3 - Antiplatelets Flashcards
What is clopidogrel used for?
- Used to prevent platelet aggregation (sometimes given to those who can’t tolerate aspirin)
- Improves outcomes w/ percutaneous coronary intervention (PCI) -> prevents thrombosis on the stent
Describe the mechanism of clopidogrel
- Clopidogrel irreversibly alkylates the receptor, so drug target (P2Y12) loses its activity and platelets can’t aggregate
- Non-competitive inhibition
- Clopidogrel enters liver and 2 steps of oxidation occurs by CYP2C19 to form the active metabolite which goes back into bloodstream and irreversibly inhibits and prevents platelet activation
What effect do genetic mutations have on clopidogrel?
Defects in metabolism will result in less active metabolite, meaning decreased function (clopidogrel must be metabolized into active metabolite)
Which allele of CYP 2C19 results in increased activity with regards to clopidogrel?
*17
What are the 4 phenotypes for CYP 2C19 relevant to clopidogrel?
- *2 through *8 = defective
- *1; *1 = EM
- *17; 17/1 = UM
- def; 1/17 = IM
- def; def = PM
What effect do alleles *2 through *8 have on CYP 2C19 activity relevant to clopidogrel?
No effect on CYP 2C19 activity
What does CYP 2C19 do in regards to clopidogrel metabolism?
Converts clopidogrel -> 2-oxo-clopidogrel -> active clopidogrel
Which phenotypes of CYP 2C19 will produce less active clopidogrel? What affect does this have?
- PM and IM
- Puts them at risk for tx failure aka higher risk for blood clotting on stents w/ angioplasty and MI
Describe what to do w/ clopidogrel for all situations OTHER THAN PCI
- Initiate clopidogrel at standard dose
- Then determine the genotype:
- UM (1/17 or 17/17) = decreased platelet aggregation = continue w/ standard dose
- EM (1/1) = normal platelet aggregation = continue w/ standard dose
- IM (*1/def) = increased platelet aggregation, increased risk for adverse CV events = use alternate therapy (ex: prasugrel, ticagrelor)
- PM (def/def) = increased platelet aggregation, increased risk for adverse CV events = use alternate therapy (ex: prasugrel, ticagrelor)
Describe the mechanism and metabolism of prasugrel. Why isn’t it used first line instead of clopidogrel?
- Undergoes only one oxidation step to reach active form; not CYP2C19, so genotype doesn’t affect active prasugrel formation
- Irreversible inhibitor of P2Y12 on platelets (same as clopidogrel)
- Prevents platelet activation and inhibits platelet aggregation
- Higher risk of bleeding than clopidogrel so not 1st choice (clopidogrel is first choice)
Describe the metabolism and mechanism of ticagrelor
- Competitive antagonist of P2Y12 receptor (doesn’t alkylate the receptor)
- Doesn’t require metabolism to make it into an active form
- Activity not influenced by CYP2C19 polymorphisms
- Given w/ ASA for secondary prevention of atherothrombotic events in px w/ ACS who are getting PCI and/or CABG
- For acute coronary syndromes, 180 mg loading dose and 90 mg BID
Describe the effect of PgP-1 on clopidogrel
- Efflux pump (pumps clopidogrel out of intestinal cells back into the intestine)
- When PgP-1 is inhibited less, clopidogrel is pumped out of intestinal cells so less is converted to 2-oxo-clopidogrel => decreased active metabolite
Describe the impact of ABCB1 3435 C>T
- *ABCB1 = gene for P-gP
- For acute coronary syndrome (ie: MI or unstable angina) undergoing percutaneous intervention (PCI) -> px get clopidogrel loading dose + daily dose after stent to prevent thrombosis
- Homozygous at ABCB1 3435C>T (ie: 3435T/ 3435T) had higher risk of CV death, MI or stroke than homozygous wild-type and heterozygous
- Risk is independent of CYP2C19 genotype
Which genotype of ABCB1 and CYP 2C19 had the highest risk of CV death, MI, or stroke after 30 day tx of clopidogrel?
- ABCB1 3435 C>T homozygous (3435T/ 3435T)
- CYP 2C19 *1/def or def/def
Typical clopidogrel dose for PCI
600 mg loading and 75 mg daily
