Anticoagulants Flashcards
Coagulation factors are present in blood as…because…
Zymogens
Serine proteases
Cofactors
Gives tight regulation of the cascade to prevent solidification of all blood
Where are heparins naturally produced?
Mast cells
Vascular endothelium
Where are heparins extracted from for pharmaceutical use?
Porcine intestinal mucosa
Bovine lung
How do heparins work?
Inhibits coagulation in vitro and vivo - enhance antithrombin III activity by 1000 fold.
Unfractionated heparin has a onset time of ?
T1/2 30 mins AT LOW DOSE
T1/2 2hrs AT HIGH DOSE (mixed elimination)
How does unfractionated heparin work?
Binds to antithrombin and causes conformational change, increasing activity of ATIII.
What is the aim of giving anticoagulants ?
Prevent thrombus formation and growth
For unfractionated heparin to inhibit IIa what must it do?
Heparin must bind simultaneously antithrombin (ATIII) and IIa
For unfractionated heparin to inhibit Xa what must happen?
Unfractionated heparin must bind antithrombin (ATIII)
Name a low molecular weight heparin
Dalteparim
Enoxaparin
What is the difference in administration between unfractionated and LMW heparin?
Unfractionated- typically IV bolus/infusion, subcutaneous for prophylaxis with lower bioavailability.
LMW- almost always subcutaneous, enoxaparin given IV for ACS
What is the bioavailability and half life like for LMWH?
> 90%
T1/2 - 2 hours or more independent of dose
Why does LMWH have a more predictable dose response?
It doesn’t bind to endothelial cells, plasma proteins and macrophages as it is too short/
what is the main difference between inhibition of the cascade between unfractionated and LMW heparin?
LMWH only able to inhibit Xa, through enhancing antithrombin activity.
What is the difference between fondaparinux and other LMWH?
Fondaparinux - selectively inhibits Xa by binding to ATIII, with a half life of 18hrs
What is the difference in dose response between the two types of heparins?
Unfractionated - non-linear
LMWH- predictable
What is the metabolism difference between the two types of heparins?
Unfractionated - dose dependant; protein binding, depolymerisation, desulfation (first and zero order).
LMWH- rapid liver or slower renal excretion
What is the difference in monitoring heparins?
Unfractionated- unpredictable, monitor activated partial thrombi plastic time
LMWH- generally no monitoring, since dose response is predictable
What is the difference in action time between the heparins?
Unfractionated- IV infusion fast
LMWH- slow subcut
When would you choose to use unfractionated heparin over LMWH?
When there is severe renal impairment and fine control is required.
What are some of the uses of heparin?
Prevent VTE- perioperative prophylaxis
Pregnancy- unable to cross placenta
VTE- initial treatment prior to oral agents
Acute coronary syndromes- short term to reduce recurrence / extension of coronary artery thrombosis post MI.
What is the antidote to heparin and how does it work?
Protamine sulphate - forms inactive complex with heparin. Dissociates heparin from ATIII, irreversible binding amount guided by heparin dose.
Greater effect with unfractionated. No effect on fondaparinux.
What are some of the ADR to heparin?
Bruising & bleeding - site of injections, intracranial, GI, epistaxis. Hepatic/renal impaired, elderly or those with carcinomas at higher risk
Herparin induced thrombocytopenia
Hyperkalaemia - inhibition of aldosterone secretion
Osteoporosis - long term use, higher risk with unfractionated and more prevalent in pregnancy.
What is a vitamin K antagonist and its mechanism of action?
Warfarin - competitive inhibition if VKOR preventing activation of vitamin k to active reduced form. This inhibits factors II,VII,IX,X as they require vitamin K as a cofactor to become action.
