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3154 Haematology > IC3 Antiplatelets > Flashcards

IC3 Antiplatelets Flashcards

1
Q

What are the 4 stages of hemostasis and thrombosis?

A
  1. Vasoconstriction
  2. Primary hemostasis - platelet aggregation
  3. Secondary hemostasis - thrombin activation
  4. Clot stabilizzation
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2
Q

Which stage of thrombosis do antiplatelets act on?

A

Primary hemostasis (platelet aggregation)

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3
Q

What is adenosine?

A

Endogenous inhibitor of platelet aggregation

Adenosine is an inhibitory mediator part of the endogenous mechanism that prevents excessive platelet aggregation, thereby reducing risk of thrombosis

It does so by activating adenosine A2 receptors in inactive platelets, to increase platelet cAMP levels, thereby inhibiting platelet activation and aggregation

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4
Q

What is PDE3?

A

PDE3 in inactive platelets are responsible for breaking down cAMP in order to activate the platelet

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5
Q

Dipyridamole MOA

A

Dipyridamole is an adenosine reuptake inhibitor and PDE3 inhibitor (both cause increase in cAMP within the inactive platelets, which inhibits platelet activation and aggregation)

Adenosine reuptake inhibitor:

  • inhibits adenosine reuptake into platelets and RBCs, thereby increasing plasma conc. of adenosine
  • adenosine act on A2 receptors on inactive platelets to inhibit platelet activation and aggregation

PDE3 inhibitor:

  • Inhibition of PDE3 which breaks down cAMP, will increase cAMP levels
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6
Q

How does dipyridamole cause vasodilatory effects?

A

Dipyridamole may inhibit adenosine reuptake as well as PDE in vascular smooth muscle cells (incr cAMP)

*Adenosine causes vasodilation
*PDE inhibitors causes vasodilation
*Because incr cAMP causes vasodilation

This causes vasodilation of vascular smooth muscles

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7
Q

Vasodilation caused by dipyridamole is a ______ adverse effect

A

Dose-limiting adverse effects

Therefore limiting Dipyridamole’s clinical antiplatelet efficacy

High doses may cause vasodilation and reflex tachycardia

*Typically used in combi with Aspirin for secondary prevention of ischemic stroke

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8
Q

What might be a use of Dipyridamole - for its potent vasodilator effect?

A

Dipyridamole can be infused intravenously as an alternative to exercise for myocardial perfusion imaging

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9
Q

Onset of dipyridamole

A

Fast onset after oral administration (20-30min)

Peak effect 2-2.5h

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10
Q

Duration of action of dipyridamole

What preparation is used?

A

Short DOA ~3h
(Fastest offset compared to other antiplatelets, allows for rapid reversal in the event of bleeding)

Therefore, modified-release preparation is used to ensure release over longer period of time, and to reduce frequency of dosing

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11
Q

Adverse effects of dipyridamole

A

Headache, hypotension
Dizziness, flushing
GI disturbances - diarrhea, N&V

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12
Q

Contraindications with dipyridamole

A

Hypersensitivity to drug

Caution in hypotension and severe CAD

  • trigger reflex tachycardia => angina, ECG abnormalities, MI
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13
Q

DDI with dipyridamole

A

Adenosine (anti-arrhythmic)

  • Dipyridamole increases adenosine plasma concentration

Cholinesterase inhibitors

  • Dipyridamole decreases cholinesterase inhibitors, may aggravate myasthenia gravis

Other anticoagulants or antiplatelets

  • Incr risk of bleeding, particularly with heparin
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14
Q

Role of COX-1

How is it restored?

