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

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