anticoagulation: pharm Flashcards
Three major natural anticoagulant pathways
- Tissue factor pathway inhibitor (TFPI)
- Protein C / Protein S pathway
- Anti-thrombin III ** (AT-III)
antithrombin AT inhibits coagulation:
- thrombin IIa
- FIXa
- FXa
- FXIa
what accelerates AT inhibitor function by more than 1000x
heparin sulphate
Heparin (3)
- unfractionated heparin
- low molecular weight heparins
- synthetic pentasacchardie
vitamin K antagonist
warfarin
direct thrombin inhibitors do not need _____ to work
AT-III
unfractionated heparin
- bioavailability
- administration
- half-life
- induces conformational change in _____ and augments it for neutralization of (4)
- impairs ____ function
- major adverse rxn
- low bioavailability
- poorly absorbed through GI thus it needs to be with SQ or IV
- 1-2 hr. half life
- induces conformational change in AT-III and augments it for neutralization of thrombin, Xa, IXa, XIa
- impairs platelet function
- HIT- heparin induced thrombocytopenia
HIT
- immune mediated?
- occurs
- happens more in
- males vs females
- thrombocytopenia
- b/c ab complex activated endothelial cells it leads to
- treatment
- yep- IgG against heparin PF4 complex
- occurs 4-10 days after starting heparin
- UF> LMWH
- females>males
- low platelet count
- thrombosis
- stop all heparin and give a direct thrombin inhibitor instead until platelet count is normal and then we can start warfarin
heparin neutralizing protein in alpha granules
platelet factor 4
LMWH
- common example
- synthetic analogue
- difference to UFH
- fondaparinux? significance?
- PTT prolongation?
- monitoring?
- platelet effect
- enoxaprin-lovenox
- pentasaccharide
- b/c chains are smaller than UFH, LMWH inhibits factor Xa» IIa-thrombin
- fondaparinux is a pure anti-Xa inhibitor which mediates effects through AT-III but there is no affinity for PF4 thus no HIT
- PTT is minimally prolonged b/c thrombin is not max. inhibited
- monitor- anti-Xa assay
- less anti-platelet effect than UFH
Anti- Xa: anti-IIa
UFH vs LMWH
UFH- 1:1
LMWH: 2:1 or 4:1
monitoring
UFH vs LMWH
UFH: APTT
LMWH: anti-Xa assay
frequency of HIT
UFH vs LMWH
UFH: high
LMWH: low
fondaparinux has an antidote
nope
reversal of heparin (2)
- discontinue drug
2. protamine sulphate UFH»LMWH
oral agent approved for stroke prevention in non-valvular atrial fibrillation; DVT, PE
dabigatran (direct thrombin inhibitor)
direct thrombin inhibitor
- hepatic clearance
- renal clearance
- how does it work?
- chances of HIT
- true or false: anticoag. response if predictable since they do not bind to endothelium or plasma proteins
- drug interactions
- antidote
- monitoring
- argatroban
- bivalirudin- off label for HIT
- inactivates thrombin bound to fibrin
- not neutralized by PF4 released from platelets thus no HIT or thrombocytopenia
- true
- no know drug interactions
- no antidote
- no monitoring
DTIs inactivate thrombin but unlike heparin it does so in an
antithrombin -independent fashion
Warfarin
- administration
- half life
- circulation
- activity
- inhibits
- VKORCI is a key enzyme in
- gamma carboxylation adds ____ which serve to
- variability
- oral- rapid absorption from gut
- 36-42 hr half life
- circulates free and bound to plasma proteins
- only free warfarin is active
- inhibits vit.k epoxide reductase subunit 1
- VKORCI is a key enzyme in recycling of Vit. K
- gamma carboxylation adds Gla residues to serve to anchor the clotting factors to phospholipid membranes via Ca2+ bridges
- variable response within a single patient
warfarin has Dose variability amongst patients due to variable metabolism
yep
Warfarin lab monitoring
- PT
- PTT
- Thrombin time
- PT- acute prolongation due to fall in FVII
- PTT- prolonged after a few days with decreased II, IX and X
- thrombin time is not affected by warfarin
thromboplastin reagent used in the PT assay is assigned an ISI (International Sensitivity Index) calibrated against a primary WHO standard thromboplastin
INR
Bridging from Heparin or DTI to Warfarin
- start warfarin while patient is still on heparin/DTI
- continue heparin/DTI doses until at least 5 days to ensure full anticoag.
- continue heparin/DTI until INR shows therapeutic levels
complications of warfarin (3)
- bleeding- supratherapeutic INR
- skin necrosis in patients with protein C deficiency
- teratogenic avoid in pregnancy
direct oral agent
- approved for use in stroke prevention in atrial fibrillation, DVT, PE
- antidote for 1
- monitoring
- direct factor Xa inhibitor and antidote and monitonring
- dabigatran
- idarucizumab–humanized monoclonal antibody fragment which binds to dabigatran
- no monitoring
- rivaroxaban- andexxa alpha is the antidote and for monitoring you can use anti-Xa levels for monitoring
A human protein derived from tissue culture using recombinant technology
(a native protein so no immune response)
rtPA
rtPA:
- act
- degrades
- cleared from plasma
- directly activates plasminogen
- degrades fibrin clot
- cleared from plasma in 4-8 minutes
indications for trhombolytic therapy (2)
- occluded central venous catheters (alteplase)
2. life or limb threatening situations
complications of thrombolytic therapy
- intracranial hemorrhage
are there contraidications to thrombolytic therapy
yep, major bleeds
Thromboxane A2 inhibitor
aspirin- anti-platelet agent
ADP-receptor antagonists
- Clopidogrel (Plavix)
- Prasugrel (Effient)
- anti-platelet agent
GPIIb/IIIa blockers
eptifibatide (Integrilin)
- anti-platelet blocker
PAR-1 receptor antagonists (thrombin)
Vorapaxar (Zontivity)
- antiplatelet agent
irreversibly acetylates cyclooxygenase preventing arachidonic acid conversion to prostaglandin and Thromboxane; impaired platelet aggregation
** indicated by secondary stroke, TIA
aspirin
via P2Y12 receptor – inhibits platelet aggregation
*indicated for ACS and PCI
ADP receptor antagonists
These drugs reversibly inhibit platelet aggregation by binding of GPIIb/IIIa – the site fibrinogen binding between platelets
GPIIb-IIIa antagonists
Thrombin receptor antagonists- thrombin activates platelets via PAR1 and 4
PAR-1 receptor antagonists (protease activated receptor)
