Continuing Education Activity

Cilostazol is a quinolone derivative primarily used for the treatment of intermittent claudication due to peripheral vascular disease; this is the FDA approved indication. Cilostazol also has an indication as secondary prevention for patients with a history of transient ischemic attacks or non-cardioembolic ischaemic stroke. Cilostazol improves walking distance through the promotion of 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 primarily used in the treatment of intermittent claudication associated with early-stage peripheral vascular disease.[1] Intermittent claudication is a condition 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 demonstrated to be significantly more effective than clopidogrel and aspirin alone for long-term prevention of severe vascular events in patients with a history of transient ischemic attack or non-cardioembolic ischemic stroke.[3] 

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).[4] Phosphodiesterase III enzymes are primarily located within the cardiac sarcoplasmic reticulum, as well as in the smooth muscle of arteries and veins where they are involved in the regulation of 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 increased concentrations of the active form of protein kinase A (PKA), and increased PKA is directly related to the inhibition of platelet aggregation.[5] Elevated concentrations of intracellular of PKA also elicit a vasodilatory effect on smooth muscle cells by preventing contraction through the inactivation of myosin light-chain kinase.[6] 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.[7] With the inactivation of myosin light-chain kinase by PKA, the myosin-actin interaction cannot occur, and thus, there is an inability to generate smooth muscle contraction.

Cilostazol has also recently demonstrated the ability to reduce plasma triglycerides and increase HDL cholesterol concentrations.[8] 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 to inhibit VLDL secretion.[9] 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.[10]

Drug 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. Cilostazol is predominately eliminated by urinary excretion of metabolites (74%), with the remainder being excreted fecally (20%).[11]

Administration

Cilostazol can be dosed and administered as follows:

For intermittent claudication:

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

For thrombotic complications of coronary angioplasty:

• Oral 100 mg 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.

Cilostazol should be administered orally with water 30 minutes before or 2 hours after meals (breakfast and dinner). 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] Do not take cilostazol with grapefruit juice, as this may impair drug metabolism.[13] Peak pharmacodynamic effects (increased heart rate, antiplatelet activity, decrease in diastolic blood pressure) usually occur within 6 hours.[14] Symptomatic relief of intermittent claudication may be experienced within 2 to 4 weeks; however, it can take up to as to 12 weeks to obtain the optimal therapeutic effect. Dosage of cilostazol can be reduced or discontinued without a rebound phenomenon.

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%).[15] 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, ephemeral, or alleviated with symptomatic treatment and seldom demand treatment withdrawal.[11]

Contraindications

Drugs that exhibit vasodilator-type properties generally reduce 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, and patients with a history of ischemic heart disease may incur increased risk for exacerbation of angina pectoris or myocardial infarction.[16] Thus, contraindications include the use of cilostazol in these populations.

Cilostazol may induce tachycardia, palpitations, tachyarrhythmia, and/or hypotension.[17] Caution is also necessary when prescribing cilostazol to individuals with atrial or ventricular ectopy and/or those with atrial fibrillation or flutter. Left ventricular outflow tract obstruction is also another observation in patients with sigmoid shaped interventricular septums undergoing cilostazol therapy.[18] 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.

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 episodes of bleeding and easy bruising or other signs such as pyrexia and sore throat, which might suggest the early development of blood dyscrasia. A complete blood count is necessary if there is a suspected infection, or if any other clinical evidence suggests blood dyscrasia. If the patient shows any clinical or laboratory evidence of a hematologic abnormality, cilostazol therapy should discontinue immediately.

Caution is necessary when co-administering cilostazol with any other pharmacologic agent that has the potential to 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 unanticipated, prolonged, or excessive bleeding.

Toxicity

There is limited 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 the event of an overdose, patients require careful observation and providing supportive treatment. Cilostazol is highly protein-bound and is therefore unlikely to be efficiently removed by hemodialysis or peritoneal dialysis. Emptying the stomach by gastric lavage may be appropriate if needed. The oral lethal dose of cilostazol is over 5.0 g/kg in rats and mice and more than 2.0 g/kg in dogs.

Enhancing Healthcare Team Outcomes

Healthcare professionals such as nurse practitioners, pharmacists, and physicians who plan to use cilostazol should possess full knowledge regarding the indications and contraindications of the drug. Cilostazol's primary use is in the treatment of intermittent claudication, which correlates typically with early-stage peripheral artery disease.[19]

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 a history of supraventricular arrhythmias or heart disease. Additionally, exercise caution when co-administering cilostazol with any other pharmacologic agent that may reduce blood pressure due to the possibility of an additive hypotensive effect and subsequent reflex tachycardia, therefore pharmacists should watch for these potential drug interactions and report back to the clinician and nurse. Both pharmacists and nurses can counsel patients on optimal dosing and administration with regard to meals. Patients receiving cilostazol requires close monitoring for tachyarrythmias, hypotension, and/or signs of blood dyscrasia, which will largely be a function of nurses, which can also report these findings to the prescribing clinician. The interprofessional health care team should work collaboratively to ensure patients taking cilostazol obtain regular follow-up, and the appropriate medical professionals weigh in as needed in the care of these patients for optimal healthcare outcomes. [Level V]