Phosphodiesterase inhibitors heart failure

High risk Has unstable or symptomatic angina, despite treatment Has poorly controlled hypertension Has severe congestive heart failure (NYHA Class III or IV) Had a recent myocardial infarction or stroke within the past 2 weeks Has moderate or severe valvular heart disease Phosphodiesterase inhibitor is contraindicated... 

Low risk Has asymptomatic cardiovascular disease Has well-controlled hypertension Has mild, stable angina Has mild congestive heart failure (NYHA Class 1) Palient can be started on phosphodiesterase inhibitor... 

Cilostazol is a selective cAMP phosphodiesterase inhibitor. It inhibits platelet aggregation and is a direct arterial vasodilator. It is used for the symptoms of intermittent claudication in individuals with peripheral vascular disease. Side-effects of cilostazol include headache, diarrhea, increased heart rate, and palpitations. Drugs similar to cilostazol have increased the risk of death in patients with congestive heart failure. 

Venodilators Releases nitric oxide (NO) activates guanylyl cyclase (see Chapter 12) Venodilation reduces preload and ventricular stretch Acute and chronic heart failure angina Oral 4-6 h duration Toxicity Postural hypotension, tachycardia, headache Interactions Additive with other vasodilators and synergistic with phosphodiesterase type 5 inhibitors... 

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... 

Amsallem E, Kasparian C, Haddour G, et al. Phosphodiesterase III inhibitors for heart failure. Cochrane Database Syst Rev. 2005 CD002230. 

ANTIHYPERTENSIVES AND HEART FAILURE DRUGS PHOSPHODIESTERASE TYPE 5 INHIBITORS ... 

The phosphodiesterase III inhibitors have no known direct dysrhythmogenic effects. However, the authors speculated that raised concentrations of cAMP may have contributed to the ventricular tachycardia, mainly because ventricular dysrhythmias have been mentioned with other agents of the same family in patients with heart failure. Whether some populations are particularly vulnerable is unknown. 

Long-term treatment with inhibitors of phosphodiesterase type III is associated with increased mortality in congestive heart failure (SEDA-17, 217). 

Milrinone is an inhibitor of phosphodiesterase type III. Although the long-term oral use of such inhibitors is associated with an increase in mortality (SEDA-17, 217), milrinone has been used intravenously in patients with heart failure, both for short-term and longer-term therapy (SEDA-21, 196) (SEDA-22, 203) (SEDA-23, 109). It has been suggested to be particularly useful in tiding patients over while they are waiting for definitive treatment. 

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. 

The under-reporting of the results of clinical trials in patients with heart failure has been reviewed (7). Some trials that have been unpublished or published only in abstract or preliminary form have involved drugs with positive inotropic effects, such as the phosphodiesterase inhibitor vesnarinone (SEDA-23, 195), the beta-adrenoceptor partial agonist xamoterol, and the dopamine receptor agonist ibopamine. 

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). 

Nony P, Boissel JP, Lievre M, Leizorovicz A, Haugh MC, Fareh S, de Breyne B. Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients. A meta-analysis. Eur J Clin Pharmacol 1994 46(3) 191-6. 

Pimobendan is an inhibitor of phosphodiesterase type III with calcium sensitizing properties in the myocardium. It has been associated with a worrisome albeit non-significant increase in mortality in patients with chronic congestive heart failure (1). 

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). 

Some PHOSPHODIESTERASE INHIBITORS (e.g. cnoximone and milrinone) are valuable, and some exert most of their effect on the myocardium (those acting at a heart-specific subtype of this enzyme (type III phosphodiesterase) to raise the intracellular concentration of cAMP) and may be used as positive INOTROPIC AGENTS in the short-term treatment of severe congestive heart failure. 

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. 

Trade names Amcoral Cartonic Vestistol Indications Congestive heart failure Category Phosphodiesterase inhibitor Half-life 4.6 hours... 

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