DRUG INTERACTIONS OF

ANTIPLATELETS (PART 5)
(DRUG INTERACTIONS OF PHOSPHODIESTERASE
INHIBITORS)

Dr P.NAINA MOHAMED PhD

Pharmacologist
 INTRODUCTION
• CILOSTAZOL IS A SELECTIVE INHIBITOR OF PHOSPHODIESTERASE 3 (PDE3) AND IT
IS AN ANTIPLATELET DRUG AND A VASODILATOR.
• CILOSTAZOL IS APPROVED FOR THE TREATMENT OF INTERMITTENT
CLAUDICATION IN PATIENTS WITH PERIPHERAL VASCULAR DISEASE.
• INTERACTION BETWEEN ONE OR MORE CO-ADMINISTERED MEDICATIONS
LEADING TO CHANGE IN THEIR EFFECTIVENESS OR TOXICITY, IS TERMED AS
“ADVERSE DRUG INTERACTION”.
• ANTIPLATELETS CAN INTERACT WITH PRESCRIPTION DRUGS, OVER-THE-
COUNTER (OTC) MEDICATIONS, HERBAL PRODUCTS, DIETARY SUPPLEMENTS,
VITAMINS, FOODS, DISEASES, AND GENETICS (FAMILY HISTORY).
 ANTIPLATELETS
• IRREVERSIBLE CYCLOOXYGENASE (COX) INHIBITORS
 ASPIRIN

• ADENOSINE DIPHOSPHATE (ADP) RECEPTOR INHIBITORS

 CLOPIDOGREL
 PRASUGREL
 TICAGRELOR
 TICLOPIDINE

• ADENOSINE REUPTAKE INHIBITORS

 DIPYRIDAMOLE

• GLYCOPROTEIN IIB/IIIA INHIBITORS (IV USE ONLY)

 ABCIXIMAB
 EPTIFIBATIDE
 TIROFIBAN

• PHOSPHODIESTERASE INHIBITORS
 CILOSTAZOL

• PROTEASE-ACTIVATED RECEPTOR-1 (PAR-1) ANTAGONISTS

 VORAPAXAR
MECHANISM OF ACTION OF CILOSTAZOL

Inhibition of platelet
Higher
Inhibition of Prevention aggregation &
Protein
Cilostaz phosphodie of Increased Prevention of
kinase activation of Myosin
ol sterase 3 degradation cAMP levels
A (PKA) light-chain kinase
(PDE3) of cAMP (MLCK) resulting in
activation Vasodilation

HTTPS://WWW.NCBI.NLM.NIH.GOV/PMC/ARTICLES/PMC2544362/
 CILOSTAZOL & OMEPRAZOLE

Omeprazole inhibits
Cilostazol + CYP2C19-mediated Elevated risk of
Omeprazole metabolism of Bleeding
Cilostazol

• CILOSTAZOL SHOULD BE ADMINISTERED IN A DOSE OF 50MG TWICE A DAY,

DURING COADMINISTRATION OF OMEPRAZOLE.
HTTPS://LINK.SPRINGER.COM/ARTICLE/10.2165/00003088-199937002-00006
 CILOSTAZOL & FLUOXETINE

Fluoxetine inhibits CYP2C19-

Cilostazol + Fluoxetine mediated metabolism of Cilostazol & Elevated risk of Bleeding
SSRIs induced antiplatelet activity

• MONITOR THE PATIENTS FOR SIGNS OF INCREASED BLEEDING.

• CONSIDER REDUCING THE DOSE OF CILOSTAZOL TO 50MG TWICE DAILY, IF
NECESSARY.
 CILOSTAZOL & FLUVOXAMINE

Fluoxetine inhibits CYP2C19-

Cilostazol + Fluvoxamine mediated metabolism of Cilostazol & Elevated risk of Bleeding
SSRIs induced antiplatelet activity

• MONITOR THE PATIENTS FOR SIGNS OF INCREASED BLEEDING.

