Session 12: Anticoagulants Flashcards
Give common thromboembolic diseases.
DVT and PE
TIA
Ischaemic stroke
MI
AF
Pharmacokinetics of unfractionated heparin
Fast onset of action with a half-life of 30 min at low dose.
Half-life is 2h at higher dose
With a mixed elimination as well as unpredictable.
How is unfractionated heparin administered?
Typically IV bolus and infusion
Can be given s.c. for prophylaxis however the bioavailability is much lower in that case.
Explain the mechanism of action of unfractionated heparin.
Binds to antithrombin (ATIII) and causes conformational change as well as increasing the activity of antithrombin.
It also catalyses inhibition of thrombin (IIa). This requires heparin to simultaneously bind to ATIII and IIa.
Xa inhibition only needs ATIII binding.
Give examples of low molecular weight heparins (LMWH)
Dalteparin (most commonly prescribed)
Enoxaparin (Acute coronary syndrome)
Administration of LMWH
Almost always s.c.
However enoxaparin is given i.v. in ACS
Pharmacokinetics of LMWH
Bioavailability of >90% with a longer half-life (>2h) and independent of the dose
Why is it important that the half-life of LMWH is independent of dose?
This means that it is more predictable when given.
How does the action differ between unfractionated heparin and LMWH?
It is not long enough to bind to endothelial cells, plasma proteins and macrophages.
It is also not long enough to inactivate thrombin IIa.
This means that it specifically inhibits Xa but enhance ATIII activity.
Explain why fondaparinux might be given instead?
It is a synthetic pentasaccharide that selectively inhibits Xa by binding to ATIII.
You give it s.c. and has a half-life of 18h.
It is a great choice for vegans as heparin is extracted from pork otherwise.
When is heparin used?
Prevention of venous thromboembolism
Perioperative prophylaxis
During pregnancy as it is too big to cross the placenta
DVT and PE (usually just initial treatment)
Acute coronoary syndrome
NSTEMI
ADRs of heparin
Bruising and bleeding
Intracranial, site of injection bleeding and epistaxis
Heparin induced thrombocytopenia
Hyperkalaemia (via inhibition of aldosterone secretion)
Osteoporosis
How is heparin monitored?
By aPTT when using therapeutic doses of UFH.
The dose is then titrated to the aPTT value.
LMWH is much more predictable and only needs little monitoring if any.
Antidote of heparin
Protamine sulphate
Explain action of protamine sulphate
Forms inactive complex with heparin and is given i.v.
It dissociates heparin from ATIII, irreversibly binding.
Effects of protamine sulphate on UFH, LMWH and fondaparinux.
Greater effect on UFH than on LMWH.
There is no affect at all on fondaparinux
Give an example of a vitamin K antagonist.
Warfarin
Explain the action of warfarin.
Inhibits activation of vitamin K dependant clotting factors.
Inhibition of the conversion of vitamin K to its active form. This is by competitive inhibition of VKOR (epoxide reductase).
Give examples of clotting factors that needs active vitamin K as a cofactor in order to become activated.
Clotting factors II, VII, IX and X via hepatic synthesis requires active vitamin K.
Why is there a delay in warfarin to become active?
Because the circulating active clotting factors will be present for severel days and must be cleared and replaced with inactive clotting factors.
This can take up to 72 hours.
Half-life of warfarin.
36h-48h
Uses of warfarin.
Venous thromboembolism
PE
DVT
Superficial vein thrombosis
A-fib
After bio-prosthetic and also some mechanical heart valve replacements.
Generally used in longer term anticoagulation whereas heparin is used short term.
Pharmacokinetics of warfarin.
Good GI absorption with over 95% bioavailability if taken orally.
CYP2C9 inactivates warfarin in the liver.
Warfarin has two enantiomers with different potency and different metabolism.
