Continuing Education Activity

Cilostazol is a quinolone derivative primarily used to treat intermittent claudication due to peripheral vascular disease, the FDA-approved indication. Cilostazol is also indicated for secondary prevention in patients with a history of transient ischemic attacks or non-cardioembolic ischaemic stroke. Cilostazol improves walking distance by promoting vasodilation and antiplatelet activity with inhibition of phosphodiesterase III and subsequent increases in available cAMP. This activity reviews the indications, contraindications, and use of cilostazol and highlights the role of the interprofessional team in monitoring the adverse effects of the drug.

Objectives:

• Identify the mechanisms of action of cilostazol.
• Describe the adverse effects of cilostazol.
• Review and select appropriate monitoring of cilostazol.
• Summarize how the interprofessional team can collaborate to optimize therapeutic results with cilostazol.

Indications

Cilostazol is a quinolone derivative and is FDA approved for the treatment of intermittent claudication associated with early-stage peripheral vascular disease.[1] Intermittent claudication is caused by the narrowing of arteries that supply the legs with oxygenated blood. Patients with intermittent claudication develop pain when walking due to a lack of oxygen-containing blood reaching the operating leg muscles. Cilostazol decreases the pain of intermittent claudication by dilating these arteries, which improves blood flow and oxygen to the legs. Cilostazol is an effective therapy for improving walking distances in patients with intermittent claudication, and the artery disease guidelines of the American College of Cardiology/American Heart Association reference a therapeutic trial of cilostazol.[2][Level I]

Cilostazol has also been used off-labeled for the long-term prevention of severe vascular events in patients with a history of transient ischemic attack or non-cardioembolic ischemic stroke.[3] Cilostazol is also used off-labeled for percutaneous coronary intervention (PCI, following elective stent placement).[4]

Mechanism of Action

Cilostazol is a phosphodiesterase III (PDE3) inhibitor. PDE3s are enzymes that utilize a catalytic core to hydrolyze cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP).[5] Phosphodiesterase III enzymes are primarily located within the cardiac sarcoplasmic reticulum and in the smooth muscle of arteries and veins, where they regulate cardiac and vascular smooth muscle contractility. Cilostazol exerts its action by inhibiting phosphodiesterase activity and suppressing cAMP degradation. The inhibition of PDE3 allows for a rise in cAMP in platelets and blood vessels. Increased concentrations of cAMP subsequently lead to increase concentrations of the active form of protein kinase A (PKA), and increased PKA is directly related to the inhibition of platelet aggregation.[6] Elevated concentrations of intracellular PKA also elicit a vasodilatory effect on smooth muscle cells by preventing contraction through the inactivation of myosin light-chain kinase.[7] 

Myosin light-chain kinase normally phosphorylates the light chain of myosin in the presence of calcium and calmodulin, which activates myosin to interact with actin. With the inactivation of myosin light-chain kinase by PKA, the myosin-actin interaction cannot occur, and thus, there is an inability to generate a smooth muscle contraction.[8]

Cilostazol has also recently been demonstrated to reduce plasma triglycerides and increase HDL cholesterol concentrations.[9] The precise mechanisms of cilostazol's ability to lower plasma triglycerides and increase HDL are currently not understood; however, the lipoprotein effects of cilostazol are likely a result of the inhibition of cyclic nucleotide phosphodiesterase with a precipitant elevation of intracellular cAMP. As of now, several possible mechanisms have been proposed by which increased cAMP could result in lowered plasma triglycerides. One possible explanation is the reduction of hepatic triglyceride secretion (either directly or indirectly) by the increased effectiveness of glucagon in inhibiting VLDL secretion.[10] Alternatively, increased cAMP intracellular concentrations have demonstrated the ability to promote the release of lipoprotein lipase from rat adipocytes, which could also result in reduced plasma triglycerides.[11] 

Pharmacokinetics

Absorption: Cilostazol is absorbed after oral administration. A high-fat meal increases absorption, with an approximately 90% increase in peak serum concentration and a 25% increase in plasma concentration of the drug over time.[12]

Distribution: Cilostazol is 95% to 98% protein-bound, predominantly to albumin. The free fraction of cilostazol is 27% higher in subjects with renal impairment than in healthy volunteers.

