Platelet antiaggregants

Drug interaction

The class of antiplatelet drugs include:

1. Irreversible cyclooxygenase inhibitors: Aspirin

2. Adenosine diphosphate (ADP) receptor inhibitors: Cangrelor, Clopidogrel, Prasugrel, Ticagrelor

3. Adenosine reuptake inhibitors: Dipyridamole

4. Glycoprotein IIB/IIIA inhibitors (intravenous use only): Abciximab, Eptifibatide, Tirofiban

5. Phosphodiesterase inhibitors: Cilostazol

6. Protease-activated receptor-1 (PAR-1) antagonists: Vorapaxar (Zontivity)

1. Irreversible cyclooxygenase inhibitors

Aspirin (acetylsalicylic acid)

DrugPharmacodynamic interactionsPharmacokinetic interactions Cautions
ACEIs/ARBsAspirin antagonize their antihypertensive effects and may increase the risk of renal impairment
AntiacidsRenal excretion of aspirin is increased by alkaline urine due to some antacidsClinical significance is uncertain with low-dose aspirin
Antidiabetic drugsIncrease the risk of hypoglycemiaAspirin is displace these drugs from protein binding sites increasing their free plasma levels
Antiepileptics:
- Phenytoin
- Valproic acid
Aspirin can displace these drugs from their plasma protein binding sites
AntihypertensivesAspirin inhibits the synthesis of protaglandins and can decrease the antihypertensive effects of ACEIs, ARBs, thiazides and loop diuretics, spironolactone and beta-blockersMonitor BP
Carbonic anhidrase inhibitors:
- Acetazolamide
Increased risk of aspirin toxicityThe increase With caution
CorticosteroidsIncreases the risk of gastrointestinal ulceration and bleedingWith caution
DigoxinAspirin impairs the renal excretion of digoxin, increasing its plasma levels.Monitoring of plasma concentrations digoxin is recommended.
Drugs associated with bleeding risk:
- Alcohol
- Anticoagulants
- Antiplatelet agents
- Dextran
- Dipyridamole
- Glucocorticoids
- NSAIDs
- Prostacyclin
- Thrombolytics
- Warfarin
Increase the risk of bleeding.
Increased risk of GI bleeding with alcohol, corticosteroids and other NSAIDs
Aspirin can displace warfarin from their protein binding sitesIf GI bleeding or ulceration occurs the treatment should be withdrawn
Drugs that increase GI ulceration:
- Deferasirox
- Corticosteroids
- SSRIs
Increase the risk of bleedingCaution and monitor GI bleeding
If GI bleeding or ulceration occurs the treatment should be withdrawn
Immunusuppessive drugs:
- Ciclosporin
- Tacrolimus
This combination may increase the risk of nephrotoxicityMonitor the renal function
LithiumAspirin impairs the renal excretion of lithium, increasing tits plasma levelsMonitoring of plasma concentrations and dose adjustment of lithium are recommended.
Liver enzyme inducers:
- Phenytoin
- Phenobarbital
- Rifampicin
They decrease the efficacy of aspirin
MethotrexateIncreases the risk of adverse effectsAspirin displaces methotrexate from plasma proteins and reduces its renal excretionThe use of methotrexate (at doses >15 mg/week) with aspirin 75 mg is contraindicated
NSAIDs:
- Ibuprofen
- Naproxen
They may reversibly block COX-1 preventing its inhibition by aspirin and its cardioprotection and stroke preventionThis combination should be avoided
SpironolactoneAspririn reduces the natriuretic effect of spironolactone Monitor the diuretic response to spironolactone
SSRIs:
- Paroxetine
- Sertraline
- Venlafaxine
Increase the risk of bleeding
Thiazide diureticsAspirin reduces the renal excretion of uric acid, may exacerbate hyperuricemia and precipitate goutMonitor uric acid plasma levels
Uricosuric drugsAspirin may reduce the efficacy of sulfinpyrazoneAspirin inhibits the kidneys’ ability to excrete uric acidMonitor uric acid plasma levels
Aspirin should not be prescribed in patients with hyperuricemia, or gout

2. Adenosine P2Y12 Receptor Antagonists

Cangrelor, Clopidogrel, Prasugrel, Ticagrelor

DrugPharmacodynamic interactionsPharmacokinetic interactions Cautions
Drugs associated with bleeding risk:
- Alcohol
- Anticoagulants
- Antiplatelet agents
- Dextran
- Dipyridamole
- NSAIDs
- Prostacyclin
- Thrombolytics
- Warfarin
Increase the risk of bleedingConcomitant use should be undertaken with caution.
Concomitant administration of clopidogrel with oral anticoagulants is not recommended
Morphine/OpiatesReduces drug efficacyDecreases gastrointestinal motility In patients with ACS, in whom morphine cannot be withheld and fast P2Y12 inhibition is crucial, the use of a parenteral P2Y12 inhibitor may be considered
SSRIs
SNRIs
They affect platelet activation, and may increase the risk of bleedingThey should be coadministred with caution

