DOBUTAMINE

Originator

Dobutrex,Lilly,UK,1977

Uses

Cardiotonic.

Uses

Dobutamine is predominantly a β1-agonist, with some activity at β2- receptors. Its primary effect is an increase in cardiac output as a consequence of increased contractility and HR and decreased afterload. Systolic arterial pressure may therefore increase, but peripheral resistance is reduced or unchanged. It is primarily used as an inotrope (inodilator) in low CO states. D obutamine increases SA node automaticity and conduction velocity in the atria, ventricles and AV node, with tachyarrhythmias occurring at higher doses. Dobutamine is administered as an i.v. infusion at a dose range of 0.5– 40 μg kg–1 min–1.

Definition

ChEBI: A catecholamine that is 4-(3-aminobutyl)phenol in which one of the hydrogens attached to the nitrogen is substituted by a 2-(3,4-dihydroxyphenyl)ethyl group. A beta1-adrenergic receptor agonist that has cardiac stimulan action without evoking vasoconstriction or tachycardia, it is used as the hydrochloride to increase the contractility of the heart in the management of acute heart failure.

Manufacturing Process

In a stainless steel hydrogenation bottle were placed 17.6 g (0.1 mol) of 4-(pmethoxyphenyl)-3-buten-2-one, 80 ml of ethyl acetate, and 1 g of Raney nickel catalyst. The hydrogenation bottle was attached to a Paar low-pressure hydrogenation apparatus and the solution was hydrogenated under an initial hydrogen pressure of 50 psi. The hydrogenation was carried out at room temperature and after about 12 hours one equivalent of hydrogen had been absorbed. The catalyst was filtered from the reduction mixture and 18.1 g (0.1 mol) of homoveratrylamine were added to the reduction mixture.
To the reduction mixture was then added 3.5 g of 5% palladium on carbon catalyst and the mixture was hydrogenated under a hydrogen pressure of 50 psi at room temperature for 12 hours. The catalyst was removed by filtration and the filtrate was evaporated to a small volume. The concentrated filtrate was dissolved in diethyl ether and the ethereal solution was saturated with anhydrous hydrogen chloride. The reduction product, 3,4-dimethoxy-N-[3-(4- methoxyphenyl)-1-methyl-n-propyl]phenethylamine was precipitated as the hydrochloride salt. The salt was filtered and recrystallized from ethanolmelting at about 147°C to 149°C.
To a solution of 101.2 g of the trimethoxy secondary amine, obtained as described above, in 3,060 ml of glacial acetic acid was added 1,225 ml of 48% hydrobromic acid and the reaction mixture heated at the reflux temperature for 4 hours. The reaction mixture was then cooled and evaporated to a small volume. The crystalline residue which formed was filtered and dried in vacuo. The dried crystalline residue was then triturated with ethyl acetate and redried to yield 97.3 g of crude crystalline material. The crude product was dissolved in 970 ml of warm water to obtain a yellow solution. To the solution was added successively by dropwise addition 75 ml of 1 N and 75 ml of 2 N hydrochloric acid. Following the dropwise addition, the solution was allowed to stir with ice cooling. The impurities which precipitated were removed by filtration through a gauze filter. Concentrated hydrochloric acid was then added dropwise. When approximately 50 to 75 ml of the concentrated acid had been added with ice bath cooling a pale yellow oil precipitated along with a while solid precipitate. With continued stirring of the cold solution, the pale yellow oil crystallized.
The cold solution was then allowed to stand overnight and all crystalline material filtered through a sintered glass filter. The filtrate was treated with an additional 300 ml of concentrated hydrochloric acid to yield a heavy white precipitate. The precipitate was filtered, dried and combined with the initial precipitate obtained as described above. The combined precipitated product, 3,4-dihydroxy-N-[3-(4-hydroxyphenyl)-1-methyl-n-propyl-β-phenethylamine hydrochloride, had a melting point of about 184°C to 186°C after recrystallization from boiling 4 N hydrochloric acid.

brand name

Dobutrex (Lilly）.

Therapeutic Function

Cardiotonic

Drug interactions

Potentially hazardous interactions with other drugs
Anaesthetics: risk of ventricular arrhythmias with isoflurane - avoid.
Antidepressants: risk of hypertensive crisis with MAOIs and moclobemide.
Beta-blockers: possibly severe hypertension and bradycardia with non-cardioselective beta-blockers.
Dopaminergics: effects possibly enhanced by entacapone; avoid with rasagiline.

Metabolism

Dobutamine is metabolised in the liver and other tissues by catechol-o-methyltransferase to an inactive compound, 3-0-methydobutamine and by conjugation with glucuronic acid.
Conjugates of dobutamine and 3-0-methyldobutamine are excreted mainly in urine and to a minor extent in faeces.