Amiodarone

Description

From the chemical point of view, amiodarone is completely different from other antiarrhythmics. It has two iodide atoms and a diethylaminoethanol group as substituents in the benzoyl part, and overall it is very similar to the structure of thyroxin-like molecules.

Originator

Cordarone,Labaz,France,1971

Uses

antibacterial

Uses

Amiodarone is a non-selective ion channel blocker. Antiarrhythmic (class III).

Definition

ChEBI: A member of the class of 1-benzofurans that is 1-benzofuran substituted by a butyl group at position 2 and a 4-[2-(diethylamino)ethoxy]-3,5-diiodobenzoyl group at position 3. It is a cardiovascular drug used for the treatment of cardiac dysrhythmias.

Indications

Clinical use of amiodarone is limited because of its high toxicity, which consists of cardiac block, bradycardia, cardiac insufficiency, damaged thyroid gland function, neuropathology, and increased sensitivity to light, all of which significantly limit use of amiodarona, and it is only used in therapy for extremely serious tachyarrhythmias such as reoccurring ventricular fibrillation and hemodynamic unstable ventricular tachycardia, and only under supervision of a physician in a clinical situation.

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.

brand name

Cordarone (Wyeth-Ayerst).

Therapeutic Function

Coronary vasodilator

Biological Functions

Amiodarone (Cordarone) is an iodine-containing benzofuran derivative identified as a class III agent because it predominantly prolongs action potentials. Amiodarone also blocks sodium and calcium channels and is a noncompetitive β-receptor blocker.Amiodarone is effective for the treatment of most arrhythmias. Toxicity associated with amiodarone has led the U. S. Food and Drug Administration (FDA) to recommend that it be reserved for use in patients with life-threatening arrhythmias.

General Description

Amiodarone, 2-butyl-3-benzofuranyl-4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl ketone (Cordarone),was introduced as an antianginal agent. It has very pronouncedclass III action and is especially effective in maintainingsinus rhythm in patients who have been treated bydirect current shock for atrial fibrillation. Like class IIIantiarrhythmic drugs, amiodarone lengthens the effective refractoryperiod by prolonging the action potential duration inall myocardial tissues. Amiodarone is eliminated very slowlyfrom the body, with a half-life of about 25 to 30 days after oraldoses. Although the drug has a broad spectrum of antiarrhythmicactivity, its main limitation is a slow onset of action.Drug action may not be initiated for several days, and thepeak effect may not be obtained for several weeks.

Mechanism of action

Amiodarone’s antiarrhythmic action is connected to its ability to block K
, Na
, and Ca2
channels while noncompetitively blocking α- and β-adrenergic receptors of the heart, thus prolonging the action potential and effective refractive period of atrial cells, atrioventricular junctions, and ventricles of the heart, which is accompanied by decreased automatism of sinus node and slowing of atrioventricular conductivity.

Clinical Use

Amiodarone has adverse effects involving many differentorgan systems. It also inhibits metabolism of drugscleared by oxidative microsomal enzymes. It contains iodinein its molecular structure and, as a result, has an effecton thyroid hormones. Hypothyroidism occurs in up to 11%of patients receiving amiodarone. The principal effect isthe inhibition of peripheral conversion of T4 to T3. Serumreverse T3 (rT3) is increased as a function of the dose as wellas the length of amiodarone therapy. As a result, rT3 levelshave been used as a guide for judging adequacy of amiodaronetherapy and predicting toxicity.

Side effects

Amiodarone’s most significant adverse effects include hepatitis, exacerbation of arrhythmias, worsening of congestive heart failure, thyroid dysfunction, and pulmonary fibrosis. Pulmonary fibrosis is frequently fatal and may not be reversed with discontinuation of the drug. Interestingly, despite significant prolongation of the QT interval, the risk of torsades de pointes is relatively low. Patients with underlying sinus node dysfunction tend to have significant worsening of nodal function, frequently requiring pacemaker implantation. Corneal microdeposits develop in most adults receiving amiodarone. As many as 10% of patients complain of halos or blurred vision. The corneal microdeposits are reversible with stoppage of the drug.
Photosensitization occurs in 10% of patients. With continued treatment, the skin assumes a blue-gray coloration. The risk is increased in patients of fair complexion. The discoloration of the skin regresses slowly, if at all, after discontinuation of amiodarone.
Amiodarone inhibits the peripheral and possibly intrapituitary conversion of thyroxine (T4) to triiodothyronine (T3) by inhibiting 5 -deiodination. The serum concentration of T4 is increased by a decrease in its clearance, and thyroid synthesis is increased by a reduced suppression of the pituitary thyrotropin T3. The concentration of T3 in the serum decreases, and reverse T3 appears in increased amounts.Despite these changes, most patients appear to be maintained in an euthyroid state. Manifestations of both hypothyroidism and hyperthyroidism have been reported.
Tremors of the hands and sleep disturbances in the form of vivid dreams, nightmares, and insomnia have been reported in association with the use of amiodarone. Ataxia, staggering, and impaired walking have been noted. Peripheral sensory and motor neuropathy or severe proximal muscle weakness develops infrequently. Both neuropathic and myopathic changes are observed on biopsy. Neurological symptoms resolve or improve within several weeks of dosage reduction.

Safety Profile

Poison by intravenous and intraperitoneal routes. Human systemic effects by ingestion: photosensitivity of the skin. A flammable liquid. When heated to decomposition it emits very toxic fumes of Iand NO,. A coronary vasoddator

Synthesis

Amiodarone, 2-butyl-3-benzofuranyl-4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl ketone (18.1.21), is synthesized in the following manner. Benzofuran is acylated by butyric acid anhydride in the presence of phosphorous acid, forming 2-butyroylbenzfuran (18.1.16). Reduction of the carbonyl group in a Wolff¨CKizhner reaction using hydrazine hydrate gives 2-butylbenzofurane (18.1.17). This is acylated with 4-methoxybenzoic acid chloride, giving 2-butyl-3-(4-methoxybenzoyl)benzofuran (18.1.18), which undergoes demethylation by pyridine hydrochloride, forming 2-butyl-3-(4-hydroxy-benzoyl)-benzofuran (18.1.19). The resulting product is iodized in the presence of potassium iodide, forming 2-butyl-3-benzofuranyl-4-(2-hydroxy-3,5-diiodophenyl) ketone (18.1.20), which is reacted further with 2-diethylaminoethylchoride, giving desired amiodarone (18.1.21) .

Drug interactions

Amiodarone increases the hypoprothrombinemic response to warfarin (an oral anticoagulant) by reducing its metabolism. Patients receiving digoxin may undergo an increase in serum digoxin concentrations when amiodarone is added to the treatment regimen. Amiodarone interferes with hepatic and renal elimination of flecainide, phenytoin, and quinidine.

Precautions

Amiodarone is contraindicated in patients with sick sinus syndrome and may cause severe bradycardia and secondand third-degree atrioventricular block. Amiodarone crosses the placenta and will affect the fetus, as evidenced by bradycardia and thyroid abnormalities. The drug is secreted in breast milk.