Introduction
Cilostazol is an oral antiplatelet and vasodilating agent classified as a quinolinone derivative. It is primarily indicated for the symptomatic improvement of intermittent claudication in patients with peripheral arterial disease. Approved by the FDA in 1999, cilostazol represents an important therapeutic option for improving walking distance in appropriately selected patients.
Mechanism of Action
Cilostazol exerts its therapeutic effects through multiple mechanisms. Its primary action is inhibition of phosphodiesterase type III (PDE3), resulting in increased intracellular cyclic adenosine monophosphate (cAMP) levels. This leads to:
- Platelet aggregation inhibition
- Vasodilation of vascular smooth muscle
- Inhibition of vascular smooth muscle cell proliferation
Additionally, cilostazol demonstrates mild positive inotropic effects and increases cardiac output without significantly affecting heart rate or blood pressure at therapeutic doses.
Indications
- Symptomatic treatment of intermittent claudication in patients with peripheral arterial disease
- Reduction of symptoms of intermittent claudication (increased walking distance)
Dosage and Administration
Standard dosing: 100 mg orally twice daily, taken at least 30 minutes before or 2 hours after breakfast and dinner Dosage adjustment:- Hepatic impairment: Consider reducing dose to 50 mg twice daily
- Renal impairment: No specific dosage adjustment recommended
- CYP2C19 poor metabolizers: Consider dose reduction
- Elderly: No specific dosage adjustment required
- Should be taken on an empty stomach
- Treatment discontinuation should be considered if no therapeutic benefit is observed within 3 months
- Not recommended for use in patients with heart failure
Pharmacokinetics
Absorption: Well absorbed orally with absolute bioavailability of ~90%; high-fat meals increase Cmax by 90% and AUC by 25% Distribution: Volume of distribution: 2.7 L/kg; 95-98% protein bound, primarily to albumin Metabolism: Extensive hepatic metabolism via CYP3A4 (74%) and CYP2C19 (20%); forms active metabolites (3,4-dehydro-cilostazol and 4'-trans-hydroxy-cilostazol) Elimination: Primarily urinary excretion (74%) with fecal elimination (20%); elimination half-life: 11-13 hoursContraindications
- Congestive heart failure of any severity
- Hypersensitivity to cilostazol or any component of the formulation
- Hemostatic disorders or active pathologic bleeding
- Severe hepatic impairment
- Concomitant use with strong CYP3A4 or CYP2C19 inhibitors
Warnings and Precautions
Cardiovascular effects: May cause tachycardia, palpitations, and arrhythmias; use with caution in patients with stable coronary artery disease Bleeding risk: Increases risk of bleeding; monitor for signs of bleeding complications Hepatic impairment: Use with caution in moderate hepatic impairment; contraindicated in severe impairment Thrombocytopenia: Has been associated with decreased platelet counts; monitor periodically Surgery: Discontinue at least 4-5 days prior to elective surgical proceduresDrug Interactions
Strong CYP3A4 inhibitors: Clarithromycin, ketoconazole, itraconazole, ritonavir - Contraindicated (increases cilostazol exposure by ~70%) Strong CYP2C19 inhibitors: Omeprazole, esomeprazole - Contraindicated Anticoagulants: Warfarin, direct oral anticoagulants - Increased bleeding risk Antiplatelet agents: Aspirin, clopidogrel, prasugrel - Increased bleeding risk Grapefruit juice: May increase cilostazol concentrationsAdverse Effects
Common (≥5%):- Headache (27-34%)
- Diarrhea (12-19%)
- Abnormal stools (12-15%)
- Palpitations (5-10%)
- Dizziness (6-10%)
- Thrombocytopenia
- Serious bleeding events
- Tachycardia and arrhythmias
- Angina pectoris
- Supraventricular tachycardia
Monitoring Parameters
- Walking distance and claudication symptoms at baseline and periodically
- Complete blood count with platelets at baseline and periodically
- Cardiovascular status (heart rate, rhythm, blood pressure)
- Signs and symptoms of bleeding
- Liver function tests in patients with hepatic impairment
- Drug interactions and concomitant medications
Patient Education
- Take medication on an empty stomach (30 minutes before or 2 hours after meals)
- Do not stop taking abruptly without consulting healthcare provider
- Report any signs of bleeding (unusual bruising, blood in urine/stool)
- Monitor for palpitations or rapid heartbeat
- Inform all healthcare providers about cilostazol use before any procedures
- Avoid grapefruit and grapefruit juice while taking this medication
- Improvement in walking distance may take several weeks to months
- Do not use if you have heart failure
- Report any new or worsening symptoms promptly
References
1. FDA Prescribing Information: Cilostazol tablets 2. Bedenis R, Stewart M, Cleanthis M, et al. Cilostazol for intermittent claudication. Cochrane Database Syst Rev. 2014;(10):CD003748 3. Thompson PD, Zimet R, Forbes WP, et al. Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication. Am J Cardiol. 2002;90(12):1314-1319 4. Robless P, Mikhailidis DP, Stansby GP. Cilostazol for peripheral arterial disease. Cochrane Database Syst Rev. 2008;(1):CD003748 5. Pratt CM. Analysis of the cilostazol safety database. Am J Cardiol. 2001;87(12A):28D-33D 6. Uchida S, Kato S, Marumo F. Update on clinical use of cilostazol. Cardiovasc Drug Rev. 2004;22(3):211-221