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PR3154 > IC3- Antiplatelets > Flashcards

IC3- Antiplatelets Flashcards

1
Q

What is the general MOA of antiplatelets?

A

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

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2
Q

What are the 4 different types of antiplatelets and the name of the agent under each type?

(Only the ones we are focusing on)

A
  1. Adenosine uptake & PDE3 inhibitor (Dipyridamole)
  2. Irreversible COX-1 inhibitor (Aspirin)
  3. ADP receptor (P2Y12 inhibitors) (Clopidogrel, Ticagrelor)
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3
Q

MOA of Dipyridamole? (Adenosine uptake & PDE3 inhibitor)

A
  1. 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
  2. Vasodilator as also inhibits adenosine reuptake and PDEs in vascular SM
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4
Q

Is dipyridamole used as monoTx or as a adjunctive antiplatelet? Why?

A

Dose-limiting effects due to its additional vasodilatory effects.

Hence used as adjunctive agent to other antiplatelets.

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5
Q

What is another indication of dipyridamole due to its vasodilatory effects?

A

Infused IV as alternative to exercise for myocardial perfusion imaging

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6
Q

What is the onset, peak effect and DOA of dipyridamole?

What do we say about the reversibility of dipyridamole?

A
  • Onset: 20-30 min (fast); peak effect 2-2.5h
  • DOA: ~3h (short- rapid reversal) → hence usually modified release
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7
Q

ADEs of dipyridamole? (5)

A
  • *HEADACHE
  • *HYPOTENSION
  • Dizziness
  • Flushing
  • GI disturbance (d, n/v)
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8
Q

Contraindications for dipyridamole? (4)

A
  • Hypersensitivity
  • Caution in hypotension
  • Caution in severe coronary artery disease
  • Caution for bleeding when combined with heparin or other anticoagulants/ antiplatelets
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9
Q

DDIs of dipyridamole?

A
  • ↑ adenosine: ↑ cardiac adenosine levels and effects
  • ↓ cholinesterase inhibitors: may aggravate myasthenia gravis
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10
Q

What are the functions of COX-1 (found in platelets) and COX-2 (produced by endothelial cells) enzymes?

A
  1. 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)
  2. 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)
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11
Q

What is the MOA of aspirin?

Does it act equally on both COX-1 or COX-2?

A
  • Non-selective, non-steroidal IRREVERSIBLE inhibitor of both COX-1 and COX-2
  • Inhibits COX-1 more → inhibits platelet production of TXA2
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12
Q

Is OD dosing or Q4-6H dosing for aspirin more effective? Explain why

A

OD dosing more effective.

Aspirin given less frequently → allows endothelial production of PGI2 to recover while irreversible inhibition of platelets persist

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12
Q

Is low dose or high dose of aspirin more effective?

What are the doses?

A

Low dose (75-325 mg loading dose OR 40-160 mg daily) more effective than high dose (500 mg-1 g)

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12
Q

ADEs of aspirin? (2)

A
  • 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
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13
Q

Caution for aspirin?

A

Caution in pts with platelet and bleeding disorders

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14
Q

DDIs of aspirin?

A

↑ bleeding risk 🩸:
- Combination with other antiplatelets and anticoagulants

15
Q

How is ADP related to GPIIb/IIIa receptors and platelet aggregation?

A

ADP released from dense granules of platelets → act on ADP P2Y12 receptors → activate GPIIb/IIIa receptors → stimulate platelet recruitment and aggregation

16
Q

General MOA of ADP (P2Y12) receptor inhibitors?

A

Inhibit ADP P2Y12 receptors → block ADP-mediated increase in cell surface expression of active GPIIb/IIIa receptors → inhibiting platelet recruitment and aggregation

17
Q

What is the dosing of P2Y12 inhibitors?

How do you compare it to aspirin?

A

Loading dose regimens used to accelerate approach of steady state.

Advantage over aspirin: faster onset of peak clinical effect

18
Q

What is the difference between Clopidogrel and Ticagrelor in terms of their inhibition of P2Y12? And their lasting effect on platelets?

A

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)

19
Q

Onset of Clopidogrel?

A

Delayed (peak action 6-8h)

20
Q

ADEs of Clopidogrel? (7)

A
  • *Haemorrhage/ bleeding (inclu intracranial bleeding)
  • Easy bruising
  • Dyspepsia (~5%)
  • Rashes (~5%)
  • Bronchospasm
  • *Dyspnea
  • *Hypotension
21
Q

Contraindications of Clopidogrel? (3)

A
  • Hypersensitivity
  • Active pathological bleeding
  • Caution in pts at risk of bleeding (eg. risk of intracranial haemorrhage/ trauma/ surgery)
22
Q

Why is there interindividual variability in response to Clopidogrel?

A

Variant alleles of CYP2C19: - Interindividual variability due to reduced metabolism to active metabolite → diminished antiplatelet response

23
Q

DDIs of Clopidogrel?

A

↑ bleeding risk:
- *Warfarin, *NSAIDs and salicylates
- Rifamycins

↓ antiplatelet effect:
- Macrolides
- Moderate - Strong CYP2C19 inhibitors (eg PPIs, fluoxetine, ketoconazole etc)

24
Q

Advantage of Ticagrelor over Clopidogrel in terms of onset and peak effect?

A

Faster onset and peak effect than Clopidogrel

25
Q

ADEs of Ticagrelor? (5)

A
  • *Haemorrhage/ bleeding (inclu intracranial bleeding)
  • *Bradycardia (slower than normal HR)
  • *Dyspnea
  • Cough
  • Easy bruising
26
Q

Contraindications of Ticagrelor? (6)

A
  • *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
27
Q

DDIs of Ticagrelor?

A

↑ 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)

PR3154 (11 decks)

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