Drug Profile of Cilostazol - a Reversible Selective Inhibitor of Phosphodiesterase III

C. Vinodhini

The word “Claudication” comes from the Latin term “Claudicare” meaning to
limp. It is the most common symptom of extremity peripheral artery disease (PAD)
⁷. It is due to a temporary inadequate supply of oxygen to
the muscles of the leg.

The poor oxygen supply is a result of narrowing of the arteries that supply
the leg with blood. This limits the supply of oxygen to the leg muscles and
is felt especially when the oxygen requirement of these muscles rise with exercise
(or) walking and it disappears with rest.

It is characterized by pain, ache, cramp, tightness/ sense fatigue in leg muscles
with activity. Symptoms relieved by rest which results in reduced mobility and
quality of life.

Intermittent claudication is temporary artery narrowing due to spasm
of the artery (vasospasm), permanent artery narrowing due to atherosclerosis,
(or) the complete blockage of an artery due to decrease blood flow to the leg.
It is more common in men than in women. The condition affects 1-2% of the population
under 60 years of age. 3-4% of persons age 60 to 70 and over 5% of persons over
70 years.

Cilostazol is a new drug available for the treatment of symptoms of intermittent
claudication. It helps the people to walk a longer distance¹ before
leg pain starts. Cilostozol is in the FDA pregnancy category C.

Chemical structure (Molecular formular : C₂oH₂₇N₅O₂)

It is chemically ¹⁴ 6-[4-(1- cyclohexyl – 1H- tetrazol -5- yl)-butoxy]-3,4-
dihydro-2(1H)-Quinolinone (or) 6-[4-(1-cyclohexyl-1H-tetrazol -5-yl)-butoxy]-3,4-dihydro-carbostyril.

Mechanism of action

Cilostazol is a reversible selective inhibitor of phosphodiesterase
III (PDE-III)⁸ thereby suppressing cyclic Adenosine Mono Phosphate
(cAMP) degradation^1,4,5. It also inhibits adenosine uptake into cells
which augments the cAMP – elevating effect of PDE III inhibition. It exerts
anti-platelet and antithrombotic effect by inhibiting both primary and secondary
platelet aggregation induced by ADP, collagen, arachidonic acid epinephrine,
thrombin and shear stress⁴ without affecting bleeding time. Cilostazol
causes vasodilation by inhibiting calcium induced contraction of smooth muscle
cells and thus reduce plasma triglyceride levels and increase plasma high density
lipoprotein cholesterol levels.

Pharmacokinetics

Cilostazol is well absorbed after oral administration. A high fat meal
⁵ increase absorption with an approximately 90% increase in C max
and 25% increase in AUC. Cilostazol is extensively metabolized by liver cytochrome
P-450 enzyme, mainly CYP3A4 and to some degree CYP2C19, to active metabolites^1,4,5.
Two metabolites are active, most active being 3,4 – dehydrocilostazol
(DHC), 4-7 times more active than parent compound and it accounts for at least
50% of pharmacological activity of cilostazol. Another metabolite 4 -trans –
hydroxy cilostazol (HC) 1/5^th active as parent. Pharmacokinetics
of cilostazol are approximately dose – proportional. Cilostazol and its metabolite
have apparent elimination half – lives of about 11-13 hours.  

Cilostazol is 95 – 98% protein bound^1,4,5 especially to albumin.
Mild hepatic impairment did not affect protein binding. Cilostazol is eliminated
predominantly by metabolism and subsequent urinary excretion of metabolites. 

Indications

Cilostazol is indicated for the reduction of symptoms of intermittent claudication.
It is also used off label for the prevention of restenosis following angioplasty
either alone or in combination with other platelet inhibitors like aspirin and
ticlopidine Based on literature reports, cilostazol is comparable in safety and
efficacy to aspirin and ticlopidine for the prevention of stent thrombosis after
implantation^2,3. Other off label uses that need more research to determine
safety and efficacy include the treatment of bradyarrythmias, cerebro-vascular
disease and graft – Vs-host disease⁴.

