Amrinone

Amrinone is an Inotropic agent belonging to Phosphodiesterase Enzyme Inhibitor.

Amrinone is approved for the treatment of the short-term management of congestive heart failure, relieving symptoms of the condition such as fatigue, weakness, edema, dyspnea, orthopnea, and paroxysmal nocturnal dyspnea.

Amrinone had a volume of distribution of 1.2 liters/kg, and following a distributive phase half-life of about 4.6 minutes in plasma, had a mean apparent first-order terminal elimination half-life of about 3.6 hours.

The common side effects associated with Amrinone include nausea, vomiting, thrombocytopenia, hypotension, chest pain, hypersensitivity, myositis, vasculitis, nail discoloration, Inj site pain, and reduced tear production.

Amrinone is available in the form of dosage forms such as injections.

Amrinone is available in India, Europe, China, USA.

Amrinone, belonging to Phosphodiesterase Enzyme Inhibitor, acts as an Inotropic agent. Amrinone works by increasing the level of a chemical messenger (cAMP), which helps the smooth muscles to relax. Thus, dilates the blood vessels for better blood flow into the heart. It also promotes the heart's contractile ability to pump more blood.

Amrinone is a phosphodiesterase inhibitor that has vasodilating and positive inotropic properties. It causes an increase in cyclic adenosine monophosphate leading to greater contractile force in cardiac muscle

The onset of action of Amrinone occurs within 5-10 minutes.

The Duration of Action for Amrinone occurs within 0.5-2 hours.

The Tmax was found within 1.4 hours and Cmax in blood reached up to 102 ± 27 ng/ml

• For Injection:

Each dose should be given by the intravenous infusion over 10 - 20 minutes. The total loading dose should be administered in divided doses with approximately half of the total dose given as the first dose and further fractions of the total dose given at intervals of 4 - 8 hours.

Amrinone is approved in the treatment of the short-term management of congestive heart failure, relieving symptoms of the condition such as fatigue, weakness, edema, dyspnea, orthopnea, and paroxysmal nocturnal dyspnea.

Amrinone is a phosphodiesterase-III (PD3) inhibitor. Inhibition of normal phosphodiesterase-III activity results in a reduction in the hydrolysis of cyclic adenosine monophosphate (cAMP); subsequently, increasing its intracellular concentrations. An increased concentration of cyclic adenosine monophosphate may upregulate the cyclic adenosine monophosphate/protein kinase A/calcium pathway in cardiac myocytes.

Amrinone is approved for use in the following clinical indications:

• Short-term management of congestive heart failure
• Relieving symptoms of the condition such as fatigue, weakness, edema, dyspnea, orthopnea, and paroxysmal nocturnal dyspnea.

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

Amrinone is available in dosage strength as 5mg/ml.

Amrinone is available in the form of injections.

Amrinone should be used for the treatment in the short-term management of congestive heart failure.

Heart Failure: Limit sodium to no more than 2,300 mg a day (eating only 1,500 mg a day is an even more effective goal). Reduce saturated fat to no more than 6% of daily calories and total fat to 27% of daily calories.

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

Amrinone may be contraindicated in the following

• The FDA stipulates that those patients who have a known hypersensitivity to Amrinone should not receive the drug.
• Given that the drug contains sodium metabisulfite, the FDA includes administering Amrinone as a contraindication if the patient has a known hypersensitivity to bisulfites.
• Additionally, clinicians should not give Amrinone to patients with aortic or pulmonic valvular disease.
• It should be administered with caution if the patient is taking disopyramide due to the drug combination’s potential to induce severe hypotension.

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

Amrinone contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Precautions

General

• Amrinone should not be used in patients with severe aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction. Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis.
• During intravenous therapy with Amrinone, blood pressure and heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decreases in blood pressure.
• Patients who have received vigorous diuretic therapy may have insufficient cardiac filling pressure to respond adequately to Amrinone, in that case, cautious liberalization of fluid and electrolyte intake may be indicated.
• Supraventricular and ventricular arrhythmias have been observed in the very high-risk population treated. While Amrinone per se has not been shown to be arrhythmogenic, the potential for arrhythmia, present in congestive heart failure itself, may be increased by any drug or combination of drugs.

