Bestazol 50/Bestazol 100 Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Cilostazol and several of its metabolites are PDE 3 inhibitors, inhibiting PDE 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. It reversibly inhibits platelet aggregation induced by various stimuli, including thrombin, adenosine diphosphate (ADP), collagen, arachidonic acid, epinephrine and shear stress.
Cardiovascular Effect: 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 animal studies, cilostazol increased heart rate, myocardial contractile force, coronary blood flow, ventricular automaticity, left ventricular contractility and atrioventricular conduction. In humans, dose-proportional heart rate increased were observed at therapeutic doses. Non-dose-related increases in ventricular premature beats and transient ventricular tachycardia were observed in high numbers of cilostazol-treated patients than in those treated with placebo.
Pharmacokinetics: Absorption: Cilostazol is absorbed after oral administration. A high-fat meal increases absorption, with an approximately 90% increase in maximum plasma concentration (C_max) and a 25% increase in the area under the plasma concentration-time curve (AUC). Absolute bioavailability is not known.
Distribution: 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: Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4 and, to a lesser extent, 2C19. Two metabolites are active, with 1 metabolite (3,4-dehydro-cilostazol) appearing to account for at least 50% of the pharmacologic (PDE 3 inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional.
Excretion: Cilostazol metabolites largely excreted in urine. Cilostazol and its active metabolites have apparent elimination half-lives of about 11 to 13 hours. They accumulate about 2-fold with chronic administration and reach steady-state blood levels within a few days. Following oral administration of radio-labeled cilostazol 100 mg, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4 to 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 the 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 the urine as 4'-trans-hydroxy-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 Function Impairment: The total pharmacologic activity of cilostazol and its metabolites was similar in subjects with mild to moderate renal impairment and in healthy subjects. Severe renal function impairment increases metabolite levels and alters protein binding of the parent and metabolites. The expected pharmacologic activity, based on plasma concentrations and relative to PDE 3 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%).