Lecture - Pharmacology (Sammut Anticoagulants)

Question 1

Slide 49 has the whole lecture in 1 slide:

1. What are the three classes of medications you can use for anti-haemostatic action (aka prevent or treat thrombus)?
2. What’re the five drugs in this lecture and under what class do each come?

Answer 1

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Question 2

Basics

1. Thromboembolic diseases can happen because of what? (Virchow’s traid, yes, but what sort of conditions can lead to thrombi forming?)
2. What can thrombus lead to?
3. There are endogenous mechanism players that will normally stop us from forming thrombi - what are these three? And how do they work?

Question 3

Mechanisms of thrombus formation following intimal damage

1. Platelet a____
   - what is decreased (something that is synthesised by endothelial cells and isnt since damaged cells)
   - platelets adhere to what (it becomes exposed)?
   - aggregated platelets intitally generate what?
2. Platelet s____ c_____
   - t_____: potently activates platelets (causes platelet shape change)
3. Platelet _____ Release leading to aggregation and consolidation
   - thrombin: also causes platelets to release more what? This includes what? What do these two do?
4. F____ stabalises platelets
   - thrombin also facilitates what?
   - fibrin polymerises to form what and stabalises what?
5. Okay, go read slide 14 but honestly, I doubt you need to know it

Answer 3

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Question 4

#1 Drugs to prevent haemostasis: Antiplatelet agents

Oral Low Dose Aspirin:

1. What’s another name of aspirin?
2. So it inhibits platelet aggregation, reduces risk of thrombus formation. But how does it actually work? Like what does it irreversibly bind to and and then reduce what?
3. There are two types of COX - which one does it have minimal effect on? Where do you find the two types of COX? Why does it have minimal effect on one of them?
   - lose dose vs high dose aspirin and liver - tell me about that
4. SO explain how both the platelet COX-1 inhibition and vascular endothelium COX-2 inhbition can inhibit or lead to thrombus formation
5. Does aspirin work?

Answer 4

3. So there is a platelet COX-1 and an endothelial COX-2. It will nonselectively bind to both but have more effect on COX-1 and reduce the TXA2 production for the lifetime of the platelet (~7-9 days). TXA2 is a platelet activator and a vasoconstricitor. But it will have minimal effect on the PGI2 produced by endothelial COX-2 since:
   - if drug passes from liver to systemic ciruclation = it will imapct on endothelium. Usually, at low dose, the aspirin doesnt pass the liver since the liver’s enzyme (esterase) will metabolise it all. But like, with platelets, they dont have nucleus (no DNA) so they can’t have a rapid turnover/replacement of COX like endothelium can. This is why the production of TXA2 is irreversibly inhibited (since they can’t regenerate COX-2)
   - so as the aspiring comes into contact with aspirin, COX-1 is inhibited (this is in the hepatic circulation). Then it’ll go to the liver and it’s negated (esterase action in liver will temabolise it and deactivate acetylsalicylate to salicylate). But if you have a higher dose then it’ll go through and effect the COX-2 since not all of it will be negated by the liver. This will cause the side effects.
4. So it seems like if COX-1 is active, you’ll produce TXA2 (which is a platelet aggregator and vasoconstrictitor) so will promote a thrombus forming. On the other hand, COX-2 will produce prostacyclin (PGI2) and that will inhibit platelet aggregation, promote vasodilation - this will inhibit thrombus formation. So if you have high dose aspirin, you might actually end up leading to thrombus formation (so low dose is good because you’ll target TXA2 formation and leave PGI2 alone).
5. Well, it just says it’s got benefit for people who already have occulusive vascular disease. But if you give it to a person with no hisotry or no CVD then you can do more harm than good because it can reduce mucous production in intestine (which is a protective barrier) so get ulceration, gastric bleeding etc.

Question 5

#1 Drugs to prevent haemostasis: Antiplatelet agents

Clopidogrel

1. It’s a valuable drug for when?
2. What’s the mechanism of action?
3. How does ADp activate platelets to aid platelet aggregation and promote fibrinogen binding?

Answer 5

2. Non competitively blocks ADP receptor (purinergic P2Y receptors). It will prevent the activation of GP2b-3a receptor and reduce the platelet activation - it is synergistic with aspirin.

Question 6

2 Prevent haemostasis: Anticoagulants

1. Why use these?
2. What are the four examples? Which one do we focus on?

Answer 6

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Question 7

#2 Prevent haemostasis: anticoagulants

UF Heprain

1. So this was used before - what’s the mechanism of action?
2. Given how?
3. It has a danger of h____
4. What’s its antagonist?
5. What is HIT and what does it have to do with UFH?

Low Molecular Weight Heparin

1. What’s an example of a brand?
2. Potentiates the action of _____ on factor 10a etc
3. What is it less effective on?
4. What’s the delivery? Duration of action?
5. Eliminated in what?
6. Does it have more bioavailability than UFH?
7. What about its adverse effects compared with UFH?
8. Is it as readily reversed? By what antagonist?
9. Why use Enoxaparin? (indications). Like, to prevent what, to treat what, and for c____ s_____
10. Generally it’s given sub cutaneouslly - what is not given through normally and definitely not as what?
11. What are the risks even with LMWH? Explain them too.
12. What is the action of Enoxaprin assessed by?

Question 8

#2 Prevent haemostasis: anticoagulants

VKAs = Vitamin K antagonist (VKAs)

Warfarin:

1. What is the delivery method?
2. What is the mechansim of action? Include the name of the enzyme it inhibits
3. It therefore prevents haemostasis how?
4. Overall, VKAs reduce formation of _______
5. And when things go bad (bleeding with overdose or INR >___), you can reverse it. What is the reversal of action in order? Like, what do you do?
   - withdraw what?
   - administer what?
   - if bleeding then adminster either of what two things?
6. The biggest concern about warfarin and its adverse effects is what? (window..)
7. What are 5 other adverse effects of warfarin - some of these really should be logical
   - what’s the paradoxical microvasculature thrombosis about? (slide 35 in Faed Thrombosis 2)
8. Important kinetic aspects
   - when’s the peak blood conc reached? Does that coincide with the therapeutic effect? So what should you measure?
9. What is warfarin metabolised via? (3 cytochromes you should know). Now, there are 2 isoforms - which one is most important? What CYPs metabolise them?
10. So Warfarin interacts with just about anything
11. What drugs reduce warfain levels (INR depression) and what potentiate them? One highlighted drug on each side
    - also explain the alcohol thing here
12. What’re the new anticoagulant agens?

Answer 8

6. Very narrow therapeutic index

Question 9

3 Prevent haemostasis: Fibrinolytics

1. Why use these?
2. So what do you use?
   - what sort of protease are they? synthesised normally by what?
   - promote _____ by converting what to what to degrade fibrin?
   - two examples of rt-Pas (what does that stand for?) that’re manufactured using rDNA technology
   - increases survical post-_____ or ______
   - optimal outcome, must be given _____

Answer 9

1. Because if thrombus has already formed, we can just break it down after the formation

Question 10

#3 Prevent haemostasi (okay, at this stage we’re just breaking stuff down, not preventing it): Fibrinolytics

Recombinant Tissue Plasminogn Activator (rtPA) e.g. Alteplase

1. How do you give alteplase in MI, ischaemic stroke (not the delivery, but the duration)
2. What’s its adverse effect?
3. Metabolised by what to what? What’s the initial half life? What’s the terminal half life? What’s the differnece beteen half lives?
4. You can suffer direct what with ______ ______ _____ use. Contraindicated with ______
5. Go look at the slide 46

Answer 10

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