A

Platelets express COX-1 which produces TXA2 that promotes platelet aggregation

COX-1 can only be restored by formation of new platelets ~7-10days (since platelets do not have nucleus)

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15
Q

Role of COX-2

A

Endothelial cells in the walls of the blood vessels express COX-2 which produces PGI2 that inhibits platelet aggregation

COX-2 restored by synthesis of new COX-2 enzyme by endothelial cells ~3-4h

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16
Q

Aspirin MOA

Why is Aspirin more antiplatelet compared to other NSAIDs

A

Irreversible non-selective COX inhibitor, inhibits COX-1 more than COX-2

More antiplatelet than other NSAIDs as it is IRREVERSIBLE COX inhibitor

Reversible NSAIDs => balance between COX1 and COX2 (TXA2 and PGI2) will be reestablished once drug is cleared, hence no more antiplatelet effect

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17
Q

Explain the difference in dosing between Aspirin as an antiplatelet VS Aspirin as an analgesic

A

Antiplatelet: low dose (75-325mg LD, 40-160mg MD), once daily dosing

Analgesic: high dose (500mg-1g), every 4-6h

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18
Q

Why is Aspirin a more potent antiplatelet agent when it is dosed less frequently at lower doses?

A

Dosed less frequently: allow endothelial cell synthesis of new COX-2 enzyme within 3-4h, so as to recover PGI2 antiplatelet function (sustained inhibition of COX-2 is NOT desired)

Low dose: lesser inhibition of COX-2 is desired so that PGI2 > TXA2

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19
Q

Why does it take 3-4h after administration of Aspirin to see clinically significant antiplatelet effect?

A

COX-2 enzymes newly synthesized after 3-4h, therefore restore PGI2 antiplatelet effects

20
Q

Why does it take 2-3days of continuous daily administration of Aspirin to achieve maximal antiplatelet effect?

A

Low dose aspirin is unable to inhibit every platelet, hence takes a few days to build up the maximal number of platelets that can be inhibited

21
Q

Adverse effects of Aspirin

A
  • incr risk of bleeding and bruising
  • upper GI events (gastric ulcers, bleeding)
22
Q

How does Aspirin cause GI bleed?

A

COX-1 inhibition reduces the production of PGE2, which protects the GI mucosa integrity by reducing acid secretion and increasing bicarbonate and mucus secretion, and increasing mucosal blood flow

23
Q

List the ADP P2Y12 receptor inhibitors

A

Clopidogrel
Prasugrel
Ticagrelor

24
Q

Explain the role of ADP and GP IIb/IIIa receptors

A

ADP released form dense granules of platelets, act on ADP P2Y12 receptors and activate platelet surface GP IIb/IIIa receptors

Fibrinogen binds to GP IIb/IIIa receptors to link up adjacent platelets, causing platelet aggregation

25
Q

MOA of ADP P2Y12 receptor inhibitors

A

Binds to ADP P2Y12 receptor and blocks ADP-mediated increase in cell surface expression of active BP IIb/IIIa receptor, therefore reducing platelet aggregation, preventing thrombus development

26
Q

P2Y12 inhibitors have ____ onset than Aspirin

A

Faster onset

27
Q

P2Y12 inhibitors require __________ to further accelerate approach to steady state antiplatelet effects

A

Loading doses

28
Q

Difference between Clopidogrel, Prasugrel, Ticagrelor binding to P2Y12 receptor

A

Clopidogrel - PRODRUG, binds IRREVERSIBLY to ADP binding site on P212 receptor

Ticagrelor - binds REVERSIBLY to allosteric site on P2Y12 inhibitor

Prasugrel - PRODRUG, binds IRREVERSIBLY to ADP binding site on P212 receptor

29
Q

Difference between effects on platelet function of Clopidogrel and Ticagrelor

A

Clopidogrel - effects lasts a lifetime of the affected platelet (7-10days)

Ticagrelor - effects last 2-3 days (recovery of platelet function, depending on serum concentrations of Ticagrelor)

30
Q

Difference between maintenance dosing of Clopidogrel and Ticagrelor

A

Clopidogrel - 75mg OD
Ticagrelor - 90mg BD => 60mg BD

31
Q

Which P2Y12 inhibitor has interindividual variability due to CYP mediated metabolism?

