CAM201: Haemostasis Drugs Flashcards
Describe the cellular mechanism of Aspirin
Aspirin is an anti-platelet drug.
It is an irreversible COX (cyclooxygenase) inhibitor. COX usually converts ARACHIDONIC Acid into Prostaglandin H2 (PGH2).
PGH2 is converted to Thromboxane A2 (TXA2) in platelets, and Prostacyclin (PGI1) in vessel endothelial cells.
TXA2 is involved in chemical signalling to increase Plt activation and aggregation. Thus, by de-activating COX in plts, aspirin inhibits TXA2 production, and inhibits Plt activation and aggregation.
PGI2, produced in endothelial cells, normally has a protective anti-plt function. It binds to G-protein coupled receptors on Plt cell walls and activates an intracellular cascade which results in decreased Plt activation and aggregation. It activates Adenylate Cyclase, which converts ATP to cAMP, which decreases intracellular Ca++ (which would normally be raised by TXA2 resulting in Plt activation and aggregation).
Although this function is of PGI2 is initially inhibited by aspirin permanently inactivating COX (thus preventing PGI2 production in endothelial cells), endothelial cells (unlike Plts) are nucleated. Thus, they can soon produce more COX, and thus more PGI2 - and PGI2 can resume its protective anti-plt function.
Describe the cellular mechanisms of Clopidogrel
Clopidogrel is an Anti-Platelet drug.
It acts by binding irreversible to ADP receptors on Plt cell walls, thus preventing ADP from binding.
ADP is required to raise intracellular levels of Ca++ in platelets.
Raised intracellular Ca++ levels are required for the expression of glycoprotein adhesion molecules on Plt cell wall surface, which are involved in activation and allow adhesion.
Thus, by blocking ADP binding to ADP receptors on Plts, Clopidogrel inhibits Plt activation and aggregation.
Describe the cellular mechanism of Abciximab
Abciximab is an anti-platelet drug.
It binds and blocks (Glycoprotein) 2b and 3a receptors, on the walls of activated platelets, thus preventing Plt aggregation.
Abciximan reduced Plt aggregation by 90%, and can be used with Apirin and Heparin in high risk patients
Cellular mechanisms of Streptokinase (and TPA, rTPA)
Streptokinase, TPA and rTPA are fibrinolytics/thrombolytics.
Most commonly used in DVT and PE, and ACUTE MI and Stroke (to degrade thrombus)
Streptokinase is extraced from Beta Haemolytic Streptococci.
Streptokinase is inactive until it binds to plasminogen, which it converts to plasmin. Plasmin degrades thrombi.
TPA binds preferentially to plasminogen in contact with the thrombus (clot), thus it is ‘clot-specific’.
rTPAs involve two recombinant forms of TPA which last slightly longer.
All of these drugs are Injected or IV. Streptokinase has 5 min half life. TPA and rTPA half lives are ~15 to 30 mins, respectively.
Describe the cellular mechanism of Heparin: both UFH and LMWH
Heparin (both UFH and LMWH) is an anti-coagulant.
UFH is unfractionated: thus it is comprised of both large and small sulphated glycoaminoglycans.
UFH binds to, and crates a complex with, antithrombin 3. In doing so, it creates a conformational change in antithrombin, which makes available more sites for interaction with serine proteases (coagulation factors). In doing this, Heparin accelerates the anticoagulant activity of antithrombin, which is normally slow.
LMWH is fractioned - i.e. the small sulphated glycoaminoglycans have been selected.
LMWH behaves in the same way as UFH, however it only de-activates activated FX.This is because FX is de-activated by interaction with antithrombin alone, whereas the other serine proteases must interact with both heparin and antithrombin to be de-activated. Because LMWH is smaller, it does not interact with the serine proteases*
LMWH can be administered at home by Subcutaneous injection, and takes ~ 60 mins to work
UFH can be IM or SC injection, faster working.
Describe the cellular mechanism of Rivaroxaban
Rivaroxaban is an anti-coagulant.
Rivaroxaban selectively and reversibly inhibits the action of activated FX on Prothrombin, inhibiting coagulation.
Describe the Cellular Mechanism of Warfarin
Warfarin is an anticoagulant.
Warfarin competes with oxidised Vitamin K for binding to Vitamin K Reductase.
Vitamin K Reductase normally reduces oxidised Vitamin K so that it can work as a co-factor (with carboxylase) to carboxylate Factors 2, 7, 9 and 10 into their full forms.
Unless factors 2, 7, 9, and 10 are carboxylated into their full forms, they cannot be used in coagulation.
Thus, by binding and blocking the action of Vitamin K Reductase, Warfarin prevents the full synthesis of factors 2, 7, 9, and 10. Thus, it inhibits coagulation.
Warfarin use must be closely monitored by regular measurement of INR (derived from PT). The target INR range for someone on Warfarin is 2-3.
**PT measures the extrinsic pathway: F1 (fibrinogen), FII (prothrombin), FV, FX and FVII.
**APTT measures the intrinsic pathway: FXII, XI, IX, X, V, I, II
Describe the Cellular Mechanism of Vitamin K, and its Indications
Reduced Vitamin K is a required co-factor of carboxylase, to carboxylate coagulation factors 2, 7, 9, and 10 into their full forms. These factors cannot be used unless they are carboxylated into their full forms.
Vit K may be used to treat haemorrhage which may be due to warfarin overdose.
Also used in treatment and prevention of haemolytic disease of the newborn.
How to reverse Warfarin overdose?
If not bleeding and at low risk, can cease administration of warfarin, and continue once INR is back in safe range (2-3).
If need to quickly reverse warfain effect, administer Vit K.
If an emergency (i.e. bleeding), immediate warfarin reversal can be achieved with administration of Prothrombin Complex and Fresh Frozen Plasma (FFP) which contains coagulation factors.
