Pharmacology of anticoagulants Flashcards
Aspirin
Anti-platelet agent
Inhibits platelet COX by acetylation
Prevents synthesis of thromboxane A2 (eicosanoid hormone synthesized from arachidonic acid)
Stops thromboxane A2-induced platelet activation and aggregation
Reduces platelet plug formation at early stage
Calcium chelators
Metal chelators such as citrate and EDTA
Strip Ca from Gla proteins –> cannot bind to phospholipid membranes
Reversed by adding excess Ca
Anticoagulant used by CBB for blood collection
After transfusion, citrate is used in TCA cycle to generate ATP
Coumarol drugs
blood thinners
warfarin = synthetic version
Inhibit reduction of vitamin K in the liver
Vitamin K becomes limiting –> Gla-less proteins made by liver (prothrombin, factor IX, factor X, factor VII, protein C, protein S, protein Z)
Gla-less proteins do not bind Ca so no conformational change
Gla-less proteins cannot bind to the membrane at the site of injury
Clotting inhibited until coumarol is replaced by vitamin K
Long-term anticoagulation in thrombosis-risk patients
Need continuous monitoring of coagulation potential
Warfarin PK
well absorbed po (100%)
active in vivo, as it acts on liver
delayed onset of anticoagulation
slowly/surmountably antagonized by vitamin K
Highly (99%) plasma protein bound - fat soluble vitamin
Its effect can be altered by diet (broccoli)
Good rodenticide
Prolongs prothrombin time
Warfarin indications
Prophylaxis and Tx of VTE (DVT, PE) Prophylaxis and Tx of a-fib valvular stenosis heart valve replacement MI Antiphospholipid syndrome
Warfarin CIs and precautions
Hypersensitivity to warfarin risk of hemorrhage hemorrhagic tendency inadequate lab techniques Vit-K deficiency im injections NSAIDs (aspirin)
Warfarin SEs
hemorrhages skin necrosis purple toe syndrome microembolism teratogenecity agranulocytosis, leukopenia, diarrhea, nausea, anorexia
Factors influencing dose-response of warfarin
Inaccurate lab testing poor patient compliance drug interactions levels of dietary vitamin K Alcohol hepatic dysfunction
Monitoring of warfarin therapy
Narrow therapeutic range
can increase risk of bleeding
can measure INR/PT from drop of blood on hand-held device
Heparin
Polysaccharide: mixed polymers +sulfated sugars (glucosamine, iduronate and glucuronate)
very highly negatively charged
Heparin sulfate proteoglycans are physiological form: found on endothelial cells in vessel wall
Commercial heparin: pig gut mucosal scraping
Heparin MOA
Activates antithrombin (increase in flexibility of reactive site loop)
Contains bindings sites for antithrombin and thrombin/factor Xa
Serine protease inhibitor/serpin
Thrombin/Factor Xa cleave a bond in the reactive centre loop of antithrombin –> conformational change, wraps itself around the protease –> inactivation of thrombin and factor Xa (mousetrap inhibitor)
AT + H –> AT:H (activated form) –(thrombin, factor Xa - enzymes)–> AT:E H
covalent complex between thrombin and antithrombin - inactivated
Heparin - different sizes
Unfractionated: 9-90 sugars
LMW heparin: ~23 sugars
Synthetic (fondaparinux): 5 sugars
Any size of heparin chain can accelerate the inhibition of Xa by antithrombin
Only heparins >18 sugars can accelerate the inhibition of thrombin by antithrombin
Advantages of LMW-H over UH
Decrease heparin resistance
- PK of UH influenced by binding to plasma proteins, endothelial cell surfaces, macrophages and acute phase reactants
- LMWH has decreased binding to non-anticoagulant-related proteins
No need for lab monitoring (when given on weight-adjusted basis, response is predictable and reproducible)
Higher bioavailability (90 vs 30%)
Longer plasma half-life (4-6 hrs vs 0.5-1 h)
Less inhibition of platelet function
Lower incidence of thrombocytopenia and thrombosis
Antibodies can be formed against a heparin-platelet factor 4 complex: antibodies can activate platelets leading to thrombosis and platelet consumption
- less interaction of LMWH with factor 4
Heparin: effects and route of administration
Not an anticoagulant itself active in vivo and in vitro must be injected (highly charged) effects may be reversed by protamine sulfate (a polycationic protein that complexes with heparin) causes immediate anticoagulation may cause fatal thrombocytopenia
Direct inhibition of thrombin and factor Xa
New oral anticoagulants
Computer-designed small molecule inhibitors
Bind tightly to active sites of proteases
Rivaroxaban - inhibits Xa
Dabigatran - inhibits thrombin
Advantage: do not require continuous monitoring of clotting time
Disadvantage: no current antidote
