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Inotropes and Heart : When to Use and When Not to Use 519

tension and some patients may develop refractory levels in the range of 0.5 to 0.9 ng/ml may be op-
vasodilation following mechanical circulatory assist timal. In general, digoxin levels below 1.0 ng/ml are
device implantation. These patients benefit well from safer and may even be more effective. A post-hoc
norepinephrine (vasoconstriction). Norepnephrine is subgroup analysis of the DIG study indicated that
also an useful agent in the treatment of transplant the effects of digoxin vary between men and women.
recipients with denervated hearts due to its direct Digoxin was associated with an increase in all-cause
effect on increasing cardiac inotropy independent of mortality among women, but not men, with systol-
myocardial catecholamine stores. ic heart failure. This may be explained that women
because of their lower BSA, may be more prone to
Adverse effects: Tachycardia, myocardial ischemia, harmful elevations of digoxin levels (≥1.2 ng/ml) [4]
and arrhythmia(effects similar to high doses dopa-
mine)
Phosphodiesterase Inhibitors
NON ADRENERGIC AGENTS Phosphodiesterase IIIa (PDE IIIa) is compartmen-
Digoxin talized in the cardiac and vascular smooth muscle,
where it terminates the signaling activity of cAMP by
Digoxin is the only safe and effective oral positive degrading it to AMP. Many specific inhibitors of PDE
inotropic agent. By inhibiting the sarcolemmal Na / IIIa, such as milrinone and enoximone, have been de-
+
K ATPase pump, digoxin impedes the transport of veloped to provide organ specific improvements in
+
sodium from the intracellular to the extracellular hemodynamics through increasing myocardial and
space reducing the transmembrane sodium gradient vascular smooth muscle cell cAMP concentrations.
further reducing the activity of the Na /Ca exchang- PDEIs cause significant peripheral and pulmonary
2+
+
er, thereby raising the intracellular calcium levels. The vasodilation, reducing afterload and preload, while
increase in the activator calcium is responsible for increasing inotropy. These effects make them well
both its inotropic and the arrhythmogenic effects of suited for use in patients with LV dysfunction and
cardiac glycosides.Digoxin does not affect heart rate pulmonary hypertension or in transplant recipients.
or blood pressure adversely. It does not increase the
myocardial oxygen demand nor reduce coronary per- Milrinone
fusion. It diminishes neurohormonal activation and Milrinone is a bipyridine, noncatecholamine, positive
improves hemodynamics at rest and during exercise. inotropic agent that can be given intravenously to pa-
Another advantage is that it is available in both in- tients with advanced systolic heart failure to improve
travenous and oral form. Most importantly, digoxin cardiac performance. It inhibits PDE-3, an intracellular
can improve symptoms and tends to reduce hos- enzyme that breaks down cyclic adenosine mono-
pitalization rate and if digoxin is withdrawn from a phosphate (cAMP) and thus increase cAMP, which
stable heart failure patient there is considerable risk increases calcium entry into the cardiac myocytes as
of clinically deterioration. Digoxin is cleared by renal well as the rate of removal, which in turn leads to
excretion, hence must be used cautiously in patients increased myocardial contractility. It is both a posi-
with impaired renal function.
tive inotropic agent and a peripheral vasodilator. Mil-
Uses: Atrial fibrillation occurs in roughly 20% to 30% rinone also has lusitropic properties which are mani-
of patients with heart failure and digoxin is particu- fested by improvement in diastolic function. It raises
larly useful for patients with heart failure and con- heart rate, but not to the same extent as dobutamine.
comitant atrial fibrillation when the uses of other
rate controlling drugs such as diltiazem or verapamil Milrinone is the most commonly used PDEI, but only
may be problematic. Digoxin has been used to wean 3% of patients in ADHERE and less than 1% in EHFS II
patients dependent on intra-aortic balloon pumps or received it. Patients who have had prolonged admin-
inotropic support. istration of milrinone may experience delayed dete-
rioration, so they should be observed for at least 48
The results from the DIG (Digitalis Investigation Group) hours after cessation. Milrinone is renally excreted,
study indicated that digoxin had a neutral effect on necessitating dose adjustment in the presence of
mortality, although reductions were seen in overall renal dysfunction or substitution with dobutamine.
rates of hospitalization and heart failure progression.
The DIG trial also demonstrated the importance of Adverse effects: Hypotension and atrial and ventric-
measuring digoxin levels. ular arrhythmias.
Digoxin levels ≥1.2 ng/ml may be harmful; whereas, In OPTIMECHF (Outcomes of a Prospective Trial of
Intravenous Milrinone for Exacerbations of Chronic

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