Cangrelor

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
ClopidogrelWhen clopidogrel is administered during infusion of cangrelor, the expected inhibitory effect of clopidogrel on platelets is not achieved. Administration of 600 mg clopidogrel immediately after the cessation of the cangrelor infusion results in the anticipated full pharmacodynamic effect.
PrasugrelCangrelor and prasugrel can be administered concomitantlyPatients can be transitioned from cangrelor to prasugrel when prasugrel is administered immediately following discontinuation of the cangrelor infusion or up to 1 hour (optimally at 30 minutes) before the end of the cangrelor infusion to limit recovery of platelet reactivity.

The metabolism of cangrelor is not dependent on CYPs


Clopidogrel

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Atorvastatin Competitively inhibit hepatic activation of clopidogrel, reducing clopidogrel responsivenessConcomitant use should be undertaken with caution
CYP2D6 inhibitors
- Omeprazole
Reduce the plasma levels of the active metabolite of clopidogrelAvoid this combination
CYP2C8 substrate drugs:
- Paclitaxel
- Repaglinide
Clopidogrel and its active metabolite inhibit CYP2C8 and increases the exposure of paclitaxel and repaglinideThe coadministration should be undertaken with caution.
Drugs metabolized via CYP2C9:
- Fluvastatin
- NSAIDs
- Phenytoin
- Tamoxifen
- Tolbutamide
- Torasemide
- Warfarin
Clopidogrel inhibits CYP2C9 and may interfere with the metabolism of these drugsClose monitoring f the patient is required when these drugs are co-administered with clopidogrel
Potent CYP2C19 inhibitors:
- Carbamazepine
- Efavirenz
- Esomeprazole
- Fluconazole Fluvoxamine
- Fluoxetine,
- Moclobemide
- Omeprazole
- Voriconazole
Reduces inhibition of platelet aggregationClopidogrel is metabolised to its active metabolite partly by CYP2C19 and these drugs decreased the exposure of the active metabolite of clopidogrelThey should not be coadministered with clopidogrel
Potent CYP2C19 inhibitors:
- Fluconazole
- Fluvoxamine
- Voriconazole
Clopidogrel is metabolised to its active metabolite partly by CYP2C19They reduce the levels of the active metabolite They should be administered with caution.
Proton pump inhibitors:
- Esomeprazole
- Omeprazole
Reduces inhibition of platelet aggregationDecrease the exposure of the active metabolite of clopidogrelAvoid the concomitant use of omeprazole or esomeprazole. Lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel.

No interaction between clopidogrel and Histamine H2-receptor antagonists or antacids, antidiabetics, atenolol, digoxin, estrogens, nifedipine, phenytoin, theophylline and tolbutamide


Prasugrel

Drug Pharmacodynamic interactionsPharmacokinetic interactionsCautions
Drugs metabolised by CYP2B6:
- Cyclophosphamide,
- Efavirenz
Prasugrel is a weak inhibitor of CYP2B6With caution
Proton pump inhibitorsAdministration 60 mg prasugrel loading dose without concomitant use of proton pump inhibitors may provide most rapid onset of action

No interaction between prasugrel and Histamine H2-receptor antagonists, CYP3A4 inhibitors/inducers, digoxin, ketoconazol, proton pump inhibitors, statins


Ticagrelor

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AspirinDoses of aspirin >100 mg/day reduce the effectiveness of ticagrelor
Bradycardiac drugs:
- β-blockers
- Digoxin
- Diltiazem
- Verapamil
Ticagrelor produces asymptomatic ventricular pauses and bradycardia With caution
CyclosporinInhibits P-gp and CYP3A and increases the exposure to ticagrelor. No effect on cyclosporine blood levels It should be administered with caution in patients treated with ticagrelor
CYP3A inducers:
- Carbamazepine
- Phenobarbital
- Phenytoin
- Rifampicin
Decrease the exposure to ticagrelorAvoid the combination
DigoxinIncrease the risk of bradycardiaTicagrelor increases digoxin plasma levelsClinical and/or laboratory monitoring is recommended
Drugs metabolized via CYP3A4:
- Ergot alkaloids
Ticagrelor inhibits hepatic CYP3AIncreases the plasma levels of drugs metabolized through CYP3A Avoid the administration of ticagrelor
Moderate CYP3A4 inhibitors:
- Amprenavir
- Aprepitant
- Diltiazem
- Erythromycin
- Fluconazole
- Verapamil
Increases the exposure to ticagrelorWith caution
SSRIs:
- Citalopram
- Paroxetine
- Sertraline
They may increase the risk of bleedingWith caution
Statins
- Lovastatin
- Simvastatin
Ticagrelor inhibits hepatic CYP3A and increases lovastatin and simvastatin exposureThe concomitant use of ticagrelor with doses of simvastatin or lovastatin greater than 40 mg is not recommended.
Potent CYP3A inducersSubstantially reduce ticagrelor exposureThis combination should be avoided
Potent CYP3A4 inhibitors:
- Atanazavir
- Clarithromycin
- Nefazodone
- Ritonavir
Avoid the combination

