IC3 Antiplatelets Flashcards
What are the 4 stages of hemostasis and thrombosis?
- Vasoconstriction
- Primary hemostasis - platelet aggregation
- Secondary hemostasis - thrombin activation
- Clot stabilizzation
Which stage of thrombosis do antiplatelets act on?
Primary hemostasis (platelet aggregation)
What is adenosine?
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
What is PDE3?
PDE3 in inactive platelets are responsible for breaking down cAMP in order to activate the platelet
Dipyridamole MOA
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
How does dipyridamole cause vasodilatory effects?
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
Vasodilation caused by dipyridamole is a ______ adverse effect
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
What might be a use of Dipyridamole - for its potent vasodilator effect?
Dipyridamole can be infused intravenously as an alternative to exercise for myocardial perfusion imaging
Onset of dipyridamole
Fast onset after oral administration (20-30min)
Peak effect 2-2.5h
Duration of action of dipyridamole
What preparation is used?
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
Adverse effects of dipyridamole
Headache, hypotension
Dizziness, flushing
GI disturbances - diarrhea, N&V
Contraindications with dipyridamole
Hypersensitivity to drug
Caution in hypotension and severe CAD
- trigger reflex tachycardia => angina, ECG abnormalities, MI
DDI with dipyridamole
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
Role of COX-1
How is it restored?
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)
Role of COX-2
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
Aspirin MOA
Why is Aspirin more antiplatelet compared to other NSAIDs
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
Explain the difference in dosing between Aspirin as an antiplatelet VS Aspirin as an analgesic
Antiplatelet: low dose (75-325mg LD, 40-160mg MD), once daily dosing
Analgesic: high dose (500mg-1g), every 4-6h
Why is Aspirin a more potent antiplatelet agent when it is dosed less frequently at lower doses?
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
Why does it take 3-4h after administration of Aspirin to see clinically significant antiplatelet effect?
COX-2 enzymes newly synthesized after 3-4h, therefore restore PGI2 antiplatelet effects
Why does it take 2-3days of continuous daily administration of Aspirin to achieve maximal antiplatelet effect?
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
Adverse effects of Aspirin
- incr risk of bleeding and bruising
- upper GI events (gastric ulcers, bleeding)
How does Aspirin cause GI bleed?
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
List the ADP P2Y12 receptor inhibitors
Clopidogrel
Prasugrel
Ticagrelor
Explain the role of ADP and GP IIb/IIIa receptors
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
MOA of ADP P2Y12 receptor inhibitors
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
P2Y12 inhibitors have ____ onset than Aspirin
Faster onset
P2Y12 inhibitors require __________ to further accelerate approach to steady state antiplatelet effects
Loading doses
Difference between Clopidogrel, Prasugrel, Ticagrelor binding to P2Y12 receptor
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
Difference between effects on platelet function of Clopidogrel and Ticagrelor
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)
Difference between maintenance dosing of Clopidogrel and Ticagrelor
Clopidogrel - 75mg OD
Ticagrelor - 90mg BD => 60mg BD
Which P2Y12 inhibitor has interindividual variability due to CYP mediated metabolism?
Clopidogrel - CYP2C19 polymorphism
(*2, 3: LoF) (17: GoF)
Adverse effects of Clopidogrel
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
Serious adverse effects of Clopidogrel
- Thrombotic thrombocytopenia purpura
- Severe bleeding
- Hypersensitivity
Contraindications and cautions of Clopidogrel
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)
Clopidogrel dose adjustments
- NIL for renal and hepatic
- But CI in severe live impairment
- Caution in CKD due to higher inciendece of platelet reactivity and thrombotic complications
In the event pt has to undergo cardiac surgery, when should Clopidogrel be held off?
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)
If antiplatelet agents are discontinued they should be resumed within _____
7 days
DAPT should not be discontinued in _______
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
DAPT or monotherapy TCU
DAPT: 1m, 3m, 6m
Monotherapy: TCU then test
DDIs with Clopidogrel
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
Drug-herb interaction with Clopidogrel
-Ginseng
- Vit E (>4ooIU/day)
- Omega 3 (>2g/day
All have antiplatelet effects
Ticagrelor adverse effects
- Bleeding (higher risk than Clopidogrel)
- Bradycardia*
- Dyspnea*
- Cough
Postulated MOA of bradycardia in Ticagrelor
Postulated MOA of dyspnea in Ticagrelor
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
Contraindications and cautions
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)
DDI with Ticagrelor
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)
