Cilostazol - An Overview

Overview

Cilostazol is a quinolone derivative approved by the FDA (Food and Drug Administration) to treat intermittent claudication caused by early-stage peripheral vascular disease. Cilostazol is also prescribed for secondary prevention in people who have had transient ischemic attacks or non-cardioembolic ischemic strokes. Cilostazol enhances walking distance by increasing vasodilation and antiplatelet activity, mostly through phosphodiesterase III inhibition and resultant increases in accessible cyclic adenosine monophosphate (cAMP).

Indications of Cilostazol:

• Cilostazol is a phosphodiesterase III inhibitor (PDE III inhibitor) that has been shown to improve symptoms of intermittent claudication by increasing walking distance.

Dosage:

• Dosage Form and Strength: Cilostazol is available in tablet form.

  • 50 milligrams of Cilostazol in triangular white debossed tablets.

  • 100 milligrams of Cilostazol in round white debossed tablets.

• Mode of administration: Cilostazol has to be taken orally.

• Recommended Dose: Cilostazol 100 milligrams is recommended to be taken twice daily, at least half an hour before or two hours after breakfast and evening meal. Patients may respond as soon as two to four weeks after starting the treatment, but it may take up to twelve weeks to notice favorable results. If symptoms do not improve after three months, stop Cilostazol.

• Dose Reduction With Cyp3a4 and Cyp2c19 Inhibitors: When used with strong or intermediate Cytochrome P450 3A4 (CYP3A4) inhibitors (for example - Ketoconazole, Itraconazole, Erythromycin, and Diltiazem) or CYP2C19 inhibitors (for example - Ticlopidine, Fluconazole, and Omeprazole), lower the dosage to 50 milligrams twice daily.

Contraindication:

Cilostazol is contraindicated in individuals with -

• Heart failure for any form: Cilostazol and some of its metabolites are phosphodiesterase III inhibitors.

• Several medicines having this pharmacologic effect were attributed to reducing the survival rate of individuals with class III-IV heart failure compared to placebo.

• Hypersensitivity to Cilostazol or any components used in the drug will lead to anaphylaxis and angioedema.

Warnings and Precautions:

1. Tachycardia: Cilostazol may cause tachycardia (high heart rate above 100 beats per minute), palpitation, tachyarrhythmia, or hypotension. Cilostazol leads to an increase in heart rate of five to seven beats per minute. Individuals with a history of ischemic heart disease are more likely to get angina pectoris (severe chest pain) or myocardial infarction.

2. Left Ventricular Outflow Tract Obstruction: Patients with sigmoid-shaped interventricular septum have been observed to have obstruction of the left ventricular outflow tract. After taking Cilostazol, patients should be monitored for developing a new systolic murmur or heart symptoms.

3. Hematologic Adverse Reactions: Reports of thrombocytopenia (deficiency of platelets) or leukopenia (decreased white blood cells) leading to agranulocytosis (deficiency of granulocytes in the blood) when Cilostazol was not quickly stopped. Reversal of agranulocytosis can be done by discontinuing Cilostazol. Complete blood count monitoring of platelet and white blood cells should be done regularly.

4. Hemostatic Disorders or Active Pathologic Bleeding: Cilostazol is a reversible way to block platelet aggregation. Cilostazol has not been evaluated in individuals who have hemostatic abnormalities or who are experiencing active pathologic bleeding. Cilostazol should be avoided in such individuals.

For Patients:

What Is Peripheral Vascular Disease?

Peripheral vascular disease (PVD) is a type of blood circulation disorder in which the blood vessels constrict outside of the heart and brain, leading to obstruction of the blood flow and spasms. This can occur in either the arteries or veins. PVD often causes discomfort and exhaustion, particularly in the legs and during exercise. The pain subsides with rest.

What Is Cilostazol, and What Is It Used For?

• Cilostazol belongs to a class of drugs known as phosphodiesterase type 3 inhibitors. It works by expanding some blood arteries and decreasing the clotting activity (forming clumps) of some blood cells called platelets inside the vessels.

• Cilostazol is used for patients with intermittent claudication. Intermittent claudication is a cramp-like discomfort in the legs caused by a lack of blood flow in the legs. Cilostazol enhances blood circulation in the legs, which allows patients to walk longer without discomfort.

• Cilostazol is only prescribed for individuals whose symptoms have not improved sufficiently, even after making changes in their lifestyle (such as smoking cessation and exercising regularly) and other relevant therapies.

What Should the Patient Understand Before Taking Cilostazol?

Cilostazol should not be used:

• If the patient is allergic to Cilostazol or other substances used in this drug.

• If the patient has "heart failure."

• If the patient has had a "heart attack" or cardiac surgery during the previous six months.

• If the patient is suffering or has previously experienced blackouts due to heart illness or any serious irregularities in the heartbeat.

