Usage
Cilostazol is prescribed for the improvement of maximal and pain-free walking distances in patients with intermittent claudication, a symptom of peripheral artery disease (PAD). It is classified as a phosphodiesterase III inhibitor and a platelet aggregation inhibitor. Cilostazol works by inhibiting phosphodiesterase III, which leads to increased levels of cyclic AMP (cAMP) in platelets and blood vessels. This increase in cAMP results in vasodilation and inhibition of platelet aggregation, improving blood flow to the extremities.
Alternate Names
The generic name is cilostazol. A popular brand name is Pletal.
How It Works
Pharmacodynamics: Cilostazol increases intracellular cAMP levels by inhibiting phosphodiesterase III, which leads to vasodilation and inhibition of platelet aggregation. It also exhibits mild antiproliferative effects on smooth muscle cells.
Pharmacokinetics:
- Absorption: Cilostazol is well-absorbed orally, with peak plasma concentrations reached approximately 2-4 hours after administration. Food increases the maximum plasma concentration (Cmax).
- Metabolism: Extensively metabolized in the liver, primarily by CYP3A4 and CYP2C19 enzymes, to several metabolites, including an active dehydro-cilostazol.
- Elimination: Primarily eliminated via urine (74%) and feces (20%). The half-life is approximately 11-13 hours.
Mode of Action: Cilostazol inhibits phosphodiesterase III, which is responsible for the breakdown of cAMP. This inhibition leads to an increase in cAMP levels, causing vasodilation and preventing platelet aggregation.
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Cilostazol primarily acts through the inhibition of phosphodiesterase III.
Elimination Pathways: Cilostazol is eliminated through hepatic metabolism by CYP3A4 and CYP2C19 enzymes, followed by renal and fecal excretion.
Dosage
Standard Dosage
Adults:
The standard dose is 100 mg twice daily, taken at least 30 minutes before or 2 hours after breakfast and dinner.
Children:
The safety and efficacy of cilostazol in children have not been established.
Special Cases:
- Elderly Patients: No specific dosage adjustment is generally required, but close monitoring is advised.
- Patients with Renal Impairment: Contraindicated in patients with creatinine clearance ≤25 mL/min. No dosage adjustment is needed for creatinine clearance >25 mL/min.
- Patients with Hepatic Dysfunction: Contraindicated in moderate or severe hepatic impairment. No dosage adjustment needed for mild hepatic impairment.
- Patients with Comorbid Conditions: Use with caution in patients with stable coronary artery disease, atrial or ventricular ectopy, or atrial fibrillation/flutter. Contraindicated in heart failure patients. Dose reduction to 50mg twice daily is recommended for patients on strong or moderate CYP3A4 inhibitors (e.g., some macrolides, azole antifungals, protease inhibitors) or CYP2C19 inhibitors (e.g., omeprazole, some azole antifungals).
Clinical Use Cases
Cilostazol is not indicated for use in the following clinical settings: intubation, surgical procedures, mechanical ventilation, intensive care unit (ICU) use, or emergency situations like status epilepticus or cardiac arrest. Its primary indication is intermittent claudication related to PAD.
Dosage Adjustments
Dose adjustments are required for patients with renal or hepatic impairment and concomitant use of CYP3A4 or CYP2C19 inhibitors.
Side Effects
Common Side Effects:
Headache, diarrhea, dizziness, palpitations, peripheral edema, abdominal pain, and abnormal stools.
Rare but Serious Side Effects:
Tachyarrhythmia, hypotension, thrombocytopenia, leukopenia, agranulocytosis, anaphylaxis, bleeding tendencies (including GI bleeding), and Stevens-Johnson syndrome.
Long-Term Effects:
Potential long-term effects are not well-established, but monitoring for hematological abnormalities is recommended.
Adverse Drug Reactions (ADR):
Severe allergic reactions, heart problems (tachycardia, hypotension, irregular heartbeat), and blood disorders require immediate attention.
Contraindications
Heart failure of any severity, hypersensitivity to cilostazol, hemostatic disorders or active bleeding, severe renal impairment (creatinine clearance ≤25 mL/min), and moderate to severe hepatic impairment.
