Anti-Clotting and Anti-Thrombotics Flashcards
Aspirin?
MOA => Blocks COX enzyme that converts AA to PGG2. This PGG2 is then converted to PGH2, which later becomes PGI2, PGE2, TbxA2.
Hence drop in PGI2 (produced by healthy endothelial cells).
There is a drop in TbxA2 as well, thereby reducing platelet aggregation.
Rapid inhibition that lasts for as long as the platelet is alive (7-10 days).
Used in prophylaxis for transient cerebral ischaemia / reduce risk of recurrent MI / reduce mortality in post-MI.
ADR is of course bleeding because of anti-PGI2 and TbxA2 effects
GPIIB/IIIA receptor blockers?
GPIIB/IIIA is a receptor on the platelet membrane. It receives fibrinogen, vitronectin, fibronectin, vWF. This allows cross-linking of platelets (one fibrinogen molecule joining two platelets). When this receptor is activated, it binds platelets together and keeps the platelet plug stable. It is the final step in the platelet aggregation pathway.
Blocking these receptors hence does NOT prevent platelet aggregation, but it greatly reduces the stability of the platelet plug.
Examples:
- Abciximab: Humanized monoclonal antibody against the GPIIB/IIIA complex. Reversible inhibition of fibrinogen (and other ligands) binding GPIIB/IIIA
- Eptifibatide: Analog of a terminal sequence of fibrinogen, prevents fibrinogen binding and platelet aggregation
- Tirofiban: Small molecule blocker of GPIIB/IIIA receptor
Indicated in preventing restenosis after coronary angioplasty. Used in acute coronary syndromes.
ADP receptor inhibitors?
Clopidogrel and Ticlopidine inhibit ADP receptor on platelets, which encourages aggregation.
Phosphodiesterase blockers?
Dipyridamole inhibits the action of PDE, which converts cAMP to 5’-AMP. This is good because cAMP accumulates, and inhibits the release of the serotonin and ADP granules.
Recall that physiologically, cAMP inhibits the secretion of ADP / serotonin granules; cAMP production is stimulated by PGI2, which is secreted by intact endothelial cells
Name the 4 anti-platelet agents
Aspirin, GPIIB/IIIA inhibitors (abciximab, eptifibatide, tirofiban), ADP receptor blockers (clopidrogel, ticlopidine), PDE blockers (dipyridamole)
MOA of Heparin and LMWH?
Heparin inhibits the activity of proteases in the clotting chain -2, 9, 10.
Heparin binds to and potentiates ATIII. It works to inhibit the activity of Xa and IIa. For IIa, heparin must bind to both ATIII and IIa. For Xa, heparin just binds to ATIII, which changes the ATIII configuration and increases the inhibitory effect on Xa.
LMWH cannot bind to IIa. It only has one binding site, and that is to ATIII. As such, LMWH only inhibits Xa activity.
Indications for Heparin?
DVT, PE, AMI.
Combined with thrombolytics for revascularization.
Combined with GPIIB/IIIA inhibitors during angioplasty and coronary stent surgeries
Can be used in pregnancy such as for VTE!
ADR OF HEPARIN HAEMORRHAGE. PROTAMINE SULFATE IS GIVEN IN THIS CASE!
Thrombocytopaenia may also occur, i.e. platelet count drops <100,000uL if the body makes anti-heparin antibodies and hence starts attacking platelets. This thrombocytopaenia is PARADOXICALLY A/W THROMBOSIS
MOD of Heparin?
SC or IV. WILL FORM HEMATOMA IF IM
What is protamine sulfate?
Long, cationic peptide. It is given in a heparin-induced haemorrhage to bind to and inactivate heparin
Is Heparin or Warfarin C/I in pregnancy? Why?
WARFARIN! Crosses the placenta readily and can cause haemorrhage in the fetus. May also bind to fetal proteins in bone and blood
Warfarin MOA?
Inhibits Vitamin K reductase, which allows the formation of clotting factors 2,7,9,10.
Vit K - Fat-soluble, occurs naturally in plants. It is reduced by Vit. K reductase for post-translational modification (carboxylation) of glutamate residues. Basically just making clotting factors.
Warfarin is PO!
PK of warfarin?
Given orally with good bioavailability. >99% binds to plasma albumin! Hence small Vd. Has hepatic elimination!!!
Warfarin is metabolized by CYP450. It does not activate / inhibit CYP450, but it should be noted for DDI if other CYP-affecting drugs are being used.
I.e. barbiturates, carbamazepine, phenytoin are activators of CYP.
Amiodarone, cimetidine, disulfiram, imipramine are inhibitors.
Warfarin indications?
Warfarin has the same uses as heparin (DVT, PE, AMI / combination with thrombolytics), except it is NOT GIVEN TO PREGNANT WOMEN. This is because warfarin crosses the placenta readily and can cause haemorrhage in the fetus. Warfarin may also bind to fetal proteins in bone and blood.
Vit. K itself can be given as a medication to treat or prevent bleeding from oral anticoagulants like warfarin. Can also be given to prevent haemorrhagic disease of the newborn in babies. Also just given for Vit. K deficiencies.
What can be given to treat the Warfarin usage?
Vit. K itself can be given as a medication to treat or prevent bleeding from oral anticoagulants like warfarin. Can also be given to prevent haemorrhagic disease of the newborn in babies. Also just given for Vit. K deficiencies.
Plasmin MOA?
Breaks down both soluble fibrin AND fibrinogen into FDP
PK of thrombolytics?
Can be given IV or IntraCA!
ADR of thrombolytics?
ADR like bleeding obviously. C/I in pregnancy.
Also C/I in wound healing because clots need to form for wounds to heal.
Anti-fibrinolytic agents also exist, like tranexamic acid. They work to reduce the conversion of plasminogen to plasmin.
What are the thrombolytics and their MOA?
Streptokinase, alteplase, anistreplase, urokinase.
These are all drugs that increase the conversion of plasminogen to plasmin, which breaks fibrin down into FDP
Indications for thrombolytics?
Indications:
- Emergency treatment of CA thrombosis
- Peripheral arterial thrombosis and emboli
- Ischaemic stroke, which has <4.5h window. It is very important to make sure that the stroke is being caused by an arterial blockage as opposed to haemorrhagic stroke, because thrombolytics will not help the situation / worsen it.
