Cilostazol

Cilostazol

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Systematic (IUPAC) name
6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]- 3,4-dihydro-2(1H)-quinolinone
Clinical data
Trade names	Pletal
AHFS/Drugs.com	monograph
MedlinePlus	a601038
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Oral
Pharmacokinetic data
Protein binding	95–98%
Metabolism	Hepatic (CYP3A4- and CYP2C19-mediated)
Biological half-life	11–13 hours
Excretion	Renal
Identifiers
CAS Number	73963-72-1 Y
ATC code	B01AC23 (WHO)
PubChem	CID: 2754
IUPHAR/BPS	7148
DrugBank	DB01166 Y
ChemSpider	2652 Y
UNII	N7Z035406B Y
KEGG	D01896 Y
ChEBI	CHEBI:31401 Y
ChEMBL	CHEMBL799 Y
Chemical data
Formula	C20H27N5O2
Molecular mass	369.46 g/mol
SMILES O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4
InChI InChI=1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26) Y Key:RRGUKTPIGVIEKM-UHFFFAOYSA-N Y
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Cilostazol /sᵻˈlɒstəzɒl/ is a quinolinone-derivative medication used in the alleviation of the symptom of intermittent claudication in individuals with peripheral vascular disease. It is manufactured by Otsuka Pharmaceutical Co. under the trade name Pletal.

Although drugs similar to cilostazol have increased the risk of death in patients with congestive heart failure, studies of significant size have not addressed people without the disease.

Cilostazol is a phosphodiesterase inhibitor with therapeutic focus on cyclic adenosine monophosphate (cAMP). It inhibits platelet aggregation and is a direct arterial vasodilator. Its main effects are dilation of the arteries supplying blood to the legs and decreasing platelet coagulation.

Mechanism

Cilostazol is a selective inhibitor of 3-type phosphodiesterase (PDE3) with therapeutic focus on increasing cAMP. An increase in cAMP results in an increase in the active form of protein kinase A (PKA), which is directly related with an inhibition in platelet aggregation. PKA also prevents the activation of an enzyme (myosin light-chain kinase) that is important in the contraction of smooth muscle cells, thereby exerting its vasodilatory effect.

Clinical use

Cilostazol is approved for the treatment of intermittent claudication. The typical dose is 100 mg twice a day. The effects may take as long as 3 months to be evident and has been shown to improve pain-free walking distance by 50%.

Cilostazol is also frequently used off-label, at the same dose, for treatment of intracranial atherosclerosis and secondary stroke prevention [reference Stroke. 2005; 36: 782-786 Published online before print March 3, 2005, doi:10.1161/01.STR.0000157667.06542.b7 online http://stroke.ahajournals.org/content/36/4/782.full]

In people with heart failure

Cilostazol, clearly effective for a debilitating condition whose current treatment is often inadequate, is a member of a pharmacologic class that is dangerous to people with severe heart failure and unstudied in other people. Cilostazol has been studied in people without heart failure, without evidence of harm, but much more data would be needed to determine no risk exists. Although cilostazol would not be approvable for a trivial condition the Cardio-Renal Advisory Committee and FDA concluded that fully informed patients and physicians should be able to choose to use it to treat intermittent claudication. Patient and physician labeling will describe the basis for concern and the incomplete information available.

Adverse effects

Possible side effects of cilostazol use include headache (the most common), diarrhea, severe heat intolerance, abnormal stools, increased heart rate, and palpitations.

Interactions

Cilostazol is metabolized by CYP3A4 and CYP2C19, two isoenzymes of the cytochrome P450 system. Drugs that inhibit CYP3A4, such as itraconazole, erythromycin, ketoconazole, and diltiazem, are known to interact with cilostazol. The proton pump inhibitor omeprazole, a potent inhibitor of CYP2C19, increases exposure to the active metabolite of cilostazol.

A single report has been made of grapefruit juice possibly increasing the effects of cilostazol; some drug information sources list this as a possible interaction. The FDA-approved labeling of cilostazol notes that grapefruit juice (which is a CYP3A4 inhibitor) increases the drug's maximum concentration by around 50%.

See also

• Aripiprazole — an atypical antipsychotic with similar dihydroquinolinone core structure.

External links

• Supplementary information provided by Drug Digest (Link not working 2/8/12)
• U.S. National Library of Medicine: Drug Information Portal - Cilostazol