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UFH MOA
amplifies the anticuagulant effect of antithrombin III (inhibits factors IIa and Xa).
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LMWH MOA
not big enough to bind both antithrombin III and factor IIa at the same time, only AT III (so effect largely due to influence on factor Xa)
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UFH monitoring
PTT guides UFH dosing (ideally 1.5 to 2.3 times normal)
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LMWH monitoring
more predicitable than UFH and doesn't mess with PTT, so no routine monitoring required. can look at antifactor Xa activity if needed.
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heparin contraindications
previous HIT, thrombocytopenia, active bleeding
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heparin SE
HITS (antibodies against platelet factor 4 produced, bind to platelets, activating them = thromboses, thrombocytopenia (being used up), excessive bleeding (being used up)). osteoporosis, hyperkalemia.
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heparin or warfarin in pregnancy?
heparin. warfarin not safe, revaroxaban also not safe.
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HIT and heparinoids
danaparoid has similar MOA, but not structurally related so safe to use in pts c HIT hx.
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heparin OD
UFH reversible c protamine (binds), LMWH has no antidote.
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direct factor Xa inhibitors MOA
factor Xa converts factor II to IIa (thrombin). inhibitors stop this conversion without using antithrombin III as an intermediary (like heparins)
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direct factor Xa inhibitors indications
postsurgical VTE prophylaxis, alternative to heparin in pts with severe HIT
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direct thrombin inhibitors MOA
binds to thrombin (factor IIa), inhibiting the conversion of fibrinogen to fibrin.
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direct thrombin inhibitors indications
postsurgical VTE prophylaxis. bivalirudin HIT.
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direct thrombin inhibitors reversible?
univalent inhibitors ("-gatr-") and bivalirudin are reversible, other bivalents are irreversible
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direct thrombin inhibitors advantage?
considered more predictable for anticoagulation as they are not bound to plasma proteins (heparin), are not neutralized by platelet factor 4 (heparin), and because they directly inhibit fibrin formation.
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direct thrombin inhibitors monitoring
bivalirudin can be monitored using PTT.
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vitamin K antagonists MOA
vitamin K is a key cofactor for the activation of factors II, VII, IX, and X. To work, it must be reduced by vitamin K epoxide reductase. warfarin inhibits VKOR.
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vitamin K antagonists kinetics
PO (unlike heparins). takes 2-3 days of tx before anticoagulation takes effect (because the inhibited proteins take that long to be cleared from the system)
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vitamin K contraindications
platelet disorders (if you have dysfunctional clotting cells and dysfunctional clotting proteins, you'll be in real trouble if you need a clot)
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why bridge warfarin therapy with heparin?
temporary hypercoaguable state due to inhibition of proteins C and S when first given
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warfarin target INR
2 to 3
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warfarin pharmacogenomics
there is significant genetic variability in response to warfarin owing to variants in 2C9 that metabolize the drug less efficiently and due to variants in VKOR
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salicylates MOA
like NSAIDS, salicylates inhibit cyclooxygenase (COX) enzymes, specifically irreversibly inhibiting COX-1's formation of cyclic endoperoxide
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salicylates contraindications
not for use in children (Reye's syndrome)
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salicylates SE
GI (reduced PG levels causes reduced mucous -> ulcers), bleeding, tinnitus (high doses)
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salicylates kinetics
ASA binds to platelets irreversibly, so duration of action is 5-7 days (lifespan of a platelet)
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salycilates and respiration
salycilates can stimulate respiratory centers directly or by increasing CO2 production, causing a potential acid/base issue (respiratory alkalosis)
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diflunisal
salicylate derivative that is a more potent analgesic and antiinflammatory, but isn't antipyretic
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adenosine diphosphate blockers MOA
inhibit the ADP-dependent pathway of platelet activation and subsequent sequestration.
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adenosine diphosphate blockers kinetics
clopidogrel slow, takes 5 days to achieve plateau
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ticlopidine contraindications (ADP blocker)
hematopoietic disorders (particularly neutropenia), thrombotic thrombocytopenic purpura (TTP)
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adenosine diphosphate blockers reversible?
ticagrelor reversible. all others irreversible (therefore long biologic T1/2, 5-7 day life of platelet)
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adenosine diphosphate blockers pharmacogenetics
various responses, from "clopidogrel unresponsive" (<10%) to 90% platelet inhibition, thought to be due to alterations in PGY12 receptor (VerifyNow P2Y12 assay).
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clopidogrel BBW
pts with CYP2C19*2 and CYP2C19*3 variants that there is reduced conversion of clopidogrel to its active thiol metabolite, resulting in ineffective protection.
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antiplatelet IIb/IIIa inhibitors MOA
fibrinogen and vWF bind to IIb/IIIa receptors, causing platelet binding and aggregation (activation and binding of other platelets). these drugs prevent this.
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antiplatelet IIb/IIIa inhibitors kinetics
IV. adciximab has the shortest T1/2 (10 min), but the longest effect (1 day) because it binds to the platelets
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fibrinolytics MOA
cleave plasminogen (endogenous) to form plasmin, a protease that digests fibrin, breaking up the clot. fibrin selective drugs require the presence of fibrin to cleave plasminogen, localizing their effects to the clot (in theory).
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fibrinolytics SE
non-selectives (streptokinase/urokinase) are both antigenic, so multiple uses are discouraged due to hypersensitivity reactions
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fibrinolytics bonus
tenecteplase more fibrin-specific than alteplase. reteplase works faster than alteplase.
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erythropoietins MOA
stimulates the production of RBCs (endogenous, targets progenitor cells in bone marrow, typically produced in the kidneys but a little bit in the liver)
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erythropoietins kinetics
epoetin has a shorter T1/2 (4-8h) vs darbepoetin (24h -- due to AA modifications)
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erythropoietins contraindications
uncontrolled HTN
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erythropoietins SE
iron deficiency (use an iron supplement), thrombosis (particularly c dialysis), HTN, seizures
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erythropoietins monitoring
Hem, aim for 10 (less chance of side effects). b/c RBCs have a long T1/2, dosing adjustments won't be seen for 2-6 wks.
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colony-stimulating factors MOA
stimulates the production of neutrophils and monocytes by binding to myeloid progenitor cells
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G-CSFs vs GM-CSFs?
G-CSFs stimulate neutrophils. GM-CSFs stimulate neutrophils and monocytes, as well as the actions (phagocytosis, superoxide production, cell-mediated toxicity) or neutrophils, monocytes, and eosinophils
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colony-stimulating factors kinetics
filgrastim T1/2 is 3-5h, the PEGgylated pegfilgrastim has an extended T1/2 of 40h (less easily titrated, but better for prophylaxis).
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colony-stimulating factor SE
bone loss, joint pain, renal dysfunction, acute respiratory distress, splenomegaly, sickle cell crisis
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ferrous iron vs ferric iron?
ferrous iron (Fe2+, from animals) is better absorbed than ferric iron (Fe3+, from veggies) in duodenum
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iron contraindications
previous anaphylaxis-like rxn to IV formulation (particularly iron dextran - test dose!)
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iron SE
GI including black stool.
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iron kinetics
take on an empty stomach, as many foods mess with absorption. ascorbic acid (Vit C) enhances absorption
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iron toxicity
deferoxamine (chelators), phlebotomy
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