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43 Cards in this Set
- Front
- Back
What are two different types of heparin? |
Unfractionated (UFH)
LMWH (enoxaparin, dalteparin) |
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c/c heparin and warfarin: what do they do?
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Warfarin inhibits the synthesis of functional clotting factors
Heparin inhibits activated clotting factors. |
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What "starts off" the clotting cascade?
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The binding of tissue factor and VIIa (in the presence of calcium)
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Warfarin: what exactly does it do?
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Blocks vitamin K dependent γ-carboxylation of prothrombin (II) and factors VII, IX, X in the liver.
Inhibits the formation of active, reduced form vitamin K by antagonizing hepatic epoxide and quinone reductases. Kind of blocks the "recycling of vitamin K" |
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Warfarin: what if you are CYP2C9*2 or CYP2C9*3?
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Patients that are CYP2C9*2 or CYP2C9*3 require LOWER doses of warfarin.
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Warfarin: enantiomers
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S: more potent, metabolized via CYP2C9
R: less potent, metabolized via CYP1A2, CYP3A4 |
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Warfarin: what is a simple way to think about how drugs could increase the plasma concentrations of warfarin?
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Warfarin is 95-99% bound to albumin. Anything that "bumps off" warfarin from albumin will change the concentration.
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Warfarin: what is the active constituent?
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The free, unbound drug. Warfarin is highly bound to albumin, so this may account for the small volume of distribution and for the long plasma half life (36 hours)
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Warfarin: excretion
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hepatic, feces. Patients with liver dysfunction are at a greater risk of toxicity
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Warfarin: absorption
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in the gut
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Warfarin: when is its anticoagulant effect observed? Antithrombotic effect?
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The anticoagulant (due to degradation of factor VII, half-life: 6 hours) effect is seen in 8-12 hours.
The antithrombotic effect is seen 3-5 days after initiation (due to inhibition of prothrombin, half-life of 60 hours). This delay is related to the half-lives of the various clotting factors. |
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What effect does giving larger doses of warfarin have?
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It speeds the onset of anticoagulation, but beyond a certain dose there is no increase.
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What types of drugs interact with warfarin?
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Anything that inhibits CYP metabolism
(cimetidine, amiodarone, fluconazole, TMP/SULFA) --> less degradation of warfarin --> potentiation of anticoagulation. Anything that induce hepatic microsomal enzymes: Phenytoin, rifampin, alcohol --> increased degradation of warfarin --> procoagulant state |
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Warfarin and valproic acid
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Valproic acid can "bump" warfarin off of albumin
But there is a compensatory increase in clearance of warfarin with increased plasma concentration. |
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What foods are high in vitamin K?
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Green leafy vegetables.
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Warfarin: INR goal target. How is the INR calculated?
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2.0-3.0
(PTpatient/PTcontrol)^ISI |
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Warfarin: FDA approved test looks for polymorphisms in what two genes?
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CYP2C9, VKORC1
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Warfarin: what would you say about the theraputic index?
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It's narrow
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Warfarin: AE
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- Teratogenicity: can cross plactena and cause hemorrhage in the fetus. Can also cause bone abnormalities in the fetus.
- Hemorrhage |
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Warfarin: antidotes
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- vitamin K1 (phytomenadione)
- FFP - Clotting factor concentrate containing factor IX |
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warfarin: risk of hemorrhage depends on what?
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Intensity and duration of therapy.
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Heparin: MOA
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Heparin binds to antithrombin III (AT III) and increases its affinity for thrombin, IXa, Xa by 1000x. Heparin is a catalyst in this reaction.
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c/c unfractionated (high molecular weight) heparin with LMW heparin: effects on which clotting factors, efficacy, etc.
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HMWH binds to BOTH thrombin and antithrombin. Thrombin (IIa) > Xa + IXa
LMWH (enoxaparin, dalteparin) binds to ATIII and then selectively inactivates factor Xa. LMWH has much less affinity for thrombin. LMWH is four times more active than HMWH. Xa, etc >> thrombin (IIa) |
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c/c unfractionated heparin vs. LMWH: protamine sulfate as an antidote
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Protamine sulfate (a basic substance) works well for unfractionated heparin, but not very well for LMWH.
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Heparin: AE
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Hemorrhage, especially in elderly and with heavy alcohol intake.
