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module 2b > 11/5 > Flashcards

11/5 Flashcards

1
Q

slow PT

A

(prolonged time)
defect in extrinsic or common coagulation pathways
-warfarin therapy

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2
Q

slow aPTT

A

(prolonged time)
defect in intrinsic or common coagulation pathways
-heparin therapy

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3
Q

therapeutic INR

A

2-3

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4
Q

Oral anticoagulant examples

A

coumarin

indandione - not used clinically

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5
Q

coumadin MOA

A

inhibits vitamin K-epoxide reductase - blocking reduction of vit K epoxide back to its active form
vit K is needed to form prothrombin

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6
Q

warfarin therapeutic actions

A

delayed onset - must deplete pool of circulating clotting factors, maximal effect is not observed until 3-5 days after initiation of therapy
after discontinuing therapy: factors must be resynthesized to return to normal PT

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7
Q

warfarin metabolism

A

metabolized by CYP2C9 - lots of variability

t1/2 = 36-48 hours

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8
Q

warfarin termination of action

A

is not correlated with plasma drug levels, but reestablishment of normal clotting factors

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9
Q

warfarin overdose

A

latrogenic hemmorrhage

  • discontinue warfarin therapy
  • administer Vit K1 - can activate warfarin-inhibited reductase
  • in serious hemorrhage - plasma replaces clotting factors faster tan Vit K therapy
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10
Q

warfarin adverse effects

A

latrogenic hemorrhage
-risk of bleeding increases with intensity and duration of therapy
use during pregnancy
-CI in women who are or may become pregnany
-passes freely through placenta
-spontaneous abortions
-fetal hemorrhage
-birst defect: nasal hypoplasia and abnormal bone formation

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11
Q

drug interactions with warfarin - increased prothrombin time

A

PK - amiodarone, cimetidine, disulfiram, metronidazole, fluconazole, gemfibrozil, sulfinpyrazone
PD - aspirin, cephalosporins

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12
Q

drug interaction with warfarin - decreased prothrombin time

A

PK - barbituates, cholestryamine, rifampin

PD - diuretics, vit K

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13
Q

parenteral anticoagulants

A
  • heparin (unfractionated heparin - UFH)
  • LMWH
  • non-heparinoids
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14
Q

heparin MOA

A
  • binds to positively charged to antithrombin III (AT)
  • increases the rate at which AT interacts with plasma proteases clotting factors (1000 fold increase)
  • dissociates and can interact with more AT

AT can inactivate throbmin and factors Xa, VIIa and IXa

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15
Q

heparin administration

A

intermittent IV, continuous IV, SC

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16
Q

heparin clinical use

A
  • adjust dosing according to coag tests - aPPT therapeutic range = 1.5-2 x normal
  • t1/2 30-180 min
  • anticoag effect dissappears within hours of discontinuation of therapy
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17
Q

heparin hemorrahge

A
  • iatrogenic hemorrhage
  • can occur at any site
  • risk factors: over 50, ulcer patients, severe HTN, antiplatelet drugs
  • treatment: stop heparin, adm specific antagonist if life-threatening (protamine sulfate)
18
Q

heparin other AEs

A
  • thrombocytopenia:
  • mild, transiet (25%) due to direct action on platelets
  • severe (5%) develops 7-12 days after starting therapy antibodies develop to platelet (PF4)-heparin complex

osteoporosis: associated with extended therapy (3-6 mo)

19
Q

heparin chemistry

A
  • straight-chain sulfated mucopolysaccharies produced by mast cells and basophils
  • mixture of 5-30 kDa compounds
  • extraced from porcine small intestine or bovine lung
  • anticoag activity standardized by bioassay
  • sulfate groups (negative charge) required for binding to AT
20
Q

LMWH

A

2000-9000 daltons

  • obtained from depolymerization of unfractionated porcine heparin
  • comparison to standard heparin: equal efficacy, increased bioavailability from SQ adm, less frequent dosing - longer t1/2 than heparin, no monitoring of clotting needed
21
Q

LMWH MOA

A
  • binding AT is sufficient for factor Xa inhibition
  • preferentially inhibit factor X
  • only slightly affect thrombin activity
  • Pt and aPTT are insensitive measures of activity
22
Q

advantages of LMWH

A
  • more predictable PK profile: good bioavailability from SQ inj site, less protein binding/more uniform dosing, longer half life
  • lower incidence oh thrombocytopenia and osteoporosis
23
Q

fondaparinux

A
  • factor Xa inhibitor
  • synthetic sulfated pentasaccharide
  • mechanism: indirectly inhibits factor Xa by selectively binding AT
  • given SC - can be adm at home
  • t1/2: 17 -21 hours (once daily)
  • predicatable pharmacokinetics and dose response - does not require monitoring of anticoag effects
  • LOW potential for thrombocytopenia
24
Q

fondaparinux uses

A

VTE

prophylaxis in patients undergoing hip fracture surgery, hip replacement, knee replacement, or abdominal surgery