• CONSIDER REDUCING THE DOSE OF CILOSTAZOL TO 50MG TWICE DAILY, IF
NECESSARY.
 CILOSTAZOL & ASPIRIN

Additive
Cilostazol + Elevated risk of
antiplatelet
Aspirin bleeding
activity

• MONITOR FOR SIGNS AND SYMPTOMS OF BLOOD LOSS.

 CILOSTAZOL & TICLOPIDINE

Ticlopidine inhibits CYP2C19

Increased Cilostazol exposure &
Cilostazol + Ticlopidine mediated metabolism of Cilostazol
elevated risk of Bleeding
& Additive antiplatelet activity

• MONITOR FOR SIGNS OF INCREASED BLEEDING.

• CONSIDER REDUCING THE CILOSTAZOL DOSE TO 50 MG TWICE DAILY.
 CILOSTAZOL & TICAGRELOR

Ticagrelor inhibits
CYP3A4 mediated Increased Cilostazol
Cilostazol + Ticagrelor metabolism of Cilostazol exposure & elevated risk
& Additive antiplatelet of Bleeding
activity

• MONITOR FOR SIGNS OF INCREASED BLEEDING.

• CONSIDER REDUCING THE CILOSTAZOL DOSE TO 50 MG TWICE DAILY.
 CILOSTAZOL & NEFAZODONE

Nefazodone inhibits CYP3A4

mediated metabolism of Increased Cilostazol exposure &
Cilostazol + Nefazodone
Cilostazol & Additive antiplatelet elevated risk of Bleeding
activity

• MONITOR FOR SIGNS OF INCREASED BLEEDING.

• CONSIDER REDUCING THE CILOSTAZOL DOSE TO 50 MG TWICE DAILY.
 CILOSTAZOL & AZOLE
ANTIFUNGALS

Cilostazol + Azole
Azole antifungals
antifungals
inhibit CYP3A4 Increased Cilostazol
(Ketoconazole,
mediated metabolism exposure
Fluconazole,
of Cilostazol
Itraconazole)

• CONSIDER REDUCING THE CILOSTAZOL DOSE TO 50 MG TWICE DAILY.

 CILOSTAZOL & IDELALISIB

Idelalisib inhibits
Cilostazol + CYP3A4 mediated Increased Cilostazol
Idelalisib metabolism of exposure
Cilostazol

• CONSIDER REDUCING THE CILOSTAZOL DOSE TO 50 MG TWICE DAILY.

 CILOSTAZOL & AMIODARONE

Inhibition of CYP3A4-
Increased exposure of
Cilostazol + Amiodarone mediated metabolism of
Cilostazol and Amiodarone
Cilostazol and Amiodarone

• DOSAGE ADJUSTMENTS MAY BE CONSIDERED.

 CILOSTAZOL & COBICISTAT

Cobicistat inhibits
Cilostazol + CYP3A4 mediated Increased Cilostazol
Cobicistat metabolism of exposure
Cilostazol

• CONSIDER REDUCING DOSE OF CILOSTAZOL TO 50 MG TWICE DAILY.

 CILOSTAZOL & PIPERAQUINE

Piperaquine inhibits
Cilostazol + CYP2C19 and CYP3A4 Increased Cilostazol
Piperaquine mediated metabolism exposure
of Cilostazol

• CONSIDER REDUCING DOSE OF CILOSTAZOL TO 50 MG TWICE DAILY.

• CAUTION IS ADVISED WHEN COADMINISTERING CILOSTAZOL FOR UP TO 3
MONTHS AFTER DISCONTINUATION OF PIPERAQUINE THERAPY, DUE TO THE
LONG HALF LIFE OF PIPERAQUINE.
 CILOSTAZOL & GINKGO

Ginkgo (Ginkgolide B)
inhibits Platelet activating Additive antiplatelet
Cilostazol + Ginkgo Elevated risk of bleeding
factor (PAF) induced activity
platelet aggregation