Adverse effects

Although side effects from cilostazol are not common, they can occur.
The most common adverse effects are headache, upset stomach, stomach pain, infection
abnormal stools, runny nose, sore throat, flu like symptoms, nausea, fluid retention,
pharyngitis, vision changes one sided weakness and serious allergic reactions
include rash, itching, swelling of lips, tongue or face and severe dizziness,
fast (or) irregular heartbeats.

Drug interactions

Drugs like Erythromycin, Omeperazole, Diltiazem increase the concentration
of cilostazol by blocking the action of enzymes that destroy cilostazol. A similar
interaction could occur with Ketoconazole, Itraconazole, Fluconazole, Miconazole,
Fluoxetine, Fluvoxamine, Nefazodone, Sertaline.

Heparin, Warfarin and other anti-platelet drugs like Clopidogrel, Dipyridamole,
Ticlopidine increases risk of bleeding or anti-platelet effect when used with
cilostazol. A high fat meal increases the absorption of cilostazol and intake
of grape fruit juice ^9,10,15 could increase the concentration of
cilostazol.              

Higher concentration of cilostazol increases the possibility of toxic effects.
Therefore a dose of 50 mg twice daily should be considered when drugs that may
increase the concentration of cilostazol are being used.

Contraindications

In patients with congestive heart failure, long term use of other drugs
similar to cilostazol has increased the risk of death.

Brand name

CILODOC (Lupin), PLETOZ, PLETAL: FDA had approved ¹² pletal
for the first time as a new drug for treating stable intermittent claudication. 

Dose

For intermittent claudication, recommended dose of 100mg twice daily
to be taken atleast half an hour before or two hours after dinner and breakfast
to prevent food from affecting its absorption. Patient responds to cilostazol
exerted peak benefit in 12 weeks of therapy and sometimes within 2-4 weeks of
therapy.

Dosage forms  

Cilostazol (PLETAL) comes in 100mg tablets, white round and marked Pletal
100, also comes in 50mg tablet, white triangular and marked Pletal 50.

Warning and precaution

Patients with heart, kidney or liver disease, bleeding disorders, blood
disorders, recent stroke, pregnant and lactating mothers, cigarette smokers¹⁰
and those undergoing medications like aspirin, azithromycin and other inhibitors
of CYP3A4 or CYP2C19.

Claudication Related Medications

Statins (Cholesterol lowering drugs), acetylsalicylic acid, aspirin,
pentoxifylline  and cilostazol¹³_.

Claudication Related Diseases and Conditions

High Blood Pressure, Diabetes, High cholesterol level, Peripheral vascular
disease.

Storage

Tablets should be stored¹⁰ below 25^oc (77^oF)

Risk Factors

When risk factors coexist, the risk increases several fold :-

1.Older age more than 40 years

2.Male gender

3.Smoking

4.Hypertension

5.Hyperlipaedemia

6.Diabetes mellitus

7.Hyper homocysteinemia 

Diagnosis

Intermittent claudication can be diagonised by taking history of the
patient, careful examination of the leg, pulse evaluation, ankle - brachial index
(ABI).    

Clinical trials

A current status of cilostazol, a quinlinone, possess many characteristic
that may explain its effectiveness over the multitude of agents that have been
evaluated unsuccessfully for this disease. It inhibits platelet aggregation,
increased vasodilation and also inhibits smooth muscle cell proliferation^18-21.

Beneficial effect on high density lipoprotein (HDL) cholesterol and triglyceride
levels have also been demonstrated ²².  

