DRUG INTERACTIONS OF ANTIPLATELETS (PART 1)(DRUG INTERACTIONS OF ASPIRIN)

Dr P.NAINA MOHAMED PhD

Pharmacologist

INTRODUCTION

• ANTIPLATELETS ARE THE DRUGS WHICH DECREASE THE AGGREGATION OF PLATELETS

AND INHIBIT THE THROMBUS FORMATION.

• ASPIRIN IS AN ANTIPLATELET DRUG AND IT PRODUCES ANTIPLATELET ACTIVITY IN

LOWER DOSES (75-100 MG DAILY), WHILE HIGHER DOSE OF ASPIRIN (UP TO 3600 MG

DAILY IN DIVIDED DOSES) IS REQUIRED FOR IT’S ANALGESIC EFFECTS.

• ASPIRIN HAS BEEN PRESCRIBED FOR THE PRIMARY PREVENTION OF

CARDIOVASCULAR EVENTS IN LOW RISK PATIENTS, IN RECENT YEARS.

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).

MECHANISM OF PLATELET AGGREGATION

HTTPS://WWW.NCBI.NLM.NIH.GOV/BOOKS/NBK53449/

Vascular injury Capture of plateletsAdhesion of Platelets to

the subendothelium

Activation of platelets by ADP and collagen

present at the sites of vascular injury

Increased intracellular concentration of calcium

ions

Stimulation of membrane

phospholipase A2 activity

Liberation of arachidonic acid from

membrane phospholipids

Formation of prostaglandin H2 (PGH2) from Arachidonic acid by

the enzyme Cyclooxygenase 1 (COX-1)

PGH2 is further metabolized to

Thromboxane A2 (TXA2) by thromboxane

synthase

TXA2 is a potent activator of platelets

Platelet aggregation

ANTIPLATELETS• IRREVERSIBLE CYCLOOXYGENASE (COX) INHIBITORS

ASPIRIN

• ADP RECEPTOR INHIBITORS (THIENOPYRIDINES)

CLOPIDOGREL

PRASUGREL

TICLOPIDINE

• ADP RECEPTOR INHIBITORS (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

MECHANISM OF ANTIPLATELET ACTIVITY OF ASPIRIN

• 75-100 MG DAILY DOSE OF ASPIRIN IS CAPABLE OF PROVIDING CARDIOPROTECTION THROUGH ITS ANTIPLATELET ACTIVITY.

HTTPS://WWW.NCBI.NLM.NIH.GOV/PMC/ARTICLES/PMC3195738/

AspirinIrreversible inhibition of

Cyclooxygenase 1 (COX-1)

Prevention of formation of prostaglandin H2 (PGH2) from Arachidonic acid

Decreased formation of Thromboxane A2 (TXA2)

Inhibition of Platelet activation & aggregation

ASPIRIN & LIVE INFLUENZA VIRUS VACCINE

• SYMPTOMS OF REYE'S SYNDROME INCLUDE DROWSINESS, CONFUSION, SEIZURES, COMA AND IN SEVERE CASES, REYE'S SYNDROME CAN RESULT IN DEATH.

• AVOID ADMINISTRATION OF ASPIRIN OR ASPIRIN-CONTAINING THERAPY FOR AT LEAST 4 WEEKS FOLLOWING VACCINATION WITH INFLUENZA LIVE VIRUS.

HTTP://WWW.WEBMD.COM/DRUGS/2/DRUG-1082-3/ASPIRIN-TABLET/DETAILS/LIST-INTERACTION-DETAILS/DMID-1297/DMTITLE-SALICYLATES-INFLUENZA-VIRUS-VACCINE-LIVE/INTRTYPE-DRUG

ASPIRIN & KETOROLAC

• CONCOMITANT USE OF ASPIRIN AND KETOROLAC IS CONTRAINDICATED DUE TO CUMULATIVE RISKS OF SERIOUS GI ADVERSE EVENTS (PEPTIC ULCERS, GASTROINTESTINAL BLEEDING AND GI PERFORATION).

