ACS and stroke 2 Flashcards
Why are anti-platelet drugs used?
The major role played by platelets in clot formation makes them a logical target for drugs that aim to reduce the risk of thrombosis
Aspirin
most commonly used drug for secondary prevention
irreversible inhibitor of cyclooxygenase (enzyme)
Which type of thrombosis is it most important for?
arterial thrombosis
Generation of TXA2
synthetic pathway for TXA2 begins with phospholipase A2 cleaving membrane phospholipids and releasing the fatty acid arachidonic acid into the cytoplasm
series of enzymatic steps then occurs that result in the formation of prostaglandin H2
one of these steps is catalysed by cyclooxygenase
thromboxane synthase then acts on prostaglandin H2 to produce TXA2.
if cyclooxygenase is blocked using aspirin production of TXA2 is blocked
prostaglandin H2 is actually a branch point
prostacyclin synthase (enzyme) can act on prostaglandin H2 to produce prostacyclin which is a signal that stops a chain reaction of platelet activation spreading through the circulation
Aspirin dose
Aspirin is given at a low dose once a day
Where is thromboxane A2 made?
platelets (no nuclei)
Where is Prostacyclin made?
endothelial cells (no nuceli)
What happens initially?
all COX inhibited
How can endothelial cells can overcome inhibition?
because they have a nucleus they can make more prostacyclin
What do platelets do because they cannot make new enzymes?
need new platelets to make COX
COX-2
endothelial cells have a second type of COX (COX-2) that is not as sensitive to aspirin which contributes to ability to continue prostacyclin production
Aspirin as a painkiller
Aspirin was initially marketed as a painkiller and anti-inflammatory drug but it has been largely been superseded in these roles by safer drugs such as ibuprofen and paracetamol
Its mechanism as a painkiller and anti-inflammatory overlaps with its antiplatelet actions
Which class of drugs do aspirin and ibuprofen belong to?
non-steroidal anti-inflammatory drugs (NSAIDs)
What is cyclooxygenase important for?
produces prostaglandins that act as pain signals and inflammatory mediators
Side effects of aspirin (4)
- extended bleeding
- irritating to stomach and GI tract- ulcers, bleeding, removes protective prostaglandins
- Reye’s syndrome (under 16)
- Can provoke asthma
ADP receptor inhibitors
ADP released from activated platelets and acts on a G protein coupled receptor called P2Y12 on neighbouring inactive platelets
these receptors promote activation of the platelets and increase the number of the GPIIb/IIIa glycoprotein receptors on their surface (the receptors that allow cross linking of platelets via fibrinogen)
What do drugs that block effects of ADP end with?
grel
Clopidogrel and prasugrel
Clopidogrel and prasugrel (prodrugs) are irreversible inhibitors of the P2Y12 receptor and so block the actions of ADP by essentially “killing” the receptor
How are clopidogrel and prasugrel activated?
clopidogrel must be metabolized by the enzyme CYP2C19
Issue with clopidogrel
about 30% of people have a genetic difference in this enzyme that means they cannot metabolize clopidogrel effectively
because of this issue NICE recommended that genetic testing be introduced to identify patients for whom clopidogrel would be ineffective
Why is there not the same issue with prasugrel
prasugrel is also a prodrug but is much less dependent on CYP2C19 for its metabolism to the active form and will work more consistently across all patients.
Ticagrelor
inhibitor of the P2Y12 receptor but binds to a different site to ADP (it is an allosteric or non-competitive antagonist)
unlike clopidogrel and prasugrel it is not a prodrug and it binds to the receptor reversibly
Side effects of ALL ADP receptor inhibitors
extended bleeding in a dose dependent manner
Side effects of clopidogrel
Common: gastrointestinal tract problems
Less common: dizziness, headache
