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9780521704632c12 CUFX213A/Peck 9780521618168 December 28, 2007 12:15
12 Sympathomimeticsassociated with cardiac surgery. It should be diluted with an equal volume of water or
0.9% saline in plastic syringes (crystal formation is seen when mixed in glass syringes)
and administered as an infusion of 5–20μg.kg−^1 .min−^1 ,which may be preceded by
aloading dose of 0.5 mg.kg−^1 ,and can be repeated up to a maximum of 3 mg.kg−^1.
Unlike catecholamines it may take up to 30 minutes to act.Mechanism of action
Enoximone works by preventing the degradation of cAMP and possibly cGMP in
cardiac and vascular smooth muscle. By effectively increasing cAMP within the
myocardium, it increases the slow Ca^2 +inward current during the cardiac action
potential. This produces an increase in Ca^2 +release from intracellular stores and
an increase in the Ca^2 +concentration in the vicinity of the contractile proteins, and
hence to a positive inotropic effect. By interfering with Ca^2 +flux into vascular smooth
muscle it causes vasodilatation.Effects
Cardiovascular – enoximone has been termed an ‘inodilator’ due to its positive
inotropic and vasodilator effects on the heart and vascular system. In patients
with heart failure the cardiac output increases by about 30% while end diastolic
filling pressures decrease by about 35%. The myocardial oxygen extraction ratio
remains unchanged by virtue of a reduced ventricular wall tension and improved
coronary artery perfusion. The blood pressure may remain unchanged or fall, the
heart rate remains unchanged or rises slightly and arrhythmias occur only rarely. It
shortens atrial, AV node and ventricular refractoriness. When used in patients with
ischaemic heart disease, a reduction in coronary perfusion pressure and a rise in
heart rate may outweigh the benefits of improved myocardial blood flow so that
further ischaemia ensues.
Miscellaneous – agranulocytosis has been reported.Kinetics
While enoximone is well absorbed from the gut an extensive first-pass metabolism
renders it useless when given orally. About 70% is plasma protein bound and
metabolism occurs in the liver to a renally excreted active sulphoxide metabolite
with 10% of the activity of enoximone and a terminal half-life of 7.5 hours. Only
small amounts are excreted unchanged in the urine and by infusion enoximone has
aterminal half-life of 4.5 hours. It has a wide therapeutic ratio and the risks of toxicity
are low. The dose should be reduced in renal failure.Milrinone
Milrinone is a bipyridine derivative and a selective phosphodiesterase III inhibitor
with similar effects to enoximone. However, it has been associated with an increased
mortality rate when administered orally to patients with severe heart failure.