Cilostan CR Mechanism of Action

Platelet Aggregation Inhibitor.
Pharmacology: Pharmacodynamics: Mechanism of Action: The mechanism of the effects of Cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.
Cardiovascular Effects: Cilostazol affects both vascular beds and cardiovascular function. It produces nonhomogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid or superior mesenteric arteries. Renal arteries were not responsive to the effects of Cilostazol.
In dogs or cynomolgous monkeys, Cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with Holter monitors, numerically more Cilostazol-treated patients had increases in ventricular premature beats and non-sustained ventricular tachycardia events than did placebo-treated patients; the increases were not dose-related.
Others: In subjects with severe renal impairment, the free fraction of Cilostazol was 27% higher and both C_max and AUC were 29% and 39% lower respectively than in subjects with normal renal function. The C_max and AUC of the dehydro metabolite were 41% and 47% lower respectively in the severely renally impaired subjects compared to subjects with normal renal function. The C_max and AUC of 4'-trans-hydroxy cilostazol were 173% and 209% greater in subjects with severe renal impairment. The drug should not be administered to patients with a creatinine clearance <25 mL/min.
In repeated oral administration study with beagle for 13 weeks and 52 weeks, hypertrophic endocardium and coronary arteriography disorder occurred in high dosage. Non-toxic dose is 30 mg/kg/day, 12 mg/kg/day. This change was observed only in dogs and not in rat and monkey. And inhibition of PDE III and vasodilation have occurred in same situation.
Pharmacokinetics: Absorption:Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in C_max and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of Cilostazol. Pharmacokinetics is approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11 to 13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of Cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).
Distribution: Plasma Protein and Erythrocyte Binding: Cilostazol is 95 - 98% protein bound, predominantly to albumin. The mean percent binding for 3,4-dehydro-cilostazol is 97.4% and for 4'-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.
Metabolism and Excretion: Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are CYP3A4 and, to a lesser extent, CYP2C19. The enzyme responsible for metabolism of 3,4-dehydro-cilostazol, the most active of the metabolites, is unknown.
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4'-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4'-transhydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.
Special Populations: Age and Gender: The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50-to-80-year-old age range.
Smokers: Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.
Hepatic Impairment: The pharmacokinetics of cilostazol and its metabolites were similar in subjects with mild hepatic disease as compared to healthy subjects.
Patients with moderate or severe hepatic impairment have not been studied.
Renal Impairment: The total pharmacologic activity of cilostazol and its metabolites was similar in subjects with mild to moderate renal impairment and in normal subjects. Severe renal impairment increases metabolite levels and alters protein binding of the parent and metabolites. The expected pharmacologic activity, however, based on plasma concentrations and relative PDE III inhibiting potency of parent drug and metabolites, appeared little changed. Patients on dialysis have not been studied, but it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95 - 98%).