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DRUG INTERACTIONS OF ANTIPLATELETS (PART 2)
(DRUG INTERACTIONS OF ADP RECEPTOR
BLOCKERS)
Dr P.NAINA MOHAMED PhD
Pharmacologist
INTRODUCTION• ADP RECEPTOR BLOCKERS INCLUDE
THIENOPYRIDINES (CLOPIDOGREL, PRASUGREL AND TICLOPIDINE)
NON-THIENOPYRIDINES (TICAGRELOR, CANGRELOR AND ELINOGREL).
• THIENOPYRIDINES AND NON-THIENOPYRIDINES INHIBIT P2Y12 RECEPTORS WHICH ARE INVOLVED IN PLATELET AGGREGATION.
• P2Y12 RECEPTORS ARE PURINERGIC RECEPTORS AND THEY BELONG TO THE Gi PROTEIN-COUPLED (GiPCR) RECEPTORS.
• P2Y12 RECEPTORS FUNCTION AS CHEMORECEPTORS FOR ADENOSINE DIPHOSPHATE (ADP).
• THIENOPYRIDINES ARE PRODRUGS AND ARE METABOLIZED BY CYP ENZYMES TO INHIBIT P2Y12 RECEPTORS IRREVERSIBLY.
• NON-THIENOPYRIDINES DO NOT REQUIRE METABOLIC ACTIVATION AND THEY PRODUCE REVERSIBLE INHIBITION OF P2Y12 RECEPTORS.
• INTERACTION BETWEEN ONE OR MORE COADMINISTERED 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
• ADP RECEPTOR BLOCKERS (THIENOPYRIDINES)
CLOPIDOGREL
PRASUGREL
TICLOPIDINE
• ADP RECEPTOR BLOCKERS (NON-THIENOPYRIDINES)
TICAGRELOR
CANGRELOR
ELINOGREL
• 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
ACTIVATION OF PURINERGIC RECEPTORS (P2Y1 AND P2Y12 )
ACTIVATION OF P2Y1 RECEPTORS
• ADENOSINE DIPHOSPHATE (ADP) BINDS WITH P2Y1 RECEPTORS TO INITIATE THE PLATELET RESPONSE.
ACTIVATION OF P2Y12 RECEPTORS
• ADP BINDS WITH P2Y12 RECEPTORS TO PROMOTE THE PLATELET RESPONSE.
• ADP RECEPTOR BLOCKERS THIENOPYRIDINES (CLOPIDOGREL, PRASUGREL, TICLOPIDINE) AND NON-THIENOPYRIDINES (TICAGRELOR, CANGRELOR, ELINOGREL) INHIBIT P2Y12 RECEPTORS TO EXHIBIT ANTIPLATELET ACTIVITY.
HTTPS://WWW.NCBI.NLM.NIH.GOV/PMC/ARTICLES/PMC3187865/
ADP binds to P2Y1 receptorCa2+ influx, intracellular Ca2+ mobilization
and actin polymerization
Disc shaped platelets converted into
spherical shaped
ADP binds with
P2Y12 receptors
Conformational change in
glycoprotein complexes
(GPIIb/IIIa complexes) on
the platelet surface
Fibrinogen binds to
GPIIb/IIIa complexes on a
single platelet
Fibrinogen links the
GPIIb/IIIa on adjacent
platelets together
Platelet aggregation
(Individual single
platelets are transformed
into a large mass)
MECHANISM OF ACTION OF ADP RECEPTOR BLOCKERS
HTTP://WWW.TANDFONLINE.COM/DOI/ABS/10.1080/09537109876799
• THIENOPYRIDINES (CLOPIDOGREL, PRASUGREL, TICLOPIDINE) ARE PRODRUGS AND
METABOLIZED BY CYP ENZYMES (CYP2C9 AND CYP2C19) TO PRODUCE ACTIVE METABOLITES
WHICH BIND TO P2Y12 RECEPTORS.
• BUT, NON-THIENOPYRIDINES (TICAGRELOR, CANGRELOR, ELINOGREL) DO NOT REQUIRE TO
GET METABOLIZED TO BLOCK P2Y12 RECEPTORS.
