124 Anticoagulants Flashcards
1
Q
Summary, indirect vs direct anticoagulants
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2
Q
Heparin (Unfractionated)
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- Mast cells from pig intestines make heparin
- •Inactivated in gut; given IV, sc, or sublingual
- •Heparin-AT complex inhibits IXa, Xa, XIIa, VIIa-tissue factor complex as well as thrombin
- •Inhibits smooth mus proliferation, angiogenesis
- •Binds to acute phase reactants; bound forms usually inactive
- •Metabolism: liver and kidney
- •Subcutaneous absorption (5%-50%) & half-life (50-150 min) dose-dependent, unpredictable
- •Immediate-acting anticoagulant
- •To prevent thrombosis, 5-10,000 U sc every 8-12h
- •To treat thrombosis, 80 U/kg bolus IV, then 18 U/kg/hr as continuous infusion
- •Monitor treatment because T/2 variable
- • aPTT used to monitor & adjust dose
- •Check PTT after 4 hrs; want 55-80 s value
Adverse reactions
- •Bleeding-more frequent in elderly, small, women
- •Sites of bleeding: wound/soft tissue, GI, GU, ENT, retroperitoneal, CNS, lungs
- •Thrombocytopenia, but with thrombosis-due to antibodies that agglutinate platelets
- •Osteoporosis: enhances bone resorption, inhibits bone formation
- •Mild inhibition of aldosterone increases potassium
3
Q
Low Molecular Weight Heparin
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- all given Subcutaneously, with slightly diff MWs
- •Better than unfractionated heparin (UH) for many indications:
- -prevention of DVT/PE in medical & surgical patients
- -treatment of DVT/PE
- •More expensive than UH, but given sc and require no monitoring, so outpatient use is feasible
- •Infrequently cause thrombocytopenia or osteoporosis
- US approved: Enoxaparin, Dalteparin, Tinzaparin
4
Q
Unfractionated Heparin Advantages Disadvantages
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5
Q
Fondaparinux (Arixtra®)
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6
Q
Warfarin
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- •Slow-acting; requires 5 days of dosing to achieve therapeutic INR. This is because the decrease in clotting factors is based on their half-life; VII is shortest & declines most rapidly, but low levels don’t prevent thrombosis. Need to wait until IX and X are 20%-30%-takes 5 days of dosing
Drug interactions
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•Increase sensitivity
- -Antibiotics: erythromycin, fluconazole, INH
- -Cardiac: amiodarone, propranolol
- -Anti-inflammatories: piroxicam
- -GI: cimetidine, omeprazole
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•Increase resistance
- -Antibiotics: nafcillin, rifampin
- -Anticonvulsants: most
- -Other: sucralfate, cholestyramine
7
Q
Herbals & Anticoagulants
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8
Q
International Normalized Ratio (INR), too high?
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International Normalized Ratio (INR) Derived from Prothrombin Time (PT)
- •INR is ratio of patient PT to control PT, raised to ISI (int’l sensitivity index) power:
- INR = (Patient PT/ControlPT)ISI
- •ISI is specific for each thromboplastin reagent
- Example:
- -patient PT is 15 s;
- -control PT is 10 s;
- -for an ISI of 2, INR would be 2.25
9
Q
Monitoring Warfarin Therapy + Adverse Reactions
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- •Get baseline prothrombin time; genotype & clinically assess to estimate response to warfarin:
- •Sensitive: CYP2C9*(decreases warfarin clearance), elderly, diet poor in meat, fruit, vegetables (no vit K)
- •Resistant: VKOR mutations, young, full diet
- •Start with 2.5-10 mg, check INR daily, & adjust dose to achieve INR 2-3 (trial & error method)
Adverse Reactions
- •Bleeding: vit K poor diet, malabsorption; drug-interactions that alter warfarin binding, metabolism, or elimination; liver disease; genetic polymorphisms; older age.
- •Teratogenic-avoid during pregnancy, especially weeks 6-12 (warfarin embryopathy) and near term (fetal hemorrhage)
10
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11
Q
Warfarin Necrosis/Gangrene
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12
Q
DOACs
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- •Small molecule inhibitors of FXa (apixaban, edoxaban, rivaroxaban, betrixaban) or thrombin (dabigatran)
- •Indications: atrial fibrillation (all except betrixaban); prevention of major CV events in at-risk patients (rivaroxaban+aspirin); treatment of acute DVT/PE & VTE prophylaxis in hospitalized med/surgical patients
- •Monitoring: anti-Xa/anti-thrombin assays, but usually not necessary
- •Not indicated in patients with prosthetic heart valves
DOACs affect clotting tests
- •Factor Xa inhibitors prolong the PT > aPTT, & thrombin inhibitors prolong the aPTT > PT
- •Clotting factor assays give falsely low values
- •Protein C & S values are falsely increased
- •Lupus anticoagulant tests might be reported “positive”
- •FV Leiden assayed by the activated protein C resistance test might be falsely reported as absent
- •Therefore, delay testing for 4-5 days after stopping direct anticoagulant
Reversal Agents for Blooding or Surgery
- •Direct FXa inhibitors: Andexanet
- -Acts as a decoy, simulating FXa & binds apixaban & rivaroxaban
- -Also inhibits TFPI
- •Dabigatran: Idarucizumab binds dabigatran in 1:1 molar ratio
- •Expensive, potential for thrombosis, heart attack & stroke
Drug Interactions
- •Drugs that affect P-glycoprotein alter absorption & blood levels & those that affect cytochrome P450 3A4 alter metabolism & blood levels (anti-fungal, anti-viral, antibiotic agents)
- •May need to monitor drug activity; monitoring also for extremes of age, weight; liver/kidney impairment; compliance; thrombosis/bleeding while on treatment
- •Anti-Xa assay or dilute thrombin time
13
Q
DOACs vs Warfarin
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14
Q
Direct thrombin inhibitors derived from the leech anticoagulant
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15
Q
Direct Thrombin Inhibitors
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- •Inactivate clot-bound thrombin in addition to soluble thrombin.
- •Inhibit thrombin directly, without requiring
- antithrombin as a cofactor.
- •Prolong the prothrombin time, making it difficult to monitor concurrent warfarin therapy.
- •They are not inactivated by platelet factor 4 or heparinase
- •Bivalirudin is used during angioplasty because it has a short T/2; hemostasis rapidly recovers when drug is stopped.