Metabolism: Cilostazol metabolism occurs extensively in the liver by hepatic cytochrome P450 enzymes (mainly CYP3A4 and, to a lesser extent, CYP2C19). Two metabolites are primarily active, with one appearing to account for at least half of the pharmacologic activity (PDE3 inhibition) after the administration of the drug

Excretion: Cilostazol is predominately eliminated by urinary excretion of metabolites (74%), with the remainder being excreted fecally (20%).[13]

Administration

Cilostazol is available in 50 mg and 100 mg tablets. It can be dosed and administered for the following conditions. Cilostazol should be administered orally with water 30 minutes before or 2 hours after meals (breakfast and dinner). Do not take cilostazol with grapefruit juice, which may impair drug metabolism.[14] Peak pharmacodynamic effects (increased heart rate, antiplatelet activity, decrease in diastolic blood pressure) usually occur within 6 hours.[15] Patients may experience symptomatic relief of intermittent claudication within two to four weeks; however, it can take 12 weeks to obtain the optimal therapeutic effect. The dose of cilostazol can be reduced or discontinued without a rebound phenomenon.

Intermittent Claudication

• 100 mg orally twice daily.
• 50 mg orally twice daily should be considered during the coadministration of CYP3A4 inhibitors such as diltiazem, erythromycin, ketoconazole, and itraconazole, and during coadministration of CYP2C19 inhibitors such as omeprazole.

Thrombotic Complications of Coronary Angioplasty

• 100 mg orally twice daily can be substituted for either aspirin or clopidogrel as part of a dual antiplatelet regimen in patients with coronary artery stents who have an allergy or intolerance to aspirin or clopidogrel.

Secondary Prevention of Non-cardioembolic Stroke or TIA(off-label use) 

• 100 mg orally twice daily (first-line drugs are aspirin and clopidogrel).[16]

Use in Special Population

Hepatic Impairment: The pharmacokinetic parameters of cilostazol and its metabolites are similar in healthy subjects compared to subjects with mild hepatic diseases. The use of cilostazol in patients with moderate/severe hepatic impairment is not analyzed.

Renal Impairment: The pharmacologic activity of cilostazol and its metabolites was similar in healthy subjects compared to subjects with mild to moderate renal impairment. In patients with severe renal impairment, metabolite levels are increased, altering the protein binding. However, the expected pharmacologic activity based on plasma concentrations and relative PDE III inhibiting potency of parent drug and metabolites appeared little changed. 

Pregnancy Considerations: Teratogenic Effects: Pregnancy Category C. Cilostazol is teratogenic in rats at doses fivefold the human maximum recommended human dose on a body surface area basis. There are no adequate and well-controlled studies on pregnant women.

Breastfeeding Considerations: Because there is no information on using cilostazol during breastfeeding, an alternate drug may be preferred, especially while nursing a preterm infant or newborn. If a nursing mother uses it, monitor the infant for bruising and bleeding.[17]

Adverse Effects

Cilostazol is a generally well-tolerated oral medication. Common side effects of cilostazol therapy reportedly include headache (34%), diarrhea (19%), and palpitations (10%).[18]

A slight elevation in heart rate of 5 to 7 beats/min may also occur with the administration of cilostazol. These side effects are mild to moderate in intensity, transient, or alleviated with symptomatic treatment and seldom demand treatment withdrawal.[13] Cilostazol may induce tachycardia, tachyarrhythmia, and hypotension.[19]

Postmarketing research has shown cilostazol to induce thrombocytopenia or leukopenia, progressing to agranulocytosis when drug administration does not immediately discontinue. Agranulocytosis is reversible with immediate discontinuation of the drug.[20]

