19. Antithrombotics

Question 1

What are 3 ways to damage a blood vessel?

Answer 1

Hypertension
Diabetes
High cholesterol

Slides 4-7

Question 2

What are antiplatelets, anticoagulants, and fibrinolytics?

Answer 2

Antiplatelets- not as potent, but safer
Most commonly for prevention (preventing heart attack, stroke before (primary prevention) or after (secondary) an event has already occurred)

Anticoagulants- stronger, usually required when there’s been an event
Higher bleeding risk

Fibrinolytics- typically for emergency only
Highest bleeding risk

Question 3

What is the mechanism of clot formation?

Answer 3

Platelets are the first step in forming a clot
3 steps of platelet aggregation: adhesion, recruitment/activation, aggregation

The coagulation cascade is then activated, leading to:
Generation of thrombin
Generation of fibrin (fibrin strengthens clot)

Slides 13-15

Question 4

What are antiplatelets and how they work?

Answer 4

COX-1 inhibitors (aspirin)
ADP blockers

Platelet activation mediated by many factors: thromboxane A2 (TxA2), serotonin (5-HT), adenosine diphosphate (ADP)

TxA2 generated via COX1, this increased activity of GpIIb-IIIa receptors

Slides 16-19

Question 5

What are COX-1 inhibitors (type of antiplatelet)?
Example of one drug?
Adverse effects?

Answer 5

Cyclooxygenase inhibitors are known as NSAIDs (non steroidal anti inflammatory drugs)

Acetylsalicylic Acid (ASA) is an irreversible inhibitor of COX-1
Unique among NSAIDs
Only NSAID that is used as an antiplatelet!!
Adverse effects: well tolerated at low doses, main safety issue with NSAIDs is GI ulceration, which can lead to bleeding

Slides 20-23

Question 6

What are ADP blockers (type of antiplatelet)?
Example of two drugs?
Adverse effects?

Answer 6

ADP bonds to P2Y1 and P2Y12 receptors

Irreversible P2Y12 antagonists: clopidogrel
Clopidogrel is a prodrug and must be acted upon by CYP450 isozymes to become active

Reversible P2Y12 antagonist: ticagrelor

Adverse effects: bleeding is the main safety issue, other side effects like GI upset, ticagrelor can cause difficulty breathing and reduced heart rate in some patients

Slides 26-32

Question 7

What are GpIIb-IIIa inhibitors (type of antiplatelet)?

Answer 7

Abciximab is a glycoprotein IIb-IIIa inhibitor that inhibits the ability of the platelet to anchor to surfaces or other platelets

Slide 32

Question 8

What are anticoagulants?

Types?

Answer 8

Use them after someone has had an event, in order to prevent another event (secondary prevention) heart attack, stroke
Use them in patients at higher risk of having an event (primary prevention) atrial fibrillation, deep vein thrombosis

Types: injectable (indirectly inhibit Factor Xa or Xa and IIa), oral (inhibit vitamin K, factor IIa, factor Xa)

Slides 35-37

Question 9

What is the one drug type in injectable anticoagulants?

Adverse effects?

Answer 9

Heparins
Promote activity of antithrombin (ATIII), ATIII inactivates Factor Xa

Unfractional heparin (UFH)
Prototype: heparin \_\_\_\_\_
UFH binds to thrombin (Factor IIa) as well as promote activity of antithrombin

Fractional heparin, or low molecular weight heparin (LMWH)
Prototype: enoxaparin

AE: bleeding (obvs), heparin induces thrombocytopenia syndrome (HITS) where antibodies form to platelets

Slides 38-41

Question 10

What is the comparison of unfractionated heparin (UFH) and fractionated it’s low molecular weight heparin (LMWH)?

Answer 10

UFH:
Can be given IV (used in hospitals)
Larger molecules (safety issues like HIT)

LMWH:
Given subcutaneously (easier for self administration)
LMWH are smaller molecules (more predictable PK, lower risk of reaction)

Slide 42

Question 11

What is warfarin?

Answer 11

Warfarin inhibits the activation of Vitamin K
Inhibits vitamin K reductase (VKOR)
VKOR activates vitamin K
Vitamin K is a co factor in the activation of Factors II, VII, IX, and X
Warfarin therefore prevents the activation of factors II, VII, IX, and X

The effects of warfarin are delayed (presents a challenge) since currently active vitamin K dependant clotting factors must be depleted before it works

Slide 45-47

Question 12

What is international normalized ratio (INR)?

Answer 12

Standardized test for monitoring clotting status
Measures clotting time

Used for monitoring warfarin

Lower INR= more coagulation
Thicker blood= therapeutic failure (risk of stroke, heart attack)

Higher INR= less coagulation
Thinner blood= serious adverse effects (risk of bleeding) intracranial hemorrhage

Slides 48-49

Question 13

What are the drug-drug interactions with warfarin?

What about drug-food?

Answer 13

Usually pharmacokinetic  (metabolized by CYP450 system)
Many prescription drugs inhibit or induce these isozymes 

Drug-food interactions usually pharmacodynamic, most commonly foods that contain vitamin K lead to therapeutic failure

Slides 50-54

Question 14

What are direct oral anticoagulants (DOACs)?
(Type of anticoagulants)
2 types?

Answer 14

DOACs are the first oral anticoagulants since warfarin
Originally seen as safe alternative to warfarin, fewer drug interactions, similar efficacy to warfarin
However warfarin has a reliable method for monitoring, DOACs don’t yet

Direct thrombin inhibitors (DTI):
Dabigatran

Factor Xa inhibitors:
Rivaroxaban

Slides 56-58

Question 15

What are the 2 reversal drugs for the DOACs?

Answer 15

DTI reversal drug:
Idarucizumab- binds to dabigatran and prevents it from acting on thrombin

Anti-Xa reversal drug:
Andexanet alfa- recombinant Factor X, binds to Factor Xa inhibitors instead of them bonding to Factor Xa

Question 16

What is the comparison of warfarin and DOACs?

Slide 60

Answer 16

Warfarin:
Slow onset and offset action
Variability in anticoagulant effect
Narrow therapeutic index
Food and drug interactions 
Reversal drug available 

DOACs:
Rapid onset of action 
Predictable anticoagulant effect
Specific coagulation enzyme target 
Low potential for food interactions 
Lower potential for drug interactions 
Reversal only now becoming available 

Slide 60

Question 17

What are fibrinolytics?

Answer 17

Plasmin is a protease that digests fibrin
Plasminogen activators promote the activity of plasmin
Therefore they breakdown existing clots (called fibrinolytics)
Work fast, used for patients having an event (heart attack, stroke)

Administered intravenously, close as possible to the site of clot

Slides 63-65

Question 18

What is the one fibrinolytic drug?

Answer 18

Tissue plasminogen activator (tPA)

Adverse effect:
Bleeding
Intracranial hemorrhage is biggest risk, in thrombotic stroke, ischemia leads to vascular damage, vessels become leaky and increase risk of bleeding, protocol must be followed to determine whether it is safe to use this drug in a given patient

Slide 66
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