Inotrope – Vasodilator
Action And Clinical Pharmacology: 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 it 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 and plasma level-related increase in left ventricular dP/dt, increase in forearm blood flow indicating a direct arterial vasodilator activity of the drug, and improves diastolic function as evidenced by improvement in left ventricular diastolic relaxation.
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. Both the inotropic and vasodilatory effects have been observed over the therapeutic range of milrinone plasma concentrations of 100 to 300 ng/mL.
Pharmacokinetics: Following i.v. loading injections of 12.5 to 125 g/kg to congestive heart failure patients, i.v. milrinone had a volume of distribution of 0.38 L/kg, a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13 L/kg/h. Following i.v. infusions of 0.2 to 0.7 g/kg/min to congestive heart failure patients, the drug had a volume of distribution of about 0.45 L/kg, a mean terminal elimination half-life of 2.4 hours, and a clearance of 0.14 L/kg/h. These pharmacokinetic parameters were not dose-dependent, while the area under the plasma concentration versus time curve following loading injections was significantly dose-dependent.
The steady-state milrinone plasma levels after approximately 6 to 12 hours of unchanging maintenance infusion of 0.5 g/kg/min are approximately 200 ng/mL.
Milrinone has been shown (by ultracentrifugation) to be in excess of 70% bound to human plasma proteins at plasma concentrations of 70 to 400 ng/mL.
The primary route of excretion of milrinone in man is via the urine, with much smaller amounts recovered in the feces. The major urinary excretion products in man are milrinone (83%) and its 0-glucuronide metabolite (12%). Elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first 2 hours following dosing, and approximately 90% recovered within the first 8 hours following dosing. The mean renal clearance of milrinone is approximately 0.3 L/min while that of the metabolites is even greater, indicative of active secretion.
In patients with moderate to severe renal impairment, both Cmax (210 ng/mL) and tmax (1.19 h) were increased compared to subjects with normal renal function (162 ng/mL and 0.64 h, respectively). The half-life of milrinone increased from 0.94 h in subjects with normal renal function to 1.71 h in patients with moderate renal impairment and to 3.09 h in patients with severe renal impairment.
Pharmacodynamics: In patients with congestive heart failure, i.v. milrinone produces prompt, significant improvements in cardiac output, pulmonary capillary wedge pressure, and vascular resistance without clinically significant increases in heart rate or myocardial oxygen consumption. Onset of action generally occurs within 5 to 15 minutes.
Improvement in left ventricular function and relief of congestive heart failure symptoms in patients with ischemic heart disease have been observed. The improvement has occurred without inducing symptoms or electrocardiographic signs of myocardial ischemia.
In studies in congestive heart failure patients, milrinone administered as a loading injection followed by a maintenance infusion produced the following pharmacodynamic changes
Patients evaluated for 48 hours maintained improvements in hemodynamic function, with no evidence of diminished response (tachyphylaxis), and in a small number of patients no evidence of tachyphylaxis was seen for as long as 72 hours of infusion.
The duration of therapy should depend upon patient responsiveness. Patients have been maintained on infusion of milrinone up to 5 days.
I.V milrinone is effective in fully digitalized patients without affecting glycoside plasma levels.
Milrinone has been shown to enhance atrio-ventricular nodal conduction rate (see Precautions).
Indications And Clinical Uses: For the short-term management of severe congestive heart failure including low output states following cardiac surgery. The majority of experience with the drug has been in patients receiving digoxin and diuretics. In some patients, milrinone has been shown to increase ventricular ectopy (see Warnings).
Contra-Indications: In patients who are hypersensitive to it or to any of its ingredients.
Manufacturers’ Warnings In Clinical States: Supraventricular and ventricular arrhythmias have been observed in the high risk population of congestive heart failure patients treated with milrinone. In using the drug, consideration should be given to the fact that in some patients, milrinone has been associated with an increase in ventricular ectopy including ventricular tachycardia or fibrillation (see Adverse Effects). The incidence of arrhythmias has not been shown to be related to the dose or plasma level of milrinone. Patients receiving milrinone should be closely monitored during infusion.
No clinical studies have been conducted in patients in the acute phase of post myocardial infarction. Until further clinical experience is gained, milrinone is not recommended in these patients.
Precautions: Milrinone should not be used in lieu of surgical relief of the obstruction in patients with severe obstructive aortic or pulmonic valvular disease. Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis.
Milrinone has been shown to enhance AV nodal conduction rate, indicating a potential for an increased ventricular response rate in patients with atrial flutter/fibrillation which is not being controlled with digitalis therapy. Digitalization of these patients should be considered prior to the administration of milrinone.