• If the patient is aware of a condition that raises the chances of bleeding or bruising, such as an active stomach ulcer or a stroke during the last six months, ocular problems, and suffering from uncontrolled blood pressure.

• If the patient takes anticoagulants like Aspirin, Clopidogrel, or any combination, the risk of bleeding may increase.

• If the patient suffers from liver disease, renal disease, or both.

What Are the Possible Side Effects?

Common side effects (may affect up to 1 in 10 people):

• Headache.

• Abnormal stools.

• Diarrhea.

Uncommon side effects (may affect up to 1 in 100 people):

• Palpitations in the heart.

• Dizziness.

• Rhinitis - running nose.

• Pain in the abdomen.

• Abdominal discomfort leading to indigestion.

• Feeling or being sick (nausea or vomiting).

• Loss of appetite (anorexia).

• Excessive burping or flatulence.

• Edema of ankles, feet, or face.

• Rashes or changes in the appearance of the skin.

• Itchy skin.

• Bleeding in the skin.

• General overall weakness.

Uncommon Side Effects (May Affect up to 1 in 100 People):

• Shortness of breath.

• Cough and chills.

• Bleeding unexpectedly.

• Bleeding tendency (through the nose and blood in sputum or urine).

• Decrease in red cell count in the blood.

• Dizziness on standing up due to low blood pressure.

• Fainting.

• Anxiety.

• Difficulty sleeping.

• Unusual dreams.

• Allergic reaction.

• Aches and pains.

• Increased blood sugar - hyperglycemia.

• Stomach pain (gastritis).

• Not feeling well.

Rare side effects (may affect up to 1 in 1,000 people):

• Tendency to bleed for a longer duration than normal.

• Increase in the platelets in the blood.

• Kidneys problems

The following adverse effects have been reported with Cilostazol usage, although the frequency with which they may occur is unknown:

• Variations in blood pressure.

• Moving difficulties.

• Discomfort.

• Hot flushes.

• Eczema and other skin rashes.

• Hives.

• A diminished sensation of the skin.

• Runny or sticky eyes (conjunctivitis).

• Ringing in the ears (tinnitus).

• Unusually frequent urination.

• High blood urea, uric acid, and creatinine levels may be noticed in blood tests.

What if the Patient Misses a Dose of Cilostazol?

If the patient misses a dose of Cilostazol, do not panic; patiently wait and take the next dose as usual. Take only one dose at a time to compensate for a forgotten tablet.

What if an Overdose of Cilostazol Occurs?

Suppose the patient, by any chance, takes an extra Cilostazol dose than the patient should normally take. In that case, they may get signs and symptoms such as a severe headache, diarrhea, an increased heart rate, and an irregular pulse, which they should immediately report to the consulting physician.

For Doctors:

What Is Cilostazol?

• Cilostazol is a quinolinone derivative that suppresses cellular phosphodiesterase (phosphodiesterase III in particular). The empirical formula for cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.

• Cilostazol is a white to off-white crystal or crystalline powder partially soluble in methanol and ethanol but essentially insoluble in water, 0.1 N HCl, and 0.1 N NaOH.

Dosage and Administration:

Cilostazol pills for oral use are available as 50 milligrams triangular and 100 milligrams round, white debossed tablets. In addition to the active component,

Each tablet contains inactive ingredients: carboxymethylcellulose calcium, maize starch, hydroxypropyl methylcellulose, magnesium stearate, and microcrystalline cellulose.

Clinical Pharmacology:

1. Mechanism of Action: Cilostazol and many of its metabolites suppress phosphodiesterase III activity and inhibit cAMP breakdown, resulting in a rise in cAMP in platelets and blood vessels, respectively, inhibiting platelet aggregation and vasodilation.

Cilostazol suppresses platelet aggregation generated by several stimuli, such as thrombin, adenosine diphosphate (ADP), collagen, Arachidonic acid, epinephrine, and shear stress, reversibly.

Cardiovascular Effects:

• Cilostazol affects both the vascular beds and cardiovascular function. It causes the dilation of vascular beds heterogeneously, with femoral beds dilating more than vertebral, carotid, or superior mesenteric arteries. The effects of Cilostazol did not affect the renal arteries.

• Cilostazol elevates the heart rate, myocardial contractile force, coronary blood flow, and ventricular automaticity in dogs and cynomolgus monkeys, as expected with a PDE III inhibitor. Contractility of the left ventricles was raised to the levels necessary to suppress platelet aggregation.

• Atrioventricular conduction was sped up. In humans, individuals given 50 and 100 milligrams twice daily exhibited a dose-proportional increase in heart rate of 5.1 and 7.4 beats per minute, respectively.