HTTPS://WWW.NCBI.NLM.NIH.GOV/PMC/ARTICLES/PMC3187865/
ADP receptor
Blockers
Bind to
P2Y12 receptors
Inhibit the binding
of ADP to
P2Y12 receptors
Inhibition of
platelet
aggregation
ADP BLOCKERS & ASPIRIN
THE SIGNS AND SYMPTOMS OF BLEEDING SHOULD BE MONITORED, IF ASPIRIN AND ADP
BLOCKERS (CLOPIDOGREL, PRASUGREL, TICLOPIDINE, TICAGRELOR, ETC) ARE USED
CONCURRENTLY.
HTTP://WWW.TANDFONLINE.COM/DOI/ABS/10.1080/09537105310001645960
ADP blockers +
Aspirin
Additive
antiplatelet
activity
Enhanced risk
of bleeding
ADP BLOCKERS & DIPYRIDAMOLE
MONITORING OF SIGNS AND SYMPTOMS OF BLEEDING IS WARRANTED, IF DIPYRIDAMOLE
AND ADP BLOCKERS (CLOPIDOGREL, PRASUGREL, TICLOPIDINE, TICAGRELOR, ETC) ARE
USED CONCURRENTLY.
HTTPS://WWW.NCBI.NLM.NIH.GOV/PMC/ARTICLES/PMC3187865/
ADP blockers +
Dipyridamole
Additive
antiplatelet
activity
Increased risk
of bleeding
THIENOPYRIDINES & BUPROPION
• IF BUPROPION IS USED CONCOMITANTLY WITH A THIENOPYRIDINE, DOSE
ADJUSTMENT OF BUPROPION MAY BE NECESSARY BASED ON CLINICAL
RESPONSE.
HTTP://JPET.ASPETJOURNALS.ORG/CONTENT/308/1/189.LONG
Thienopyridines
(Clopidogrel,
Ticlopidine) +
BuPROPion
Inhibition of CYP2B6-
mediated buPROPion
metabolism by
ticlopidine
Decreased exposure
of Hydroxybupropion
(Active metabolite of
buPROPion)
CLOPIDOGREL & PROTON PUMP INHIBITORS (PPIs)
HTTPS://WWW.NCBI.NLM.NIH.GOV/PMC/ARTICLES/PMC4110685/
• LANSOPRAZOLE AND DEXLANSOPRAZOLE HAVE LESS EFFECT ON THE ANTIPLATELET ACTIVITY OF CLOPIDOGREL COMPARED TO OMEPRAZOLE AND ESOMEPRAZOLE.
HTTP://WWW.SCIENCEDIRECT.COM/SCIENCE/ARTICLE/PII/S073510971200246X?VIA%3DIHUB
• AVOID PRESCRIBING OMEPRAZOLE AND ESOMEPRAZOLE FOR PATIENTS TAKING CLOPIDOGREL.
• THE PPIs LIKE PANTOPRAZOLE OR RABEPRAZOLE WOULD BE SUITABLE FOR PATIENTS TAKING CLOPIDOGREL AS DO NOT AFFECT THE PHARMACOKINETICS AND ANTIPLATELET EFFICACY OF CLOPIDOGREL.
HTTP://ONLINELIBRARY.WILEY.COM/WOL1/DOI/10.1038/CLPT.2010.219/ABSTRACT
HTTP://WWW.SCIENCEDIRECT.COM/SCIENCE/ARTICLE/PII/S1875213613003008?VIA%3DIHUB
Clopidogrel + Proton Pump Inhibitors
(PPIs) (Omeprazole, Esomeprazole,
etc)
PPIs inhibit CYP2C19-mediated
activation of Clopidogrel
Reduction in clinical efficacy of
clopidogrel and increased risk for
thrombosis
CLOPIDOGREL & CIMETIDINE
• CONCOMITANT USE OF CIMETIDINE, WITH CLOPIDOGREL SHOULD BE AVOIDED.
