Session 12 Anticoagulants Flashcards
What do anticoagulation drugs aim to do?
prevent thrombus formation and thrombus growing
What is regulation of the coagulation cascade essential for?
regulation is essential to prevent solidification of all blood
what are coagulation factors present in blood as?
they are present in blood as inactive zymogens, serine proteases and cofactors
where in the body are heparins produced naturally?
mast cells and vascular endothelium
How does unfractionated heparin work?
UFH accelerates interaction of antithrombin with both thrombin and factor Xa
To catalyse inhibition of thrombin (IIa), what does heparin need to do?
simultaneously bind antithrombin(III) and thrombin(IIa)
NB: Xa inhibition only needs antithombin(III) binding
What are two examples of low molecular weight heparins?
dalteparin
enoxaparin
Pharmacokinetics of heparin (table in slides)
UFH vs LMWH
Dose response = Bioavailability = Metabolism = Monitoring = Administration = Initiation = Half life = Action = Use =
Dose response = non-linear vs predictable
Bioavailability = s.c. variable vs predictable
Metabolism = dose dependent (protein binding, depolymerisation, desulfation - 1st and 0 order) vs rapid liver or slower renal excretion
Monitoring = unpredictable (look at aPTT) vs no monitoring just U/kg dosing
Administration = intravenous infusion (S.C) vs S.C (NOT IM)
Initiation = IV bolus then IVI vs OB/BC s.c
Half life = 30 min low dose, 2h high dose vs 2+h
Action = IVI fast anticoagulation vs s.c. slower onset
Use = severe renal impairment and fine control vs most situations
Some indications for the use of heparins?
PREVENTION of venous thromboembolism
(perioperative prophylaxis with LMWH and dose is dependent on risk)
Can be used during pregnancy as it does not cross placenta - although needs to be monitored with caution
Acute Coronary Syndromes
short term - can reduce recurrence and/or extension of coronary artery thrombosis post STEMI
ADR’s related to heparins?
bruising and bleeding = most common
- location = intracranial, at site of injection, GI, nose bleed (epistaxis)
- higher risk if hepatic or renal impairment present, elderly or in those with carcinoma
heparin induced thrombocytopenia (HIT)
* more common with UFH (compared with LMWH)
hyperkalaemia
* as there is inhibition of aldosterone secretion
osteoporosis = least common
- from long-term use
- higher risk with UFH
- more prevalent in pregnancy
How does heparin induced thrombocytopenia (HIT) occur?
if there is an autoimmune response 2-14 days after initiation of heparin
antibodies produced to heparin platelet factor 4 complex –> depletion of platelets
this can paradoxically lead to thrombosis as more platelets are activated by damaged endothelium :(
when would you use protamine sulphate and how does it work?
given to reverse the effects of heparin
it forms an inactive complex with heparin and dissociates the heparin from antithrombin(III)
irreversible binding
amount given (IV) guided by the dose of heparin
but can cause bleeding! - perform an in vitro test if unsure
which type of heparin does protamine sulphate have more of an effect on?
UFH = greater effect than LMWH
NO effect on fondaparinux
How do vitamin K antagonists work?
inhibit activation of vitamin K dependent clotting factors
inhibits conversion of vitamin K to active reduced form
competitive inhibition of VK epoxide reductase = VKOR
Which drug is a vitamin K antagonist?
warfarin
hepatic synthesis of WHICH clotting factors require active vitamin K as a cofactor?
II
VII
IX
X
2, 7, 9, 10
half-life of warfarin?
36-48 hours
day and a half - two days
What are some indications for the use of warfarin?
venous thromboembolism
PE
DVT and secondary prevention
superficial vein thrombosis
atrial fibrillation with high risk of stroke
heart valve replacement
used in longer term anticoagulation
NB: slow onset of action likely to require heparin cover if anticoagulation needed immediately (acute settings)
Outline the pharmacokinetics of warfarin
GI absorption = good
Taken = orally (bioavailability = 95%)
Significant inter individual variability due to: functional CYP2C9 polymorphisms
warfarin is a racemic mixture of two enantiomers: R and S = have different potency and are metabolised differently
What is the response of warfarin affected by?
CYP2C9
Vitamin K intake
Can warfarin be used in pregnancy?
NO
avoided at least in 1st trimester = teratogenic
and in 3rd trimester = haemorrhage risk
ADR’s of warfarin?
MAIN = BLEEDING
epistaxis and spontaneous retroperitoneal bleeding
What is the most effective warfarin antidote?
Vitamin K1
plus STOP the warfarin!
What is often required when initiating or temporarily stopping warfarin?
bridging therapy with LMWH
drug-drug interactions of warfarin?
there are loads! - the majority potentiate anticoagulation action but some do decrease the effects
amiodarone, clopidogrel, intoxicating dose of alcohol, quinolone, metronidazole - inhibition of hepatic metabolism (CYP2C9)
cephalosporins - reduce vitamin K by eliminating gut bacteria involved in production
NSAIDS and drugs that decrease GI absorption of vitamin K - displacement of warfarin from plasma albumin –> INCREASE INR
barbiturates, phenytoin, rifampicin, st johns wort - acceleration of warfarin metabolism –> DECREASE INR
why is monitoring required in those that take warfarin?
as there is a huge variation in patient response
which factor is most sensitive to vitamin K deficiency?
factor VII
so used in prothrombin time
what does INR demonstrate?
clotting time vs standard clotting time
* allows for standard corrected value compared across all laboratories
which INR values would indicate that warfarin should be used?
INR 2.5
- DVT
- PE
- AF (risk vs benefit)
INR 3-3.5
* recurrent DVT or PE in patients currently receiving anticoagulation
What are names of some direct acting oral anticoagulants? (DOAC) - direct Xa
apixaban
edoxaban
rivaroxaban
How do DOAC’s work? (direct Xa)
inhibit both free Xa AND Xa that is bound with antithrombin(III)
NB: do not directly effect thrombin (IIa)
DOAC (direct Xa)
metabolism =
excretion =
half-life =
metabolism = hepatic excretion = partly by kidneys half-life = 10 hours
DOAC (direct IIa) MoA?
selective direct competitive thrombin inhibitor of both circulating AND thrombus bound thrombin(IIa)
DOAC (direct IIa)
name of drug =
admin =
half-life =
dosing and monitoring =
name of drug = dabigatran
admin = oral
half-life = 9 hours
dosing and monitoring = standard dosing and no direct monitoring required
Advantages and disadvantages of DOAC?
good
- less frequent interactions than warfarin
- lower intracranial bleed risk than warfarin
- antidotes available (andexanet and idarucizumab)
- metabolism and elimination by several routes
bad
- bleeding (caution in GI bleed risk groups)
- dabigatran contraindicated in low creatinine clearance
- affected by CYP inhibitors
- plasma conc. reduced by: carbamazepine, phenytoin and barbiturates
- plasma conc. increased by: macrolides
- little information in use in pregnancy and breastfeeding so AVOID