• CONCOMITANT USE OF CILOSTAZOL AND GINGKO SHOULD BE AVOIDED, IF

POSSIBLE.
 CONCLUSION
• DRUG INTERACTIONS CAN RESULT IN SIGNIFICANT MORBIDITY AND
MORTALITY AND THUS MINIMIZING THE RISK FOR DRUG INTERACTIONS
SHOULD BE A GOAL IN DRUG THERAPY.
• THE PATIENTS ON ANTIPLATELET THERAPY SHOULD BRING A LIST OF ALL OF
THE DRUGS THEY ARE TAKING INCLUDING PRESCRIPTION DRUGS, OVER-THE-
COUNTER DRUGS, AND ANY SUPPLEMENTS, HERBAL OR OTHERWISE, DURING
THEIR VISIT TO THE DOCTOR OR PHARMACIST.
• THE RISK OF ADVERSE EFFECTS COULD BE REDUCED BY HEALTHCARE
PROFESSIONALS THROUGH THE SCREENING, EDUCATION, AND FOLLOW UP ON
SUSPECTED DRUG INTERACTIONS.
• IF POSSIBLE, THE PATIENTS ARE RECOMMENDED TO FILL ALL THEIR
PRESCRIPTIONS AT ONE PHARMACY.
• PHARMACISTS CAN PLAY A CRUCIAL ROLE IN IDENTIFYING POSSIBLE DRUG
INTERACTIONS BY ASKING PATIENTS ABOUT THEIR HERBAL AND OTHER
ALTERNATIVE MEDICINE PRODUCT USE.
 REFERENCES
o STOCKLEY’S DRUG INTERACTIONS, 9E
KAREN BAXTER
o GOODMAN & GILMAN'S: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 12E
LAURENCE L. BRUNTON, BRUCE A. CHABNER, BJÖRN C. KNOLLMANN
o BASIC & CLINICAL PHARMACOLOGY, 12E
BERTRAM G. KATZUNG, SUSAN B. MASTERS, ANTHONY J. TREVOR
o A MANUAL OF ADVERSE DRUG INTERACTIONS
J.P. GRIFFIN, P.F. D'ARCY
o CLINICAL MANUAL OF DRUG INTERACTION PRINCIPLES FOR MEDICAL PRACTICE
GARY H. WYNN, JESSICA R. OESTERHELD, KELLY L. COZZA, SCOTT C.
ARMSTRONG
o HANDBOOK OF DRUG INTERACTIONS: A CLINICAL AND FORENSIC GUIDE
 REFERENCES
• HTTP://WWW.MICROMEDEXSOLUTIONS.COM
• HTTPS://LINK.SPRINGER.COM/ARTICLE/10.2165%2F00003088-198917050-00003
• HTTP://ONLINELIBRARY.WILEY.COM/DOI/10.1111/J.1365-2796.2010.02299.X/FULL
• HTTPS://WWW.ACADEMIC.OUP.COM/EURHEARTJ/ARTICLE/24/19/1707/495173/DRUG-DRUG-
INTERACTIONS-INVOLVING-ANTIPLATELET
• HTTP://WWW.NATURE.COM/NRCARDIO/JOURNAL/V8/N10/FULL/NRCARDIO.2011.128.HTML
• HTTP://WWW.SCIENCEDIRECT.COM/SCIENCE/ARTICLE/PII/S2211594312000974
• HTTPS://WWW.RESEARCHGATE.NET/PUBLICATION/47788995_ANTIPLATELET_DRUG_INTERACTIONS
• HTTP://REFERENCE.MEDSCAPE.COM/DRUG-INTERACTIONCHECKER
• HTTPS://WWW.DRUGS.COM/DRUG_INTERACTIONS.HTML
• HTTP://WWW.WEBMD.COM/INTERACTION-CHECKER/
• HTTP://WWW.RXLIST.COM/DRUG-INTERACTION-CHECKER.HTM
• HTTPS://WWW.NPS.ORG.AU/AUSTRALIAN-PRESCRIBER/ARTICLES/WARFARIN-ANTIPLATELET-DRUGS-
AND-THEIR-INTERACTIONS