Amiodarone hydrochloride Chemical Properties

Melting point:

154-158°C

Flash point:

9℃

storage temp. 

2-8°C

solubility 

Soluble in chloroform, methanol.

pka

pKa (25°C) 6.56 ±0.06

color 

White

λmax

242nm(MeOH)(lit.)

Merck 

14,482

Stability:

Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 2 months.

CAS DataBase Reference

19774-82-4(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xn,T,F

Risk Statements 

20/21/22-39/23/24/25-23/24/25-11

Safety Statements 

36-45-36/37-16-7

RIDADR 

UN1230 - class 3 - PG 2 - Methanol, solution

WGK Germany 

3

RTECS 

OB1361000

HS Code 

29322090

Hazardous Substances Data

19774-82-4(Hazardous Substances Data)

Toxicity

dog,LD50,intravenous,5gm/kg (5000mg/kg),Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 23, Pg. 682, 1992.

MSDS

• Language:English Provider:SigmaAldrich

Amiodarone hydrochloride Usage And Synthesis

Description

Amiodarone HCl (19774-82-4) is a nonselective ion channel blocker. Class III antiarrhythmic.1 Induces cytochrome c release and induces apoptosis.2 An alkalizing agent which stimulates progranulin (GRN) production and prevents GRN-dependent neurodegeneration.3 Induces autophagy and suppresses hepatocellular carcinoma tumorigenesis via autophagy-mediated MIR224 degradation in vitro and in vivo.4

Chemical Properties

White Solid

Originator

Cordarone,Labaz,France,1971

Uses

Amiodarone induces an immediate influx of Ca2+ in Saccharomyces cerevisiae, followed by mitochondrial fragmentation and cell death.

Uses

Antiarrhythmic;Na+ channel blocker

Uses

A non-selective ion channel blocker. Antiarrhythmic (class III)

Uses

Amiodarone hydrochloride is a non-selective ion channel blocker with broad fungicidal activity. Amiodarone induces an immediate influx of Ca²⁺ in Saccharomyces cerevisiae, followed by mitochondrial fragmentation and cell death. Amiodarone hydrochloride has also been used in a study to determine concentrations of thyroid disrupting substances in effluents from wastewater treatment plants.

Definition

ChEBI: Amiodarone hydrochloride is an aromatic ketone.

Manufacturing Process

135 grams of 2-n-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran dissolved in 600 cc of ethyl carbonate were treated with 5.7 grams of sodium in the form of sodium methoxide in methanol. Then, β-diethylaminoethyl chloride which had been obtained from 51.6 grams of the hydrochloride in ethyl carbonate was introduced into a suspension of the sodium salt. The mixture was heated to a temperature of approximately 90°C which was maintained for approximately 2 hours. The mixture was cooled and allowed to stand overnight during which time the sodium chloride settled down.
The toluene solution containing diethylaminoethyl ether was extracted with increasingly diluted aqueous hydrochloric acid solutions while stirring. Extraction was continued until the alkalized solution produced no further precipitate. The combined aqueous solutions were washed with ether and then made strongly alkaline with aqueous sodium hydroxide. Extraction with ether was carried out three times. The organic layers were washed with water and then dried over anhydrous potassium carbonate. In order to produce the hydrochloride, the carbonate was filtered off and then the hydrochloride was precipitated from the ether solution with an ethereal hydrochloric acid solution. After the solution had been allowed to stand for a few hours, decantation was carried out and the syrupy hydrochloride residue was taken up in 500 cc of boiling acetone. The salt crystallized out by cooling. The substance was allowed to stand overnight at 0°C, and centrifuged, washed with ethyl acetate and then with ether and dried. 130 grams of 2-n-butyl-3- (3,5-diiodo-4-β-N-diethylaminoethoxybenzoyl)benzofuran hydrochloride in the form of a crystalline powder which melts at 156°C were obtained.

Therapeutic Function

Coronary vasodilator

General Description

Amiodarone, marketed as Pacerone^?, Cordarone^?, Aratac, and Atlansil, is an antiarrhythmic agent monitored by clinical labs using HPLC or LCMS to ensure patients remain within the drugs therapeutic range.

Biochem/physiol Actions

Non-selective ion channel blocker with broad fungicidal activity. Amiodarone induces an immediate influx of Ca2+ in Saccharomyces cerevisiae, followed by mitochondrial fragmentation and cell death.