HTTPS://LINK.SPRINGER.COM/ARTICLE/10.2165%2F00003088-198917050-00003

Additive Gastrointestinal

Irritation

• Enhanced gastrointestinal adverse effects (Peptic ulcers, GI bleeding and GI Perforation)

Aspirin + Ketorolac

• Increased serum ketorolac levels

Reduced Plasma protein binding of

Ketorolac

Contraindicated

ASPIRIN & CHICKEN POX (VARICELLA) VACCINE

• PEOPLE SHOULD AVOID USING SALICYLATES FOR 6 WEEKS AFTER GETTING VARICELLA VACCINE.

HTTPS://WWW.CDC.GOV/VACCINES/VPD/VARICELLA/HCP/RECOMMENDATIONS.HTML

ASPIRIN & DICHLORPHENAMIDE

• SERUM BICARBONATE CONCENTRATIONS SHOULD BE ESTIMATED REGULARLY.

HTTPS://WWW.NCBI.NLM.NIH.GOV/PMC/ARTICLES/PMC1442363/

Aspirin + Dichlorphenamide

Aspirin induce hypocapnea

(Reduced CO2 in blood)

Decreased availability of CO2 for the production

of bicarbonate

Prevention of excretion of

hydrogen ions

Elevated risk of fatal metabolic acidosis

ASPIRIN & ANTIDIABETICS

• MONITOR THE PATIENT'S BLOOD GLUCOSE AND MONITOR THE PATIENT FOR CLINICAL SIGNS OF

HYPOGLYCEMIA.

HTTPS://WWW.NCBI.NLM.NIH.GOV/PMC/ARTICLES/PMC4175901/

ASPIRIN & METHOTREXATE

• IF CONCOMITANT ADMINISTRATION OF ASPIRIN AND METHOTREXATE IS NECESSARY, MONITOR

CLOSELY FOR METHOTREXATE TOXICITY.

HTTPS://WWW.NCBI.NLM.NIH.GOV/PUBMEDHEALTH/PMH0016427/

ASPIRIN & IBUPROFEN

• DAILY ASPIRIN USERS SHOULD BE ADVISED TO INGEST ASPIRIN AT LEAST 2 HOURS PRIOR TO

IBUPROFEN.

HTTPS://WWW.RESEARCHGATE.NET/PUBLICATION/47788995_ANTIPLATELET_DRUG_INTERACTIONS

Aspirin + Ibuprofen

Ibuprofen Competes with

Aspirin for COX-1 binding site

Decreased antiplatelet effect

of Aspirin

ASPIRIN & NSAIDS

• CLOSELY MONITOR THE PATIENTS FOR GI BLEEDING AND INGEST ASPIRIN AT LEAST 2 HOURS

PRIOR TO AN INTERACTING NSAID.

HTTP://WWW.TANDFONLINE.COM/DOI/ABS/10.1517/14740338.2014.924924?JOURNALCODE=IED

S20

Aspirin + NSAIDs (Ketoprofen, Naproxen, Meloxicam, Piroxicam)

Additive GI irritationIncreased risk of serious GI adverse effects (Ulceration,

Bleeding, Perforation)

ASPIRIN & WARFARIN

• MONITOR THE PROTHROMBIN TIME (PT) OR INTERNATIONAL NORMALIZED RATIO (INR) AND WATCH

THE PATIENT FOR SIGNS OF BLEEDING IF ASPIRIN AND WARFARIN MUST BE USED TOGETHER.

HTTPS://LINK.SPRINGER.COM/ARTICLE/10.1007%2FS11239-009-0413-4

Aspirin + Warfarin

- Displacement of warfarin from plasma albumin

- Inhibition of metabolism of warfarin

- Direct hypoprothrombinemiceffect of aspirin

- Gastric erosion

Increased risk of bleeding

ASPIRIN & COUMARINS

• FREQUENT MONITORING OF THE PROTHROMBIN TIME (PT) IS INDICATED, IF CONCURRENT USE

OF ASPIRIN AND COUMARINS CANNOT BE AVOIDED.

