initiated. Repeat history, physical exam, and chest X-ray every 3 to 6 months.

Alcohol consumption with Amiodarone may increase the risk of low blood pressure and cause adverse effects, such as Dizziness, fainting, light-headedness, or headache.

Amiodarone use in breastfeeding patients is not recommended.

Pregnancy Category D

Amiodarone can cause fetal harm when administered to a pregnant woman. Although Amiodarone use during pregnancy is uncommon, there have been a few published reports of congenital goiter/hypothyroidism and hyperthyroidism. If Amiodarone is used during pregnancy, or if the patient becomes pregnant while taking Amiodarone, the patient should be apprised of the potential hazard to the fetus.

Amiodarone tablets should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus. In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose*) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose*) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of a fetal resorption. (these doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose.*) adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose*).

Grapefruit or grapefruit juice can increase the amount of Amiodarone in the body. This can make irregular heart rate more worse. Don’t drink grapefruit juice or eat grapefruit while taking this drug.

The adverse reactions related to molecule Amiodarone can be categorized as

• Common Adverse effects:

Cardiac conduction disorder (e.g. slows AV conduction), CNS effects (e.g., dizziness, blurred vision, fatigue), agranulocytosis, elevated antinuclear antibody (ANA) titre, hepatic abnormalities, fulminant hepatitis.

• Less Common adverse effects:

Thrombocytopenia, leucopenia, granulocytopenia. Cardiac disorders: Palpitations, bradycardia, tachycardia, Nausea, vomiting, dry mouth, dysgeusia, constipation, diarrhoea, abdominal pain, flatulence.

• Rare adverse effects:

Hypotension, orthostatic hypotension, Erectile dysfunction. Respiratory, thoracic and mediastinal disorders: Dyspnoea.

The clinically relevant drug interactions of Amiodarone is briefly summarized here.

Increased concentration with inhibitors of CYP3A4 (e.g. HIV-protease inhibitors, cimetidine). Reduced concentration with inducers of CYP3A4 (e.g. rifampicin, phenytoin). May induce bradycardia with β-blockers, Ca channel blockers, and other antiarrhythmic drugs. May increase risk of arrhythmia with stimulant laxatives, diuretics, systemic corticosteroids. May increase concentration of ciclosporin, clonazepam, digoxin, flecainide, procainamide, quinidine, simvastatin, warfarin. May affect drugs that are P-glycoprotein substrates.

Potentially Fatal: May cause prolongation of QT interval with fluoroquinolones, antipsychotics (e.g. chlorpromazine, thioridazine, fluphenazine), lithium, TCAs (e.g. doxepin, maprotiline, amitriptyline), halofantrine, and terfenadine.

Pediatric Use

Perfusing tachycardias:

Infants, Children, and Adolescents: IV, Intraosseous: Loading dose: 5 mg/kg (maximum dose: 300 mg/dose) over 20 to 60 minutes; may repeat twice up to a maximum total dose of 15 mg/kg during acute treatment

Ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT), shock-refractory: Infants, Children, and Adolescents: IV, Intraosseous: 5 mg/kg (maximum dose: 300 mg/dose) rapid bolus; may repeat twice up to a maximum total dose of 15 mg/kg during acute treatment

Tachyarrhythmia, including junctional ectopic tachycardia (JET), and paroxysmal supraventricular tachycardia (PSVT):

Infants, Children, and Adolescents:

Oral: Loading dose: 10 to 15 mg/kg/day in 1 to 2 divided doses/day for 4 to 14 days or until adequate control of arrhythmia or prominent adverse effects occur; dosage should then be reduced to 5 mg/kg/day given once daily for several weeks; if arrhythmia does not recur, reduce to lowest effective dosage possible; usual daily minimal dose: 2.5 mg/kg/day; maintenance doses may be given for 5 of 7 days/week.

IV: Loading dose: 5 mg/kg (maximum dose: 300 mg/dose) given over 60 minutes

Geriatric Use

Clinical studies of Amiodarone Tablets did not include sufficient numbers of subjects aged 65 And over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or Cardiac function, and of concomitant disease or other drug therapy.

Symptoms: Sinus bradycardia, heart block, ventricular tachycardia attacks, torsades de pointes, circulatory failure, hepatic injury.

Management: Symptomatic and supportive treatment. Perform gastric lavage to reduce absorption. Administer β-adrenergic agonists or glucagon if bradycardia occurs. Monitor cardiac status.

Pharmacodynamics:

• After intravenous administration, amiodarone acts to relax smooth muscles that line vascular walls, decreases peripheral vascular resistance (afterload), and increases the cardiac index by a small amount. Administration by this route also decreases cardiac conduction, preventing and treating arrhythmias.When it is given orally, however, Amiodarone does not lead to significant changes in the left ventricular ejection fraction. Similar to other antiarrhythmic agents, controlled clinical trials do not confirm that oral Amiodarone increases survival

Pharmacokinetics:

• Absorption:

The Cmax of Amiodarone in the plasma is achieved about 3 to 7 hours after administration.The general time to onset of action of Amiodarone after one dose given by the intravenous route is between 1 and 30 minutes, with therapeutic effects lasting from 1-3 hours

• Distribution:

In a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients.6 Prescribing information mentions that the volume of distribution of Amiodarone varies greatly, with a mean distribution of approximately 60 L/kg.

• Metabolism:

This drug is metabolized to the main metabolite desethylamiodarone (DEA)4 by the CYP3A4 and CYP2C8 enzymes. The CYP3A4 enzyme is found in the liver and intestines.18 A hydroxyl metabolite of DEA has been identified in mammals, but its clinical significance is unknown.

• Excretion:

Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion.4 A small amount of desethylamiodarone (DEA) is found in the urine.

1. https://pubmed.ncbi.nlm.nih.gov/10666663/
2. https://clinicaltrials.gov/ct2/show/NCT00251706

1. https://go.drugbank.com/drugs/DB01118
2. https://pubmed.ncbi.nlm.nih.gov/11179527/
3. https://reference.medscape.com/drug/pacerone-cordarone-amiodarone-342296
4. https://www.mims.com/philippines/drug/info/amiodarone?mtype=generic
5. https://www.researchgate.net/figure/Amiodarone-pharmacokinetic-parameters-Tmax-Cmax-and-AUC012min-directly-observed-or_tbl2_360324675