Milrinone

Milrinone is an Inotropic agent belonging to Phosphodiesterase Enzyme Inhibitor.

Milrinone is approved for treating short-term IV therapy for patients with acute decompensated heart failure. It is also used in the treatment of low cardiac output Syndrome, Pre-transplantation, and Adjunctive therapy in septic shock.

When administered as an IV bolus dose of 10-100 μg/kg, milrinone induces hemodynamic effects within 60 seconds. reaching a peak effect by 2-5 minutes. The plasma AUC is significantly dose-dependent. Milrinone administered intravenously to congestive heart failure patients had a volume of distribution of 0.38 L/kg (injections between 12.5-125 μg/kg) and 0.45 L/kg (infusions between 0.2-0.7 μg/kg/min. Milrinone is primarily excreted in the urine, with 60% of a dose recovered after 2 hours and 90% within eight hours. Approximately 83% of milrinone recovered in urine is unchanged while 12% is present as the main O-glucuronide metabolite.

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

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

Milrinone is available in India, Denmark, the UK, USA.

Milrinone, belonging to Phosphodiesterase Enzyme Inhibitor, acts as an Inotropic agent. Milrinone works by improving cardiac contractility (inotropy), cardiac relaxation (lusitropy), and inducing vasodilation and has the overall effect of increased cardiac output, improvement of left ventricle-arterial coupling, and enhanced cardiac mechanical efficiency

Milrinone is a phosphodiesterase inhibitor with a measured IC₅₀ value of between 0.66 and 1.3 μM. As a PDE-III inhibitor, milrinone results in an increase in intracellular cAMP, responsible for its pharmacological effects, including positive inotropy, positive lusitropy, and vasodilation.

The onset of action of Milrinone occurs within 5-15 minutes.

The Duration of Action for Milrinone occurs within 2-4 hours.

The Tmax was found within 1.19 hours and Cmax in blood reached up to 210 ng/ml.

• For Injection:

Each dose should be given by the IV 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.

Milrinone is approved for treating short-term IV therapy for patients with acute decompensated heart failure. It is also used in the treatment of low cardiac output Syndrome, Pre-transplantation, and Adjunctive therapy in septic shock.

Milrinone is a selective phosphodiesterase III inhibitor with positive inotropic and vasodilator activity but has minimal chronotropic activity. It acts on the cardiac and vascular muscles by selectively inhibiting the cyclic adenosine monophosphate (cAMP) phosphodiesterase activity resulting in an increased intracellular concentration of cAMP which produces increased myocardial contractility and vascular muscle relaxation.

Milrinone is approved for use in the following clinical indications:

• Heart failure:

Continuous infusion: IV: Initial: 0.125 mcg/kg/minute; dosing range: 0.125 to 0.75 mcg/kg/minute; titrate based on clinical end point (eg, end organ perfusion).

Use the lowest effective dose to minimize adverse effects (eg, arrhythmia, hypotension)

Although not approved there has been certain off label indication documented for Milrinone which includes:

• Postoperative inotropic support in heart transplant recipients

Continuous infusion: IV: Usual dose range: 0.375 to 0.75 mcg/kg/minute; titrate to the lowest effective dose based on clinical response and hemodynamic endpoints; wean as tolerated over the first 3 to 5 days following surgery

• Low cardiac output Syndrome and

• Adjunctive therapy in septic shock.

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

Milrinone is available in dosage strength as 10mg/ml, 20 mg/ml and 40 mg/ml

Milrinone is available in the form of injections.

Milrinone 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.

Milrinone may be contraindicated in the following

• Pulmonary valvular disease
• Hypertrophic subaortic stenosis in lieu of surgical relief of obstruction
• Severe hypovolaemia.

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

Whether given orally or by continuous or intermittent intravenous infusion, Milrinone has not been shown to be safe or effective in the longer (greater than 48 hours) treatment of patients with heart failure. In a multicenter trial of 1088 patients with Class III and IV heart failure, long-term oral treatment with Milrinone was associated with no improvement in symptoms and an increased risk of hospitalization and death. In this study, patients with Class IV symptoms appeared to be at particular risk of life-threatening cardiovascular reactions. There is no evidence that Milrinone given by long-term continuous or intermittent infusion does not carry a similar risk. The use of Milrinone both intravenously and orally has been associated with increased frequency of ventricular arrhythmias, including non-sustained ventricular tachycardia. Long-term oral use has been associated with an increased risk of sudden death. Hence, patients receiving Milrinone should be observed closely with the use of continuous electrocardiographic monitoring to allow the prompt detection and management of ventricular arrhythmias.

