Anticoagulants Flashcards
3 main classes of anti coagulants
- Anti platelets (aspirin, GpIIb/III a receptor inhibitors etc)
- Anti coagulants (Heparin, Warfarin)
- Thrombolytics (alteplase, urokinase, streptokinase, anistreplase)
What are important signals in platelet activation
Serotonin and ADP
What affects the release of serotonin and ADP?
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
MOA of Aspirin
Aspirin is an anti platelet
Inhibits COX irreversibly preventing the conversion of arachidonic acid to prostaglandins and eventually Thromboxane A2 for platelet aggregation
Adverse effects of aspirin
- Bleeding (inhibits the formation of both PGI2 and TXA2, but TXA2 takes longer to replace. PGI2 inhibits platelet aggregation)
- Gastric upset and ulcers - ‘GI bleeding’ as prostacyclins has protective functions in the GI
Clinical uses of Aspirin
- Prophylactic treatment of transient cerebral ischaemia
- To reduce the incidence of recurrent MI
- To decrease mortality in postmyocardial infarction patients
GP IIB/IIIA receptor inhibitor examples
Abciximab, Tirofiban, Eptifibatide
MOA of Gp IIB/IIIA receptor inhibitors
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)
Abciximab
- Monoclonal antibody directed against the IIb/IIa complex
- It reversibly inhibits the binding of fibrinogen and other ligands to gp IIb/IIa
Tirofiban
A small molecular blocker of the gpIIb/IIIa receptor
Eptifibatide
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
Clinical uses of Gp IIb/IIIa receptor inhibitors
Prevent restenosis after coronary angioplasty
Clopidogrel & Ticlopidine
Anti platelets
ADP receptor blockers → no platelet activation
Dipyridamole
Anti platelet
Prevent degradation of cAMP to 5’-AMP → continuous negative signal to prevent serotonin and ADP secretion → no platelet aggregation
Which factors do AT III inactivated
inactives thrombin (2a), 9a, 10a by forming stable complexes with them
MOA of heparin
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
How does heparin inhibit thrombin?
Heparin binds to both 2a and ATIII
How does heparin inhibit factor 10a
Heparin only needs to bind to ATIII
What is Low Molecular Weight Heparin
LMWH binds to ATIII and only inactivates factor 10a but not thrombin
Clinical use of heparin
- Treatment of DVT, pulmonary embolism, acute MI (although clot already formed - it helps to prevent further clotting)
- Can be used in combination with thrombolytics or Gp IIa/IIIb receptor inhibitors to prevent clotting
- Can be used when anticoagulant is needed in pregnancy ***
- Given IV or SC (IM administration can cause haematomas)
What is the difference between Heparin and Warfarin
Heparin can be used in pregnancy
Adverse effect of Heparin
- Haemorrhage:
- Stop heparin therapy + protamine sulphate (binds to and sequesters heparin) - Thrombocytopenia
MOA of Warfarin
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
Clinical uses of warfarin
Same as heparin, except contraindicated in pregnancy as it can pass the placenta and cause haemorrhagic disease in the infant
Adverse effect of warfarin
- Bleeding
- CONTRAINDICATED IN PREGNANCY
- Drug-drug interaction (metabolised by cyp450 enzyme)
Examples of thrombolytics
t-PA (alteplase), urokinase, streptokinase, anistreplase
MOA of alteplase
Tissue plasminogen activator → converts plasminogen to plasmin → plasmin breaks down insoluble fibrin mesh to fibrin degradation products
Clinical uses of thrombolytics
- Emergency treatment of coronary artery thrombosis
- Peripheral arterial thrombosis and emboli
- Ischaemic stroke (narrow therapeutic window <4.5hr)
- Intracoronary injection, IV injection
Adverse effects of thrombolytics
- Bleeding
- Contraindicated in pregnancy + healing wounds
When are thrombolytics contraindicated in?
- pregnancy
- Healing wounds
mode of action of unfractionated hepatin, and the difference from low molecular weight heparin
- 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
- 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
