Antiplatelet drugs Flashcards
Name the pharmacological classes of antiplatelet drugs
P2Y12 antagonists
Glycoprotein IIb/IIIa inhibitors
Others = aspirin, dipyridamole
What are antiplatelets used to treat?
Used to manage arterial thrombosis = these are platelet clots
NOT for VTE or DVT = these are fibrin clots
What role does ADP play in relation to P2Y12?
ADP activates P2Y12 and P2Y1
Activation of P2Y12 > dec cAMP > phosphorylation of VASP-P > active VASP is formed > platelets activated
List the relevant P2Y12 inhibitors
Clopidogrel and prasugrel
Both pro-drugs influenced by pre-hepatic and hepatic metabolism
More effective than aspirin for secondary prevention (already had one) of vascular event
What is the difference between clopidogrel and prasugrel?
Clopidogrel = trickier to activate = pathway requires more polymorphic processing enzymes. Also as an inactivation pathway led by hCE1. Esterases inactivate.
Prasugrel = easier to activate > woken by esterases and CYP3A4 (primary initial metabolic enzyme). Esterases activate.
What is the MOA of P2Y12 inhibitors?
Active metabolites > irreversible binding to platelet P2Y12 receptor > permanent inactivation > prevents ADP mediated dec of cAMP due to P2Y12 stimulation
50% faecal cleared, 50% urine cleared
How long do P2Y12 inhibitors take to have effects?
platelet aggregation inhibited by 40-60% after 3 to 7 days
How long do platelets take to clear and why is this important with P2Y12?
Platelets take 14 days to clear
P2Y12 has effect from 3 to 7 days = means 7 days without the drug before you can have surgery
ensures you’re able to clot a little but not form major blood clots or bleed out.
What factors influence P2Y12 efficacy?
20-40% non-responders, poor responders, or resistant = low inhibition of ADP-induced platelet aggregation/activation
non-genetic factors = age, diabetes, renal failure, cardiac failure
Genetic factors = CYP2C19 < many polymorphisms
Discuss the pharmacokinetics of clopidogrel
Clopidogrel enters through ABCB1 efflux pump (risk of being pumped out)
Then metabolised by many CYP-P450 enzymes, notably CYP2C19 which has a lot of genetic variability = influences its ability to inc (<3) cAMP to stop platelet aggregation
ADRs of P2Y12 inhibitors
Bleeding (less risk than aspirin)= GI haemorrhage, upper GI symptoms
Diarrhoea (more freq than aspirin)
Rash (more freq than aspirin)
Neutropenia, thrombocytopenia
Thrombotic thrombocytopenic purpura
List the relevant glycoprotein IIb/IIIa receptor blockers
Tirofiban
Eptifibatide
What is the MOA of GPIIb/IIIa receptor blockers
Block the final common pathway for platelet aggregation > inhibit bind/coupling of GPIIb and GPIIIa on the platelet, preventing fibrinogen from binding
What is the MOA of Eptifibatide
synthetic cyclic heptapeptide that mimics the whole head of fibrinogen to block target
Mimics the fibrinogen binding site to bind and competitively block the GPIIb/IIIa binding site where fibrinogen would normally bind
What is the MOA of Tirofiban
Non-peptide derivative of tyrosine, found on the head of the fibrinogen
Competes with fibrinogen for binding to the GPIIb/GPIIIa receptor
List some ADRs of GPIIb/IIIa receptor blockers
Bleeding, thrombocytopenia
Acute severe thrombocytopenia (<0.6% patients)
Risk of recurrent thrombocytopenia is inc with re-exposure to abciximab
Describe the MOA of aspirin
NSAID that inhibits COX-1 in the arachidonic acid pathway > inhibits formation of thromboxane A2 (TXA2) > inhibits TXA2 mediated vasocon and platelet aggregation
Irreversibly inhibits cyclooxygenase
What is the function of TXA2
Converted from prostaglandin H2 by thromboxane synthase into TXA > dec cAMP > stimulates platelet aggregation
What is the effect of high dose aspirin?
Inhibition of COX 1 (TXA2) and COX2 (PGI2) = lesser antiplatelet effect
What is the effect of low dose aspirin?
Low dose aspirin selectively inhibits COX1 and therefore TXA2 > inhibiting platelet aggregation
Limited effect on = arterial BP regulation, renal function, interference with anti-HTN effect on diuretics and ACEi
List aspirin ADRs
Iron deficiency, stevens johnson syndrome, toxic epidermal necrolysis, bronchospasm, GI haemorrhage, angioedema, urticaria, rhinitis, cross reactivity with other NSAIDs
intracranial haemorrhage, non-fatal extracranial haemorrhage
List dose-related symptoms of upper GI aspirin toxicity
nausea, heartburn, epigastric pain
Discuss aspirin resistance
Inability to inhibit COX-1 dependent TXA2 production
inadequate response in doses <300mg/daily
MI, cerebrovascular accident, death
Discuss aspirin resistance
Inability to inhibit COX-1 dependent TXA2 production
inadequate response in doses <300mg/daily
MI, cerebrovascular accident, death
Discuss adenosine’s antiplatelet properties
Adenosine causes hypotension (alpha2)(vasodilation) and cardiac depression (alpha1)
As it is cardio and neuro protective, will decrease platelet activity whilst also dec work of the heart
What is dipyridamole?
It is a pyrimidopyrimidine derivative which can be used alongside aspirin to prevent damage to the brain after a stroke
What is the MOA of dipyridamole?
It is a phosphodiesterase inhibitor involved in cAMP metabolism, esp type III in platelets
It inhibits platelet aggregation by inhibiting platelet uptake of adenosine > inc activation of platelet A2 receptor > inc cAMP levels, dec Ca2+ levels > dec platelet aggregation
Why is calcium important for platelet aggregation?
The combing of GPIIb/IIIa is dependent on the presence of calcium which would allow fibrin to bind
What is another mechanism of dipyridamole?
It is a thromboxane synthase inhibitor > dec TXA2 levels > stimulates release of PGI2 > inhibits cellular adenosine reuptake into platelets, RBC, and EC
ALSO > inhibits adenosine deaminase ( normally kills adenosine) > inc in adenosine
List some ADRs of dipyrdamole
headache, hypotension, bronchospasm = inc adenosine –> vasodilation
Diarrhoea = inc cAMP in bowel > inhibit PDEIII
Tachycardia = inc cAMP
Rash, urticaria, hot flushes, nausea, vomiting
Why would dipyridamole be used only in stroke and not MI/ischaemia?
Induces vasodilation > can inc pressure gradient across aortic valvue > worsen organ reperfusion
Further reperfusion could induce further ischaemic events
What is an example of dual antiplatelet therapy?
Combination of P2Y12 antagonist with aspirin
