Treatment of Intermittent Claudication with Pentoxifylline and Cilostazol

James A. Tjon and Laurel E. Riemann


Am J Health Syst Pharm. 2001;58(6) 

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Pentoxifylline and Cilostazol

Before the approval of cilostazol for marketing, pentoxifylline was the only medication whose FDA-approved labeling included the treatment of IC. Pentoxifylline, a trisubstituted methylxanthine derivative, produces dose-related hemorheologic effects, and its metabolites improve blood flow by decreasing blood viscosity and improving erythrocyte flexibility.[24,25] Patients with PVD have erythrocytes that are more rigid than in healthy patients. Decreased blood flow and increased erythrocyte flexibility with pentoxifylline therapy are thought to result from a reduction in plasma fibrinogen concentrations.[26] Pentoxifylline also works by inhibiting platelet aggregation via inhibition of membrane-bound phosphodiesterase (leading to increased levels of cyclic adenosine monophosphate [cAMP]), inhibition of thromboxane synthesis, and an increase in prostacyclin synthesis.[26] Through these effects, pentoxifylline increases blood flow to the affected microvasculature, thus improving tissue oxygenation and perfusion.[24]

Cilostazol exhibits its pharmacologic effects via antiplatelet, vasodilatory, and antithrombotic activities. Like pentoxifylline, cilostazol and several of its metabolites exhibit these antiplatelet and vasodilatory actions through the inhibition of phosphodiesterase activity. This inhibition of phosphodiesterase, specifically of isoenzyme III, results in an increase in cAMP in vascular tissue and platelets. The platelet aggregation cilostazol inhibits is normally triggered by such stimuli as thrombin, adenosine diphosphate (ADP), collagen, arachidonic acid, epinephrine, and shear stress. The inhibition by cilostazol is reversible and includes both primary and secondary platelet aggregation.

Some inotropic drugs with a similar mechanism of action (phosphodiesterase inhibition) have been associated with increased mortality in patients with congestive heart failure (CHF).[27,28] There have been no published studies assessing this possible effect of cilostazol. However, the manufacturer does have data on file indicating that cilostazol minimally increases the cardiac index, with a minimal decrease in pulmonary capillary wedge pressure (see the section on adverse effects).[29,30] Current unlabeled uses for cilostazol include prevention of restenosis after percutaneous transluminal coronary angioplasty. However, the data are limited, and further studies are needed.[31,32]

Pentoxifylline is rapidly and extensively absorbed after oral administration and is approximately 45% bound to plasma proteins. After administration of a 400-mg tablet, the maximum plasma concentration (Cmax) of the parent compound and its metabolites is 0.3 mg/L and is reached within two to four hours.[24,33] Pentoxifylline undergoes a first-pass effect. Its major metabolites are metabolites I and V, whose plasma levels are five and eight times greater, respectively, than the concentration of the parent compound. The pharmacokinetics of pentoxifylline and metabolite V are dose related and nonlinear, with the half-life and the area under the plasma concentration-versus-time curve (AUC) increasing with the dose.[24,33] The plasma half-lives of pentoxifylline and its metabolites are 0.4-0.8 and 1-1.6 hours, respectively. The primary biotransformation product is metabolite V, and excretion of the drug is mainly urinary. The pharmacokinetics of pentoxifylline have not been studied in patients with renal or hepatic dysfunction.[24,26,33]

Cilostazol is well absorbed after oral administration and is 95-98% bound to plasma proteins, primarily albumin. After a single dose, cilostazol reaches a peak plasma concentration in three to four hours. High-fat meals enhance absorption, increasing Cmaxby approximately 90% and AUC by about 25%.[29] The agent is extensively metabolized in the liver, primarily by cytochrome P-450 (CYP) isoenzymes 3A4 and 2C19. Two metabolites of cilostazol are active. The more active metabolite, 3,4-dehydrocilostazol, accounts for about 50% of the total inhibition of phosphodiesterase III. Cilostazol and its active metabolites have an elimination half-life of approximately 12 hours and are mainly excreted in the urine (74%).[29] One study found no effects of age or sex on cilostazol's safety or pharmacokinetics after multiple doses.[34] The pharmacokinetics of cilostazol and its metabolites in patients with mild hepatic disease were similar to those in healthy patients.[29] Patients with mild to moderate hepatic disease have not been studied. The total pharmacologic activity of cilostazol and its metabolites was the same in patients with mild to moderate renal insufficiency as in healthy subjects.[29]