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Cardio MT2 > MT2_6_Anticoagulant Pharma > Flashcards

MT2_6_Anticoagulant Pharma Flashcards

1
Q

Red thrombus is made of

White thrombus is made of

A

fibrin and RBCs

platelets

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2
Q

Arterial thromboses develop in an ____that usually develops on top of an _______ and causes a __

A

artery
arthersclerotic plaque
Myocardial infarct

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3
Q

Describe the mechanism of blood coagulation (primary vs secondary)

A

vasoconstriction, then platelet plugging activating fibrin clot formation

clotting factors then come in because platelets are not enough fix the problem..occurs via the coagulation cascade

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4
Q

In the coagulation cascade, what is the goal?

A

to make thrombin (factor 2A) which converts soluble fibrinogen to insoluble fibrin (to make a stable thrombus)

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5
Q

What are the three pathways of the cascade?

A

extrinsic: quick fix, less thrombin (responds to factor 3)
intrinsic: tissue damage inside, takes longer, makes a lot of thrombin
common: both extrinsic and intrinsic converge at factor 10, which converts 10 to 10a, prothrombin to thrombin, then fibrinogen to fibrin

fibrin + platelets = thrombus

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6
Q

Indirect Anticoags

Direct Coags

A

Indirect: heparin, fonda, warfarin (activates antithrombin for anticaog. activity)

Direct: desirudin, bivalirudin, argatroban, dabigatran

Direct 10a: rivaroxaban apixaban, edoxaban, betrixaban

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7
Q

What is heparin dependent on, and does it have fibrinolytic activity?

A
  • dependent on AT

- does not have fibrinolytic activity..will prevent clots from forming but not break them down

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8
Q

How is anticoagulation achieved with heparin?

Long chain inhibits…and short chain inhibits…

A
  • binding of UFH + AT = complex catalyzing inactivation of factor 2a (thrombin) and 10a

2a, 10a

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9
Q

Heparin has a __onset and __half life. It is excreted very little in the ___ therefore__. It is metabolized by the ___, and safe to use in ___ (population)

A 
quick
short
kidney
safe in renally impaired patients
liver/reticuloendothelium system
pregnant women
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10
Q

What is the dose for treating acute coronary syndrome?

DVT/PE?

Prophylaxis VTE?

A

60u/kg, then 12u/kg/hr

80u/kg, then 18u/kg/hr

5000U q8-12h SQ

can be used in bridge therapy in patients on warfarin

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11
Q

What is used to monitor heparin? (two things) When to measure?

A

aPTT, measures speed of fibrin clot..normal is 30 seconds..therapeutic range is 1.5-2.5x control

  • measure at baseline then q6hours..warfarin may prolong aPTT
  • Anti10a levels, which measure’s heparin’s ability to inhibit factor 10a
  • therapeutic range is .3-.7, measure q6hours after heparin initiation/change
  • useful for patients w inflammation or lupus inhibitor
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12
Q

What is CI in the use of heparin? (3)

Side effects?

A
  • CI: hypersensitivity to pork, bleeding, severe thrombocytopenia
  • bleeding
  • heparin induced thrombocytopenia
  • osteoporosis, vertebral fractures, alopecia, priapism purple toe syndrome
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13
Q

In type 2 HIT (heparin induced thrombocytopenia), When does it occur, what happens, and the most common complication?

A

5-10 days after heparin

can cause life and limb threatening thrombotic complications

not marked by bleeding, most common is VTE (DVT/PE)

platelet count drops, development of thrombus

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14
Q

• _ is released from activated
platelets, binds heparin and promotes__ by
moderating effects of heparin‐like molecules
•_ formed directly against complexes of
_ factor
• Antibodies bind to PF4‐heparin complexes on platelet
surface and induce platelet activation
• ___releases procoagulant platelet
microparticles, causes platelet consumption and
thrombocytopenia
• Thrombin is generated: producing venous and arterial
thrombosis of HIT

A

PF4, coagulation
IgG, heparin bound platelet
platelet activation

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15
Q

Major presentations of HITII?

A

DVT/PE, can result in a stroke, MI, and venous limb gangrene

Skin lesions at injection sites

acute systematic reactions following IV hep bolus (fever, flushing, etc.)

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16
Q

HIT II Diagnosis? (4Ts)

A

Thrombocytopenia (platelets less than 100,000 or 50% of baseline)

Timing of thrombocytopenia relative to heparin exposure (normal is 5-10 days, rapid is 24 hours, and delayed is 3-6 weeks which is more severe)

Thrombosis or other sequalae or HIT (VTE, skin lesions, systematic)

Other causes of thrombocytopenia (drugs, sepsis, etc.)

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17
Q

So, what to give patients with type I HIT? DC and give DIRECT thrombin inhibitors

A
  • argatroban
  • bivalirudin
  • fonda (not in patients with platelets less than 100,000)
  • warfarin (only when greater than 150000)

confirm with a HIPA assay,Hep PF4 ElISA assay, C-serotonin assay

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18
Q

What happens if a patient bleeds on heparin?

