Anti-Coagulant

Question 0

Warfarin (Coumadin)

Answer 0

Class: vit K antagonist, anti-coagulant
contraindicated in pregnancy
MOA: inhibits the synthesis of active coagulation factors 2, 7, 9, 10
Indication: primary and secondary prevention of venous thromboembolism, primary and secondary prevention of arterial thrombosis, stroke prevention in atrial fibrillation, mechanical heart valves, failure of antiplatelet therapy
PK: oral dose rapidly and extensively absorbed from GI, peaks 90min after ingestion, extensively protein-bound in plasma, crosses placenta, active form does not enter breast milk, metabolized via P450, metabolites excreted in urine, half life 33h
PD: prolongs PT and aPTT, slow onset action demands that warfarin be started concurrently with fast acting anticoagulants such as heparin and LMWH
ADR: bleeding, skin necrosis, teratogenic during early fetal development
Special: many conditions alter warfarin effect on anti-coagulation, such as medications, foods rich in vit k, liver disease, CHF, malnutrition, hypermetabolic states, gastric bypass surgery, pharmacogenetics. Reverse warfarin effect with vit k, fresh frozen plasma (most immediate), prothrombin complex concentrates

Question 1

Heparin

Answer 1

Class: anti-coagulant, highly sulfated glycosaminoglycan
MOA: accelerates (inhibition coagulation factors by) antithrombin
Indication: primary prevention of venous and arterial thrombosis, secondary prophylaxis of acute venous and arterial thrombosis
PK: 100% in iv, effect immediate, binds widely to plasma proteins, subcutaneous, poor bioavailability, effect 1-3h after. No po, im. Complicated non-linear clearance, initial/rapid where it binds plasma proteins and receptors on endothelial cells and macs, and second/slow renal phase
ADR: bleeding, osteoporosis, skin lesions, hypoaldosteronism, heparin-induced thrombocytopenia (type 2 HIT)–igG directed against heparin antigen on platelet, occurs in 5-15 days of initiation of therapy, generally modest thrombocytopenia effect -50k/ul
Special: does not cross placenta, anticoagulant of choice in pregnancy. Reverse heparin effect with discontinuation, protamine sulfate (though od of this will exacerbate bleeding)
C.f. Protamine sulfate ionically combines with heparin to form a stable, inactive complex.

Question 2

Argatroban, Bivalirudin

Answer 2

Class: Parentral direct thrombin inhibitor
Indication: argatroban-prevention of thrombosis in HIT, bivalirudin-percutaneous coronary intervention when heparins are contraindicated (HIT)
MOA: bind and inactivate thrombin
PK: iv use, no antidote but short half-lives .5-2h

Question 3

Davigatran (Pradaxa), Rivaroxaban (Xarelto), Apixaban (Eliquis)

Answer 3

Class: Target specific oral anticoagulants
MOA/targets: dabigatran-thrombin (IIa), ribaroxaban-Xa, apixaban-Xa
PK: oral prodrug which gets converted to active drug by liver, peak 2-3h, half life 12-17h, renal clearance/active drug metabolized by CYP3A4, peak 3h, half life 5-9h, majority renal, some biliary clearance/peak 3h, half life 9-14h, majority biliary, some renal clearance.
Dosing: all qd, bid
Only dabigatran is dialyzable

Question 4

Recombinant tissue plasminogen activator (rTPA), Urokinase plasminogen activator, Streptokinase

Answer 4

Class: fibrinolytic agent (“clot buster”)
Indication: acute ischemic stroke, coronary or peripheral arterial occlusion, massive pulmonary embolism, extensive iliofemoral DVT, clear occluded central venous catheters
MOA: the first two convert plasminogen to plasmin which degrades fibrin, the last binds to plasminogen and the complex degrades fibrin.
ADR: bleeding
C.f. Herbs/supplement/others that have anti-coagulant effect include SSRI, feverfew/willowbark, ginko, garlic, ginger, fish oil, PC-SPES

Question 5

Enoxaparin, Dalteparin, Tinzaparin

Answer 5

Class: low molecular weight heparin
PK: subcutaneous administration, allows for self injection at home
Compared to Heparin: anti-Xa:anti-IIa ratio is higher than heparin at 2-4:1 to >20:1, effects on aPTT is minimal, higher bioavailability, predominantly renal clearance, dose-independent half life 2-5h, HIT <1% lower than heparin
Disadvantages: long half life may be a problem in bleeding pt as there is no good antidote, renal excretion makes use in renal insufficiency difficult