Consumption of alcohol is not recommended while receiving this medicine as it may increase the risk of adverse effects and lowers blood pressure.

Teratogenic Effects (Pregnancy Category C)

Amrinone has been shown to produce fetal skeletal and gross external malformations at oral doses of 16 mg/kg and 50 mg/kg which were toxic for the rabbit. Studies in French Hy/Cr rabbits using oral doses up to 32 mg/kg/day did not confirm this finding. No malformations were seen in rats receiving Amrinone intravenously at the maximum dose used, 15 mg/kg/day (approximately the recommended daily intravenous dose for patients with congestive heart failure). There are no adequate and well-controlled studies on pregnant women. Amrinone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Banana: Avoid eating bananas when you are on Amrinone as it increases the potassium level in the body. Excess potassium can lead to heart failure or irregular heartbeat.
• Fiber Rich Foods: Foods rich in fiber like wheat bran muffins and psyllium interact with Amrinone and reduce the absorption of Amrinone from the digestive tract. So take Amrinone 1 hour before or 2 hours after eating foods that are rich in fiber.
• Salt Substitutes: Amrinone interacts with foods that contain salt substitutes, where potassium is replaced by sodium. Due to this interaction, the effectiveness of Amrinone in treating heart failure may be decreased.

The adverse reactions related to the molecule Amrinone can be categorized as

• Common Adverse effects:

Hemodynamic compromise, Dizziness, peripheral ischemia, dry mouth, asthenia, and somnolence.

• Less Common adverse effects:

Asymptomatic and symptomatic hypotension, burning, crawling, itching, numbness.

• Rare adverse effects:

Bradycardia, decompensated heart failure, cardiac arrest, and heart block.

The clinically relevant drug interactions of Amrinone are briefly summarized here.

Chemical interaction with precipitation occurs with Amrinone and dextrose or furosemide. Thus drug mixing should be avoided.

Potentially Fatal: Concurrent usage with disopyramide may lead to severe hypotension.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

The majority of the clinical experience increased with digoxin has been in the elderly population. This experience has not identified differences in the response or adverse effects between the elderly and younger patients. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in the dose selection, which should be based on renal function, and it may be useful to monitor renal function

Death has been reported with a massive accidental overdose (840 mg over three hours by initial bolus and infusion) of Amrinone, although the causal relationship is uncertain. Diligence should be exercised during product preparation and administration.

Doses of Amrinone may produce hypotension because of its vasodilator effect. If this occurs, amrinone administration should be reduced or discontinued. No specific antidote is known, but general measures for circulatory support should be taken.

In rats, the LD50 of Amrinone, as the lactate salt, was 102 mg/kg or 130 mg/kg intravenously in two different studies and 132 mg/kg orally (intragastrically); as a suspension in aqueous gum tragacanth the oral LD50 was 239 mg/kg.

Pharmacodynamics:

Amrinone is a positive inotropic cardiotonic with vasodilator properties, phosphodiesterase inhibitory activity, and the ability to stimulate calcium ion influx into the cardiac cell. Indeed, an increase in cyclic adenosine phosphate within the vascular smooth muscle causes a reduction in the intracellular calcium concentration; subsequently, relaxing the vascular smooth muscle. This systemic vasodilation decreases total peripheral and pulmonary vascular resistance, reducing both preload and afterload. The subsequent relative ease of blood flow around the vascular network combined with a stronger heartbeat increases stroke volume and cardiac output. These vasodilatory and positive inotropic effects are central in reversing the potentially deadly symptoms of heart failure.

Pharmacokinetics :

• Distribution:

10-22% bound to plasma proteins. The half-life after IV admin: 4-6 hr.

• Metabolism:

Partially metabolized in the liver.

• Excretion:

Renal Excretion accounts for 40% (unchanged) and plasma half-life is 4 hr (6 hr in patients with heart failure). The primary route of excretion in man is via the urine as both inamrinone and several metabolites (N-glycolyl, N-acetate, O-glucuronide, and N-glucuronide).

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