Platelet pharmacology

Question 1

What are the key phases in drug development?

Answer 1

Preclinical studies- shows drugs works in vivi, and do toxicology
Phase 1- first in man, usually healthy volunteers
phase 2- small scale in target population- assess safety, tolerability and initial efficacy
phase 3-large scale studies of safety and efficacy in target population

Question 2

How does arterial thrombosis occur?

Answer 2

As a result of atherosclerosis
-fatty streaks build up as a result of cholesterol deposition- causes inflammation
build up of plaque erodes or ruptures- exposes thrombogenic components underneath the plaque= thrombosis

Question 3

What would you see in a pathological specimen on a thrombus?

Answer 3

Atherothrombus plaque
thrombus-
darker regions: red blood cell
lighter regions: platelets and fibrin

Question 4

Whats characteristic of a later thrombus specimen?

Answer 4

Organisation of the thrombus
vascular channels within the thrombus itself-
supplying blood

Question 5

How are platelets made?

Answer 5

Bud of megakaryocytes in the bone marrow

Question 6

How do platelets change shape?

Answer 6

When activated- change shape
form pseudopodia- allow platelets to have interactions with other platelets
also increases the surface area

Question 7

Where are glycoprotein 2b/3a receptors found, how do they change when the platelet is activated?

Answer 7

Surface of the platelet- 50,000 at rest
when activated- this number doubles
activated by the release of granules from the platelet
-when theyre activated- conformation changes0 increased affinity for fibrinogen
fibrinogen links receptors- allows platelets to bind to each other

Question 8

Examples of glycoprotein 2b/3a receptor antagonists used. Why do these drugs have a narrow therapeutic window?

Answer 8

Intravenous:
abciximab
tirofiban
eptifibatide
high dependence of these platelets on these receptors
too much antagonism= toxic/ causes too much bleeding
too litte= ineffective
*probably why oral drugs didn’t work- too difficult to get within the window

Question 9

Where and when are cyclooxygenase 1 and 2 present?

Answer 9

cox 1= present all the time- including in platelets

cox 2= inducible, inflammatory stimulated

Question 10

How does aspirin work?

Answer 10

Irreversibly acetylates cox- arachidonic acid is blocked from the core of the enzyme- thus isnt converted into PGH2
PGH2 thus isn’t converted unto thromboxane A2 or prostacyclin
thromboxane A2 activates platelets via their surface receptors
permanent effect on platelets

Question 11

Why isn’t streptokinase use anymore?

Answer 11

Risk of bleeding- especially in the brain

Question 12

What is aspirin resistance? How common is it?

Answer 12

The continued secretion of thromboxane A2 by platelets in response to appropriate agonist stimulation- DESPITE therapy with aspirin at a standard dose
not common
some conditions- make them less responsive (obesity)
thought that the issue is with compliance rather than resistance

Question 13

What’s the relationship between aspirin and ibuprofen?

Answer 13

Ibuprofen can reversibly bind to cox-1
give ibuprofen first- will bind to cox1- aspirin cant bind- cleared- recovery of cox1 function
ibuprofen blocks cox1 effect

Question 14

Why dont we use cox2 inhibitors?

Answer 14

Seem to have adverse cardiovascular effects- limit their usage

Question 15

3 conclusions about aspirin?

Answer 15

1. Aspirin decreases the risk of MI, stroke and CV death in patients with atherosclerotic disease
2. Aspirin has excellent efficacy in inhibiting platelet thromboxane A2 release- but this process plays a LIMITED role in platelet reactivity - effective but weak antiplatelet drug
3. Aspirin in patients who don’t have atherosclerotic disease- increases their risk of bleeding

Question 16

What are the purinergic receptors found on the surface of platelets?

Answer 16

P2y1
P2Y12
P2X1

Question 17

What do P2Y1 and P2Y12 do?

Answer 17

1- initiates platelet aggregation

2- amplifies/sustains platelet activation and aggregation

Question 18

What are the steps in P2Y12/1 activating platelets?

Answer 18

1. ADP activates the receptors- leads to platelet activation- expression of glycoprotein 2b/3a receptors- binding of fibrinogen- binding of platelets. P2Y12 amplifies platelet activation
2. Platelet activation also leads to the release of granules- releases ADP which binds to P2Y1/12= positive feedback
3. Binding of thrombin to PAR-1 and PAR-4
4. Binding of thrombin initiates platelet activation. Activated platelets provide a surface for catalytic activity to create thrombin
   - lots of receptors involved which stimulate platelet activation- TPalpha, GPV1

Question 19

What does P2Y12 play a large role in?

Answer 19

Amplifying and sustaining thrombus formation

Question 20

What is clopidogrel?

Answer 20

Thienopyridine prodrug
converted into its active form (R-130) in the liver
R-130 binds to P2Y12
alot of clopidogrel is inactivated immediately- not an efficient process of activation

Question 21

Issues responses to clopidogrel?

Answer 21

some good responses-generated enough metabolite
some no detectable response
-not a reliable prodrug
-some people convert it more efficiently than others

Question 22

How does diabetes mellitus affect clopidogrel?

Answer 22

impaired clop response

higher % of platelet aggregation with diabetic patients on clop

Question 23

How does omeprazole affect clopidogrel?

Answer 23

omeprazole= treats reflux

blocks the conversion of clop to its active form

Question 24

How does rifampicin affect clopidogrel?

Answer 24

rifampicin= antibiotic
increases clop active metabolite production
after rifampicin and clop= number of free receptors is negligible- more effective receptor blockade

Question 25

Relationship between CYP2C19 and clopidogrel?

Answer 25

Loss of function CYP2C19 allele= lower production of clopidogrel active metabolites- reduced response to clopidogrel

Question 26

What was the result of the P2Y12 assay with clopidogrel?

Answer 26

People with a poor response to clopidogrel=

4 times higher risk of stent thrombosis compared to those with a detectable response to clopidogrel

Question 27

Factors affecting response to clopidogrel

Answer 27

Age
dose
weight
disease status- diabetes, chronic kidney disease
drug-drug interactions- omeprazole, CYP3A inhibitors
CYP2C19 lof/gof

Question 28

What is prasugrel and why is it better than clopidogrel?

Answer 28

More effective thienopyridine prodrug than clopidogrel
related to its metabolism
esterases convert it into its intermediate form
more efficient metabolite formation than clopidogrel
-prasugrel gives 10 fold higher level of active metabolite

Question 29

Drawbacks to prasugrel?

Answer 29

More fatal bleeding with prasugrel

patients who had had a stroke- higher risk of bleeding on the brain

Question 30

What is ticagrelor?

Answer 30

First oral reversibly binding P2Y12 antagonist

very effective in reducing thrombus formation

Question 31

2 ways ticagrelor is better than clopidogrel?

Answer 31

24hr loading dose of tica and clop- tica had higher levels of inhibition, but wore off earlier

1. Adv to those with major surgery- tica will wear off predictably
2. More effective in reducing cardiac death and myocardial infarction - switched from clop to tica for heart attack patients as the immediate drug prescribed
   * however- does cause more CABG bleeding- but numerically it was less because of ticas more predictable action

Question 32

Is ticagrelor cost effective?

Answer 32

NICE said yes- compared to clopidogrel

Question 33

What are other targets for antiplatelet drugs?

Answer 33

Glycoprotein 2b/3a receptors- narrow therapeutic window
PAR-1- vorapaxar caused too much bleeding
thrombin formation/action- anticoagulants e.g rivaroxaban