Phosphodiesterase inhibitors

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Phosphodiesterase inhibitors increase intracellular cAMP concentrations by inhibition of the enzyme responsible for cAMP breakdown (Fig. 7.8). Increased intracellular cAMP concentrations promote the activation of protein kinases, which lead to an increase in intracellular Ca^+. In cardiac muscle cells, this causes a positive inotropic effect and also facilitates diastolic relaxation and cardiac tilling (termed 'positive lusitropy'). In vascular smooth muscle, increased cAMP decreases intracellular and causes marked vasodilatation. Several subtypes of phosphodiesterase (PDE) isoenzyme exist in different tissues. Theophylline is a nonspecific PDE inhibitor, but the newer drugs (e.g. amrinone, enox-imone and milrinone) are selective for the PDE type III isoenzyme which occurs in the myocardium, vascular smooth muscle and platelets. PDE III inhibitors are positive inotropes and potent arterial, coronary and venodilators. They decrease preload, afterload, pulmonary vascular resistance and pulmonary capillary wedge pressure (PCWP), and increase cardiac index. Heart rate may increase or remain unchanged. In contrast to sympathomimetics, they improve myocardial function without increasing oxygen demand or causing tachyphylaxis. Their effects are augmented by the co-administration of [3] -agonists (i.e. increases in cAMP production are synergistic with decreased cAMP breakdown). They have particular advantages in patients with chronic cardiac failure, in whom downregulation of myocardial P-adrener-gic receptors occurs, so that there is a decreased inotropic response to p sympathomimetic drugs. A similar phenomenon occurs with advanced age, prolonged (>72 h) catecholamine therapy and possibly with surgical stress.

They are indicated for acute refractory cardiac failure, e.g. cardiogenic shock, or pre- or post-cardiac surgery. However, long-term treatment with oral PDE III inhibitors is associated with increased mortality in patients with congestive cardiac failure. All PDE III inhibitors may cause hypotension, and tachyarrhythmias may occur. Other adverse effects include nausea, vomiting and fever. Amrinone may cause thrombocytopenia and is available only as a parenteral preparation. The half-life of all PDE III inhibitors is prolonged several-fold in patients with cardiac or renal failure and they are commonly administered as an i.v. loading dose over 5 min with or without a subsequent i.v. infusion.

Amrinone and milrinone are derived from bipyridines, whereas enoximone is an imidazole derivative. Enoximone undergoes substantial first pass metabolism, and is rapidly metabolized to a sulfoxide compound, which is excreted via the kidneys. The elimination tj /2 of enoximone is 1-2 h in healthy individuals but up to 20 h in patients with cardiac failure. The sulfoxide metabolite is active and is less protein bound than the parent drug; its elimination may also be prolonged in cardiac or renal failure. The loading dose of enoximone is 0.5 mg kg~l followed by an infusion of 5 pg kg 1 min .

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