A

Clopidogrel - CYP2C19 polymorphism

(*2, 3: LoF) (17: GoF)

32
Q

Adverse effects of Clopidogrel

A

Hemorrhage/bleeding, intracranial bleeding

  • PPI might be used to reduce upper GI bleed, yet PPI has interactions with Clopidogrel

Less common: GI disturbances, dyspepsia, gastritis

Rare: bronchospasm, dyspnea, hypotension, cough

33
Q

Serious adverse effects of Clopidogrel

A
  • Thrombotic thrombocytopenia purpura
  • Severe bleeding
  • Hypersensitivity
34
Q

Contraindications and cautions of Clopidogrel

A

CI:

  • hypersensitivity
  • active pathological bleeding (e.g., PUD)
  • severe liver impairment (efficacy reasons, as prodrug not converted)

Caution:

  • risk of bleeding (lower GI bleed, trauma, surgery, coronary artery stents)
35
Q

Clopidogrel dose adjustments

A
  • NIL for renal and hepatic
  • But CI in severe live impairment
  • Caution in CKD due to higher inciendece of platelet reactivity and thrombotic complications
36
Q

In the event pt has to undergo cardiac surgery, when should Clopidogrel be held off?

A

24h to 5d prior to cardiac surgery

5 days - because that is the approx amount of time for recovery of platelet function (new platelet pdn)

37
Q

If antiplatelet agents are discontinued they should be resumed within _____

A

7 days

38
Q

DAPT should not be discontinued in _______

A

DAPT should not be discontinued in 90 days following post-acute coronary syndrome or 30 days following post-acute coronary stenting

For lower GI bleed and non-cardiac surgery:
DAPT needs to be continued if <30 days following bare metal stent placement, <3 months following DES placement

39
Q

DAPT or monotherapy TCU

A

DAPT: 1m, 3m, 6m

Monotherapy: TCU then test

40
Q

DDIs with Clopidogrel

A

Clopidogrel is major substrate of CYP2C19, minor substrate of CYP3A4

  • CYP2C19 inducers: Rifampicin, Ritonavir, St John’s wort
  • CYP2C19 inhibitor: Omeprazole (CI), Fluconazole, Fluoxetine
  • CYP3A4 inhibitors: Macrolides

*Inhibits diminish Clopidogrel effects since it needs to be converted to active thiol metabolite

41
Q

Drug-herb interaction with Clopidogrel

A

-Ginseng
- Vit E (>4ooIU/day)
- Omega 3 (>2g/day

All have antiplatelet effects

42
Q

Ticagrelor adverse effects

A
  • Bleeding (higher risk than Clopidogrel)
  • Bradycardia*
  • Dyspnea*
  • Cough
43
Q

Postulated MOA of bradycardia in Ticagrelor

Postulated MOA of dyspnea in Ticagrelor

A

Bradycardia:
- more relevant for parenteral formulation
- bradycardia induced by adenosine action on AV node
- risk factors: concurrent AV nodal blocking agent, underlying conduction disorders such as AV nodal block

Dyspnea (may be paroxysmal)
- Increase adenosine levels in the lungs rather than cardiac muscles or platelets, therefore causing dyspnea

44
Q

Contraindications and cautions

A

CI:
- hypersensitivity
- active pathological bleeding (e.g., PUD)
- risk of intracranial hemorrhage (this was caution in clopidogrel)
- severe liver impairment

Caution:
- risk of bleeding (lower GI bleed, trauma, surgery, elderly, mod hepatic failure)

45
Q

DDI with Ticagrelor

A

CYP3A4 major substrate (metabolize to 40% active metabolite), also CYP3A4 inhibitor, PGP inhibitor

  • Bleeding risk: anticoagulants, NSAIDs
  • Aspirin doses >100mg/day: decrease TIcagrelor effect and increase bleeding risk
  • CYP3A inducer (dcr Tica effect): dexamethasone, phenytoin
  • CYP3A strong inhibitors (incr Tica levels): clarithromycin, ketoconazole
  • May increase serum levels of simvastatin (due to CYP3A4 inhibition of Ticagrelor)
  • May increase serum levels of digoxin (due to PGP inhibition of Digoxin)

3154 Haematology (14 decks)

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