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PR3154 > IC3 Antiplatelets > Flashcards

IC3 Antiplatelets Flashcards

1
Q

State the 4 stages of hemostasis

A
  1. Vasoconstriction
  2. Primary hemostasis
  3. Secondary hemostasis
  4. Clot stabilization
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2
Q

Explain the 4 stages of hemostasis

A

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

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3
Q

Which stage of hemostasis do Antiplatelets block?

A

Primary hemostasis
(platelet adhesion, activation. & aggregation)

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4
Q

List the antiplatelet agents & what they inhibit

A

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)

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5
Q

What benefit can combining different antiplatelet agents confer?

A
  • Stronger antiplatelet effects, so used in those with higher thrombotic risks
  • But be careful to prevent excessive ↓hemostasis which can cause bruises & bleeding
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6
Q

What is the MOA of Dipyridamole?

A

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

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7
Q

What are the indications of Dipyridamole?

A
  • 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)
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8
Q

Why is the role of Dipyridamole limited to an adjunct therapy?

A
  • 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
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9
Q

How is the onset of Dipyridamole?

A
  • Fast
  • 20 to 30 min after oral administration
  • Peak effect at 2 to 2.5h
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10
Q

What is the DOA of Dipyridamole? Relate this to the formulation it is available in

A
  • Short DOA of ~3h
  • Hence usually available as MR preparation
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11
Q

What is an advantage with regards to the DOA of Dipyridamole?

A

Rapid reversal if there are concerns on haemorrhage & bleeding risks compared to other classes of antiplatelets

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12
Q

What are the adverse effects of Dipyridamole?

A
  • Headache
  • Hypotension
  • Dizziness
  • Flushing
    (vasodilatory effects)
  • GI disturbance
  • Diarrhoea
  • Nausea
  • Vomiting
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13
Q

What are the respective contraindications & precaution with Dipyridamole use?

A

Contraindications
Hypersensitivity

Caution
Hypotension (Acute hypotension can trigger reflex tachycardia → angina pectoris & ECG abnormalities or even MI)
Severe coronary artery disease

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14
Q

What are 3 drug-drug interactions of concern for Dipyridamole?

A
  • ↑ Cardiac adenosine levels & effects
  • ↓ Cholinesterase inhibitors & may aggravate myasthenia gravis
  • Caution for bleeding when combined with 🥨 heparin or other anticoagulants & antiplatelets
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15
Q

Why does Aspirin have a stronger antiplatelet effect than other NSAIDs which are more potent at inhibiting COX-1 than COX-2?

A

Aspirin is the ONLY NSAID with 🥨irreversible effect on COX enzyme inhibition
Potency & reversibility are separate parameters

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16
Q

Apart from being an antiplatelet, what other indication does Aspirin have?

A

Analgesia
as it is a non-selective COX inhibitor (inhibits both COX-1 & COX-2)

17
Q

To reap the most antiplatelet effect, should Aspirin be used at low or high doses, & how frequently should they be taken? Explain why

A
  • 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)
18
Q

Where are COX-1 enzymes expressed & what do they produce? Explain the function of what they produce

A
  • Expressed by platelets
  • Produce TXA2, which promotes platelet aggregation
19
Q

If the COX-1 enzyme is inhibited, how long does it take for recovery?

A
  • 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
20
Q

Where are COX-2 enzymes expressed & what do they produce? Explain the function of what they produce

A
  • Endothelial cells
  • Produce PGI2, which inhibits platelet aggregation
21
Q

If the COX-2 enzyme is inhibited, how long does it take for recovery?

A
  • As endothelial cells have nucleus, they are able to synthesize new COX enzymes
  • So function can be recovered quite quickly, taking 3 to 4h
22
Q

Why does it take 3 to 4 hours to observe a clinically significant antiplatelet effect of Aspirin?

A
  • 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)
23
Q

When can maximum antiplatelet effects be seen & why?

A
  • Need 2 to 3 days of continuous daily administration for maximum effects
  • Because at low doses, not all platelets are inhibited
24
Q

What is the MOA of Aspirin?

A
  • Irreversible COX inhibitor (COX-1 > COX-2)
  • Inhibits platelet production of TXA2
25
Q

What are the adverse effects of Aspirin?

A
  1. Upper GI events e.g. gastric ulcers, bleeding
  2. ↑ risk of bruising & bleeding
26
Q

What are the precautions for Aspirin use?

A

In patients with platelet & bleeding disorders

27
Q

If Aspirin is combined with other antiplatelets & anticoagulants, watch out for ______

A

bleeding (like Dipyridamole)

28
Q

Why does Aspirin cause upper GI events (UGI)?