2. Pharmacodynamics:

• Cilostazol's effects on platelet aggregation were studied in healthy individuals and patients with stable signs of cerebral thrombosis, embolism, transient ischemic stroke, or cerebral arteriosclerosis at dosages ranging from 50 milligrams to 100 milligrams three times a day. Cilostazol suppressed platelet aggregation considerably in a dose-dependent way. The effects were seen as early as three hours after the dose and continued up to twelve hours after a single dose.

• Following chronic Cilostazol treatment and discontinuation, the effects on platelet aggregation started to diminish 48 hours after discontinuation and recovered to baseline by 96 hours, with no rebound effect. A dose of 100 milligrams twice a day of Cilostazol effectively reduced platelet aggregation generated by arachidonic acid, collagen, and adenosine diphosphate (ADP). The administration of Cilostazol had no effect on bleeding time.

• The effects of Cilostazol on circulating plasma lipids have been studied in patients consuming 100 milligrams twice daily, provided a decrease in triglycerides of 29.3 mg/dL (15 percent ) and an increase in HDL-cholesterol of 4.0 mg/dL (10 percent) after 12 weeks when compared to placebo.

3. Pharmacokinetics:

• Absorption: Following oral administration, absorption of Cilostazol takes place. A high-fat meal improves absorption by roughly a 90 percent increase in C max and a 25 percent rise in AUC. Absolute bioavailability still needs to be clarified. Cilostazol is extensively metabolized in the liver by cytochrome P-450 enzymes, primarily 3A4 and, to a smaller extent, 2C19, with byproducts primarily eliminated in urine. Two metabolites are active, with one metabolite accounting for at least 50 percent of the pharmacologic (PDE III inhibition) action following Cilostazol treatment.

• Pharmacokinetics is dosage dependent. Cilostazol and its active metabolites tend to have elimination half-lives of eleven to thirteen hours. Cilostazol and its active metabolites accumulate approximately two-fold after chronic treatment and reach steady-state blood levels in a few days. In healthy individuals and patients with intermittent claudication because of peripheral artery disease, the pharmacokinetics of Cilostazol and its two primary active metabolites were identical (PAD).

• Distribution: Cilostazol is 95 to 98 percent protein bound, primarily to albumin. 3,4-dihydro-cilostazol binding is 97.4 percent and 66 percent for 4'-trans-hydroxy-cilostazol. Protein binding was unaffected by mild hepatic impairment. The free fraction of Cilostazol in participants with renal impairment was 27 percent greater than in healthy volunteers. Cilostazol was not clinically significantly displaced from plasma proteins by Erythromycin, Quinidine, Warfarin, or Omeprazole.

• Metabolism: Cilostazol is mostly excreted by metabolism and subsequently by the excretion of other metabolites through urine. According to in vitro investigations, the principal isoenzymes involved in the metabolism of Cilostazol are CYP3A4 and, to a smaller extent, CYP2C19. The enzymes required for metabolizing the most active metabolite, 3,4-dihydro-cilostazol, still need to be determined. Following oral administration of 100 milligrams of radiolabeled Cilostazol, Cilostazol accounted for 56 percent of total analytes in plasma, 15 percent was 3,4-dihydro-cilostazol (which is four to seven times as active as Cilostazol), and 4 percent was 4'-trans-hydroxy-cilostazol (20 percent as active a Cilostazol).

• Elimination: The primary route of elimination (74 percent ) is through urine, with the remaining expelled in feces (20 percent). There was no detectable quantity of unaltered Cilostazol in the urine, and less than 2 percent of the dosage was eliminated as 3,4-dehydro cilostazol. In urine, approximately 30 percent of the dosage was eliminated as 4'-trans-hydroxy-cilostazol. The remaining was eliminated as various metabolites, with none exceeding 5 percent. There was no indication of induction of hepatic micro enzymes.

Special Populations

1. Age and Gender: The total and unbound oral clearances of Cilostazol and its metabolites, modified for body weight, were not substantially altered by age (50 to 80 years) or gender.

2. Smokers: According to population pharmacokinetic research, smoking reduced exposure to Cilostazol by roughly 20 percent.

3. Hepatic Impairment: The pharmacokinetics of Cilostazol and its metabolites were comparable in individuals with moderate hepatic dysfunction and healthy participants. There has been no research on patients with moderate or severe hepatic impairment.

4. Renal Impairment: Cilostazol and its metabolites had comparable overall pharmacologic activity in patients with mild to moderate renal impairment as in healthy persons. Severe renal impairment elevates metabolite levels and changes the parent's drug-protein binding capacity. However, depending on plasma concentrations and the relative PDE III inhibitory efficiency of the parent drug and metabolites, the predicted pharmacologic action is slightly modified. Patients on dialysis have yet to be investigated, although due to its strong protein binding (95 to 98 percent), Cilostazol is unlikely to be eliminated efficiently by dialysis.