Anticoagulant drugs Flashcards
List the pharmacological classes of the relevant anticoagulants
Heparin
Direct thrombin inhibitors
Factor Xa inhibitors
Vitamin K antagonists
What are the type of heparin?
Standard/ unfractionated heparin = Heparin
LMWH = enoxaparin, dalteparin, nadroparin
Heparinoid = danaparoid
What is the MOA of Heparin?
Heparin binds to antithrombin > elongation of antithrombin binding site > the antithrombin then binds to thrombin > blocks binding of thrombin to fibrin
targets unbound thrombin
Which is more selective for factor Xa, LMWH or Danaparoid?
Danaparoid is more selective for factor Xa than LMWH
What do LMWH have the greatest effect on?
Greater effect on factor Xa than thrombin
List the ADRs of Heparin
Bleeding (dose dependent), bruising, pain in injection site, skin necrosis (injection site)
mild reversible thrombocytopenia
hyperkalaemia (monitor for use of ACEi, ARB, K+ sparring diuretics)
inc liver aminotransferase
Osteoporosis and alopecia (long term)
Allergic reaction (urticaria, anaphylaxis) = the drug is a protein
What is classes as severe thrombocytopenia?
Platelet count drops by 30-50% below normal –> heparin use in contraindicated in this circumstance cuz it can further decrease platelet count
When does heparin induced thrombocytopenia usually occur?
occurs within 5-10 days of treatment
may be earlier if patient has been exposed to heparin (<100 days)
delayed onset = several weeks after stopping heparin
Compare Heparin with LMWH and Danaparoid
In renal impairment, risk of bleeding is greater with LMWH and will require dose adjustment. Conversely, heparin has a lesser risk of bleeding in severe renal failure. With both Danaparoid and LMWH heparin in renal failure, monitor Xa levels.
Danaparoid, less risk of bleeding and used over Heparin or LMWH in heparin induced thrombocytopenia (HIT).
LMWH carry a lesser risk of osteoporosis
What should be monitored with heparin use? How?
Heparin in monitored with aPTT or APTT time = activated partial thromboplastin time
APTT time = measures activity of intrinsic coagulation pathway
What is the antidote to heparin?
Protamine sulfate
Describe the MOA of protamine sulfate
combines with heparin > forms inactive complex - onset 5 mins
*only partially effective in reversing LMWHs, not used for danaparoid
*has anticoagulant effect in overdose or absence of heparin
*Not used fir denaparoid overdose
What are the to sub types of direct thrombin inhibitors?
Bivalent = two binding points
Univalent = one binding point
List the drug names of the relevant direct thrombin inhibitors
Bivalirudin
Dabigatran etexilate (pro drug) –> dabigatran
What is the MOA of bivalirudin (bivalent direct thrombin inhibitor)?
Dabigatran binds to both exosite 1 and exosite 2 of thrombin > prevents the binding of fibrin to thrombin > inhibits platelet aggregation
Both bound and unbound thrombin
What is the MOA of dabigatran (univalent direct thrombin inhibitor)?
Bivalirudin binds to thrombin in the fibrin binding site > prevents fibrin from binding to thrombin > prevents platelet aggregation
Both bound and unbound thrombin
What are some characteristics of direct thrombin inhibitors?
Reversible inhibition
prevent conversion of fibrinogen to fibrin –> Inhibits thrombus formation
Inhibits thrombus induced platelet aggregation -> stops surface thrombin from binding/rec other platelets
antiplatelet effect = reducing thrombin-mediated activation of platelets
What are the ADRs of direct thrombin inhibitors?
Bleeding, signs of bleeding (anaemia, hypotension)
GI symptoms - Gastritis, dyspepsia, GI bleeding, oesophageal ulcers
What is used to reverse the actions of direct thrombin inhibitors?