Drug Interactions
Cilostazol interacts with CYP3A4 and CYP2C19 inhibitors (e.g., ketoconazole, itraconazole, erythromycin, diltiazem, omeprazole), other antiplatelet agents (e.g., aspirin, clopidogrel), and anticoagulants (e.g., warfarin). Alcohol may increase the risk of bleeding. Grapefruit juice may increase cilostazol levels. Consult drug interaction resources for a comprehensive list due to the large number of potential interactions.
Pregnancy and Breastfeeding
Pregnancy Safety Category: C. Use with caution during pregnancy only if the benefits outweigh the risks. Animal studies show risk of fetal harm, but adequate human studies are lacking.
Breastfeeding: Cilostazol is excreted in animal milk; human data are limited. It is not recommended for use while breastfeeding.
Drug Profile Summary
- Mechanism of Action: Inhibits phosphodiesterase III, increasing cAMP levels, leading to vasodilation and inhibition of platelet aggregation.
- Side Effects: Headache, diarrhea, dizziness, palpitations, edema. Serious side effects include bleeding, heart problems, and blood disorders.
- Contraindications: Heart failure, hypersensitivity, active bleeding, severe renal/hepatic impairment.
- Drug Interactions: CYP3A4/2C19 inhibitors, other antiplatelet/anticoagulants.
- Pregnancy & Breastfeeding: Use with caution if pregnant; not recommended while breastfeeding.
- Dosage: 100 mg BID (50mg BID with CYP inhibitors).
- Monitoring Parameters: Platelet and WBC count, heart rate and rhythm, blood pressure, signs of bleeding.
Popular Combinations
Cilostazol is typically used as a single agent for intermittent claudication. Combination with other antiplatelet agents or anticoagulants should be done with caution due to increased bleeding risk.
Precautions
- General Precautions: Screening for heart failure, bleeding disorders, renal/hepatic dysfunction is essential.
- Specific Populations: See Dosage section for details regarding pregnant/breastfeeding women, children, and the elderly.
- Lifestyle Considerations: Patients should continue lifestyle modifications (e.g., smoking cessation, exercise) and other relevant medical therapies (e.g., lipid-lowering agents).
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Cilostazol?
A: The standard dosage for adults is 100 mg twice daily, taken 30 minutes before or 2 hours after meals. Dosage adjustments are needed for patients with renal/hepatic impairment and concomitant use of CYP3A4 or CYP2C19 inhibitors (50mg BID). Pediatric use is not established.
Q2: What is the primary indication for Cilostazol?
A: Intermittent claudication associated with peripheral artery disease (PAD).
Q3: What is the mechanism of action of Cilostazol?
A: Cilostazol inhibits phosphodiesterase III, leading to increased cAMP levels, resulting in vasodilation and inhibition of platelet aggregation.
Q4: What are the most common side effects of Cilostazol?
A: Headache, diarrhea, dizziness, and palpitations.
Q5: When should Cilostazol be discontinued?
A: If symptoms are unimproved after 3 months or if serious side effects occur.
Q6: Is Cilostazol safe to use in patients with heart failure?
A: No, Cilostazol is contraindicated in patients with heart failure of any severity.
Q7: Does Cilostazol interact with other medications?
A: Yes, Cilostazol interacts with several medications, notably CYP3A4 and CYP2C19 inhibitors. Always consult drug interaction checkers before co-prescribing.
Q8: Can Cilostazol be used during pregnancy or breastfeeding?
A: Cilostazol should be used with caution during pregnancy only if the benefits clearly outweigh the risks. It is not recommended during breastfeeding.
Q9: What monitoring parameters are important for patients taking Cilostazol?
A: Monitor for signs of bleeding, complete blood counts (including platelet counts), heart rate and rhythm, and blood pressure.
Q10: What precautions are necessary before prescribing Cilostazol?
A: Screen for heart failure, active bleeding, hepatic or renal insufficiency, and concomitant medications, especially CYP3A4 and CYP2C19 inhibitors.
