Pharmacology of Anticoagulants

Question 1

How clots form

Answer 1

1. Vessel damage
2. Platelets adhere to site of injury
3. Activation of clotting cascade n activated platelet surface by tissue factor (factor VIIa)

Question 2

Fibrin clot formation - function of fibrin deposition

Answer 2

Fibrin deposition stabilizes the platelet thrombus

Question 3

Targets for anti-coagulation

Answer 3

1. Anti-platelet agents
2. Chelate calcium ions
3. Inhibit liver carboxylation of Gla proteins
4. Accelerate inhibition of thrombin and factor Xa by antithrombin
5. Directly inhibit thrombin and factor Xa
6. Thrombolytic agents

Question 4

Anti-platelet agents

Answer 4

Asprin

Question 5

Chelate calcium ions

Answer 5

• citrate

- EDTA

Question 6

Inhibit liver carboxylation of Gla proteins

Answer 6

-coumarol drugs such as coumadin and warfarin

Question 7

Drugs that accelerate inhibition of thrombin and factor Xa by antithrombin

Answer 7

Heparin

Question 8

Drugs that directly inhibit thrombin and factor Xa

Answer 8

New oral anticoagulants

Question 9

Drugs that are thrombolytic agents

Answer 9

tPA

Question 10

MOA of asprin

Answer 10

1) Inhibits platelet cyclo-oxygenase by acetylation
2) Prevents synthesis of thromboxane A2
3) Stops thromboxane A2 -induced platelet activation and aggregation thereby reducing platelet plug formation at early stage

Question 11

Calcium chelators MOA

Answer 11

• i.e. metal chelators such as citrate and EDTA
  1) Strip Ca2+ from Gla proteins
  2) Non-Ca2_ Gla proteins cannot bind to phospholipids
  3) Reversed by adding excess Ca2+

Question 12

Coumarol drugs MOA

Answer 12

1) inhibit reduction of vitamin K in the liver
2) Vitamin K becomes limiting and Gla-less proteins made by liver (inhibit liver carboxylation of Gla proteins: prothrombin, factor IX, factor X, factor VII, protein C, protein S)
3) Gla-less proteins do not bind Ca2+ so no conformational change
4) Gla-less proteins cannot bind to membrane at the site of injury
5) Clotting inhibited until coumarol is replaced by vitamin K

Question 13

History coumarol drugs

Answer 13

• dicoumarol discovered when cows bled after eating sweet clover
• warfarin is a synthetic version

Question 14

Warfarin bioavailability

Answer 14

Well absorbed orally (100% bioavailability)

Question 15

Warfarin onset

Answer 15

-delayed onset of anticoagulation

Question 16

Surmounting warfarin

Answer 16

Surmountably antagonized by vitamin K

Can have its effect altered by diet (broccoli)

Question 17

Warfarin solubility

Answer 17

Highly (99%) plasma protein bound - fat soluble vitamin

Question 18

net effect of warfarin

Answer 18

Prolong prothrombin time

Question 19

Indications for warfarin (6)

Answer 19

1. Prophylaxis and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism)
2. Prophylaxis and treatment of atrial fibrillation
3. Valvular stenosis
4. Heart valve replacement
5. Myocardial infarction
6. Antiphospholipid syndrome

Question 20

Contraindications and precautions

Answer 20

1. Hypersensitivity to warfarin
2. Condition with risk of hemorrhage
3. Hemorrhagic tendency
4. Inadequate laboratory techniques
5. Vitamin K deficiency
6. Intramuscular injections
7. Non-steroidal anti-inflammatory drugs (asprin)

Question 21

Side effects of warfarin

Answer 21

1. Hemorrhage
2. Skin necrosis
3. Purple toe syndrome
4. Microembolism
5. Teratogenecity
6. Agranulocytosis
7. Leukopenia
8. Diarrhea
9. Nausea
10. Anorexia

Question 22

Factors influencing dose response

Answer 22

1. Inaccurate laboratory testing
2. Poor patient compliance
3. Concomitant medications
   (drug interactions)
4. Levels of dietary vitamin K
5. Alcohol
6. Hepatic dysfunction

Question 23

Why monitor warfarin therapy

Answer 23

1. Narrow therapeutic range

2. Increased risk of bleeding

Question 24

How to monitor warfarin therapy

Answer 24

-measure PT and INR from drop of blood (hand-held devices)

Question 25

Composition of heparin

Answer 25

-polysaccharide composed of mixed polymers of sulfated sugars (glucosamine, iduronate, glucuronate)

Question 26

Charge of heparin

Answer 26

Very negatively charged

Question 27

Heparin MOA

Answer 27

1) Contains binding sites for antithrombin and thrombin/factor Xa - antithrombin = serine protease inhibitor (serpin) 2) Cleaved antithrombin undergoes a conformation change = mousetrap inhibitor 3) Mouse trap inhibitor wraps round a protease and renders the thrombin inactive 4) thrombin or factor Xa is rendered inactive AT + H AT:H (activated complex) -- (thrombin factor Xa)--> AT:E + H (covalent complex between thrombin an antithrombin = inactive)

Question 28

Variability in function of thrombins based on size

Answer 28

- any size of heparin chain can accelerate the inhibition of factor Xa by antithrombin - only heparin chains > 18 sugars can accelerate the inhibition of thrombin by antithrombin (heparin must bind to AT and thrombin)

Question 29

Advantages of LMWH over UH

Answer 29

1) Decreased heparin resistance 2) No need for laboratory monitoring 3) Higher bioavailability (90% vs 30%) 4) Longer plasma half life (4-6 hrs versus 0.5 to 1 hr) 5) Less inhibition of platelet function 6) Lower incidence of thrombcytopenia and thrombosis 7) Antibodies can be formed against a heparin-platelet factor 4 complex - these platelets can ativate platelets leading to thrombosis and platelet consumption (less interact of LMWH with platelet factor 4 so less chance of heparin-dependent IgG antibodies)

Question 30

Decreased heparin resistance with LMWH vs UH why?

Answer 30

Pharmacokinetics of UH are influenced by binding of plasma proteins, endothelial cell surface, macrophages an acute phase reactants -LMWH has decreased binding to non anticoagulant related proteins

Question 31

Why no need for laboratory monitoring

Answer 31

When given on weight -adjusted bases LMWH response is predictable and reproducible

Question 32

How to reverse the effects of heparin

Answer 32

Effects may be reversed by protamine sulfate (a polycationic protein that complexes with heparin)

Question 33

Immediate effect of heparin

Answer 33

Causes immediate anticoagulation

Question 34

Worst side effects of heparin

Answer 34

May cause fatal thrombocytopenia

Question 35

Direct inhibition of thrombin and factor Xa MOA

Answer 35

Computer-designed small molecule inhibitors Bind tightly to active site of proteases a) Rivaroxaban - inhibits factor Xa b) Dabigatran - inhibits thrombin

Question 36

Advantage/disadvantage of direct inhibition of thrombin and factor Xa

Answer 36

- Advantage: do not require continuous monitoring of clotting time - Disadvantage = no current antidote

Question 37

Thrombolytic agents MOA

Answer 37

-activate plasminogen to plasmin

Question 38

Example of thrombolytic agents

Answer 38

1) Tissue plasminogen activator 2) Urokinase 3) Streptokinase (bacterial)

Question 39

Use of thrombolytic agents

Answer 39

Used for ischemic stroke (caused by blood clot)