IC3 Antiplatelets Flashcards
What are the four stages of hemostasis & thrombosis?
- vasoconstriction
- primary hemostasis (platelet adhesion, recruitment, aggregation)
- secondary hemostasis (fibrin polymerization)
- clot stabilization (maturation of fibrin meshwork)
Which stage of hemostasis & thrombosis do antiplatelets work on?
primary hemostasis
What is the general mechanism of action of antiplatelets? (Hint: Primary & secondary functions)
Primary
- Directly prevent platelet adhesion, activation & aggregation
Secondary
- Prevent activation of clotting factors
- Inhibit development of fibrin meshwork
(these 2^ processes are mediated by platelet adhesion/activation/aggregation; therefore, by blocking the first process, it blocks these downstream processes too)
What are the 4 main antiplatelet drugs we need to know?
- Dipyridamole
- Aspirin
- Clopidogrel
- Ticagrelor
What is the overarching effect of dipyridamole?
↑ cAMP levels –> ↑ Inhibition of platelet activation & aggregation
What are the mechanisms of action of dipyridamole?
- Adenosine reuptake inhibitor
- PDE3 inhibitor
Explain the mechanisms of action of dipyridamole
Adenosine reuptake inhibitor
By inhibiting adenosine reuptake into platelets & rbc, there is a higher plasma conc of adenosine –> more adenosine available to bind to and activate A2 receptor on platelets –> ↑ cAMP levels –> ↑ Inhibition of platelet activation & aggregation
PDE3 inhibitor
PDE3 enzyme metabolizes cAMP. therefore, by inhibiting PDE3 –> ↑ cAMP levels –> ↑ Inhibition of platelet activation & aggregation
What is the dose-limiting adverse effect of dipyridamole?
Vasodilation
Dipyridamole PK:
1. Duration of onset
2. Duration to peak activity
3. Duration of action
- Fast; 20-30min
- 2-2.5h
- Short; ~3h
What is the advantage of dipyridamole due to its PK?
Rapid reversal is an advantage if there is concern for risk of bleeding
What is the disadvantage of dipyridamole due to its PK?
needs to be given TDS-QDS –> hard to ensure adherence; therefore, no longer commonly used (especially since there are better agents like clopi/tica)
What are the side effects of dipyridamole?
- headache (v common)
- hypotension
- dizziness
- flushing
- GI (N/V, diarrhoea)
What causes the side effects of dipyridamole?
Vasodilation effect
What are the contraindication to dipyridamole?
Drug hypersensitivity
What conditions should we be cautious of when prescribing dipyridamole?
- hypotension
- severe coronary artery disease
(Induction of acute hypotension may trigger reflex tachycardia –> angina pectoris + ECG abnormalities + MI)
What are the drugs that displays DDI with dipyridamole?
- adenosine
- cholinesterase inhibitors (for myasthenia gravis)
- other APs/ACs/fibrinolytics
Describe the DDIs with dipyridamole
dipyridamole ↑ adenosine effects –> ↑ cardiac adenosine levels & effects
dipyridamole ↓ cholinesterase inhibitor effects –> may aggravate myasthenia gravis
risk of bleeding when combined with other APs/ACs/fibrinolytics
What is the mechanism of action of aspirin?
Irreversible COX inhibitor
Explain the mechanism of action of aspirin
Aspirin inhibits COX-1 in platelets –> ↓ TXA2 which PROMOTES platelet aggregation
Aspirin inhibits COX-2 in endothelial cells –> ↓ PGI2 which INHIBITS platelet aggregation
however, as aspirin is an irreversible inhibitor, it causes the irreversible inhibition of COX-1 in platelets. therefore, since platelets have no nucleus, for them to have functional COX-1 enzymes, new platelets have to be produced from megakaryocytes, which takes 7-10 days
VS
endothelial cells have nucleus, thus are able to synthesize new COX-2 in 3-4h; during this duration, low dose aspirin would have been cleared by then. therefore, newly produced COX-2 in endothelial cells will NOT be inhibited, allowing for the synthesis of PGI2
this allows for endothelial cell production of PGI2 to recover WHILE irreversible inhibition of COX-1 persists
therefore, it takes 3-4h to see clinically significant antiplatelet effect with aspirin
since not all platelets will be inhibited by aspirin, it takes 2-3 days of continuous daily administration to achieve maximal AP effects
What is the difference when aspirin is used for antiplatelet effect and for analgesic effect?