Clinical Use

Cardiac arrhythmias

Veterinary Drugs and Treatments

Because of its potential toxicity and lack of experience with use in canine and equine patients, amiodarone is usually used when other less toxic or commonly used drugs are ineffective. It may be useful in dogs and horses to convert atrial fib into sinus rhythm and in dogs for arrhythmias associated with left ventricular dysfunction. In horses, one horse with Ventricular tachycardia was converted into sinus rhythm using amiodarone.
As the risk of sudden death is high in Doberman pinschers exhibiting rapid, wide-complex ventricular tachycardia or syncope with recurrent VPC’s, amiodarone may be useful when other drug therapies are ineffective.

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: additive effect and increased risk of myocardial depression; increased risk of ventricular arrhythmias with disopyramide or dronedarone - avoid; increased flecainide concentration - halve flecainide dose; increased procainamide concentration - avoid.
Antibacterials: increased risk of ventricular arrhythmias with parenteral erythromycin, cotrimoxazole levofloxacin and moxifloxacin - avoid; increased risk of ventricular arrhythmias with delamanid; avoid with fidaxomicin; possibly increased risk of ventricular arrhythmias with telithromycin.
Anticoagulants: metabolism inhibited (increased anti-coagulant effect); increased dabigatran concentration (reduce dabigatran dose).
Antidepressants: increased risk of ventricular arrhythmias with citalopram and escitalopram, tricyclic antidepressants and venlafaxine - avoid.
Antiepileptics: phenytoin and fosphenytoin metabolism inhibited (increased concentration).
Antifungals: avoid with fluconazole due to risk of QT prolongation.
Antihistamines: increased risk of ventricular arrhythmias with mizolastine - avoid.
Antimalarials: increased risk of ventricular arrhythmias with chloroquine, hydroxychloroquine, mefloquine and quinine and possibly with piperaquine with artenimol and artemether/ lumefantrine - avoid.
Antimuscarinics: increased risk of ventricular arrhythmias with tolterodine.
Antipsychotics: increased risk of ventricular arrhythmias with antipsychotics that prolong the QT interval; increased risk of ventricular arrhythmias with amisulpride, benperidol, droperidol, haloperidol, phenothiazines, pimozide or zuclopenthixol - avoid; increased risk of ventricular arrhythmias with sulpiride.
Antivirals: increased risk of ventricular arrhythmias with fosamprenavir ritonavir, saquinavir and telaprevir - avoid; concentration possibly increased by atazanavir; possible increased risk of bradycardia with daclatasvir, ledipasvir, sofosbuvir and simeprevir; avoid with indinavir, reduce the dose of the others.
Atomoxetine: increased risk of ventricular arrhythmias.
Beta-blockers, diltiazem, and verapamil: increased risk of bradycardia, AV block and myocardial depression; increased risk of ventricular arrhythmias with sotalol - avoid.
Ciclosporin: increased levels of ciclosporin possible.
Cobicistat: concentration possibly increased by cobicistat - avoid.
Colchicine: possibly increased colchicine toxicity.
Cytotoxics: possibly increased afatinib concentration (separate administration by 6-12 hours); possibly increased risk of ventricular arrhythmias with panobinostat and vandetanib - avoid; concentration of ibrutinib possibly increased - reduce dose of ibrutinib; avoid with idelalisib; increased risk of ventricular arrhythmias with arsenic trioxide, bosutinib and ceritinib.
Digoxin: increased concentration (halve digoxin maintenance dose).
Fingolimod: possible increased risk of bradycardia.
Grapefruit juice: may increase concentration of amiodarone - avoid.
Ivabradine: increased risk of ventricular arrhythmias - avoid.
Lipid-lowering drugs: give lomitapide 12 hours after amiodarone; increased risk of myopathy with simvastatin - do not exceed 20 mg of simvastatin.1 Lithium: increased risk of ventricular arrhythmias - avoid.
Pentamidine: increased risk of ventricular arrhythmias - avoid.

Metabolism

Amiodarone is metabolised in the liver; the major metabolite, desethylamiodarone, also has antiarrhythmic properties. There is very little urinary excretion of amiodarone or its metabolites, the major route of excretion being in faeces via the bile; some enterohepatic recycling may occur.

storage

Store at +4°C

References

1) Yamase et al. (2012), Effectiveness of amiodarone versus bepridil in achieving conversion to sinus rhythm in patients with persistent atrial fibrillation: a randomized trial; Heart, 98 1067 2) Di Matola et al. (2000), Amiodarone induces cytochrome c release and apoptosis through an iodine-independent mechanism; J. Clin. Endocrinol. Metab., 85 4323 3) Capell et al. (2011), Rescue of progranulin deficiency associated with frontotemporal lobar degeneration by alkalizing reagents and inhibition of vacuolar ATPase; J. Neurosci., 31 1885 4) Lan et al. (2014), Autophagy-preferential degradation of MIR224 participates in hepatocellular carcinoma tumorigenesis; Autophagy, 10 1687

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