A
  • COX-1 produces protective prostaglandin in stomach which are involved in ↓ acid secretion, ↑ bicarbonate, mucus secretion, mucosal blood flow
  • But Aspirin inhibits such production by inhibiting COX-1
  • e.g. Low-dose aspirin indicated for cardioprotective effects is associated with a 2 to 4-fold ↑ in UGI events
29
Q

What is the MOA of ADP P2Y12 receptor inhibitors?

A
  • Prevents release of ADP from dense granules of platelets
  • ADP acts on ADP P2Y12 receptors & plays a central role in activating Glycoprotein IIb/IIIa receptors, platelet recruitment & aggregation
  • GP IIb/IIIa receptors subsequently bind to fibrinogen to link adjacent platelets together
30
Q

What are the similarities & differences of Clopidogrel & Ticagrelor?

A
  • Both are ADP P2Y12 receptor inhibitors
  • Binding site Clopidogrel is a prodrug with an active metabolite that binds to the ADP binding site on the P2Y12 inhibitor but Ticagrelor & its metabolites binds to a different site to inhibit G protein activation & signalling
  • Type of binding Clopidogrel binds irreversibly while Ticagrelor binds reversibly
  • Dosing frequency Clopidogrel often dosed OD while Ticagrelor is BD
  • Recovery of platelet function Clopidogrel’s effects on platelet function last for the lifetime of the affected platelets, which is ~7 to 10 days but Ticagrelor’s depend on its serum concentrations & its active metabolites, takes 2 to 3 days (faster offset)
  • Time to onset, peak effects Ticagelor has a faster onset & peak effect than Clopidogrel
31
Q

Suggest why a delayed onset & inter-individual variability is often observed for Clopidogrel

A

CYP2C19-mediated metabolism causes the production of active metabolite, causing a delayed onset (peak action 6 to 8h) & inter-individual variability

32
Q

How would you expect Prasugrel’s properties to be?

A
  • Likely more similar to Clopidogrel than Ticagrelor “grel”
  • A prodrug, binds irreversibly
  • It is actually slightly more potent & largely dependent on CYP3A4 & CYP2D6 for metabolism
33
Q

Which antiplatelet class uses loading-dose regimens to accelerate approach to steady state?

A

ADP P2Y12 inhibitors

34
Q

Compare the adverse effects of Clopidogrel & Ticagrelor

A

Clopidogrel
Haemorrhage/bleeding, including intracranial bleeding
Easy bruising
Dyspepsia, rashes
Bronchospasm
(more rarely) Dyspnea, hypotension

Ticagrelor
Haemorrhage/bleeding, including intracranial bleeding
Easy bruising
Bradycardia
Cough
Dyspnea

35
Q

Compare the contraindications of Clopidogrel & Ticagrelor

A

Clopidogrel
Hypersensitivity
Active pathologic bleeding

Ticagrelor
Hypersensitivity
Active pathologic bleeding or intracranial hemorrhage
Severe hepatic impairment
Breastfeeding women

36
Q

Compare the precautions of Clopidogrel & Ticagrelor

A

Clopidogrel
At risk of bleeding (e.g. risk of intracranial haemorrhage, trauma, surgery)
Variant alleles of CYP2C19 associated with ↓metabolism to active metabolite & diminished antiplatelet response (causing ↑use of Prasugrel as an alternative)

Ticagrelor
At risk of bleeding (e.g. risk of intracranial haemorrhage, trauma, surgery)
Elderly
Moderate hepatic failure

37
Q

What are the drug-drug interactions of concern for Clopidogrel?

A
  1. Increase risk of bleeding
    Warfarin, NSAIDs & salicylates
    Rifamycins may increase the antiplatelet effect
  2. May reduce the antiplatelet effect
    Macrolides
    Strong to moderate CYP2C19 inhibitors (e.g. PPIs, fluoxetine, ketoconazole etc) may reduce the antiplatelet effect
38
Q

What are the drug-drug interactions of concern for Ticagrelor?

A
  1. Anticoagulants, fibrinolytics, & long-term NSAIDs may ↑bleeding risk
  2. Aspirin doses >100 mg/day ↓Ticagrelor effect but ↑bleeding risk (DON’T DO THIS)
  3. CYP3A inducers (e.g. dexamethasone, phenytoin, etc) may ↓Ticagrelor level & antiplatelet effect
  4. CYP3A strong inhibitors (e.g. clarithromycin, ketoconazole etc) may
    ↑Ticagrelor level & risk of adverse reactions
39
Q

Rank the following drugs based on how quickly their antiplatelet effects would reverse upon discontinuation (fastest to slowest):
Aspirin, Dipyridamole, Ticagrelor, Clopidogrel

A

Dipyridamole > Ticagrelor > Clopidogrel > Aspirin

PR3154 (3 decks)

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