• CONSIDER USING OTHER H2 BLOCKERS SUCH AS RANITIDINE OR FAMOTIDINE OR
ANTACID.
HTTPS://WWW.NATURE.COM/AJG/JOURNAL/V104/N12/FULL/AJG2009525A.HTML
Clopidogrel +
Cimetidine
Cimetidine inhibits
CYP2C19 mediated
activation of
Clopidogrel
Decreased clinical
efficacy of
Clopidogrel
CLOPIDOGREL & CALCIUM CHANNEL BLOCKERS (CCBS)
• CAUTION IS ADVISED IF CALCIUM CHANNEL BLOCKERS (CCBS) AND CLOPIDOGREL
ARE USED CONCURRENTLY. AND MONITOR PATIENTS FOR LOSS OF CLOPIDOGREL
EFFICACY.
HTTPS://TH.SCHATTAUER.DE/EN/CONTENTS/ARCHIVE/ISSUE/1069/MANUSCRIPT/128
74.HTML
Clopidogrel + Calcium
Channel Blockers (CCBs)
(Amlodipine, Verapamil,
Diltiazem, Nifedipine, etc)
Calcium Channel Blockers
(CCBs) inhibit CYP3A4-
mediated activation of
Clopidogrel activation
Decreased antiplatelet
effect and increased risk
of thrombotic events
CLOPIDOGREL & SSRIs OR SNRIs
PHARMACODYNAMIC INTERACTION:
HTTP://JAMANETWORK.COM/JOURNALS/JAMAINTERNALMEDICINE/FULLARTICLE/217660
PHARMACOKINETIC INTERACTION:
HTTP://ONLINELIBRARY.WILEY.COM/DOI/10.1046/J.1472-8206.2003.00193.X/FULL
• USE CAUTION WITH THE CONCOMITANT USE OF CLOPIDOGREL AND SSRIs OR SNRIs.
HTTP://ONLINELIBRARY.WILEY.COM/DOI/10.1111/FCP.12021/FULL
Clopidogrel + SSRIs
(Fluoxetine, Paroxetine,
etc) or SNRIs
(Fluvoxamine,
Sibutramine, etc)
SSRIs or SNRIs limit
uptake of blood serotonin
by platelets
Lower concentration of
serotonin within the
platelets
Inhibition of serotonin
induced platelet
aggregation
Increased risk of
abnormal bleeding
Clopidogrel + SSRIs (Fluoxetine,
Paroxetine, etc) or SNRIs (Fluvoxamine,
Sibutramine, etc)
SSRIs or SNRIs may inhibit the CYP3A4,
CYP3A5, CYP2C9 and CYP2C19 induced
activation of Clopidogrel
Decreased antiplatelet effect
CLOPIDOGREL & REPAGLINIDE
• THE BLOOD GLUCOSE SHOULD BE MONITORED AND THE DOSE OF REPAGLINIDE
SHOULD BE ADJUSTED, IF CLOPIDOGREL AND REPAGLINIDE USED
CONCOMITANTLY.
HTTP://ONLINELIBRARY.WILEY.COM/DOI/10.1038/CLPT.2014.141/FULL
Clopidogrel + Repaglinide
Glucuronide metabolite of
Clopidogrel inhibit the
CYP2C8 mediated
metabolism of Repaglinide
Elevated plasma
concentrations of
Repaglinide
Increased Hypoglycemic
risk
CLOPIDOGREL & PACLITAXEL
• CONCOMITANT USE REQUIRES MONITORING.
