Amrinone

Description

Amrinone is a positive inotropic agent useful in the management of severe congestive heart failure. It is effective even in unresponsive, fully digitalized patients.

Description

Amrinone is an inhibitor of phosphodiesterase 3 (PDE3; IC₅₀ = 19.5 μM). It increases developed tension and contractile force in isolated cat papillary muscle. Amrinone (1-10 mg/kg) has positive inotropic effects, increasing the rate and force of heart contraction in anesthetized and unanesthetized dogs.

Chemical properties

Crystalline Solid

Originator

Sterling-Winthrop (USA)

The Uses of Amrinone

Amrinone is used for short-term treatment of cardiac insufficiency that does not respond to treatment of other drugs.

The Uses of Amrinone

A selective cAMP phosphodiesterase (PDE-3) inhibitor with positive inotropic and vasodilatory activity. Cardiotonic

The Uses of Amrinone

analgesic, antipyretic, antiinflammatory

Indications

Used in the treatment of congestive heart failure.

Background

Amrinone (or inamrinone) is a type 3 pyridine phosphodiesterase inhibitor. It is used in the treatment of congestive heart failure.

What are the applications of Application

Amrinone is a selective cAMP phosphodiesterase inhibitor

Definition

ChEBI: Amrinone is a 3,4'-bipyridine substituted at positions 5 and 6 by an amino group and a keto function respectively. A pyridine phosphodiesterase 3 inhibitor, it is a drug that may improve the prognosis in patients with congestive heart failure. It has a role as an EC 3.1.4.* (phosphoric diester hydrolase) inhibitor.

Manufacturing Process

A mixture containing 10g of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, 200 ml of dimethylformamide and 1.5 g of 10% palladium-on-charcoal was hydrogenated under pressure (50 psi) at room temperature until the uptake of hydrogen ceased (about 30 minutes). The reaction mixture was filtered through infusorial earth and the filtrate was heated in vacuum to remove the solvent. The residual material was crystallized from dimethylformamide, washed successively with ethanol and ether, and dried in a vacuum oven at 80°C for 8 hours to yield 6 g of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, melting point 294° to 297°C with decomposition.

brand name

Inocor (Sterling Winthrop).

Therapeutic Function

Cardiotonic

General Description

During normal heart function, cAMP performsimportant roles in regulating intracellular calcium levels.That is, certain calcium channels and storage sites forcalcium must be activated by cAMP-dependant protein kinases.Because cAMP plays an indirect role in the contractilityprocess, agents that inhibit its degradation will providemore calcium for cardiac contraction. One phosphodiesteraseenzyme that is involved in the hydrolysis of myocardiumcAMP is F-III. Amrinone, 5-amino (3,4 -dipyridin)-6 1 (H)-one (Inocor), possesses positive isotropic effects as aresult of its ability to inhibit this phosphodiesterase. In 1999,the USP Nomenclature Committee and the United StatesAdopted Names (USAN) Council approved changing thenonproprietary name and the current official monograph titleof amrinone to inamrinone. This change in nomenclature wasa result of amrinone being confused with amiodarone becauseof the similarity of the names. This was reported to cause confusionbetween the products that led to medication errors,some of which resulted in serious injury or death.

Pharmacokinetics

Amrinone is a positive inotropic cardiotonic with vasodilator properties, phosphodiesterase inhibitory activity, and the ability to stimulate calcium ion influx into the cardiac cell.

Safety Profile

Poison by ingestion andintravenous routes. Human systemic effects by ingestion:cardiac arrhythmias, liver function, thrombocytopenia. Anexperimental teratogen. Other experimental reproductiveeffects. When heated to decomposition it emits toxicfumes o

Synthesis

Amrinone, 3-amino-5-(4-piridinyl)-2(1H)-pyridinone (17.2.4), can be synthesized from piridine-4-acetic acid, the reaction of which with a mixture of diemthylformamide?a phosphorous oxychloride gives 2-(4-piridyl)-3-dimethylaminoacrolein (17.2.1). Reacting this with cyanoacetamide gives 3-cyano-5-(4-piridyl)-2(1H)-pyidinone (17.2.2). Hydrolysis of the cyano group of this product gives 3-carbamyl-5-(4-piridyl)-2(1H)-pyidinone (17.2.3). A Hofmann rearrangement of this product (using bromine in sodium hydroxide) gives amrinone (17.2.4).
An alternative method for the synthesis of amrinone from 3-cyano-5-(4-piridyl)-2(1H)- pyridinone (17.2.2) is based on it?ˉs acidic hydrolysis to the corresponding acid, 3-carboxy- 5-(4-piridyl)-2(1H)-pyridinone (17.2.5), nitration of which with nitrous acid in the presence of sulfuric acid forms 3-nitro-5-(4-piridyl)-2(1H)-pyridinone (17.2.6). Reducing the nitro group of this product with hydrogen gives the desired amrinone (17.2.4).

Metabolism

Hepatic.