Idarucizumab
It is a humanised monoclonal antibody fragment
Describe the MOA of idarucizumab
Binds to dabigatran and metabolites > forms stable inactive complex
immediate effect
List the relevant factor Xa inhibitors
Rivaroxaban (oral), apixaban (oral), fondaparinux (IV)
What is the MOA of direct Xa inhibitors?
Bind and inhibit factor Xa > prevents the conversion for factor II (prothrombin) to factor IIa (thrombin) > preventing the conversion of fibrinogen to fibrin > prevents platelet aggregation and coagulation
List the ADRs of factor Xa inhibitors
Bleeding (signs of bleeding = anaemia, tachycardia, hypotension)
What are some concerns with factor Xa inhibitor use?
No method to guide dosing
No antidote
List the relevant vit k antagonist
Warfarin (also phenidione)
What is the MOA of warfarin?
Warfarin inhibits VKORC (vitamin K epoxide reductase) > inhibits formation of Vit K epoxide to active Vit KH2 > inhibition of vit K dependent clotting factor synthesis
Knowing that warfarin is a racemic mixture, which isoform is more potent?
S isomer of warfarin is 5 times more potent anticoagulant
What P450 enzyme inactivates warfarin?
CYP2C9 = highly polymorphic
Discuss some facts about warfarin
Effect of warfarin dependent on clearance of preformed clotting factors
Initial INR inc occurs 24-36 hrs after first dose, this is not associated with antithrombotic effect
Takes 2 half-lives to express antithrombotic effect (up to 5 days), max effect 48 hrs after administration, can last for next 5 days
When is warfarin use indicated?
Prevention/treatment of VTE
Prevention of thromboembolism in patient with prosthetic hear valve
Prevention of stroke in people with hx of MI, inc embolic risk
non-valvular AF and high risk of stroke or systemic emboli
TRUE or FALSE
Warfarin is not a narrow therapeutic index drug
FALSE
Warfarin is a narrow therapeutic index drug, completely orally absorbed
peak action - after 4 hrs
Mostly hepatically cleared
t1/2= 20 to 60 hrs (mean 40hrs)
What is used to monitor warfarin?
Prothrombin time (PT) = determines prothrombin ratio (PR) and international normalised ratio (INR)
PT = responds to reduction of three of the four vit K clotting factors (II, VII, X)
Discuss the INR for warfarin
INR = 5 - high chance of bleeding
INR = 0.5 - high chance of clotting
Normal INR range = 0.9 - 1.3
What are the INR targets for warfarin therapy?
Less intense range INR = 2.0-3.0
High intense range INR = 2.5-3.5 (bigger clot risk)
What factors influence warfarin?
drug interactions
elderly = exaggerated response due to less vit k
Heavy alcohol = inc liver metabolism, less Vit K, inc risk of falls, poor diet, poor compliace
Amount of Vit K in diet = watch for dark green veggies high in vit K
When should monitoring be done for warfarin?
INR tested = after starting, after stopping/changing dose of other meds, other situations that could affect INR
INR: measure once a week after change in med to reflect clinically sig interaction
When is bleeding rate doubled for warfarin use?
INR increase from 2.0-2.9 to 3.0-4.4
50% bleeding = INR <4.0
What are some bleeding risk factors for warfarin?
> 65 y/o
Uncontrolled hypertension
Hx GI haemorrhage, active peptic ulcer, hepatic insufficiency
Thrombocytopaenia
HX stroke, cognitive, psychological impairment
Renal insufficiency
recent trauma, hx falls
excessive alcohol, mediations
What is used to reverse wrafarin?
Phytomenadione (Vit K1) is used to reverse warfarin = delayed
Fresh frozen plasma with clotting factors
List some ADRs with warfarin use
skin necrosis
purple discolouration of toes
alopecia, fever, rash
nausea, vomiting, diarrhoea
hepatic dysfunction, allergic reaction
What are the considerations for warfarin in pregnancy?
Category D = risk of teratogenicity, foetal or placental haemorrhage
May be used in tri2 = may be more effective than heparins in women with prosthetic heart valves
