Heart failure, acute inotropic agents

Noradrenaline and adrenaline are the classic catecholamines and neurotransmitters in the sympathetic nervous system. Noradrenaline stimulates the following subtypes of adrenoceptors P, a, U2. It has positive inotropic and chronotropic activities as a result of /3i-receptor stimulation. In addition, it is a potent vasoconstrictor agent as a result of the stimulation of both subtypes (ai,a2) of a-adrenoceptors. After intravenous infusion, its effects develop within a few minutes, and these actions disappear within 1-2 minutes after stopping the infusion. It may be used in conditions of acute hypotension and shock, especially in patients with very low vascular resistance. It is also frequently used as a vasoconstrictor, added to local anaesthetics. Adrenaline stimulates the following subtypes of adrenoceptors /3i, P2, oil, 0L2. Its pharmacological profile greatly resembles that of noradrenaline (see above), as well as its potential applications in shock and hypotension. Like noradrenaline, its onset and duration of action are very short, as a result of rapid inactivation in vivo. Both noradrenaline and adrenaline may be used for cardiac stimulation. Their vasoconstrictor activity should be kept in mind. A problem associated with the use of /3-adrenoceptor stimulants is the tachyphylaxis of their effects, explained by the /3-adrenoceptor downregulation, which is characteristic for heart failure. 

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. 

Paradoxically, these agents—not positive inotropic drugs—are the first-line therapies for chronic heart failure. The drugs most commonly used are diuretics, ACE inhibitors, angiotensin receptor antagonists, aldosterone antagonists, and blockers (Table 13-1). In acute failure,... 

P-Adrenergic stimulation improves cardiac performance by positive inotropic effects and vasodilation. Dobutamine (see p. 66) is the most commonly used inotropic agent other than digitalis. Dobutamine leads to an increase in intracellular cAMP, which results in the activation of protein kinase. Slow calcium channels are one important site of phosphorylation by protein kinase. When phospho-rylated, the entry of calcium ion into the myocardial cells increases, thus enhancing contraction (Figure 16.11). Dobutamine must be given by intravenous infusion, and is primarily used in the treatment of acute heart failure in a hospital setting. 

Adverse effects and contraindications of calcium channel blockers are described in Table 16. Verapamil, diltiazem, and first-generation dihydropyridines also should be avoided in patients with acute decompensated heart failure or LV dysfunction because they can worsen heart failure and potentially increase mortality secondary to their negative inotropic effects. In patients with heart failure requiring treatment with a calcium channel blocker, amlodipine is the preferred agent. ... 

Comparative studies Unlike traditional inotropic agents, levosimendan is thought to have a lower potential to cause dysrhythmias, because it does not increase intracellular calcium concentrations and myocardial oxygen consumption. Levosimendan and dobuta-mine have been compared in 50 patients with acute decompensated heart failure (NYHA class III-IV, ejection fraction <35%), mean age 68 years [20 ]. Heart rate and the number of ventricular extra beats increased significantly during infusion of levosimendan and dobutamine, but the increase in ventricular coupled beats was significant only with dobutamine. There were more episodes of non-sustained ventricular tachycardia and paroxysmal atrial fibrillation with levosimendan, but the difference was not significant. 

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