IC3 Antiplatelets Flashcards
(39 cards)
State the 4 stages of hemostasis
- Vasoconstriction
- Primary hemostasis
- Secondary hemostasis
- Clot stabilization
Explain the 4 stages of hemostasis
Vasoconstriction
Reflex vasoconstriction occurs at the site of injury due to endothelin release from endothelial cells
Primary hemostasis
Platelets adhere & undergo a shape change to be activated → release ADP, TXA2 to recruit more platelets → stimulate further platelet aggregation (hemostatic plug)
Secondary hemostasis
The release of tissue factor causes phospholipid complex expression which activates prothrombin to thrombin → thrombin converts fibrinogen to fibrin, promoting fibrin polymerization
Clot stabilization
As platelet contracts, factor XIIIa is activated to stabilize fibrin → fibrin network matures (fibrin covalently cross links) → traps more platelet + blood cells
Which stage of hemostasis do Antiplatelets block?
Primary hemostasis
(platelet adhesion, activation. & aggregation)
List the antiplatelet agents & what they inhibit
Dipyridamole
Adenosine uptake and PDE3 inhibitor
(prevents platelet activation)
Aspirin
COX-1 inhibitor
(prevents the production of cyclic endoperoxides from arachidonic acid, which is required for TXA2 synthesis)
Clopidogrel, Ticagrelor
ADP (P2Y12) receptor inhibitors
(prevents ADP release)
What benefit can combining different antiplatelet agents confer?
- Stronger antiplatelet effects, so used in those with higher thrombotic risks
- But be careful to prevent excessive ↓hemostasis which can cause bruises & bleeding
What is the MOA of Dipyridamole?
cAMP inhibits platelet activation & aggregation
Inhibits platelet activation & aggregation by ↑cAMP within
platelets
1. Inhibits adenosine reuptake → ↑ plasma adenosine → ↑ activation of A2 receptors on inactive platelets → ↑ cAMP
2. Inhibits Phosphodiesterase 3 (PDE3) to ↓ degradation of cAMP within platelets
What are the indications of Dipyridamole?
- Adjunct antiplatelet (low dose) in combination with other antiplatelets (e.g. aspirin) &/or anticoagulants (e.g. warfarin)
- IV infusion as an alternative to exercise for myocardial perfusion imaging (due to its strong vasodilatory effects, it can trigger reflex tachycardia & ↑cardiac perfusion, simulating exercise)
Why is the role of Dipyridamole limited to an adjunct therapy?
- Adenosine is a vasodilator
- PDEs degrade cAMP, & cAMP is also a vasodilator
- Since it inhibits adenosine reuptake & PDEs in vascular smooth muscle, it causes vasodilation (an adverse effect)
- So the dose-limiting adverse effects limit its clinical antiplatelet efficacy
How is the onset of Dipyridamole?
- Fast
- 20 to 30 min after oral administration
- Peak effect at 2 to 2.5h
What is the DOA of Dipyridamole? Relate this to the formulation it is available in
- Short DOA of ~3h
- Hence usually available as MR preparation
What is an advantage with regards to the DOA of Dipyridamole?
Rapid reversal if there are concerns on haemorrhage & bleeding risks compared to other classes of antiplatelets
What are the adverse effects of Dipyridamole?
- Headache
- Hypotension
- Dizziness
- Flushing
(vasodilatory effects) - GI disturbance
- Diarrhoea
- Nausea
- Vomiting
What are the respective contraindications & precaution with Dipyridamole use?
Contraindications
Hypersensitivity
Caution
Hypotension (Acute hypotension can trigger reflex tachycardia → angina pectoris & ECG abnormalities or even MI)
Severe coronary artery disease
What are 3 drug-drug interactions of concern for Dipyridamole?
- ↑ Cardiac adenosine levels & effects
- ↓ Cholinesterase inhibitors & may aggravate myasthenia gravis
- Caution for bleeding when combined with 🥨 heparin or other anticoagulants & antiplatelets
Why does Aspirin have a stronger antiplatelet effect than other NSAIDs which are more potent at inhibiting COX-1 than COX-2?
Aspirin is the ONLY NSAID with 🥨irreversible effect on COX enzyme inhibition
Potency & reversibility are separate parameters
Apart from being an antiplatelet, what other indication does Aspirin have?
Analgesia
as it is a non-selective COX inhibitor (inhibits both COX-1 & COX-2)
To reap the most antiplatelet effect, should Aspirin be used at low or high doses, & how frequently should they be taken? Explain why
- Low dose OD e.g. 75 to 325 mg loading dose or 40 to 160 mg OD more effective than a high dose of e.g. 500 mg to 1g
- Normally, Aspirin inhibits COX-1 > COX-2
- If used at high doses, it will more strongly block PGI2 production for a longer duration (PGI2 inhibits platelet aggregation) → inhibit endogenous antiplatelet effects → more pro-platelet effect
- So if used at low dose, it can irreversibly inhibit COX-1 then be cleared from plasma soon after (so no longer inhibit COX-2, allows recovery of endothelial cell production of PGI2)
- Hence, OD dosing is also more effective than every 4 to 6h (which would be ideal for analgesic effects instead)
Where are COX-1 enzymes expressed & what do they produce? Explain the function of what they produce
- Expressed by platelets
- Produce TXA2, which promotes platelet aggregation
If the COX-1 enzyme is inhibited, how long does it take for recovery?
- Takes 7 to 10 days
- Because platelets have no nucleus & Aspirin irreversibly inhibits COX-1, new COX-1 enzymes cannot be produced unless new platelets are present
- So effect can only be restored by formation of new platelets
- & this takes 🥨 7 to 10 days
Where are COX-2 enzymes expressed & what do they produce? Explain the function of what they produce
- Endothelial cells
- Produce PGI2, which inhibits platelet aggregation
If the COX-2 enzyme is inhibited, how long does it take for recovery?
- As endothelial cells have nucleus, they are able to synthesize new COX enzymes
- So function can be recovered quite quickly, taking 3 to 4h
Why does it take 3 to 4 hours to observe a clinically significant antiplatelet effect of Aspirin?
- By 3 to 4h, low dose Aspirin would have been largely cleared
- So the new COX-2 enzyme would be uninhibited (recall Aspirin is non-selective)
When can maximum antiplatelet effects be seen & why?
- Need 2 to 3 days of continuous daily administration for maximum effects
- Because at low doses, not all platelets are inhibited
What is the MOA of Aspirin?
- Irreversible COX inhibitor (COX-1 > COX-2)
- Inhibits platelet production of TXA2