PRECAUTIONS

General

Milrinone should not be used in patients with severe obstructive 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.

Supraventricular and ventricular arrhythmias have been observed in the high-risk population treated. In some patients, injections of Milrinone have been shown to increase ventricular ectopy, including nonsustained ventricular tachycardia. The potential for arrhythmia, present in congestive heart failure itself, may be increased by many drugs or combinations of drugs. Patients receiving Milrinone should be closely monitored during infusion.

Milrinone produces a slight shortening of AV node conduction time, indicating a potential for an increased ventricular response rate in patients with atrial flutter/fibrillation which is not controlled with digitalis therapy.

During therapy with Milrinone, blood pressure and heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decreases in blood pressure.

If prior vigorous diuretic therapy is suspected to have caused significant decreases in cardiac filling pressure, Milrinone should be cautiously administered with monitoring of blood pressure, heart rate, and clinical symptomatology.

• Use in Acute Myocardial Infarction

No clinical studies have been conducted in patients in the acute phase of post-myocardial infarction. Until further clinical experience with this class of drugs is gained, Milrinone is not recommended in these patients.

• Laboratory Tests

Fluid and Electrolytes: Fluid and electrolyte changes and renal function should be carefully monitored during therapy with Milrinone. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose digitalized patients to arrhythmias. Therefore, hypokalemia should be corrected by potassium supplementation in advance of or during the use of Milrinone.

• Drug Interactions

No untoward clinical manifestations have been observed in limited experience with patients in whom Milrinone was used concurrently with the following drugs: digitalis glycosides; lidocaine, quinidine; hydralazine, prazosin; isosorbide dinitrate, nitroglycerin; chlorthalidone, furosemide, hydrochlorothiazide, spironolactone; captopril; heparin, warfarin, diazepam, insulin; and potassium supplements.

• Chemical Interactions

There is an immediate chemical interaction which is evidenced by the formation of a precipitate when furosemide is injected into an intravenous line of an infusion of Milrinone. Therefore, furosemide should not be administered in intravenous lines containing milrinone.

• Carcinogenesis, Mutagenesis, Impairment of Fertility

Twenty-four months of oral administration of Milrinone to mice at doses up to 40 mg/kg/day (about 50 times the human oral therapeutic dose in a 50 kg patient) was unassociated with evidence of carcinogenic potential. Neither was there evidence of carcinogenic potential when Milrinone was orally administered to rats at doses up to 5 mg/kg/day (about 6 times the human oral therapeutic dose) for twenty-four months or at 25 mg/kg/day (about 30 times the human oral therapeutic dose) for up to 18 months in males and 20 months in females. Whereas the Chinese Hamster Ovary Chromosome Aberration Assay was positive in the presence of a metabolic activation system, results from the Ames Test, the Mouse Lymphoma Assay, the Micronucleus Test, and the in vivo Rat Bone Marrow Metaphase Analysis indicated an absence of mutagenic potential. In reproductive performance studies in rats, Milrinone had no effect on male or female fertility at oral doses up to 32 mg/kg/day.

• Animal Toxicity

Oral and intravenous administration of toxic dosages of Milrinone to rats and dogs resulted in myocardial degeneration/fibrosis and endocardial hemorrhage, principally affecting the left ventricular papillary muscles. Coronary vascular lesions characterized by periarterial edema and inflammation have been observed in dogs only. The myocardial/endocardial changes are similar to those produced by beta-adrenergic receptor agonists such as isoproterenol, while the vascular changes are similar to those produced by minoxidil and hydralazine. Doses within the recommended clinical dose range (up to 1.13 mg/kg/day) for congestive heart failure patients have not produced significant adverse effects in animals.

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

Pregnancy Category C

Oral administration of Milrinone to pregnant rats and rabbits during organogenesis produced no evidence of teratogenicity at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively. Milrinone did not appear to be teratogenic when administered intravenously to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times the maximum recommended clinical intravenous dose) or pregnant rabbits at doses up to 12 mg/kg/day, although an increased resorption rate was apparent at both 8 mg/kg/day and 12 mg/kg/day (intravenous) in the latter species. There are no adequate and well-controlled studies on pregnant women. Milrinone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Maintain a low salt diet and minimize eating processed foods as they contain more sodium. Try to replace salt with spices or herbs to add flavour to the food.

