Milrinone

Milrinone is a positive inotrope and vasodilator, with little chronotropic activity. It also improves left ventricular diastolic relaxation. It differs in structure and mode of action from the digitalis glycosides, catecholamines or angiotensin converting enzyme inhibitors. It is a selective inhibitor of peak III phosphodiesterase isoenzyme in cardiac and vascular muscle. It produces slight enhancement of A-V node conduction, but no other significant electrophysiological effects.

In clinical studies Milrinone Injection has been shown to produce prompt improvements in the haemodynamic indices of congestive heart failure, including cardiac output, pulmonary capillary wedge pressure and vascular resistance, without clinically significant effect on heart rate or myocardial oxygen consumption.

Haemodynamic improvement during intravenous milrinone therapy is accompanied by clinical symptomatic improvement in congestive cardiac failure, as measured by change in New York Heart Association classification.

Following intravenous injections of 12.5 to 125mcg/kg to congestive heart failure patients, Milrinone Injection had a volume of distribution of 0.38 l/kg/hr, a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13 l/kg/hr.

Following intravenous infusions of 0.2 to 0.7mcg/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/hr. These pharmacokinetic parameters were not dose-dependent, and the area under the plasma concentration versus time curve following injection was significantly dose-dependent.

The primary route of excretion of milrinone in man is via the urine. Elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first two hours following dosing, and approximately 90% recovered within the first eight hours following dosing. The mean renal clearance of milrinone is approximately 0.3 l/min, indicative of active secretion.

Paediatric population

Milrinone is cleared more rapidly in children than in adults, but infants have significantly lower clearance than children, and preterm infants have even lower clearance. As a consequence of this more rapid clearance compared to adults, steady-state plasma concentrations of milrinone were lower in children than in adults. In paediatric population with normal renal function steady-state milrinone plasma concentrations after 6 to 12 hours continuous infusion of 0.5 to 0.75 μg/kg/min were about of 100 to 300 ng/ml.

Following intravenous infusion of 0.5 to 0.75 μg/kg/min to neonates, infants and children after open heart surgery, milrinone has a volume of distribution ranging from 0.35 to 0.9 litres/kg with no significant difference across age groups. Following intravenous infusion of 0.5 μg/kg/min to very preterm infants to prevent low systemic outflow after birth, milrinone has a volume of distribution of about 0.5 litres/kg.

Several pharmacokinetic studies showed that, in paediatric population, clearance increases with increasing age. Infants have significantly lower clearance than children (3.4 to 3.8 ml/kg/min versus 5.9 to 6.7 ml/kg/min). In neonates milrinone clearance was about 1.64 ml/kg/min and preterm infants have even lower clearance (0.64 ml/kg/min).

Milrinone has a mean terminal half-life of 2 to 4 hours in infants and children and a mean terminal elimination half-life of 10 hours in preterm infants.

It was concluded that the optimal dose of milrinone in paediatric patients in order to obtain plasma levels above the threshold of pharmacodynamic efficacy appeared higher than in adults, but that optimal dose in preterms in order to obtain plasma levels above the threshold of pharmacodynamic efficacy appeared lower than in children.

Patent ductus arteriosus

Milrinone is cleared by renal excretion and has a volume of distribution that is restricted to extracellular space which suggests that the fluid overload and hemodynamic changes associated with patent ductus arteriosus may have an effect on distribution and excretion of milrinone.

Juvenile animals

A preclinical study was performed to clarify the ductus-dilating effects of PDE 3 inhibitors in near-term rat pups and their differential effects in near-term and preterm foetal rats. Postnatal ductus arteriosus dilatation by milrinone was studied with three doses (10, 1 and 0.1mg/kg). The dilating effects of milrinone in the foetal ductus constricted by indomethacin were studied by simultaneous administration of milrinone (10, 1 and 0.1mg/kg) and indomethacin (10 mg/kg) to the mother rat at D21 (near-term) and D19 (preterm). This in vivo study has shown that milrinone induces dose-dependent dilation of the foetal and the postnatal constricted ductus arteriosus. Dilating effects were more potent with injection immediately after birth than at 1 hour after birth. In addition, study showed that the premature ductus arteriosus is more sensitive to milrinone than the mature ductus arteriosus.