Ticagrelor is primarily a CYP3A4 substrate and a mild inhibitor of CYP3A4. Ticagrelor is also a P-glycoprotein (P-gp) substrate and a weak P-gp inhibitor and may increase the exposure of P-gp substrates.

No interaction with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers, atorvastatin, b-blockers, ethinyl estradiol, levonorgestrel, tolbutamide.


3. Adenosine reuptake inhibitors

Dipyridamole

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AdenosineIncreases the cardiovascular effects of adenosineThe dose of adenosine should be halved
Antihypertensives
- Cholinesterase inhibitors
Increases the risk of hypotension Dipyridamole may counteract their effects, potentially aggravating myasthenia gravis. Caution in patients with severe CAD or hypotension Dipyridamole can potentially aggravate myasthenia gravis
Drugs that affect gastric pH:
- Antiacids
- Histamine H2-receptor antagonists
- Proton pump inhibitors
May reduce theefficacy of dipyridamoleThey can reduce the bioavailability of immediate-release formulationsUse modified-release formulations
Drugs associated with bleeding risk:
- Heparins
- Platelet antiaggregants
- Riociguat.
Increases the risk of bleedingCaution with the combination
VasodilatorsIncreases the risk of hypotensionCaution in patients with severe CAD or hypotension

4. Glycoprotein IIb/IIIa receptor antagonists

Abciximab, tirofiban and eptifibatide

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Drugs associated with bleeding risk:
- Alcohol
- Anticoagulants
- Antiplatelet agents
- Dextrans
- Dipyridamole
- NSAIDs
- Prostacyclins
- Thrombolytics
Increased risk of bleedingCareful monitoring for bleeding

Administration of abciximab may result in HACA formation that could potentially cause allergic or hypersensitivity reactions, thrombocytopenia, or diminished benefit (6% of patients).

Adrenaline, dopamine, theophylline, antihistamines and corticosteroids should be available for immediate use. If allergic reactions or anaphylaxis appear, the infusion should be stopped immediately


5. Phosphodiesterase inhibitors

Cilostazol

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Antiplatelet drugsIncrease the risk of bleedingWith caution
AspirinCilostazol increases the inhibition of ADP-induced ex vivo platelet aggregation
Dihydropyridine calcium channel blockersReflex tachycardia, palpitations, peripheral edemaWith caution
Diltiazem Increases cilostazol exposure
ErythromycinIncreases cilostazol exposure
SmokingDecreases cilostazol exposure by about 20%.
CYP3A4 inhibitors:
- Azole antifungals: Fluconazole, Itraconazole, Ketoconazole, Miconazole
- Diltiazem
- Erythromycin
- Grapefruit juice
Increase cilostazol plasma levels
With caution
Oral anticoagulantsIncrease the risk of bleedingWith caution
SmokingDecreases cilostazol exposure by about 20%.
Potent CYP3A4 inducers:
- Rifampicin
Decrease cilostazol plasma levels. With caution

6. Protease-activated receptor-1 (PAR-1) antagonists

Vorapaxar

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Potent CYP3A inhibitors:
- Azole antifungals: Itraconazole, Ketoconazole, Posaconazole
- Conivaptan
- HIV-protease inhibitors: Boceprevir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Telaprevir
- Macrolide: Clarithromycin, Telithromycin
- Nefazodone
Increase the bleeding riskIncrease the plasma levels of vorapaxarAvoid the combination
Potent CYP3A inducers Decrease the plasma levels of vorapaxarAvoid the combination

Vorapaxar does not affect prasugrel pharmacokinetics and prasugrel did not affect vorapaxar pharmacokinetics.

There are no pharmacokinetic or pharmacodynamic interaction between vorapaxar and warfarin


Abbreviations

ACE: angiotensin converting enzyme
ACEIs: angiotensin-converting enzyme inhibitors
ACS: acute coronary syndromes
ARBs: angiotensin receptor blockers
BP: blood pressure
COX-1: cyclooxygenase  1
CYP: Cytochrome P450 family
GI: gastrointestinal
HACA: human anti-chimeric antibody
H2: histamine H2 receptor
NSAIDs: nonsteroidal anti-inflammatory drugs
P-gp: P glycoprotein
SNRIs: serotonin norepinephrine reuptake inhibitors
SSRIs: Selective serotonin reuptake inhibitors.