Anticoagulants Flashcards
Describe the coagulation cascade
Intrinsic pathway - exposed collagen: 12, 11, 9, 8
Extrinsic pathway - tissue factor: 7
common pathway - 10a (5a) prothrombin2 -> thrombin 2a fibrinogen -> fibrin (13) -> fibrin clot
See slide 4
Coagulation factors present in blood as inactive zymogen, serine proteases & cofactors
What happens to regulate the coagulation cascade naturally?
Number of intrinsic inhibitors of this pathway including antithrombin 3
Vascular endothelium regulates many mediators
Calcium - important cofactor
How do heparin work? What are the two types? Compare the two types
Inhibits coagulation in vitro and in viva - enhanced antithrombin 3 activity 1000-fold
Also inhibits factors: 12a, 11a, 9a, 10a, thrombin 2a
Unfractionated heparins - large 5-30 KDa, subcut, 30min t1/2 low doses/ 2hrs high, uses: severe renal impairment & fine control
Low molecular weight heparins - 1-5 KDa, rapid liver or slower renal excretion, subcut, t1/2 2+hrs, uses: most situations
Describe unfractionated heparin, how it is given and how it works
t1/2 30min low dose, 2hr higher doses, fast onset of action
Typical IV bolus & infusion, subcut for prophylaxis much lower bioavailability
Binds to antithrombin causing conformational change & increased activity of AT3 this binding also cause 10a inhibition, also binds to 2a to catalyse inhibition
Describe low molecular weight heparin, give examples, how it is given, how does it work?
Bioavailability >90%, longer t1/2 2+ hrs independent of dose
E.g. dalteparin, enoxaparin
Most predictable dose response as doesn’t bind to endothelial cells, plasma proteins & macrophages as not long enough
Doesn’t inactive thrombin
Inhibits 10a by enhancing AT3
Fondaparinux - synthetic selectively inhibits 10a by binding AT3 - subcut
Indications for heparins
Prevention of venous thromboembolism
Perioperative prophylaxis with LMWH duration & dose dependant on risk
Used during pregnancy with monitoring
VTE - DVT & PE
Initial treatment prior to oral agents
Long term in some groups
Acute coronary syndrome - short term reducing recurrence/ extension coronary artery thrombosis post STEMI - PCI and non PCI NSTEMI
Adverse reactions heparin
Brushing, bleeding (intracranial, site of injection, GI epistaxis hepatic and renal impairment, elderly or those with carcinoma at higher risk
Heparin induced thrombocytopenia, automimmune response 2-14 days after initiation of heparin antibodies to heparin platelet factor 4 complex, depletion of platelets, can lead to thrombosis as more platelets activates
Hyperkalaemia - inhibition aldosterone
Osteoporosis - rare long term use, higher risk with UFH and more prevalent in pregnancy
Heparin monitoring
- activated partial thromboplastin time (aPTT) - UFH dose titrations against this value
LMWH much more predictable in action little monitoring
Heparin reversal
Protamine sulphate
Forms inactive complex with heparin - given I.v dissociates heparin from AT3 , irreversible binding, dose guided by heparin dose, can cause bleeding - in vitro test if unsure
- greater effect with UFH, no affect on fondaparinux
How does warfarin work?
VitMin K antagonist - inhibits activation of VK dependent clotting factors which convert VK to active reduced form - competitive inhibition of VKOR (epoxide reductase)
Hepatic synthesis of active clotting factors 2/7/9/10 require active VK cofactor
Circulating active clotting factors present several days so delayed onset of action
t1/2 36-48hrs
Indications for warfarin
Venous thromboembolism PE DVT Superficial vein thrombosis A fib with high stroke risk Cardio version ❤️valve replacement bio prosthetic/ some mechanical
Generally used longer term anticoagulation
Slow onset of action likely needs heparin cover if acute need
Warfarin pharmacokinetics
Good GI absorption
Taken orally - 95% bioavailability
CYP2C9 polymorphism - significant inter individual variability, VK intake also affects
[plasma] doesn’t correlate directly with clinical effect
Mixture of 2 enantiomers - R and S have different potency and metabolised differently
Crosses placenta - avoided at least 1st (teratogenic) & 3rd trimester (haemorrhage)
Adverse drug reactions to warfarin
BLEEDING
Epistaxis
Spontaneous retroperitoneal bleeding
Antidote to warfarin
VK1, prothrombin complexConcentrate I.V
Warfarin drug drug reactions
Huge number
Inhibition of hepatic metabolism especially CYP2C9: amiodarone, clopidogrel, intoxicating dose alcohol, quinolone, metronidazole
Reduce VK - cephalosporin antibiotics (eliminate gut bacteria)
Displacement from albumin - NSAIDS, drugs decrease GI absorption of VK, likely increase INR
Acceleration of warfarin metabolism: barbiturates, phenytoin, rifampicin, St. John wort, likely decrease INR
