Thrombolytics, Anticoagulants and Anti-Platelet Drugs

Question 1

What is the principle complication of anticoagulant therapy?

Answer 1

BLEEDING!!

Question 2

When do we interfere with hemostasis?

Answer 2

• Treat bleeding disorders due to deficiencies and disease, etc.
• Prevention and treatment of thrombosis

Question 3

What are the thrombosis that we prevent and treat?

Answer 3

1. Venous thrombosis (life threatening, esp. in lung)
   - Inherited disorders characterized by tendency to form thrombi
   - Increased risk due to prolonged bed rest, surgery, cancer, atrial fibrillation, etc.
2. Arterial thrombosis
   - Platelet activation is central

Question 4

What are the therapeutic uses of thrombolytics, anticoagulants and anti-platelet drugs?

Answer 4

• Venous thromboembolism
• Unstable angina
• Acute myocardial infarction
• Stroke
• Prevent thrombosis during angioplasty and cardiopulmonary bypass
• Etc.

Question 5

What are the stages of clot formation?

Answer 5

1. Platelet
2. Activated platelet
3. Fibrinogen
4. Fibrin clot

Question 6

What are the four stages of hemostasis?

Answer 6

Phase I: Vascular constriction limits the flow of blood to the area of injury
Phase II: Platelets become activated and aggregate at the site of injury, forming a temporary, loose platelet plug (Primary Hemostasis)
Phase III: A fibrin mesh (also called the clot) forms and entraps the plug (Secondary Hemostasis)
Phase IV: The clot is dissolved in order for normal blood flow to resume following tissue repair

Question 7

Do platelets have COX2?

Answer 7

NO

Question 8

Can platelets make more COX?

Answer 8

NO

Question 9

Can endothelial cells make more COX?

Answer 9

YES

Question 10

Why don’t the other NSAIDs work well as anti-platelet agents?

Answer 10

NSAIDs are irreversible!! Aspirin is not!

Question 11

What new anti-platelet drugs will be coming?

Answer 11

• Inhibitors of PAR-1, the major thrombin receptor on platelets (Vorapaxar - indicated for reduction of thrombotic cardiovascular events in pts. with history)
• Reversible inhibitors of ADP receptors

Question 12

What helps convert fibrinogen to fibrin?

Answer 12

Thrombin!

Question 13

What enzyme converts prothrombin to thrombin (IIa)

Answer 13

Xa

Question 14

How does Fibrinogen become Fibrin?

Answer 14

Fibrinogen (little molecule) sticks to platelets — (thrombin - IIa) –> Fibrin (crosslinked fibrinogen)

Question 15

What does Antithrombin do and how does it relate to treatment?

Answer 15

• Antithrombin inactivates thrombin!

- We want to make antithrombin work better so we can get rid of thrombin and stop the fibrin clot from forming

Question 16

What test can you use to measure the intrinsic pathway?

Answer 16

aPTT

Question 17

How does the aPTT work?

Answer 17

• Recalcified plasma normally clots in 2-4 minutes
• If you add negatively charged PL and particulates, Factor XII is activated and it clots faster –> activated partial thromboplastin time
• If the aPTT is prolonged (and PT normal), then the person is considered to have a defect in the intrinsic pathway
• Normal PTT times require the presence of the following coagulation factors: I, II, V, VIII, IX, X, XI & XII

Question 18

What drug is PTT used to monitor?

Answer 18

Heparin!

Question 19

What factors does Heparin affect?

Answer 19

Factor II & X

Question 20

What tests do you use to measure the extrinsic pathway?

Answer 20

PT and derived INR

Question 21

How does PT and derived INR work?

Answer 21

• Recalcified plasma clots in 12-14 seconds if you add thromboplastin (TF + phospholipids)
• If PT is prolonged (and aPTT normal), then the person has a defect in the extrinsic pathway
• PT measures factors I (fibrinogen), II (prothrombin), V, VII, and X

Question 22

What is Factor I?

Answer 22

Fibrinogen

Question 23

What is Factor II?

Answer 23

Prothrombin

Question 24

If aPTT and PT prolonged. . .

Answer 24

. . .there is a defect in the common pathway

Question 25

Why do you need to give heparin early on while warfarin is taking effect?

Answer 25

You need to give Heparin early on so that coagulation is controlled while warfarin taking effect. Protein C and S are inhibited before Factors 2, 7, 9 and 10 - this makes blood hypercoagulable before the INR starts to increase. Warfarin has a narrow therapeutic index.

Question 26

What is the more active form of Warfarin?

Answer 26

S- form (it's metabolized by different cytochromes than R- isoform)

Question 27

What affects the susceptibility of vitamin K reductase (VKORC1) to warfarin-induced inhibition?

Answer 27

Polymorphisms in the C1 subunit of vitamin K reductase (VKORC1). These polymorphisms can influence warfarin dosage requirements [affect warfarin pharmacodynamics]

Question 28

What other polymorphisms can affect warfarin pharmacokinetics?

Answer 28

Common genetic polymorphisms in CYP2C9 can influence warfarin metabolism -- 30% are slow metabolizers

Question 29

How can polymorphisms influence dosage?

Answer 29

Differences like these can require anywhere from 20-70% or more change in dosage in different people.

Question 30

What's importnat to know about warfarin??

Answer 30

MANY MANY DRUG INTERACTIONS

Question 31

What are pharmacokinetic properties?

Answer 31

Absorption, Distribution, Elimination (what body does to drug)

Question 32

What is a pharmacodynamic property?

Answer 32

Site of action (what drug does to the body)

Question 33

What are pharmacokinetics?

Answer 33

- Absorption, distribution, metabolism, and elimination (ADME) - For oral anticoagulants pharmacokinetic drug interactions are primarily due to: - --Enzyme induction - --Enzyme inhibition - --Reduced plasma protein binding

Question 34

What are pharmacodynamics?

Answer 34

- Biochemical or physiological effects of drugs and their mechanism of action - Individuals vary in the magnitude of their response to the same concentration of drug - For oral anticoagulants, pharmacodynamic drug interactions are primarily due to: - --Reduced clotting factor synthesis - --Competitive antagonism with Vitamin K - --Hereditary resistance to oral anticoag.

Question 35

What do you do if a patient has BLEEDING side effect from TOO MUCH WARFARIN?

Answer 35

- Stop the drug - Add Vitamin K - -Phytonadione (vitamin k1) - -Or prothrombin complex concentrates - -Or recombinant factor VIIa - -Or. . .