25
orally active factor Xa inhibitors
rivaroxaban - treatment and prevention of VT and PE - prevention of thrombosis in NV Atrial Fib apixaban (eliquis) -prevention of thrombosis in NV Atrial Fib both: dose reduction in patients with impaired renal function, increased risk of stroke upon discontinuation edoxaban (Savaysa) - treatment of VT and PE after 5-10 days with parenteral anticoag - prevention of thrombosis in NV Atrial Fib - renal excretion - not used in patients with CrCl > 95 ml/min - increased risk of ischemic events upon premature discontinuation - risk of hematoma/paralysis in patients undergoing spinal puncture or epidural anesthesia
26
direct thrombin inhibitors
non-heparinoid parenteral agents - do not act through ATIII | -inhibit free thrombin and fibrin-bound thrombin
27
lepirudin
direct thrombin inhibitor - recombinant hirudin grown in yeast - small protein - highly specific direct inhibitor of thrombin - irreversible inhibition - no effect on AT - aPTT values increase dose-dependently - excreted via the kidney - hypersensitivity reaction
28
bivaliruden (angiomax)
- 20 AA, synthetic peptide - binds to catalytic site and exosite I of thrombin - binding is reversible with rapis onset and short duration - given IV during percutaneous coronary angioplasty - eliminated by renal excretion - low risk of bleeding, doesn't induce Ab formation
29
argatroban
direct thrombin inhibitor - binds reversibly to the active site of thrombin - does not require AT for activity - can inhibit free & clot-associated thrombin - therapy monitored using aPTT - given IV, t1/2 40-50 minutes - metabolized in liver (CYP3A4/5) - approved for prophylaxis or treatment in pts w HIT
30
dabigatran (pradaxa)
- oral direct thrombin inhibitor - indicated for prevention of stroke and systemic embolism in patients with NV Afib - eliminated by renal excretion - avoid in cases of severe renal impairment - laboratory assessment of coagulation state is not required - actively reversed by praxbind IV
31
when the BV defect has healed...
the fibrinolytic pathway is activated to dissolve the clot
32
fibrinolytic pathway
- plasminogen, an anticoag protein, circulated in inactive form and is deposited on to growing clot - tissue plasminogen activator (a serine protease) can activate plasminogen to plasmin - plasmin is a proteolytic enzyme that digests firbin and fibrinogen
33
recombinant tPA
tPA = tissue plasminogen activator alteplase, reteplase, urokinase catalyzes plasminogen -> plasmin
34
streptokinase activator complex
forms with plasminogen to act as plasmin
35
indications for thrombolytic therapy
- acute MI - initiate ASAP after onset - acute ischemic thromotic stroke - initiate within 3 hours after onset and exclusion of intracranial hemorrhage - PE
36
tpa examples
- binds fibrin and activated bond plasminogen 100x more rapidly than in circulation - alteplase: human tpa, 527 aa, binds fibrin - reteplase: human tpa, deletion of aa (355/527), potent, fast, lacks fibrin binding domain - less specific - tenecteplase - mutant tpa, longer t1/2, IV bolus, fibrin specific
37
tpa
- IV only - short duration - t1/2 = 5-10 min - clearance by liver and kidney - AE: bleeding
38
streptokinase
MOA: forms 1:1 complex with plasminogen to produce an active enzyme complex that catalyzes conversion of inactive plasminogen to active plasmin; does not directly degreade clots - has intrinsic enzyme activity dosing: IV loading dose to saturate Ab against protein - AE: bleeding, allergic rxns
39
urokinase
MOA: 411 AA protease from human kidney cells, directly cleaves plasminogen to plasmin, lacks fibrin specificity NOT AVAILABLE IN US
40
anti-fibrinolytic agents
used to stop bleeding caused by thrombolytic agents aminocaproic acid, tranexamic acid, lysine -plasmin binds to fibrin through a lysine binding site to activate fibrinolysis -drugs act as a lysine analog to bind the receptor on plasminogen and plasmin -the result is a blockade f plasmin to target fibrin
41
anti-fibrinolytic agents uses and risks
- treat bleeding associated with thrombolytic therapy - adjunct in hemophilia - re-bleeding from intracranial aneurysms major risks: IV thrombosis as result of fibrinolysis inhibition, thrombi formed during therapy are not easily lysed

module 2b (9 decks)

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