antiplatelet effect requires LOW DAILY DOSE (75-100mg) OD
VS
analgesic effect requires HIGH DOSE Q4-6H
aspirin at low doses is selective for COX-1 –> allows for greater inhibition of TXA2 production > PGI2 production = overall inhibition of platelet aggregation + when given OD, it allows PGI2 production to recover while TXA2 pxn is irreversibly inhibited
aspirin at high doses inhibits both COX-1 and COX-2 –> less inhibition of platelet aggregation + when given frequently, PGI2 pxn cannot recover to establish antiplatelet effect
What are the side effects of aspirin?
- upper GI (UGI) events (eg. gastric ulcer, bleeding) (COX-1 produces protective PGs in stomach)
- ↑ risk of bleeding & bruising
What conditions should we be cautious of when prescribing aspirin?
platelet and bleeding disorders
What DDI does aspirin have?
when combined with other APs/ACs/fibrinolytics –> risk of bleeding
What drug class does clopidogrel and ticagrelor belong to?
ADP P2Y12 inhibitors
Describe the mechanism of action of P2Y12i
Inhibition of P2Y12 receptors –> Prevents ADP released from activated platelets from binding to P2Y12 and increasing platelet expression of GPIIb/IIIa receptor –> Inhibits platelet recruitment + aggregation
What are the side effects of clopidogrel and ticagrelor?
- bleeding
- easy bruising
- dyspnea, bradycardia (adenosine S/E of tica)
Describe MOA of clopidogrel
- prodrug
- active metabolite IRREVERSIBLY inhibits P2Y12 receptor
What is the duration of action of clopidogrel?
7-10 days (lifetime of platelet)
What are the contraindications of clopidogrel?
- drug hypersensitivity
- active pathologic bleeding (eg. ulcer)
What conditions should we be cautious of when prescribing clopidogrel?
patients at risk of bleeding (eg. risk of intracranial hemorrhage, trauma, surgery)
What affects clopidogrel metabolism?
variant alleles of CYP2C19 that is a/w reduced metabolism of clopidogrel to active metabolite (ie. reduced AP effect)
What drugs cause an increase in AP effect (ie. increased risk of bleeding) when used with clopidogrel?
- warfarin
- NSAIDS
- salicylates
- rifampicin (2C19 inducer)
What drugs cause a decrease in AP effect (ie. increased risk of clotting) when used with clopidogrel?
- macrolides
- moderate to strong 2C19 inhibitors (eg. PPI, fluoxetine, ketoconazole)
Describe MOA of ticagrelor
REVERSIBLY, non-competitively binds at a diff site (not ADP binding site) to inhibit G protein activation and signalling
What is the duration of action of ticagrelor?
2-3 days (shorter than clopidogrel since ticagrelor is reversible)
What are the contraindications of ticagrelor?
- drug hypersensitivity
- SEVERE hepatic impairment (↓ CL)
- breastfeeding
- hx of intracranial hemorrhage in the past 6m (only cautioned for clopidogrel as it is less potent)
- active pathologic bleeding
What conditions should we be cautious of when prescribing ticagrelor?
- patients at risk of bleeding (eg. peptic ulcer, trauma, surgery)
- elderly
- MODERATE hepatic impairment
What drugs cause an increase in AP effect (ie. increased risk of bleeding) when used with ticagrelor?
- ACs, fibrinolytics
- Long-term NSAIDS
- 3A4 inhibitors (eg. clarithromycin, ketoconazole)
- high aspirin dose >100mg/day (NOTE: ↓ ticagrelor effects but ↑ bleeding risk)
What drugs cause a decrease in AP effect (ie. increased risk of clotting) when used with ticagrelor?
3A4 inducers (eg. dexamethasone, phenytoin)
