IC3- Antiplatelets Flashcards
What is the general MOA of antiplatelets?
Block platelet aggregation and PRIMARY haemostasis
*Recall- primary haemostasis: platelets adhere → secrete contents (ADP, Thromboxane A2 (Tbx A2) → recruits more platelets → platelet aggregation and plug
What are the 4 different types of antiplatelets and the name of the agent under each type?
(Only the ones we are focusing on)
- Adenosine uptake & PDE3 inhibitor (Dipyridamole)
- Irreversible COX-1 inhibitor (Aspirin)
- ADP receptor (P2Y12 inhibitors) (Clopidogrel, Ticagrelor)
MOA of Dipyridamole? (Adenosine uptake & PDE3 inhibitor)
- Inhibits platelet activation and aggregation by ↑ cAMP within platelets:
- Adenosine reuptake inhibitor → ↑ plasma (extracellular) adenosine activation of A2 receptors on platelets
- PDE3 inhibitor → ↓ cAMP degradation into AMP → ↑ cAMP in platelets → inhibits platelet activation and aggregation - Vasodilator as also inhibits adenosine reuptake and PDEs in vascular SM
Is dipyridamole used as monoTx or as a adjunctive antiplatelet? Why?
Dose-limiting effects due to its additional vasodilatory effects.
Hence used as adjunctive agent to other antiplatelets.
What is another indication of dipyridamole due to its vasodilatory effects?
Infused IV as alternative to exercise for myocardial perfusion imaging
What is the onset, peak effect and DOA of dipyridamole?
What do we say about the reversibility of dipyridamole?
- Onset: 20-30 min (fast); peak effect 2-2.5h
- DOA: ~3h (short- rapid reversal) → hence usually modified release
ADEs of dipyridamole? (5)
- *HEADACHE
- *HYPOTENSION
- Dizziness
- Flushing
- GI disturbance (d, n/v)
Contraindications for dipyridamole? (4)
- Hypersensitivity
- Caution in hypotension
- Caution in severe coronary artery disease
- Caution for bleeding when combined with heparin or other anticoagulants/ antiplatelets
DDIs of dipyridamole?
- ↑ adenosine: ↑ cardiac adenosine levels and effects
- ↓ cholinesterase inhibitors: may aggravate myasthenia gravis
What are the functions of COX-1 (found in platelets) and COX-2 (produced by endothelial cells) enzymes?
- COX-1 (found in platelets): synthesis of TXA2 (platelet agonist) which promotes aggregation and further vasoconstriction. Can only be restored by formation of new platelets (7-10d)
- COX-2 (produced by endothelial cells): production of PGI2 → which inhibit platelet aggregation (endogenous antiplatelet effect). Restored by synthesis of new COX enzyme (3-4h)
What is the MOA of aspirin?
Does it act equally on both COX-1 or COX-2?
- Non-selective, non-steroidal IRREVERSIBLE inhibitor of both COX-1 and COX-2
- Inhibits COX-1 more → inhibits platelet production of TXA2
Is OD dosing or Q4-6H dosing for aspirin more effective? Explain why
OD dosing more effective.
Aspirin given less frequently → allows endothelial production of PGI2 to recover while irreversible inhibition of platelets persist
Is low dose or high dose of aspirin more effective?
What are the doses?
Low dose (75-325 mg loading dose OR 40-160 mg daily) more effective than high dose (500 mg-1 g)
ADEs of aspirin? (2)
- Upper GI effects (UGI) → gastric ulcers, bleeding (inhibits COX-1 production of protective PG in stomach) (that’s why low-dose aspirin for cardioprotective effects is a/w 2-4x increase in UGI events)
- ↑ risk of bleeding and bruising
Caution for aspirin?
Caution in pts with platelet and bleeding disorders
DDIs of aspirin?
↑ bleeding risk 🩸:
- Combination with other antiplatelets and anticoagulants
How is ADP related to GPIIb/IIIa receptors and platelet aggregation?
ADP released from dense granules of platelets → act on ADP P2Y12 receptors → activate GPIIb/IIIa receptors → stimulate platelet recruitment and aggregation
General MOA of ADP (P2Y12) receptor inhibitors?
Inhibit ADP P2Y12 receptors → block ADP-mediated increase in cell surface expression of active GPIIb/IIIa receptors → inhibiting platelet recruitment and aggregation
What is the dosing of P2Y12 inhibitors?
How do you compare it to aspirin?
Loading dose regimens used to accelerate approach of steady state.
Advantage over aspirin: faster onset of peak clinical effect
What is the difference between Clopidogrel and Ticagrelor in terms of their inhibition of P2Y12? And their lasting effect on platelets?
Clopidogrel (prodrug): IRREVERSIBLY binds to ADP binding site on P2Y12 receptor (effect on platelet lasts for lifetime of the platelet ~7-10d)
Ticagrelor: REVERSIBLY binds to different site from ADP binding site to inhibit GPIIb/IIIa activation and signalling (recovery of platelet function depends on serum conc. of ticagrelor and its active metabolites ~2-3d)
Onset of Clopidogrel?
Delayed (peak action 6-8h)
ADEs of Clopidogrel? (7)
- *Haemorrhage/ bleeding (inclu intracranial bleeding)
- Easy bruising
- Dyspepsia (~5%)
- Rashes (~5%)
- Bronchospasm
- *Dyspnea
- *Hypotension
Contraindications of Clopidogrel? (3)
- Hypersensitivity
- Active pathological bleeding
- Caution in pts at risk of bleeding (eg. risk of intracranial haemorrhage/ trauma/ surgery)
Why is there interindividual variability in response to Clopidogrel?
Variant alleles of CYP2C19: - Interindividual variability due to reduced metabolism to active metabolite → diminished antiplatelet response
DDIs of Clopidogrel?
↑ bleeding risk:
- *Warfarin, *NSAIDs and salicylates
- Rifamycins
↓ antiplatelet effect:
- Macrolides
- Moderate - Strong CYP2C19 inhibitors (eg PPIs, fluoxetine, ketoconazole etc)
Advantage of Ticagrelor over Clopidogrel in terms of onset and peak effect?
Faster onset and peak effect than Clopidogrel
ADEs of Ticagrelor? (5)
- *Haemorrhage/ bleeding (inclu intracranial bleeding)
- *Bradycardia (slower than normal HR)
- *Dyspnea
- Cough
- Easy bruising
Contraindications of Ticagrelor? (6)
- *Hypersensitivity
- *Severe hepatic impairment
- *Lactating mothers
- *Hx of intracranial haemorrhage
- *Active pathological bleeding
- Caution in pts at risk of bleeding (eg PUD, trauma, surgery), elderly and moderate hepatic failure
DDIs of Ticagrelor?
↑ bleeding risk 🩸:
- Anticoagulants, fibrinolytics & long-term NSAIDs
- Aspirin doses > 100 mg/day (also ↓ ticagrelor effect), DO NOT COMBINE
↑ antiplatelet effect (and risk of ADEs):
- CYP3A strong inhibitors (eg. clarithromycin, ketoconazole etc)
↓ antiplatelet effect:
- CYP3A inducers (eg. dexamethasone, phenytoin etc)
