22 - Anticoagulants Flashcards
What two things are needed to control bleeding?
Haemostatic platelet plug and fibrin mesh
How do anticoagulant drugs work and what are some examples?
They prevent thrombus formation and the thrombus growing
What is the mechanism of action of heparin and where is it produced naturally in the body?
Enhances Antithrombin III activity via unique pentasaccharide sequence
Deactivates thrombin, Factor Xa, IIa, IXa
Usually made in mast cells and vascular endothelium
What are the two different types of heparin and how are they administered?
Given parenterally (sub cut/IV) as poor GI absorption
- Low molecular weight heparin (only subcut - enzymatically made from UFH)
- Unfractionated heparin (IV for continuous or subcut)
Apart from inactivating thrombin, what other clotting factors does heparin inhibit?
- Deactivates thrombin, Factor Xa, IIa, IXa, (probably VIIa, XIa, XIIa)
What are the differences between UFH and LMWH in terms of their action on thrombin and ATIII?
- LMWH only deactivates Xa
- UFH deactivates Xa and Thrombin
Compare and contrast UFH and LMWH based on the following factors:
- Dose-response
- Bio-availability
- Action
- Administration
- Initiation
LMWH used more!!! less monitoring needed
What are some of the characteristics of unfractionated heparin?
- Fast onset
- Short half life so need IV bolus
- Unpredictable
- SC if prophylaxis
- Needs to bind ATIII and IIa to inhibit thrombin but only need ATIII binding with Xa inhibition
Which heparin needs monitoring and why?
Unfractionated with APTT test as affecting intrinsic pathway
What are some of the characteristics of low molecular weight heparin?
- More predictable as higher bioavailability and does not bind to endothelial cells, plasma proteins and macrophages as not long enough
- Longer half life
- Given subcut
- Only inhibits Xa
What are some examples of LMWH’s?
- Dalteparin
- Enoxaparin
- Fondaparinux (synthetic so cheaper and good for veggies)
What are some indications for heparin use?
- Prevention of venous thromboembolism before surgery or for immobile patients (LMWH)
- DVT/PE give LMWH before warfarin to achieve loading dose
- Acute coronary syndromes use LMWH
- Pregnancy instead if warfarin as too large to cross placenta but monitor carefully
What are some adverse drug reactions to heparin?
- Bruising/bleeding intracranially, at site of injection, GI, epistaxis and if old, renally/hepatically impaired or carcinoma, at great risk of bleeding
- Heparin induced thrombocytopenia (more common in UFH)
- Hyperkalaemia due to inhibition of aldosterone sedcretion as acts on mineralcorticoid receptors
- Osteoporosis with long term use and in pregnancy, more common in UFH
What is heparin induced thrombocytopenia?
Autoimmune response up to 2 weeks after initiation of heparin
- Antibodies to heparin platelet factor 4 so depletion of platelets
- Paradoxically lead to more thrombosis as more platelets activated by damaged endothelium
How are the effects of heparin reversed? (e.g if administered too much so bleeding risk or allergy risk)
Protamine Sulphate
- Forms inactive irreversible complex with heparin causing it to disocciate from ATIII. Cationic peptide that binds to heparin forming inactive ion pair
- Given IV
- Greater effect with UFH, no effect on fonaparinux
What is the mechanism of action of warfarin?
Vitamin K antagonist: stops conversion of vit K to active reduced form by competitively inhibiting reduction of Vitamin K by VKOR
Prevents hepatic synthesis of active clotting factors 2, 7, 9, 10 as they need vit K as a co factor
Why is there a delay in onset of action of warfarin?
- Circulating active clotting factors are present for a few days, must be cleared and replaced with inactive clotting factors
- Given once a day, half life of 36 to 48 hours
- Heparin cover for first few days
When is warfarin used?
- Same setting as heparin but long term, e.g PE, venous thromboembolisms, DVT secondary prevention
- AF with high risk of stroke or before cardioversion
- Heart valve replacement with bio prosthetic valve and some mechanical
What are the pharmacokinetics of warfarin?
- Good GI absorption (95%) so taken orally
- Metabolised by CYP2C9 which is highly polymorphic
- Plasma concentration does not correlate with clinical effect
- Response affected by CYP2C9 and Vit K intake
- Heavily protein bound so may be displaced by drugs like NSAIDs
Why should warfarin not be given in pregnancy or before surgery?
- Crosses placenta and highly tetarogenic in first trimester and haemorraghic in third trimester
- Stopped 3 days before surgery as long half life and given heparin. Prevent risk of bleeding. Bridging therapy is LMWH
What are some adverse drug reactions of warfarin?
- Bleeding (epistaxis and retroperitoneal common)
- Tetarogenic
What is the antidote for warfarin?
- Parenteral Vitamin K1: acts slowly as need to synthesis new clotting factors
- Prothrombin complex concentrate
- Stop warfarin
- Fresh frozen plasma can immediately increase clotting factors
What are some drug interactions with warfarin?
- Anything that affects CYP2C9 can increase anticoagulant affect of warfarin
- Inhibitors of CYP2C9 (increase INR): amiodarone, clopidogrel, alcohol binge, quinolones, metronidazole
- Inducers of CYP2C9 (decrease INR): barbiturates, phenytoin, rifampicin, St John’s Wort
- Drugs reducing Vit K enhancing effect of warfarin: cephalosporins
- Displacement of warfarin from albumin: NSAIDS
How do we monitor warfarin use and what are the target values for monitoring?
- Need healthy diet and lifestyle
- Factor 7 most sensitive to Vit K deficiency so used this, use PT time (INR)
- INR 2.5 for DVT, PE, AF
- INR 3-3.5 for recurrent DVT
- Usually 2-3
What are DOACs and what is their mechanism of action?
Direct Oral Anticoagulants
Inhibit Xa and Xa bound to ATIII (Selective Xa inhibitors): apixaban, edoxaban, rivaroxaban
IIa (thrombin) competitive inhibitor (Direct Thrombin Inhibitors): dabigatran
How are DOACs administered and when are they used?
- Orally
- Little monitoring needed but could be bad if patient is non-complier
- Used for the same things as warfarin
What are some ADRs associated with DOACs?
- Cannot use in renal failure as renally excreted (especially dabigatran)
- Bleeding risk but lower intracranial bleeding risk than warfarin
- Avoid in pregnancy and breastfeeding
What are the antidotes for DOACs?
Andexanet
Idarucizumab (Dabigatran)
What are some DDIs with DOACs?
- Less interactions than warfarin but:
- [plasma] reduced by carbamazepine, phenytoin and barbiturates
- [plasma] increased by macrolides
How do we treat pneumonia?
- May give doxycycline for better compliance and if allergic to penicillins
- Co-amoxiclav if CURB65>3
If someone had a renal issue and needed a heparin for PE, which one would you give?
Unfractionated heparin as LMWH cannot be used in renal impairment
How do you transfer a patient from warfarin to a DOAC?
