Cardiac failure phosphodiesterase inhibitors

Vasodilators are a group of dtugs, which relax the smooth muscle cells of the blood vessels and lead to an increased local tissue blood flow, a reduced arterial pressure and a reduced central venous pressure. Vasodilators reduce the cardiac pre-load as well as after-load and thereby reduce cardiac work. They are used in a variety of conditions including hypertension, cardiac failure and treatment/prevention of angina pectoris. Major groups are Ca2+-channel blockers (e.g. dihydropyridines), NO-donators (e.g. organic nitrates), K+-channel openers (minoxidil), phosphodiesterase inhibitors (e.g. sildenafil), Rho-kinase inhibitors (e.g. Y27632) or substances with unknown mechanism of action (e.g. hydralazine). Inhibitors of the... 

High risk Has unstable or symptomatic angina, despite treatment Has uncontrolled hypertension Has severe congestive heart failure (NYHA class III or IV) Had a recent myocardial infarction or stroke within past 2 weeks Has moderate or severe valvular heart disease Has high-risk cardiac arrhythmias Has obstructive hypertrophic cardiomyopalhy Phosphodiesterase inhibitor is contraindicated sexual intercourse should be deferred... 

Digoxin remains the mainstay of treatment for patients with chronic myocardial failure. Other drugs with inotropic and/or vasodilator properties, including the catecholamines and phosphodiesterase III (PDE) inhibitors, are used in the treatment of acute cardiac failure. The inotropic actions of most of these drugs result from a direct or indirect elevation of [Ca2-i-]i (intracellular Ca2+ concentration). This acts as a trigger for a process which leads to increased contractile state and cardiac contraction (Figures 8.3 and 8.4). Myofilament calcium sensitisers increase the sensitivity of contractile proteins to calcium. Some newer drugs, such as vesnarinone, have multiple mechanisms of action. 

The phosphodiesterase inhibitors, enoximone and milrinone have positive inotropic effect due to selective myocardial enzyme inhibition and may be used for short-term treatment of severe congestive cardiac failure. Evidence from longer term use indicates that these drugs reduce survival. 

On the premise that phosphodiesterase inhibitors also inhibit the production of cytokines, milrinone has been used in the treatment of nine patients with the systemic inflammatory response sjmdrome and compared with seven patients with congestive heart failure (4). In both groups mikinone significantly altered cardiac index, pulmonary capillary wedge pressure, and left ventricular stroke work index. In the patients with cardiac failure it also reduced systemic vascular resistance index, and the dose of adrenaline had to be increased substantially during milrinone infusion to counteract vasodilatation. 

Although the phosphodiesterase inhibitors are effective in the treatment of acute cardiac failure in various settings, overall mortality during long-term treatment of heart failure is increased, and these drugs should not be used for that purpose (8). 

PHOSPHODIESTERASE INHIBITORS acting at a heart-specific subtype of this enzyme (type III phosphodiesterase), prevent the intracellular degradation of cyclic AMP (cAMP) and thereby raise the intracellular concentration of cAMP. This exerts a positive inotropic affect for the same reason as P-adrenoceptor activation, and may be used in the shortterm treatment of severe congestive cardiac failure, e.g. enoximone and milrinone. 

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. 

Inamrinone, milrinone Phosphodiesterase type 3 inhibitors decrease cAMP breakdown Vasodilators lower peripheral vascular resistance also increase cardiac contractility Acute decompensated heart failure IV only duration 3-6 h Toxicity Arrhythmias Interactions Additive with other arrhythmogenic agents... 

Crataegus species (hawthorn, maybush, whitethorn) contain a variety of flavonoids, including rhamnosides, schaf-tosides, and spiraeosides. They have a positive inotropic effect on the heart by a mechanism different from that of cardiac glycosides, catecholamines, and the phosphodiesterase type III inhibitors (1) and are effective in mild heart failure (2). 

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