Platelet pharmacology Flashcards
Stages of drug development
1) medicinal chemistry - identification of drug target, design and optimisation of drug
2) preclinical studies - toxicology and proves in vivo efficacy and tolerance
3) PHASE 1 CLINICAL TRIALS - ‘first in man’ - use healthy volunteers
4) PHASE 2 CLINICAL TRIALS - small scale study in patients, safety assesment
5) PHASE 3 CLINICAL TRIALS - large scale studies to test efficacy and potency of drugs
Platelets - what is their structure and how are they formed?
Formed from fragmentation of megakaryocytes found in bone marrow.
Smooth, plated anucleic structure with small dips called CANALICULI
Platelets - whats happens when they activate,
When they activate, they form pseudopodia (projections) that increase platelet surface area and allow platelet aggregation
Have glycoprotein ||b/|||a receptors and around 50-100k per resting platelet
Platelet activation - impact on platelet and why?
Increases number of receptors and the affinity of glycoprotein for fibrinogen –> this allows for better linkage between receptors and platelets
Problem with platelets (pathology) - what can result?
- Arterial thrombosis can occur which can lead to an atherosclerosis.
- This causes fixed narrowing of blood vessels and exposure of thrombogenic componants if plaque ruptures
- This can lead to angina or stenosis!!
Asparin - mechanism of action
Targets COX1/2 enzyme. Prevents the binding of Arachodonic acid to the active site of the enzyme –> inhibits production of Prostoglandin H –> Thromboxane A2 not activated and bound to surface receptor of platelet to cause aggregation.
Does this by ACETYL GROUP from Asparin donating a SERINE RESIDUE in the catalytic pocket of COX enzyme
Why is asparin so effective?
COX1 is constituatively present in platelets and cannot be activated until new enzymes are produced to allow arachadonic acid to bind – effect of asparin irreversible (produced every 7 days!)
Resistance to asparin - incidence and potential reasons?
Very rare –> continuous secretion of thromboxane A2 occurs
In study only 1/96 people (could therefore be due to lack of compliance) –> also could be ibuprofen (drug irreversibly binds to COX1 enzyme (competitive inhibitor)
||B / |||a receptor antagonists - how are they administered and what is their impact? Problem?
- IV only
- block the receptors on platelets to prevent aggregation
- increases risk of bleeding
- decreases ischaemic events
NARROW THERAPEUTIC WINDOW
P2Y12 receptor - what are they
ATP and ADP outside platelets act as signalling molecules and bind to the receptors to cause activation
Platelet granules - what are they and how are they involved in feedback?
Platelet granules release ADP upon activation of platelets and activate molecules like thrombin via PAR (protease activated) receptors
These act in a positive foodback loop to stimulate more release of ADP
P2Y12 receptors KO mice - observations
KO mice produced and cremasteric arteriole lasered to create injury
- Sustained thrombus formation seen in the control mouse but not in the KO mouse
CLOPIDOGREL - mechanism of action and results and problems?
Pro drug that in its active form binds to P2Y12 receptors to prevent platelet aggregation!
Reduced ischaemic events
Impaired response seen in patients – may be due to diabetes? Not completely reliable –> only small amount of drug in its’ active form
Why the variation in response to Clopidogrel?
- Genetics
- Mutation in allele CYP2C19
- Patient variation in drug responses
- Age
- Weight
- Renal disease
- Diabetes
- Previous disease states
PRASUGREL - mechanism of action and problems?
More effective pro drug than Clopidogrel
60x more potent pharmacologically
Works in same way but esterases that —| Clopidogrel actually convert Pras to its intermediate product
MORE FATAL BLEEDING SEEN