During therapy with milrinone, blood pressure and heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decrease in blood pressure.
Patients who have received vigorous diuretic therapy may have insufficient cardiac filling pressure to respond adequately to milrinone, in which case cautious liberalization of fluid and electrolyte intake may be indicated.
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 milrinone administration.
Renally Impaired Patients: Data obtained from patients with severe renal impairment (creatinine clearance = 0 to 30 mL/min) but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of milrinone. Reductions in the infusion rate may be necessary in patients with renal impairment (see Dosage).
Geriatrics: Experience so far suggests that no special dosage recommendations for the elderly patient are necessary.
Pregnancy: Milrinone did not appear to be teratogenic when administered i.v. to pregnant rats at doses up to 3 mg/kg/day or pregnant rabbits at doses up to 12 mg/kg/day, although an increase in resorption rate was apparent at both 8 and 12 mg/kg/day (i.v.) in the latter species.
There are no studies in pregnant women. Milrinone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: Caution should be exercised when milrinone is administered to nursing women, since it is not known whether it is excreted in human milk.
Children: Safety and effectiveness in children have not been established.
Drug Interactions: No untoward clinical manifestations have been observed in 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: Precipitation occurs immediately when furosemide is mixed with milrinone solution. Therefore, furosemide should not be administered in i.v. lines containing milrinone.
Other drugs should not be mixed with milrinone until further compatibility data are available.
Animal Toxicity: Oral and i.v. 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.
Adverse Reactions: In clinical trials involving 413 patients who received milrinone, the most frequent adverse effects observed were ventricular arrhythmias (12.6%) and the most severe adverse effect observed was ventricular fibrillation (0.2%).
Adverse reactions occurring in patients treated with milrinone are shown below in order of decreasing frequency (percentages indicated in parentheses): ventricular arrhythmias (12.6), ventricular ectopic activity (9.0), ventricular tachycardia (3.6), ventricular fibrillation (0.2), supraventricular arrhythmias (3.6), hypotension (3.1), headache (2.4), angina pectoris/chest pain (1.4), hypokalemia (0.7), thrombocytopenia (0.5), tremor (0.5).
Symptoms And Treatment Of Overdose: Symptoms and Treatment: No specific antidote to milrinone is known, but general measures for circulatory support should be taken. Milrinone may produce hypotension because of its vasodilator effect. In case of overdose, administration of milrinone should be reduced or temporarily discontinued until the patient’s condition stabilizes.
Dosage And Administration: Prior correction or adjustment of fluid/electrolytes may be necessary to obtain a satisfactory response with milrinone (see Precautions).
Milrinone injection is a clear colorless to pale yellow solution. Vials should be inspected visually and should not be used if particulate matter or discoloration is present.
Suitable diluents include normal or half normal saline or sterile 5% dextrose solution.
Diluted solution should be used within 24 hours.
Furosemide should not be added to milrinone injection due to a chemical interaction.
Drug Administration: Milrinone should be administered with a loading dose followed by a continuous infusion (maintenance dose) according to the following guidelines (see Table II).
The infusion rate should be adjusted according to hemodynamic and clinical response. Patients should be closely monitored. In controlled clinical studies most patients showed an improvement in hemodynamic status as evidenced by increases in cardiac output and reduction in pulmonary capillary wedge pressure. Dosage may be titrated to the maximum hemodynamic effect but should not exceed 1.13 mg/kg/day. Duration of therapy should depend upon patient responsiveness.
Reconstituted Solutions: For ease of administration milrinone may be diluted with suitable diluents such as normal or half normal saline or sterile 5% dextrose solution, or may be used undiluted if suitable equipment is available.
Diluted solutions should be used within 24 hours.
For detailed information regarding dilution, see above.
Since precipitation occurs immediately when furosemide is mixed with milrinone solution, furosemide should not be administered in i.v. lines containing milrinone.
Availability And Storage: Each mL of sterile, clear, colorless to pale yellow solution contains: milrinone lactate equivalent to 1 mg milrinone and anhydrous dextrose USP 47 mg, in water for injection. The pH is adjusted to between 3.2 and 4.0 with lactic acid or sodium hydroxide. The total concentration of lactic acid can vary between 0.95 and 1.29 mg/mL. Single dose vials of 10 and 20 mL. Store vials at room temperature (15 to 30°C). Avoid freezing.
PRIMACOR® Sanofi Milrinone Lactate Inotrope – Vasodilator
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