HTTPS://WWW.NCBI.NLM.NIH.GOV/PMC/ARTICLES/PMC1499595/PDF/BMJCRED00617-0036.PDF

Aspirin + Coumarins and other anticoagulants

(Acenocoumarol, Dicumarol, Phenprocoumon,

Anisindione, Phenindione)

- Hypoprothrombinemia

- Inhibition of platelet aggregation

- Displacement of Coumarins and other anticoagulants from protein binding sites

Increased risk of bleeding

ASPIRIN & FIBRINOLYTICS

• CLOSE MONITORING FOR BLEEDING IS RECOMMENDED, IF CONCOMITANT USE IS REQUIRED.

HTTPS://WWW.NCBI.NLM.NIH.GOV/PUBMED/1834805

ASPIRIN & ANTIPLATELETS

• MONITOR THE SIGNS AND SYMPTOMS OF ACTIVE BLEEDING, IF COADMINISTRATION CANNOT

BE AVOIDED.

HTTP://ONLINELIBRARY.WILEY.COM/DOI/10.1111/J.1365-

2796.2010.02299.X/ABSTRACT;JSESSIONID=3DFE9823DD3790D3C64469AEC534BB43.F04T04

Aspirin + Antiplatelets (Clopidogrel, Prasugrel, Ticagrelor, Ticlopidine,

Dipyridamole, Abciximab, Eptifibatide, Tirofiban)

Additive inhibition of platelet aggregation

Increased risk of bleeding

ASPIRIN & TREPROSTINIL

• MONITOR FOR SIGNS AND SYMPTOMS OF BLEEDING.

HTTPS://WWW.NCBI.NLM.NIH.GOV/PMC/ARTICLES/PMC3555423/

Aspirin + Treprostinil

Additive antiplatelet

effects

Increased risk of bleeding

ASPIRIN & ANAGRELIDE

• CLOSE MONITORING OF SIGNS AND SYMPTOMS OF BLEEDING MAY BE WARRANTED.

HTTPS://WWW.NCBI.NLM.NIH.GOV/PUBMED/16398570

Aspirin + Anagrelide

Anagrelide inhibits maturation of

magakaryocytes in to platelets

Additive antiplatelet activity

Increased risk of bleeding

ASPIRIN & CILOSTAZOL

• IF CONCURRENT USE IS REQUIRED, ADMINISTER ASPIRIN AND CILOSTAZOL WITH CARE AND

MONITOR FOR SIGNS AND SYMPTOMS OF BLOOD LOSS.

HTTP://WWW.SCIENCEDIRECT.COM/SCIENCE/ARTICLE/PII/S1078588409000446

Aspirin + Cilostazol

Cilostazol also inhibits platelet

aggregation

Additive Antiplatelet

activity

Increased risk of bleeding

ASPIRIN & ACE INHIBITORS

• THE CLINICIAN SHOULD WEIGH THE BENEFITS AGAINST THE RISKS OF COMBINING THESE TWO

AGENTS.

HTTP://ONLINELIBRARY.WILEY.COM/DOI/10.1111/J.1527-5299.2000.80174.X/FULL

Aspirin + ACE Inhibitors (Captopril, Enalapril,

Imidapril, Temocapril, Delapril, Ramipril,

Perindopril, Cilazapril)

Aspirin blocks cycloxygenase and

decreases the production of vasodilator and

natriuretic Prostaglandins

Decreased effects of ACE Inhibitors

ASPIRIN & CORTICOSTEROIDS

• MONITOR PATIENTS FOR DECREASED EFFECTIVENESS OF ASPIRIN.

HTTPS://LINK.SPRINGER.COM/ARTICLE/10.2165%2F00003088-198917050-00003

Aspirin + Corticosteroids (Prednisolone, Prednisone,

Dexamethasone, etc.)

Corticosteroids increase the elimination of Aspirin

Sub therapeutic Aspirin serum concentrations

ASPIRIN & GTN (NITROGLYCERIN)

• MONITOR FOR AN EXAGGERATED RESPONSE TO NITROGLYCERIN, AS EVIDENCED BY HEADACHE

AND SYNCOPE.

HTTPS://WWW.NCBI.NLM.NIH.GOV/PUBMED/6420164

Aspirin + GTN (Nitroglycerin)

Decreased clearance of Nitroglycerin

Elevated Nitroglycerin

concentrations

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

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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