Anticoagulant drugs Flashcards by Anika Gouws

List the pharmacological classes of the relevant anticoagulants

Heparin

Direct thrombin inhibitors

Factor Xa inhibitors

Vitamin K antagonists

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What are the type of heparin?

Standard/ unfractionated heparin = Heparin

LMWH = enoxaparin, dalteparin, nadroparin

Heparinoid = danaparoid

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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

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Which is more selective for factor Xa, LMWH or Danaparoid?

Danaparoid is more selective for factor Xa than LMWH

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What do LMWH have the greatest effect on?

Greater effect on factor Xa than thrombin

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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

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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

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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

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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

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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

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What is the antidote to heparin?

Protamine sulfate

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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

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What are the to sub types of direct thrombin inhibitors?

Bivalent = two binding points

Univalent = one binding point

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List the drug names of the relevant direct thrombin inhibitors

Bivalirudin

Dabigatran etexilate (pro drug) –> dabigatran

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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

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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

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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