Pharmacology of Anticoagulants Flashcards
1. Describe the pharmacodynamics, pharmacokinetics, adverse effects and indications of/for heparin (unfractionated and low molecular weight) 2. Describe the pharmacodynamics, pharmacokinetics, adverse effects, drug interactions and indications of/for warfarin and the newer oral anticoagulants 3. Describe the mechanism of action, adverse effects and indications of/for thrombolytic agents
How clots form
- Vessel damage
- Platelets adhere to site of injury
- Activation of clotting cascade n activated platelet surface by tissue factor (factor VIIa)
Fibrin clot formation - function of fibrin deposition
Fibrin deposition stabilizes the platelet thrombus
Targets for anti-coagulation
- Anti-platelet agents
- Chelate calcium ions
- Inhibit liver carboxylation of Gla proteins
- Accelerate inhibition of thrombin and factor Xa by antithrombin
- Directly inhibit thrombin and factor Xa
- Thrombolytic agents
Anti-platelet agents
Asprin
Chelate calcium ions
- citrate
- EDTA
Inhibit liver carboxylation of Gla proteins
-coumarol drugs such as coumadin and warfarin
Drugs that accelerate inhibition of thrombin and factor Xa by antithrombin
Heparin
Drugs that directly inhibit thrombin and factor Xa
New oral anticoagulants
Drugs that are thrombolytic agents
tPA
MOA of asprin
1) Inhibits platelet cyclo-oxygenase by acetylation
2) Prevents synthesis of thromboxane A2
3) Stops thromboxane A2 -induced platelet activation and aggregation thereby reducing platelet plug formation at early stage
Calcium chelators MOA
- i.e. metal chelators such as citrate and EDTA
1) Strip Ca2+ from Gla proteins
2) Non-Ca2_ Gla proteins cannot bind to phospholipids
3) Reversed by adding excess Ca2+
Coumarol drugs MOA
1) inhibit reduction of vitamin K in the liver
2) Vitamin K becomes limiting and Gla-less proteins made by liver (inhibit liver carboxylation of Gla proteins: prothrombin, factor IX, factor X, factor VII, protein C, protein S)
3) Gla-less proteins do not bind Ca2+ so no conformational change
4) Gla-less proteins cannot bind to membrane at the site of injury
5) Clotting inhibited until coumarol is replaced by vitamin K
History coumarol drugs
- dicoumarol discovered when cows bled after eating sweet clover
- warfarin is a synthetic version
Warfarin bioavailability
Well absorbed orally (100% bioavailability)
Warfarin onset
-delayed onset of anticoagulation
Surmounting warfarin
Surmountably antagonized by vitamin K
Can have its effect altered by diet (broccoli)
Warfarin solubility
Highly (99%) plasma protein bound - fat soluble vitamin
net effect of warfarin
Prolong prothrombin time
Indications for warfarin (6)
- Prophylaxis and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism)
- Prophylaxis and treatment of atrial fibrillation
- Valvular stenosis
- Heart valve replacement
- Myocardial infarction
- Antiphospholipid syndrome
Contraindications and precautions
- Hypersensitivity to warfarin
- Condition with risk of hemorrhage
- Hemorrhagic tendency
- Inadequate laboratory techniques
- Vitamin K deficiency
- Intramuscular injections
- Non-steroidal anti-inflammatory drugs (asprin)
Side effects of warfarin
- Hemorrhage
- Skin necrosis
- Purple toe syndrome
- Microembolism
- Teratogenecity
- Agranulocytosis
- Leukopenia
- Diarrhea
- Nausea
- Anorexia
Factors influencing dose response
- Inaccurate laboratory testing
- Poor patient compliance
- Concomitant medications
(drug interactions) - Levels of dietary vitamin K
- Alcohol
- Hepatic dysfunction
Why monitor warfarin therapy
- Narrow therapeutic range
2. Increased risk of bleeding
How to monitor warfarin therapy
-measure PT and INR from drop of blood (hand-held devices)
Composition of heparin
-polysaccharide composed of mixed polymers of sulfated sugars (glucosamine, iduronate, glucuronate)
Charge of heparin
Very negatively charged
Heparin MOA
1) Contains binding sites for antithrombin and thrombin/factor Xa
- antithrombin = serine protease inhibitor (serpin)
2) Cleaved antithrombin undergoes a conformation change = mousetrap inhibitor
3) Mouse trap inhibitor wraps round a protease and renders the thrombin inactive
4) thrombin or factor Xa is rendered inactive
AT + H AT:H (activated complex) – (thrombin factor Xa)–> AT:E + H (covalent complex between thrombin an antithrombin = inactive)
Variability in function of thrombins based on size
- any size of heparin chain can accelerate the inhibition of factor Xa by antithrombin
- only heparin chains > 18 sugars can accelerate the inhibition of thrombin by antithrombin (heparin must bind to AT and thrombin)
Advantages of LMWH over UH
1) Decreased heparin resistance
2) No need for laboratory monitoring
3) Higher bioavailability (90% vs 30%)
4) Longer plasma half life (4-6 hrs versus 0.5 to 1 hr)
5) Less inhibition of platelet function
6) Lower incidence of thrombcytopenia and thrombosis
7) Antibodies can be formed against a heparin-platelet factor 4 complex - these platelets can ativate platelets leading to thrombosis and platelet consumption (less interact of LMWH with platelet factor 4 so less chance of heparin-dependent IgG antibodies)
Decreased heparin resistance with LMWH vs UH why?
Pharmacokinetics of UH are influenced by binding of plasma proteins, endothelial cell surface, macrophages an acute phase reactants
-LMWH has decreased binding to non anticoagulant related proteins
Why no need for laboratory monitoring
When given on weight -adjusted bases LMWH response is predictable and reproducible
How to reverse the effects of heparin
Effects may be reversed by protamine sulfate (a polycationic protein that complexes with heparin)
Immediate effect of heparin
Causes immediate anticoagulation
Worst side effects of heparin
May cause fatal thrombocytopenia
Direct inhibition of thrombin and factor Xa MOA
Computer-designed small molecule inhibitors
Bind tightly to active site of proteases
a) Rivaroxaban - inhibits factor Xa
b) Dabigatran - inhibits thrombin
Advantage/disadvantage of direct inhibition of thrombin and factor Xa
- Advantage: do not require continuous monitoring of clotting time
- Disadvantage = no current antidote
Thrombolytic agents MOA
-activate plasminogen to plasmin
Example of thrombolytic agents
1) Tissue plasminogen activator
2) Urokinase
3) Streptokinase (bacterial)
Use of thrombolytic agents
Used for ischemic stroke (caused by blood clot)
