Congestive heart failure positive inotropic action

Coined WS, Wright RF, Braunwald E. New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. N Engl J Med 1986 314(5) 290-9 1986 314(6) 349-58. 

Myocardial cell membrane ATPase, the enzyme present in heart muscle, is the site of action of the cardiac steroid glycosides, which have a specific action on the heart muscle. These drugs increase the force of contraction of the muscle (positive inotropic effect) as well as its conductivity and automaticity. They are also valuable in treating congestive heart failure, in which the circulatory needs of organs are no longer satisfied, and heart arrhythmias, in which the rhythm of the cardiac contractions is upset. The effect of the drug is that the force of contraction increases and the heart rate is slowed (chronotropic effect). Consequently, the cardiac output is elevated while the size of the heart decreases. 

Dopamine itself has long been used as an inotropic agent in acute treatment of congestive heart failure. Both that compound and a number of its analogues have a positive action on contractility as a consequence of their adrenergic agonist activity. 

Jaski BE, Filer MA, Wright RF, Braunwald E, Colucci WS. Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside. J Clin Invest 1985 75(2) 643-9. 

Sulmazole (AR-L 115) (37), an imidazopyridine derivative, increased dp/dt max. by 58% and heart rate by 12 beats/min in anesthetized cats after 1 mg/kg i.v. Systolic blood pressure was decreased by 13 mm Hg.l42 Oral administration augmented dp/dt max. up to 92% for 5 to 12 hours in conscious dogs.143 Despite similar PDE-inhibitory activity of 37 and theophylline, it seems likely that effects other than PDE-inhibi-tion contribute to the positive inotropic action.144 Measurement of the effect of 21 on relations between free Ca++, bound Ca ", and ATPase activity of dog cardiac myofibrils indicates that the positive inotropic actions may involve direct activation of myofibrils by an increased affinity of thin filament receptors for Ca++.145 Several clinical studies in heart failure showed that in patients with congestive cardiomyopathy and with coronary artery disease, 22 improved hemodynamics and regional wall motion via decrease in pre- and afterload and Increase in contractility, myocardial oxygen consumption and coronary sinus flow, with no myocardial ischemia.14 149... 

The cardiac glycosides have two main actions and two main applications. They reduce conductivity within the atrioventricular (AV) node, hence are used for treating supraventricular tachycardias (especially atrial fibrillation), and they have a positive inotropic effect (i.e. increase the force of contraction), hence are used for congestive heart failure, although this use has declined. 

Inhibitors of a heart-specific subtype (type III) phosphodiesterase, which are positive inotropics, may be used in the short-term treatment of severe congestive cardiac failure, e.g. amrinone, enoximone and milrinone. However, developments of oral formulations of drugs of this type have been halted by the results of the PROMISE trial (Prospective Randomised Milrinone Survival Evaluation trial) which documented a paradoxical increase in mortality in class IV heart failure patients randomised to receive milrinone. However, some benzimidazole derivatives with class III phosphodiesterase inhibitor actions seem to be beneficial in heart failure. The agent vesnarinone is an orally active compound that may act as a class III phosphodiesterase inhibitor but appears to be a vasodilator with multiple mechanisms. See HEART FAUURE TREATMENT INOTROPIC AGENTS. 

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