HTTP://ONLINELIBRARY.WILEY.COM/WOL1/DOI/10.1002/CPT.674/ABSTRACT
Clopidogrel + Paclitaxel
Glucuronide metabolite of
Clopidogrel inhibit CYP2C8-
mediated Paclitaxel metabolism
Elevated plasma concentrations
of Paclitaxel
Increased risk of Paclitaxel
toxicity (Neutropenia,
Neuropathy, etc)
CLOPIDOGREL & AZOLE ANTIFUNGALS
• IF POSSIBLE, CONCOMITANT USE OF CLOPIDOGREL WITH KETOCONAZOLE CAN
BE AVOIDED. CONCOMITANT USE OF
HTTP://ONLINELIBRARY.WILEY.COM/WOL1/DOI/10.1038/SJ.CLPT.6100139/ABS
TRACT
Clopidogrel + Azole
Antifungals
(Ketoconazole,
Fluconazole, etc)
Azole antifungals
inhibit CYP3A4 and
CYP2c19 mediated
activation of
Clopidogrel
Decreased antiplatelet
activity
CLOPIDOGREL & GRAPEFRUIT JUICE (GFJ)
• THE PATIENTS TAKING CLOPIDOGREL SHOULD BE ADVISED TO AVOID DRINKING
GRAPEFRUIT JUICE (GFJ).
HTTP://ONLINELIBRARY.WILEY.COM/WOL1/DOI/10.1038/CLPT.2013.192/ABSTRA
CT
Clopidogrel +
Grapefruit Juice
(GFJ)
Furanocoumarins of
GFJ inhibit CYP3A4
and CYP2C19
Decreased
activation of
Clopidogrel
Diminished
antiplatelet effect
CLOPIDOGREL & FELBAMATE
• IT IS ADVISABLE TO AVOID FELBAMATE IN PATIENTS TAKING CLOPIDOGREL.
HTTP://WWW.SCIENCEDIRECT.COM/SCIENCE/ARTICLE/PII/S1555415510004320
HTTP://JAMANETWORK.COM/JOURNALS/JAMA/FULLARTICLE/185262
Clopidogrel &
Felbamate
Felbamate can inhibit
CYP2C19-mediated
activation of
Clopidogrel
Decreased plasma
concentration of
active metabolite of
Clopidogrel
Reduced clinical
efficacy of
Clopidogrel
CLOPIDOGREL & ETRAVIRINE
• AVOID THE CONCOMITANT USE OF CLOPIDOGREL WITH ETRAVIRINE , IF
POSSIBLE.
HTTP://WWW.SCIENCEDIRECT.COM/SCIENCE/ARTICLE/PII/S1555415510004320
HTTP://JAMANETWORK.COM/JOURNALS/JAMA/FULLARTICLE/185262
Clopidogrel +
Etravirine
Etravirine can
inhibit
CYP2C19-
mediated
activation of
Clopidogrel
Decreased
plasma
concentration
of active
metabolite of
Clopidogrel
Reduced
clinical
efficacy of
Clopidogrel
TICLOPIDINE & TIZANIDINE
• MONITOR FOR SIGNS AND SYMPTOMS OF HYPOTENSION IF TIZANIDINE IS USED
CONCURRENTLY WITH TICLOPIDINE.
HTTPS://ACADEMIC.OUP.COM/JAMIA/ARTICLE/19/5/735/715212/HIGH-
PRIORITY-DRUG-DRUG-INTERACTIONS-FOR-USE-IN
Ticlopidine + Tizanidine
Ticlopidine inhibits
CYP1A2-mediated
metabolism of Tizanidine
Increased Tizanidine
plasma concentrations
Enhanced hypotensive
and sedative effects
TICLOPIDINE & THEOPHYLLINE
• SERUM CONCENTRATIONS OF THEOPHYLLINE SHOULD BE CLOSELY MONITORED WHEN TICLOPIDINE IS ADDED, DISCONTINUED, OR WHEN DOSING CHANGES OCCUR.
• DOSING ADJUSTMENTS OF THEOPHYLLINE MAY BE NECESSARY.
HTTP://ONLINELIBRARY.WILEY.COM/DOI/10.1038/CLPT.1987.39/ABSTRACT
HTTPS://LINK.SPRINGER.COM/ARTICLE/10.2165%2F00003088-199120010-00005
Ticlopidine +
Theophylline
Ticlopidine
decreases the
metabolism
theophylline
Theophylline toxicity
(Nausea, Vomiting,
Palpitations,
Seizures)
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 DRUGINTERACTIONS 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
ASHRAF MOZAYANI, LIONEL RAYMON
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
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• 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
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