P2Y12 Inhibitors Flashcards
(13 cards)
P2Y12
- stabilises aggregation
- ADP acts on P2Y12 in auto and paracrine mechanisms
- PIP3 production inhibits Rasa3 so platelets remain activated
P2Y12 KO
- in some conditions, KO prevented aggregation
- suggests a good target for an antithrombotic agent
P2Y12 inhibition
- clopidogrel = 1st in class
- cangrelor, prasugrel and ticagrelor followed
- cangrelor and prasugrel developed before any knowledge of P2Y12
Testing bleeding with P2Y12 antagonists
- test bleeding time in mice
- when cut part of the tail off
- is this a good model for human bleeding?
- cutting arteries and veins in mouse tail
- but most human bleeding is due to vein and capillary damage! - not a great model for the human disease state
Thienopyridines
- structures very different to the endogenous ATP (antagonist) and ADP (agonist)
- clopidogrel is a prodrug ad active metabolite is formed by generation of a thiol group
- clopidogrel irreversibly inhibits P2Y12 through covalent bonding
- CAPRIE trials
CAPRIE trials
- clopidogrel versus aspirin in patients at risk of ischaemic events
- large relative benefit over aspirin but small absolute benefit
- approved by FDA as alternative to aspirin
- e.g. due to allergies or high GI bleeding with aspirin
Clopidogrel variability
- some patients taking clapidogrel had no change compared to those that didn’t
- variation in metabolism: CYP2C19 and CYP3A phase 1 reactions
- CYP2C19 has a common loss of function polymorphism *2 (as well as other LOF polymorphisms)
- even heterozygotes, with one *2 (v. common) prevents clopidogrel having effect
- due to inability to produce the active metabolite
Clopidogrel drug-drug interactions
- with proton pump inhibitors e.g. omeprozole = affects absorption capacity
- smoker’s paradox = works better in smokers
Cangrelor
- ATP analogue
- competitive, reversible antagonist
- IV infusion as too charged for oral dosing
- very rapid onset
- ideal in emergency
- plasma half life = 3-9minutes
CHAMPION trials:
- unusual endpoints made analysis complex
- trial terminated due to apparent lack of efficacy
CHAMPION-PHOENIX
- patients arriving for PCI
- given cangrolar and aspirin, then moved onto clopidogrel after procedure
- cangrelor infusion better than clopidogrel dose
- decreased MI, little effect on bleeding
- rejected then approved by FDA
Ticagrelor
- removed charged phosphates from cangrelor so could be given orally
- no metabolism needed so less variation
- faster onset than clopidogrel
- non-competitive antagonist? may be inverse agonist?
- binding site near ADP site
- faster offset (reversible)
Ticagrelor - second mechanism of action
ticagrelor is only P2Y12 inhibitor to decrease deaths compared to aspirin - why? second mechanism of action?
- also decreases adenosine levels
- provides cardioprotection from injury, myocardial regeneration and vasodilatation
- side effects: dyspnea, arrhythmia and anxiety/agitation
- 2nd mechanism of action may make it better?
- or reduced adenosine pulls down the immune system so reduced pulmonary infection or sepsis
Ticagrelor trials
range of trials have suggested ticagrelor may be beneficial in:
- ACs
- strokes
- stable coronary disease
- peripheral artery disease
- type 2 diabetes
ticagrelor may be linked to more cancer deaths = is it really better?
ticagrelor better everywhere BUT the USA - why?
- in most countries, aspirin dose is low, so adding ticagrelor is better
- in USA, high aspirin does used so adding ticagrelor makes risks outweigh benefits
Prasugrel
- metabolism by esterases
- and then a CYP which isn’t CYP2C19 as this is highly polymorphic
- simpler so faster metabolism
- more consistent response
- decreased CV events but increased major bleeds in trials
more consistent inhibitor:
- allows use for people unaffected by clopidogrel
- but also more side effect incidence
- better to switch for high risk patients but not worth the risk of switching low risk patients
Clopidogrel
- approved as alternative to aspirin
- dual therapy beneficial
- but bleeding risk increases with dual therapy
- dual therapy reduces non-fatal MIs but not deaths
overall:
- clopidogrel decreases thrombosis but increases bleeding
- composite of a small-ish effect multiplied across a large at-risk population
- absolute risk reduction depends on patient risk
