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Human Pharmacy > Antiplatelet drugs > Flashcards

Antiplatelet drugs Flashcards

1
Q

Name the pharmacological classes of antiplatelet drugs

A

P2Y12 antagonists

Glycoprotein IIb/IIIa inhibitors

Others = aspirin, dipyridamole

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2
Q

What are antiplatelets used to treat?

A

Used to manage arterial thrombosis = these are platelet clots

NOT for VTE or DVT = these are fibrin clots

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3
Q

What role does ADP play in relation to P2Y12?

A

ADP activates P2Y12 and P2Y1

Activation of P2Y12 > dec cAMP > phosphorylation of VASP-P > active VASP is formed > platelets activated

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4
Q

List the relevant P2Y12 inhibitors

A

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

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5
Q

What is the difference between clopidogrel and prasugrel?

A

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.

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6
Q

What is the MOA of P2Y12 inhibitors?

A

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

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7
Q

How long do P2Y12 inhibitors take to have effects?

A

platelet aggregation inhibited by 40-60% after 3 to 7 days

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8
Q

How long do platelets take to clear and why is this important with P2Y12?

A

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.

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9
Q

What factors influence P2Y12 efficacy?

A

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

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10
Q

Discuss the pharmacokinetics of clopidogrel

A

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

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11
Q

ADRs of P2Y12 inhibitors

A

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

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12
Q

List the relevant glycoprotein IIb/IIIa receptor blockers

A

Tirofiban

Eptifibatide

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13
Q

What is the MOA of GPIIb/IIIa receptor blockers

A

Block the final common pathway for platelet aggregation > inhibit bind/coupling of GPIIb and GPIIIa on the platelet, preventing fibrinogen from binding

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14
Q

What is the MOA of Eptifibatide

A

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

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15
Q

What is the MOA of Tirofiban

A

Non-peptide derivative of tyrosine, found on the head of the fibrinogen

Competes with fibrinogen for binding to the GPIIb/GPIIIa receptor

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16
Q

List some ADRs of GPIIb/IIIa receptor blockers

A

Bleeding, thrombocytopenia

Acute severe thrombocytopenia (<0.6% patients)

Risk of recurrent thrombocytopenia is inc with re-exposure to abciximab

17
Q

Describe the MOA of aspirin

A

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

18
Q

What is the function of TXA2

A

Converted from prostaglandin H2 by thromboxane synthase into TXA > dec cAMP > stimulates platelet aggregation

19
Q

What is the effect of high dose aspirin?

A

Inhibition of COX 1 (TXA2) and COX2 (PGI2) = lesser antiplatelet effect

20
Q

What is the effect of low dose aspirin?

A

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

21
Q

List aspirin ADRs

A

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

22
Q

List dose-related symptoms of upper GI aspirin toxicity

A

nausea, heartburn, epigastric pain

23
Q

Discuss aspirin resistance

A

Inability to inhibit COX-1 dependent TXA2 production

inadequate response in doses <300mg/daily

MI, cerebrovascular accident, death

24
Q

Discuss aspirin resistance

A

Inability to inhibit COX-1 dependent TXA2 production

inadequate response in doses <300mg/daily

MI, cerebrovascular accident, death

25
Q

Discuss adenosine’s antiplatelet properties

A

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

26
Q

What is dipyridamole?

A

It is a pyrimidopyrimidine derivative which can be used alongside aspirin to prevent damage to the brain after a stroke

27
Q

What is the MOA of dipyridamole?

A

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

28
Q

Why is calcium important for platelet aggregation?

A

The combing of GPIIb/IIIa is dependent on the presence of calcium which would allow fibrin to bind

29
Q

What is another mechanism of dipyridamole?

A

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

30
Q

List some ADRs of dipyrdamole

A

headache, hypotension, bronchospasm = inc adenosine –> vasodilation

Diarrhoea = inc cAMP in bowel > inhibit PDEIII

Tachycardia = inc cAMP

Rash, urticaria, hot flushes, nausea, vomiting

31
Q

Why would dipyridamole be used only in stroke and not MI/ischaemia?

A

Induces vasodilation > can inc pressure gradient across aortic valvue > worsen organ reperfusion

Further reperfusion could induce further ischaemic events

32
Q

What is an example of dual antiplatelet therapy?

A

Combination of P2Y12 antagonist with aspirin

Human Pharmacy (11 decks)

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