Mechanism of cardiotonic steroids

Milrinone is a new inotropic agent for the treatment of refractory congestive heart failure. Our understanding of the mechanisms(s) of action of this synthetic cardiotonic drug is incomplete. We examined the effects of milrinone and the parent compound amrinone on sarcoplasmic reticulum function (45Ca-uptake and Ca-ATPase); radioligand binding to adenosine, beta-adrenergic, and cholinergic muscarinic receptors; cyclic AMP accumulation; and inhibition of various forms of cyclic AMP phosphodiesterases. Comparisons were made to observe how these effects correlate with the inotropic response of heart. Milrinone was shown to be a potent phosphodiesterase inhibitor that was 40 times more potent than amrinone and 10 times more potent at inhibiting the high-affinity (Km = microM) form (Ki = 22 microM) than the low-affinity (Km = 140 microM) form (Ki = 225 microM) of cyclic AMP phosphodiesterase in heart. The potency of milrinone as a phosphodiesterase inhibitor was the same in the presence and absence of calcium. Concentrations of milrinone that increased cyclic AMP accumulation also produced positive inotropy. A comparison of milrinone with amrinone and methylxanthines revealed the order of potency to be isobutylmethylxanthine greater than milrinone greater than theophylline greater than caffeine greater than amrinone. Milrinone and amrinone had no effect on 45Ca-uptake or Ca-ATPase activity in myocyte sarcoplasmic reticulum. However, milrinone did bind weakly to adenosine receptors (KD = 466 microM) but not to cholinergic muscarinic or beta-adrenergic receptors. Also, in combination with isoproterenol high concentrations of milrinone blocked the negative inotropic response to the adenosine agonist phenylisopropyladenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

The major side effect of digitalis compounds is cardiac arrhythmia, especially atrial tachycardias and atrioventricular block. Digitalis compounds are contraindicated in patients who are hypokalemic, or who have atrioventricular block or Wolff-Parkinson-White (WPW) syndrome. Impaired renal function leads to enhanced plasma levels of digoxin because digoxin is eliminated by the kidneys. Lean, elderly patients are more susceptible to digitalis toxicity because they often have reduced renal function, and their reduced muscle mass increases plasma digoxin levels at a given dose because muscle Na + /K + -ATPase acts as a large binding reservoir for digitalis. A 2012 analysis of the AFFIRM trial determined that digoxin significantly increased all-cause mortality in patients with atrial fibrillation. This calls into question the practice of using digoxin for lowering ventricular rate in patients with atrial fibrillation.

Mechanism of cardiotonic steroids

mechanism of cardiotonic steroids

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