Review Question - QID 100522

Similar to milrinone, cilostazol inhibits phosphodiesterase-3 (PDE-3), therefore decreasing the degradation of cyclic AMP (cAMP) in a variety of cell types. Higher levels of cAMP increase the force of contraction by cardiac myocytes (positive inotropy).

In vascular smooth muscle, an increase in cAMP concentration leads to increased activity of protein kinase A (PKA), which phosphorylates and inactivates myosin light chain kinase (MLCK). This leads to a relaxation of the vascular smooth muscle and vasodilation. Cilostazol is approved for use in intermittent claudication. In cardiac myocytes, cAMP once again activates PKA, which then serves to phosphorylate calcium channels in the sarcoplasmic reticulum, increase calcium concentration in the cell, and, therefore, increase the force of contraction. Thus, PDE3 inhibitors cause vasodilation and an increase in the force of contraction, and this is the mechanism by which milrinone and amrinone provide benefit in decompensated heart failure.

Schror et al. review the pharmacology of cilostazol. In addition to its antithrombotic effects and ability to inhibit platelet aggregation, cilostazol has been shown to have both chronotropic and positive inotropic effects, which are thought to be likely cAMP-mediated. Cilostazol also inhibits adenosine uptake and modifies cAMP-controlled gene expression.

Chavey et al. review systolic heart failure management. FIrst-line therapies include beta blockers, ACE inhibitors and aldosterone antagonists. Phosphodiesterase inhibitors, such as milrinone and amrinone, are useful for hospitalized patients with decompensated heart failure who need inotropic support when ongoing diuretic therapy is inadequate.

Illustration A: Adenylate cyclase and phosphodiesterases oppose each other eith regard to their action on the cAMP system. Whereas adenylate cyclase creates cAMP and is activated by Beta-1 and Beta-2 receptors, phophodiesterases cleave cAMP and can be modulated by certain drugs, i.e. cilostazol.

Incorrect Answers:
Answer 1: The vasodilatory effects of a PDE inhibitor would lower left ventricular end-diastolic volume (LVEDV) due to the relaxation of veins and, therefore, decrease in preload.
Answer 3: Negative chronotropy is not an effect of PDE inhibitors
Answer 4: Angioedema is a rare side effect of ACE inhibitors that manifests as swelling of the lips and larynx.
Answer 5: Unlike other drugs affecting the cardiovascular tone, PDE inhibitors are not used as antiarrhythmics (beta blockers, calcium channel blockers).