PRIMACOR is a positive inotrope and vasodilator, with little chronotropic activity
different in structure and mode of action from either the digitalis glycosides
PRIMACOR, 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 PRIMACOR
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
PRIMACOR 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 PRIMACOR produces increases in the slope of the left
ventricular pressure-dimension relationship, indicating a direct inotropic effect
of the drug. PRIMACOR 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, PRIMACOR 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%, few of which were thought to be drug-related.
Following intravenous injections of 12.5 mcg/kg to 125 mcg/kg to congestive
heart failure patients, PRIMACOR had a volume of distribution of 0.38 liters/kg,
a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13
liters/kg/hr. Following intravenous infusions of 0.20 mcg/kg/min to 0.70 mcg/kg/min
to congestive heart failure patients, the drug had a volume of distribution
of about 0.45 liters/kg, a mean terminal elimination half-life of 2.4 hours,
and a clearance of 0.14 liters/kg/hr. These pharmacokinetic parameters were
not dose-dependent, and the area under the plasma concentration versus time
curve following injections was significantly dose-dependent.
PRIMACOR has been shown (by equilibrium dialysis) to be approximately 70% bound
to human plasma protein.
The primary route of excretion of PRIMACOR in man is via the urine. The major
urinary excretions of orally administered PRIMACOR 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 two hours
following dosing and approximately 90% recovered within the first eight hours
following dosing. The mean renal clearance of PRIMACOR is approximately 0.3
liters/min, indicative of active secretion.
In patients with heart failure due to depressed myocardial function, PRIMACOR
produced a prompt dose and plasma concentration related increase in cardiac
output and decreases in pulmonary capillary wedge pressure and vascular resistance,
which were accompanied by mild-to-moderate increases in heart rate. Additionally,
there is no increased effect on myocardial oxygen consumption. In uncontrolled
studies, hemodynamic improvement during intravenous therapy with PRIMACOR was
accompanied by clinical symptomatic improvement, but the ability of PRIMACOR
to relieve symptoms has not been evaluated in controlled clinical trials. The
great majority of patients experience improvements in hemodynamic function within
5 to 15 minutes of the initiation of therapy.
In studies in congestive heart failure patients, PRIMACOR when administered
as a loading injection followed by a maintenance infusion produced significant
mean initial increases in cardiac index of 25 percent, 38 percent, and 42 percent
at dose regimens of 37.5 mcg/kg/0.375 mcg/kg/min, 50 mcg/kg/0.50 mcg/kg/min,
and 75 mcg/kg/0.75 mcg/kg/min, respectively. Over the same range of loading
injections and maintenance infusions, pulmonary capillary wedge pressure significantly
decreased by 20 percent, 23 percent, and 36 percent, respectively, while systemic
vascular resistance significantly decreased by 17 percent, 21 percent, and 37
percent. Mean arterial pressure fell by up to 5 percent at the two lower dose
regimens, but by 17 percent at the highest dose. Patients evaluated for 48 hours
maintained improvements in hemodynamic function, with no evidence of diminished
response (tachyphylaxis). A smaller number of patients have received infusions
of PRIMACOR for periods up to 72 hours without evidence of tachyphylaxis.
The duration of therapy should depend upon patient responsiveness.
PRIMACOR has a favorable inotropic effect in fully digitalized patients without
causing signs of glycoside toxicity. Theoretically, in cases of atrial flutter/fibrillation,
it is possible that PRIMACOR may increase ventricular response rate because
of its slight enhancement of AV node conduction. In these cases, digitalis should
be considered prior to the institution of therapy with PRIMACOR.
Improvement in left ventricular function in patients with ischemic heart disease
has been observed. The improvement has occurred without inducing symptoms or
electrocardiographic signs of myocardial ischemia.
The steady-state plasma milrinone concentrations after approximately 6 to 12
hours of unchanging maintenance infusion of 0.50 mcg/kg/min are approximately
200 ng/mL. Near maximum favorable effects of PRIMACOR on cardiac output and
pulmonary capillary wedge pressure are seen at plasma milrinone concentrations
in the 150 ng/mL to 250 ng/mL range.