Milrinone

Summary

Synopsis

Milrinone is a bipyridine derivative of amrinone, with approximately 10 to 75 times greater positive inotropic potency, and separate direct vasodilatory properties. As with amrinone, the relative importance of these properties to treatment of congestive heart failure still remain controversial. The mode of action of milrinone appears to be due in part to selective inhibition of a specific cardiac phosphodiesterase with a subsequent increase in intracellular cyclic adenosine monophosphate and alteration in intracellular and extracellular calcium transport. Clinical experience has involved both short and long term treatment of a limited number of patients with moderate to severe congestive heart failure refractory to conventional therapy. Milrinone has usually been administered as intravenous bolus doses (12.5 to 75 μg/kg) and/or continuous intravenous infusion (0.5 μg/kg/ min), or orally (30 to 40 mg/day in divided doses). Milrinone rapidly improves cardiac performance by enhancing myocardial contractility, and by decreasing systemic vascular resistance (afterload), left ventricular filling pressure (preload), and pulmonary arterial pressure. Exercise performance improvement occurs with enhancement of left ventricular performance but without a significant increase in myocardial oxygen consumption or significant decrease in mean arterial pressure. Milrinone has been compared with dobutamine, nitroprusside and captopril in preliminary short term studies in patients with severe congestive heart failure. Milrinone significantly increased stroke work index and decreased left ventricular filling pressure compared to nitroprusside. When compared with dobutamine, both drugs improved cardiac index (to a similar degree), but milrinone significantly reduced right atrial pressure, pulmonary capillary wedge pressure and left ventricular end-diastolic pressure. One small study suggests that short term effects of intravenous milrinone may be superior to those of oral captopril, and it appears that the addition of captopril to milrinone therapy may produce a synergistic haemodynamic effect.

Preliminary long term studies suggest that tolerance to the haemodynamic effects of milrinone does not occur, and that the drug is well tolerated and without the thrombocytopenic effects, fever and gastrointestinal complications observed with amrinone. However, it has not been demonstrated that milrinone improves the prognosis of the disease or the overall mortality and its propensity to produce arrhythmias has not been fully agreed upon. Until these questions have been adequately addressed, milrinone will probably remain a drug used only in patients with severe congestive heart failure refractory to more established treatments.

Pharmacodynamic Studies

Milrinone produces concentration-dependent inotropic effects in isolated atrial and papillary muscles from a number of animal species, with an attenuation of inotropic effects occurring at high concentrations. In dog Purkinje fibres, milrinone significantly prolonged action potential duration.

Single intravenous bolus doses, continuous infusions or oral doses in anaesthetised or conscious healthy dogs produced significant dose-related increases in contractile force and heart rate with minimal effects on systolic and diastolic blood flow at lower doses. At higher doses (up to 1.0 mg/kg), milrinone decreased both systolic and diastolic blood pressure, and produced dose-related increases in left ventricular filling pressure. Pretreatment with reserpine, indomethacin, α - and β-adrenergic blockers, histamine antagonists, ganglionic or cholinergic blocking agents does not affect the inotropic responses to milrinone. Intravenous administration of milrinone to anaesthetised dogs with experimentally induced heart failure improved cardiac output and increased contractile force.

Milrinone significantly increased renal artery blood flow with significant decreases in renal vascular resistance in anaesthetised dogs. Similarly, a substantial increase in human renal blood flow has been demonstrated following single oral doses. However, the effect of multiple doses of milrinone on renal blood flow was less consistent. In one study, 1 month’s oral therapy produced marked improvement in forearm vascular resistance with no significant change in renal blood flow, renal vascular resistance or glomerular filtration rate, whereas other short term studies have demonstrated significant increases in renal artery blood flow with corresponding decreases in renal vascular resistance.

Milrinone appears to have significant direct vasodilatory (particularly of the systemic beds) and smooth muscle relaxant activity as evidenced by in vitro and in vivo studies in both animal models and humans. Milrinone reduces both right atrial pressure and systemic arterial pressure despite an increase in cardiac output. However, nitroprusside is more effective as a vasodilator than milrinone. The observed effects of milrinone on blood pressure in congestive heart failure patients are variable with both increases and decreases in peak arterial pressure being seen.

Milrinone markedly improves conduction and action potential in depressed animal heart preparations, although enhancement of atrioventricular conduction is the only significant electrophysiological change observed in congestive heart failure patients.

Milrinone’s mechanism of action remains controversial but appears to involve the inhibition of the cardiac phosphodiesterase fraction which is specific for cyclic adenosine monophosphate and suggests that the drug’s effect may be dependent on intracellular and extracellular calcium transport.

Pharmacokinetic Studies

The pharmacokinetics of milrinone have been studied following single and repeated oral doses, single intravenous bolus doses and after continuous intravenous infusion. Initial studies suggest that the pharmacokinetic profile of milrinone does not change with repeated doses. Peak plasma concentrations of 133 to 454 μg/L (intravenous bolus doses of 12.5 to 75 μg/kg), 81 to 277 μg/L (intravenous infusion of 0.2 to 0.7 μg/kg/min) and 63 to 294 μg/L (oral doses of 2.5 to 10mg) have been recorded in patients with congestive heart failure.

Volume of distribution was 0.32 L/kg after intravenous bolus administration of milrinone in healthy subjects, and 0.3 to 0.42 L/kg (intravenous bolus), 0.47 L/kg (intravenous infusions) and 0.53 to 0.56 L/kg (oral) in congestive heart failure patients. Bio-availability is approximately 85 to 92% after oral administration.

