Antiplatelet

Question 1

Aspirin

Answer 1

• cyclo-oxygenase inhibitor
• potent platelet aggregating agent thromboxane A2 (TXA2) formed from arachidonic acid by COX-1
• aspirin inhibits COX-1 mediated production of TXA2 and reduces platelet aggregation
• inhibits the conversion of arachidonic acid to prostaglandins H2
• this occurs at low dose (75mg); “baby aspirin”
• IRREVERSIBLE

Question 2

Why does aspirin not completely inhibit platelet aggregation?

Answer 2

-there are other mediators and mechanisms that occur which are independent of COX-1

Question 3

How does aspirin work in higher doses?

Answer 3

• inhibits endothelial prostacyclin (PGI2)

- absorbed by passive diffusion: hepatic hydrolysis to salicylic acid

Question 4

What are the side effects and considerations of aspirin?

Answer 4

• bleeding time prolonged: haemorrhagic stroke, GI bleeding (peptic ulcer)
• Reye’s syndrome: avoid if <16 years
• hyper sensitivity
• 3rd trimester: premature closure of DA

-other antiplatelet and anticoagulants (additive/synergistic action)

Question 5

Why does aspirin’s inhibition last the lifespan of platelet (7-10 days)?

Answer 5

-platelets lack nuclei, so once aspirin inhibits COX-1, it can’t produce anymore platelets

Question 6

What indications can aspirin be used for?

Answer 6

• secondary prevention of stroke and TIA
• secondary prevention of acute coronary syndrome (ACS)
• post primary percutaneous coronary intervention (PCI) and stent to reduce ischaemic complications
• secondary prevention of MI in stable angina or peripheral vascular disease
• often co prescribed with other antiplatelet agents
• ACS: give initial once only 300mg loading dose (chewable is best)
• acute ischaemic stroke: initial 300mg daily for 2 weeks
• gastric protection for long term use in at risk patients (PPI)

Question 7

ADP receptor antagonists (clopidogrel, prasugrel, ticagrelor)

Answer 7

• inhibit binding of ADP to P2Y12 receptor in order to inhibit activation of GPIIb/IIIa receptors
• it is independent of COX pathway
• reduces the amount of calcium being released which inhibits activation of GP receptors
• clopidogrel and prasugrel are irreversible inhibitors of P2Y12 and are pro drugs that need hepatic metabolism
• clopidogrel has slow onset of action without loading dose, inter-individual variability in antiplatelet action
• ticagrelor and prasugrel have more rapid onset
• ticagrelor is reversible at different site to clopidogrel, and has active metabolites

Question 8

WHat are the side effects and considerations of ADP receptor antagonists?

Answer 8

• bleeding, thrombocytopenia
• GI upset, dyspepsia and diarrhoea
• caution with renal and hepatic impairment
• clopidogrel requires CYPs for activation and CYP2C19 can be interfered with so must consider use of other PPIs with clopidogrel (DONT USE OMEPRAZOLE)
• ticagrelor can interact with CYP inhibitors and inducers (i.e. CYP3A4)
• caution when co-prescribed with other antiplatelet and anticoagulants or NSAIDs as it can cause bleeding
• clopidogrel needs stopping about 7 days before surgery
• ticagrelor needs stopping about 5 days before surgery

Question 9

What are the indications of ADP receptor antagonists?

Answer 9

• used for a wide variety of presentations where antiplatelet is needed
• use clopidogrel where aspirin is contraindicated, NSTEMI patients for up to 12 months, PPCI considerations
• STEMI with stent for up to 12 months
• stop before coronary artery bypass graft
• risk of cardiovascular events vs. Bleeding risk
• ischaemic stroke and TIA long term secondary prevention
• prasugrel with aspirin in ACS patients undergoing PCI up to 12 months

Question 10

WHat is the difference between ticagrelor plus aspirin and clopidogrel plus aspirin

Answer 10

• ticagrelor plus aspirin better at reducing rate of death from vascular causes at 12 months
• faster onset of action, more predictable
• increased bleeding risk possibly

Question 11

Glycoproteins IIb/IIIa inhibitors (abciximab)

Answer 11

• blocks binding of fibrinogen and von Willebrand factor (vWF)
• target final common pathway: more complete platelet aggregation
• abciximab: antibody that blocks GPIIb/IIIa receptors
• > 80% reduction in aggregation: bleeding risk
• given iv with bolus
• side effects: bleeding, dose adjustment for body weight, thrombocytopenia, hypotension, bradycardia
• considerations: caution with other antiplatelet and anticoagulant agents
• specialist use in high risk percutaneous transluminal coronary angioplasty patients

Question 12

Phosphodiesterase inhibitors (dipyridamole)

Answer 12

• inhibits cellular reuptake of adenosine
• as a result plasma adenosine increases which inhibits platelet aggregation via A2 receptors
• also acts as phosphodiesterase inhibitor (like viagra) which prevents cAMP degradation which inhibits expression of GPIIb/IIIa
• side effects: flushing, headache, hypersensitivity
• consideration: caution with antihypertensive, antiplatelets and anticoagulants
• secondary prevention of ischaemic stroke and TIAs
• adjunct for prophylaxis of thromboembolism following valve replacement

Question 13

Fibrinolytic agents (thrombolysis) “clot busters” (streptokinase, alteplase)

Answer 13

• fibrinolytics dissolve the fibrin mesh work of thrombus
• streptokinase promotes plasminogen
• alteplase promotes the plasminogen activators
• alteplase used in acute ischaemic stroke <4.5 hours
• side effect: bleeding
• streptokinase can only be used ONCE as antibodies develop to it
• intracranial haemorrhage needs ruling out