Contraindications

Box Warning: According to the manufacturer's labeling, Cilostazol administration is contraindicated in patients with heart failure of any grade. Cilostazol and many of its metabolites are inhibitors of phosphodiesterase III. Several drugs with the pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV heart failure.[21]

Drugs with vasodilator-type properties generally decrease systemic blood pressure, resulting in a reduction in lower limb perfusion pressure. These agents may also cause a steal of blood from ischemic regions in which blood vessels are already maximally dilated. Therefore, there have been questions regarding the justification for treatment with vasodilators in claudication with absolute contraindication in patients with a history of heart failure. Phosphodiesterase inhibitors have demonstrated decreased survival compared with placebo in patients with class III to IV heart failure. Patients with a history of ischemic heart disease may incur an increased risk of angina pectoris or myocardial infarction exacerbation.[22] Thus, cilostazol is contraindicated in these populations.

Caution is also necessary when prescribing cilostazol to individuals with atrial or ventricular ectopy and those with atrial fibrillation or flutter. Left ventricular outflow tract obstruction is another observation in patients with sigmoid-shaped interventricular septums undergoing cilostazol therapy.[23]

Monitoring

Patients with an increased risk for serious cardiac events due to increased heart rate (patients with stable coronary disease) require close monitoring during treatment with cilostazol. Patients also need monitoring for bleeding episodes and easy bruising or other signs such as pyrexia and sore throat, suggesting the early development of blood dyscrasia. A complete blood count is necessary if a suspected infection or other clinical evidence suggests blood dyscrasia. If the patient shows any clinical or laboratory evidence of a hematologic abnormality, cilostazol therapy should be discontinued immediately.

Caution is necessary when co-administering cilostazol with any other pharmacologic agent that can reduce blood pressure due to the possibility of an additive hypotensive effect with reflex tachycardia. Dual administration of cilostazol with other antiplatelet drugs also requires caution as there is a risk for spontaneous, prolonged, or excessive bleeding.[24]

Toxicity

The oral lethal dose of cilostazol is over 5 g/kg in rats and mice and more than 2 g/kg in dogs. There is a lack of data on acute overdosage with cilostazol in humans. The signs and symptoms of an acute cilostazol overdose can present as a severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmia. In an overdose, patients require careful observation and provide supportive treatment. Cilostazol is highly protein-bound and unlikely to be efficiently removed by hemodialysis or peritoneal dialysis. Emptying the stomach by gastric lavage may be appropriate if needed.[25]

Enhancing Healthcare Team Outcomes

Healthcare professionals such as specialists, nurse practitioners, physician assistants, and physicians who plan to prescribe cilostazol should possess full knowledge regarding the indications and contraindications of the drug. Cilostazol's primary use is treating intermittent claudication, which typically correlates with early-stage peripheral artery disease.[26]

Prescribing clinicians (MDs, DOs, NPs, PAs) should know that the drug is usually administered twice daily as a 100 mg oral dose shortly before or after meals. Consider possible adverse side effects when using cilostazol in patients with supraventricular arrhythmias or a history of heart disease. Additionally, exercise caution when co-administering cilostazol with any other pharmacologic agent that may reduce blood pressure due to an additive hypotensive effect and subsequent reflex tachycardia; therefore, pharmacists should watch for these potential drug interactions and report back to the prescribing clinicians. Both pharmacists and nurses can counsel patients on optimal dosing and possible adverse reactions.

Patients receiving cilostazol should be closely monitored for tachyarrythmias, hypotension, and signs of blood dyscrasia, which will primarily be a function of nurses and report these findings to the prescribing clinician. The interprofessional health care team should work collaboratively to ensure patients taking cilostazol obtain regular follow-ups. The specialty medical professionals should weigh in as needed in the care of these patients for optimal healthcare outcomes. [Level 5]