In animal species, the major metabolic pathways for milrinone metabolism appear to be oxidative and conjugative, with glucuronidation being the major pathway of bio-transformation, although the parent drug is the major excretion product. Elimination half-life of milrinone is approximately 48 to 56 minutes in healthy subjects following intravenous or oral administration of 10 to 125 μg/kg and 1.0 to 12.5mg, respectively, but is extended to 3.2 hours in patients with severe chronic renal failure. In patients with congestive heart failure, elimination half-lives of 1.2 to 2.7 hours are seen. Plasma clearance following oral and intravenous administration of milrinone is about 18 to 24 L/h in healthy subjects, about 7.8 to 12 L/h in congestive heart failure patients and about 1.8 L/h in patients with chronic renal failure.

Therapeutic Trials

Milrinone has been used only in the treatment of moderate to severe congestive heart failure (New York Heart Association functional Class HI and IV) refractory to conventional therapy. Patients treated with milrinone usually continued receiving cardiac glycosides and diuretic therapy whereas vasodilator drugs were usually discontinued. Single-dose and short term administration using oral and intravenous doses demonstrated significant improvement in left ventricular filling pressure (10 to 34%), cardiac index (10 to 76%) and left ventricular stroke work index (21 to 57%), and significant decreases in left ventricular end-diastolic pressure (31 to 45%), pulmonary capillary wedge pressure (4 to 52%), pulmonary arterial pressure (10 to 29%), right atrial pressure (13 to 60%), systemic vascular resistance (14 to 42%) and peripheral vascular resistance (17 to 53%). Left ventricular ejection was consistently improved by milrinone therapy. Following intravenous administration, peak haemodynamic responses occurred after 5 to 10 minutes and lasted about 1 hour, whereas following oral administration of milrinone, peak haemodynamic effects occurred at 1.2 to 2.1 hours and persisted for up to 6 hours. Many studies found dose-dependent haemodynamic responses to both oral and intravenous administration of milrinone although some inconsistencies in this trend have been observed. Repeated oral administration, and continuous intravenous infusion or intravenous bolus administration have demonstrated no evidence of tolerance to the haemodynamic effects of milrinone.

Long term therapy in relatively small numbers of congestive heart failure patients has shown oral milrinone to be well tolerated with few side effects. Substantial improvement in cardiac haemodynamics and reduction in fatigue were usually seen within the first 1 to 2 weeks of therapy and most studies reported sustained haemodynamic benefits during long term therapy. However, improvements in long term survival following milrinone therapy have yet to be demonstrated and as there are no placebo-controlled studies it is not possible to discount a training effect. Haemodynamic deterioration has been observed following withdrawal of long term milrinone therapy, but which haemodynamic parameters are modified and to what extent the underlying disease has progressed or been retarded has yet to be clarified.

Significant improvement in exercise capacity along with increases in cardiac index, cardiac output, stroke volume index, improvement in left ventricular function and maximal oxygen uptake have been seen following single and repeated doses of intravenous and oral milrinone in patients with congestive heart failure. In one study these improvements were sustained for at least 3 months, and were more significant than those produced by digoxin.

Milrinone has been evaluated in several single-dose or short term comparative studies with other inotropic and vasodilator agents including dobutamine, nitroprusside and captopril. When dobutamine infusion (0.5 to 1.0 μg/kg/min) was compared with intravenous milrinone (50 to 75 μg/kg), both drugs produced similar sustained improvement in cardiac index; however, milrinone significantly decreased pulmonary capillary wedge pressure, right atrial pressure, left ventricular end-diastolic pressure and mean systemic arterial pressure more than dobutamine, whereas dobutamine increased heart rate to a greater extent than did milrinone, thereby increasing myocardial oxygen demand which was not evident with milrinone. Milrinone (12.5 to 75 μg/kg) increased cardiac output to a much greater extent than did nitroprusside infusions (10 to 300 μg/min), with left ventricular end-diastolic pressure being significantly lower with milrinone. In addition, stroke volume and stroke work index were higher with milrinone and milrinone exhibited a significant dose-related increase in peak rate of change of left ventricular filling pressure. Heart rate was also more significantly increased with milrinone. In studies comparing captopril with milrinone it was observed that milrinone increases cardiac index to a greater extent than does captopril. Improvements in renal blood flow were seen with both drugs. Captopril significantly decreased systemic arterial pressure which was not observed with milrinone, whereas milrinone produced greater improvement in ventricular performance. Neither drug had any significant effect on heart rate. There is some evidence to suggest the potential for synergistic clinical effects with milrinone and captopril. In preliminary long term comparative studies milrinone showed evidence of producing more sustained and significant improvements in haemodynamic measurements than digoxin in both resting and exercised patients, although, again, improvements in long term mortality rates were not demonstrated.

Side Effects

Thus far, the side effects that have been reported with milrinone are few in number, but may not represent a true and complete profile that only long term use in a large number of patients may reveal. Preliminary data from studies so far conducted have shown that milrinone use has been associated with a low frequency of headache, mild diarrhoea, hyperthyroidism, increased frequency of anginal pain, and fluid retention. Thrombocytopenia does not appear to be a major adverse effect with milrinone, as it was with amrinone, although it does occur in a small proportion of patients. The most worrisome possibility is that of increased incidence of cardiac arrhythmias with milrinone, and this requires further investigation.

Dosage and Administration

Most studies using intravenous doses suggest that bolus doses of 25 μg/kg or infusion doses of up to 0.7 μg/kg/min produce the optimal therapeutic response (improved haemodynamic indices and acceptable tolerance). Higher doses may not necessarily improve the haemodynamic response to milrinone but may increase unwanted effects. With oral dosages, maximal improvements occur with 10mg doses at 6-hourly dosing intervals.