Several published pieces on this compound are worth summarizing:-

i. Beebe et al, evaluated two doses of cilostazol and found that patients
reported increase walking distance and quality of life, both on disease – specific
questionnaires and on generalized ones such as the SF – 36 ²³

ii. Money and colleagues, studied cilostazol in a 16 – week trial that
analyzed potential patient variation with acute dosing and found no temporal
relationship between dosing and walking distance thereby pointing to a mechanism
of action beyond that of vasodilatation alone²⁴.

iii. Elam et al, evaluated cilostazol in patients with intermittent
claudication but also found that cilostazol decreased plasma glycerides by 18%
and concurrently raised plasma HDL level by 10% ^22.

iv. Dawson et al, reported the largest claudication study in United
states and included the active control of pentoxifylline and placebo. These
researches found that cilostazol was superior to pentoxifylline and placebo
in both the maximum distance walk on the treadmill (a 54% increase from baseline)
and the time to patients first experience of pain (a nearly 100% increase from
baselines). No difference was found between placebo and pentoxifylline.

v. Paul D, Thompson and et al ^17, have examined the
adverse effect of cilostazol in eight randomized, double blind, placebo controlled
trials, in 2702 patients with stable, moderate to severe claudication for the
duration of 12 to 24 weeks. Cilostazol therapy increased maximal and pain free
walking distances by 50% and 67% respectively. In subgroup analysis cilostazol
increased pain free and maximal walking distance similarly in men and women,
in older (³ 65 years) and younger patients, and in patients with and without
diabetes.

There were no changes in haematologic parameters, liver function, electrolytes,
or renal function during cilostazol treatment.

In one study, cilostazol was superior to Pentoxifylline. In the other comparison
with pentoxifylline neither drug was superior to placebo^6. The effectiveness
of cilostazol in the symptomatic treatment of claudication is well – established
by the results of 6 adequate and well – controlled studies. There are no data
bearing on longer term aspects of treatment such as limb preservation, rate
of progression etc.    

US FDA has approved two drugs for the management of Intermittent claudication
Pentoxifylline and Cilostazol^26. Mechanism of action that provides
symptom relief with pentoxifylline is poorly understood but is thought to involve
RBC deformability as well as reduction in fibrinogen concentration, platelet
adhesiveness and whole blood viscosity.

In addition to pentoxifylline and cilostazol clinical trials indicates many
other drugs may relieve the symptoms of intermittent claudication like Ginkgo
biloba¹⁶ available as an OTC extract provide symptom relief comparable
to pentoxyfylline.

But pentoxifylline is not recommended for intermittent claudication because

v Inconsistent and modest benefit; non significant increase in walking ability.

v Not more effective than placebo when increasing walking ability (or) functional
status.

v Most trials not properly designed.

v Study sample size and pentoxifylline response inversely correlated.

Conclusion

Cilostazol is a reversible selective inhibitor of phosphodiesterase III. This
drug is the first to be approved by FDA for treating stable intermittent claudication
in more than 15 years.  It has been evaluated for safety or effectiveness
among patients with more severe peripheral vascular disease who have claudication
pain at rest, leg ulcer or gangrene.  Clinical studies in several thousand
patients did not identify serious toxicity but there are two important concerns
that are identified in physician labelling for the drug and in a patient – directed
brochure such as (i) Drug shown increased deaths rates in patients with severe
heart failure (ii) Drug has not been studied in combination with clopidogrel,
a drug recently approved for use in patients with peripheral vascular disease.
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^8.
We conclude that cilostazol significantly increases walking distance and quality
of life measures in patients with claudication without major adverse effects¹⁷.

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Pharmacokinetic data of cilostazol

About Authors

*Ms.C.Vinodhini, M.Pharm

*Address for Correspondence:
Lecturer, Sri ramachandra College of Pharmacy, Sri Ramachandra Medical College
and Research Iinstitute (d.u), Porur, Chennai-116

Ms.Sabamaanvizhi, M.Pharm

Lecturer, College of Pharmacy, SRMC&RI(DU), Phone: : 91-9841162130, Email:
sabamaanvizhi@yahoo.co.in

Mr.P.Aravanan, M.Pharm

Lecturer, College of Pharmacy, SRMC&RI(DU), Phone: 91-9444716807, Email:
p_aravanan@hotmail.com