Anticoagulants

Question 1

3 main classes of anti coagulants

Answer 1

1. Anti platelets (aspirin, GpIIb/III a receptor inhibitors etc)
2. Anti coagulants (Heparin, Warfarin)
3. Thrombolytics (alteplase, urokinase, streptokinase, anistreplase)

Question 2

What are important signals in platelet activation

Answer 2

Serotonin and ADP

Question 3

What affects the release of serotonin and ADP?

Answer 3

Prostacyclin from intact endothelial cells –> negative signal to serotonin and ADP secretion –> no platelet activation

Thromboxane A2 from damaged endothelial cells –> positive signal for serotonin and ADP secretion –> platelet activation

Question 4

MOA of Aspirin

Answer 4

Aspirin is an anti platelet

Inhibits COX irreversibly preventing the conversion of arachidonic acid to prostaglandins and eventually Thromboxane A2 for platelet aggregation

Question 5

Adverse effects of aspirin

Answer 5

1. Bleeding (inhibits the formation of both PGI2 and TXA2, but TXA2 takes longer to replace. PGI2 inhibits platelet aggregation)
2. Gastric upset and ulcers - ‘GI bleeding’ as prostacyclins has protective functions in the GI

Question 6

Clinical uses of Aspirin

Answer 6

1. Prophylactic treatment of transient cerebral ischaemia
2. To reduce the incidence of recurrent MI
3. To decrease mortality in postmyocardial infarction patients

Question 7

GP IIB/IIIA receptor inhibitor examples

Answer 7

Abciximab, Tirofiban, Eptifibatide

Question 8

MOA of Gp IIB/IIIA receptor inhibitors

Answer 8

Inhibiting GP IIb/IIIa will prevent fibrinogen cross-linking platelets → no clot formation → no fibrin mesh needed to stabilise the platelet aggregation

(GP IIb/IIIa is a platelet membrane protein (receptor) for platelets to receive the fibrin meshes)

Question 9

Abciximab

Answer 9

• Monoclonal antibody directed against the IIb/IIa complex
• It reversibly inhibits the binding of fibrinogen and other ligands to gp IIb/IIa

Question 10

Tirofiban

Answer 10

A small molecular blocker of the gpIIb/IIIa receptor

Question 11

Eptifibatide

Answer 11

An analog of the sequence at the extreme carbonyl terminal of the delta chain of fibrinogen which mediates the binding of fibrinogen to the receptor

Question 12

Clinical uses of Gp IIb/IIIa receptor inhibitors

Answer 12

Prevent restenosis after coronary angioplasty

Question 13

Clopidogrel & Ticlopidine

Answer 13

Anti platelets
ADP receptor blockers → no platelet activation

Question 14

Dipyridamole

Answer 14

Anti platelet
Prevent degradation of cAMP to 5’-AMP → continuous negative signal to prevent serotonin and ADP secretion → no platelet aggregation

Question 15

Which factors do AT III inactivated

Answer 15

inactives thrombin (2a), 9a, 10a by forming stable complexes with them

Question 16

MOA of heparin

Answer 16

Allows antithrombin to deactivate the factors better by binding to ATIII and causing a conformational change for more rapid interaction between ATIII and the clotting factor → inactivating clotting factors in the clotting pathway → prevent clotting

Question 17

How does heparin inhibit thrombin?

Answer 17

Heparin binds to both 2a and ATIII

Question 18

How does heparin inhibit factor 10a

Answer 18

Heparin only needs to bind to ATIII

Question 19

What is Low Molecular Weight Heparin

Answer 19

LMWH binds to ATIII and only inactivates factor 10a but not thrombin

Question 20

Clinical use of heparin

Answer 20

1. Treatment of DVT, pulmonary embolism, acute MI (although clot already formed - it helps to prevent further clotting)
2. Can be used in combination with thrombolytics or Gp IIa/IIIb receptor inhibitors to prevent clotting
3. Can be used when anticoagulant is needed in pregnancy ***
4. Given IV or SC (IM administration can cause haematomas)

Question 21

What is the difference between Heparin and Warfarin

Answer 21

Heparin can be used in pregnancy

Question 22

Adverse effect of Heparin

Answer 22

1. Haemorrhage:
   - Stop heparin therapy + protamine sulphate (binds to and sequesters heparin)
2. Thrombocytopenia

Question 23

MOA of Warfarin

Answer 23

Warfarin inhibits vitamin K reductase → vitamin K always in the oxidised form → no gamma-carboxylation of factors 2,7,9,10 → no clotting cascade + fibrin mesh formation

Question 24

Clinical uses of warfarin

Answer 24

Same as heparin, except contraindicated in pregnancy as it can pass the placenta and cause haemorrhagic disease in the infant

Question 25

Adverse effect of warfarin

Answer 25

1. Bleeding
2. CONTRAINDICATED IN PREGNANCY
3. Drug-drug interaction (metabolised by cyp450 enzyme)

Question 26

Examples of thrombolytics

Answer 26

t-PA (alteplase), urokinase, streptokinase, anistreplase

Question 27

MOA of alteplase

Answer 27

Tissue plasminogen activator → converts plasminogen to plasmin → plasmin breaks down insoluble fibrin mesh to fibrin degradation products

Question 28

Clinical uses of thrombolytics

Answer 28

1. Emergency treatment of coronary artery thrombosis
2. Peripheral arterial thrombosis and emboli
3. Ischaemic stroke (narrow therapeutic window <4.5hr)
4. Intracoronary injection, IV injection

Question 29

Adverse effects of thrombolytics

Answer 29

1. Bleeding
2. Contraindicated in pregnancy + healing wounds

Question 30

When are thrombolytics contraindicated in?

Answer 30

• pregnancy
• Healing wounds

Question 31

mode of action of unfractionated hepatin, and the difference from low molecular weight heparin

Answer 31

1. binds and activates plasma protease inhibitor antithrombin III → conformational change → exposes its active site –> forms more inactive complexes with coagulation factor IIa, IXa & Xa by 1000 folds
2. stimulates tissue factor pathway inhibitor (TFPI) release from endothelium to prevent activation of coagulation factor Xa

it has a longer polysaccharide side chain that can envelope thrombin, therefore giving enhanced anti Xa and IIa activity