Osteoporosis when taking heparin for several weeks. UFH > LMWH Thrombocytopenia: - Non-immune mediated (HAT) - Immune mediated (HIT) |
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HIT: pathogenesis
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Heparin --> antibodies to platelets --> thrombocytopenia
Heparin --> antibodies to platelets --> activation of platelets --> thrombosis LMWH does not affect platelet aggregation! |
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c/c LMWH and UFH: HIT
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LWMH does not affect platelet aggregation and therefore does not cause HIT!
HIT: 1-4% of patients on UFH for a minimum of 7 days will show signs. If you see HIT, discontinue heparin and administer fondaparinux. |
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Bivalirudin
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Anticoagulant: direct thrombin inhibitor
Synthetic 20 aa peptide Reversible Uses: Unstable angina Revascularization procedures. AE: minor bleeding "binds to thrombin and binds to receptor" (?) |
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c/c Bivalirudin and heparin
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Bivalirudin:
+ Predictable anticoagulation effect (B doesn't bind to plasma proteins) + No HIT - Excretion = urine, so half-life elimination increased as renal function diminishes. Renal dysfunction = reduction of dose needed. |
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What is the most common thrombotic complication of heparin?
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Venous thrombosis
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The interaction between heparin and AT III is mediated by what structure/molecule?
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"By a unique pentasaccharide sequence"
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Fondaparinux, Idraparinux
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Have an identical sequence to heparin's unique pentasaccharide sequence.
MOA: indirectly inhibits thrombin generation/activity Common AE: injection site hemorrhage Serious AE: anemia, major bleeding. Theraputic advantage: risk for heparin induced thrombocytopenia is greatly reduced. Indraparinux has a longer half-life. Uses: to prevent DVT (post orthopedic surgery), treatment of DVT, pulmonary embolism. |
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Idraparinux: advantages
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Increased half-life
Once a week dosing regimen |
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Name some anti-platelet agents and their MOAs
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Abciximab (REOPRO), Eptifibatide, Tirofiban: target the GPIIb/IIIa receptor complex to inhibit platelet aggregation.
Clopidogrel: ADP receptor antagonist Aspirin: Irreversible inhibition of cyclooxygenase |
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What are the drugs that are given for Acute coronary syndrome?
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Clopidogrel + aspirin.
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ASA inhibits COX leading to decreased production of what?
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Of thromboxane A2
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Clopidogrel: AE
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Pruritus, purpura, dyspepsia, rash.
Bleeding risk is low Rates of minor and major bleeding were higher in patients treated with clopidogrel + aspirin vs. placebo + aspirin. Can cause TTP (thrombic thrombocytopenic purpura) Contraindicated in patients with peptic ulcer or intracranial hemorrhage. |
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Clopidogrel: what type of drug, activated and metabolized where?
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Prodrug. Activated and metabolized in the liver via CYP2C19.
Dose adjustment may be needed for patients with hepatic disease. |
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Clopidogrel: drug-drug interactions
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Any substrate of CYP2C19
Inhibitors of CYP2C19 metabolism: PPIs (lansoprazole, rabeprazole), chloramphenicol, cimetidine, fluoxetine, ketoconazole, ticlopidine Other anticoagulants NSAIDs - Aspirin, naproxen, ibuprofen Herbals: Cat's claw, dong quai, evening primrose, feverfew, garlic, ginger, ginkgo, red clover, horse chestnut, green tea, ginseng |
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Name some thrombolytic agents (recombinant tissue plasminogen activators). Where is their site of action?
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Alteplase (Activase)
Reteplase (RETAVASE) Tenecteplase (TNKase) Site of action = clot (fibrin) |
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Tissue plasminogen activators: MOA
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cleaves plasminogen to active plasmin --> lysis of clot matrix.
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c/c Alteplase, Reteplase, Tenecteplase: half-lives, dosing, excretion
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Tissue plasminogen activator
Half-life: 5-10 min Hepatic metabolism Low antigenicity High fibrin specificity Low half-life Reteplase and Tenecteplase: have a longer half life - allow for bolus dosing! |
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What drug is used to inhibit fibrinolysis?
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Aminocaprocic acid (EACA)
Lysine analog that competes with lysine for binding sites on plasminogen and plasmin. Blocks interaction of plasmin with fibrin Main action mediated through inhibition of plasminogen activators rather than exerting antiplasmin activities. If administered IV, need slow dosing to prevent hypotension. |