The adverse reactions related to the molecule Milrinone 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 Milrinone are briefly summarized here.

Administered concomitantly with cardiac glycosides, lidocaine, quinidine, hydralazine, prazosin, isosorbide dinitrate, nitroglycerin, chlorthalidone, furosemide, hydrochlorothiazide, spironolactone, captopril, heparin, warfarin, diazepam, insulin, and potassium supplements without unusual adverse effects.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

There are no special dosage recommendations for elderly patients. Ninety percent of all patients administered milrinone in clinical studies were within the age range of 45 - 76 years, with a mean age of 61 years. Patients in all age groups demonstrated clinically and statistically significant responses. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not disclosed any age-related effects on the distribution and elimination of Milrinone.

• Symptoms: Hypotension, cardiac arrhythmia.
• Management: General supportive treatment

Pharmacodynamics:

• Milrinone is a positive inotrope and vasodilator, with little chronotropic activity different in structure and mode of action from either the digitalis glycosides or catecholamines.
• Milrinone, at relevant inotropic and vasorelaxant concentrations, is a selective inhibitor of peak III cAMP phosphodiesterase isozyme in cardiac and vascular muscle. This inhibitory action is consistent with cAMP-mediated increases in intracellular ionized calcium and contractile force in cardiac muscle, as well as with cAMP-dependent contractile protein phosphorylation and relaxation in vascular muscle. Additional experimental evidence also indicates that Milrinone is not a beta-adrenergic agonist nor does it inhibit sodium-potassium adenosine triphosphatase activity as do the digitalis glycosides.
• Clinical studies in patients with congestive heart failure have shown that Milrinone produces dose-related and plasma drug concentration-related increases in the maximum rate of increase of left ventricular pressure. Studies in normal subjects have shown that Milrinone produces increases in the slope of the left ventricular pressure-dimension relationship, indicating a direct inotropic effect of the drug. Milrinone also produces dose-related and plasma concentration-related increases in forearm blood flow in patients with congestive heart failure, indicating a direct arterial vasodilator activity of the drug.
• Both the inotropic and vasodilatory effects have been observed over the therapeutic range of plasma milrinone concentrations of 100 ng/mL to 300 ng/mL. In addition to increasing myocardial contractility, Milrinone improves diastolic function as evidenced by improvements in left ventricular diastolic relaxation. The acute administration of intravenous milrinone has also been evaluated in clinical trials in excess of 1600 patients, with chronic heart failure, heart failure associated with cardiac surgery, and heart failure associated with myocardial infarction. The total number of deaths, either on therapy or shortly thereafter (24 hours) was 15, less than 0.9%, a few of which were thought to be drug-related.

Pharmacokinetics :

• Absorption

When administered as an IV bolus dose of 10-100 μg/kg, milrinone induces hemodynamic effects within 60 seconds reaching a peak effect by 2-5 minutes. The plasma AUC is significantly dose-dependent.

• Distribution

Milrinone administered intravenously to congestive heart failure patients had a volume of distribution of 0.38 L/kg (injections between 12.5-125 μg/kg) and 0.45 L/kg (infusions between 0.2-0.7 μg/kg/min.

• Metabolism

Animal studies suggest that two oxidative pathways are involved in milrinone metabolism, albeit only involving a small proportion of the administered dose. The major metabolite is the O-glucuronide metabolite.

• Elimination

Milrinone is primarily excreted in the urine, with 60% of a dose recovered after two hours and 90% within eight hours. Approximately 83% of milrinone recovered in urine is unchanged while 12% is present as the main O-glucuronide metabolite. Milrinone administered intravenously to congestive heart failure patients had a clearance of 0.13 L/kg/hr (injections between 12.5-125 μg/kg) and 0.14 L/kg/hr (infusions between 0.2-0.7 μg/kg/min.

1. https://www.mims.com/india/drug/info/milrinone?type=full&mtype=generic

2. https://www.rxwiki.com/milrinone

3. https://reference.medscape.com/drug/milrinone-342433

4. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019436s021s022lbl.pdf

5. https://www.lhsc.on.ca/critical-care-trauma-centre/milrinone-primacor

6. https://www.ncbi.nlm.nih.gov/books/NBK532943/#article-25168.s5

7. Colucci WS. Cardiovascular effects of milrinone. American Heart Journal. 1991 Jun 1;121(6):1945-7. Doi: https://doi.org/10.1016/0002-8703(91)90829-7