A

due to short half life, a reversal agent is not needed, so just stop the infusion.

Protamine sulfate is usually used in a bleed

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19
Q

Why would I use heparin? Why not?

A
  • good for bleeding risk, surgical candidate, quick onset and offset, and good for patients with bad kidneys
  • variation in response, does not affect fibrin 2a and 10a, so does not lyse the clot, HIT/osteo, intensive monitoring
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20
Q

Why would low molecular weight heparins be preferred? (4)

A

reduced binding to plasma proteins gives more predictability regarding dose response

also, less monitoring, less HIT, SQ (so can be used outpatient)

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21
Q

Similar to UFH, LMWH requires___

The shorter chain allows for more ____

A

Antithrombin

selectivity to 10a (not 2a)

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22
Q

LMWH half life?
Renal excretion?
Protein Binding
Protamine Reversal

A

4 hours (longer than UFH)

Renally excreted therefore adjust

does not bind to heparin binding proteins

partial reversal

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23
Q

For enoxaparin (LMWH) what are the main indications?(4)

A

VTE prophylaxis

  • ab surgery, VTE prophylaxis (40mgSQ q24)
  • hip/knee: 30mg sq q12
  • crcl less than 30 (30mg sq q24)

VTE treatment

UA/NSTEMI/STEMI MI

Heart Valves

  • 1mg/kg sq q12h or 1.5mg sq q24
  • for crcl less than 30, 1mg/kg sq q24
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24
Q

When a patient is on a LMWH, what do you monitor?

A
  • Hgb, Hct, platelets, bleeding

- anti 10 a sometimes…only if patient is obese, renal insufficiency, pregnant.

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25
Q

Enox CI

A
  • pork allergy, bleeding
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26
Q

BBW for Enox

A

epidermal or spinal hematomas in patients getting LMWH + anesthesia…can result in paralysis

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27
Q

What is the MOA of warfarin? It is an __antagonist

It inhibits the ___ subunit of ___to reduce regeneration of vitamin K

It inhibits the synthesis of clotting factors ______

A
  • vitaminK

C1…VKORC1

7, 9, 10, 2 (SNTT)

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28
Q

What are the main indications for warfarin?

A
  • all purpose anticoag
  • VTE
    A fib, a flutter
  • thrombus
  • prosthetic heart valves
  • Thrombophilia antiphospholipid syndrome
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29
Q

The onset of anticoagulation for warfarin is ___
Peak effect is ___
INR may increase in ___

A
  • 1-3 days
  • 5-7 days
  • 36-72 hours

basically, it has a long onset

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30
Q

warfarin has R and S enantiomers. S has more anticoagulant effect, but more DDIs. How is it metabolized?

A

Through CYP2C9

  • 2*: decrease by 30%
  • 3* decrease by 80%
    • therefore decrease the dose of warfarin

R is through 3A4, 1A2

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31
Q

What are the variables that contribute to warfarin dose response variations?

A
  • DDIs
  • dietary vitamin K
  • genetic polymorphisms for CYP2C9, VKORC1 (AA phenotype)
  • hepatic congestion, impairment
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32
Q

What are some of the drugs that will potentiate warfarin’s effect (therefore more bleeding?)

A
  • thyroid supplements
  • antibiotics/fungals
  • amiodarone
  • cimetidine, allopurinol, fluoxetine, apap, alcohol
33
Q

What are some of the drugs that will decrease warfarin’s effect?

A

rifampin
CBZ
barbituates
ethanol

34
Q

When counseling a patient about vit K and diet, what do you say?

A
  • consistency with diet

- foods that contain high vitamin k include greens, cauliflower, soybeans

35
Q

What to monitor for with warfarin?

A
  • PT/INR
  • Hbg/Hct, platelets
  • LFT, urinalysis, stool, pregnancy

monitor INR daily then reduce over time

36
Q

What is the most common INR goal?

A

2-3 (mechanical aortic valve with Low risk)

2.5-3.5 (mechanical mitral valve, mechanical aortic valve w high risk factors) e.g. a fib, low ejection fraction , mechanical valve with systemic embolism..

basically anything w mechanical valve with a high risk

37
Q

starting dose for warfarin?

A

less than 5mg/day in the first 1-2 days then titrate based on INR

38
Q

Dr. wants rapid anticoagulation. What to recommend?

A
  • UFH/LMWH bridge

- overlap with parental anticoag for 5 days, target INR higher than 2 for 2 days before dc the parental heparin

39
Q

How long does it take for warfarin to achieve full anticoag effect?

A
  • 4-5 days due to the half lives of all the clotting factors
40
Q

When do bleeds usually occur on warfarin (INR?) what to do if there is a bleed?

A
  • INR >5
  • Vit K (phytonadione) (large doses can make patients resistant for up to one week)
  • PO more preferred, but INR will drop in 1-2 days, give when INR is greater than 10
  • IV is faster in 12 hours
  • SQ not preferred.
41
Q

When is PCC4 (Kcentra) used?

BBW?

A

for serious bleeds, INR greater than 2

  • contains factors SNTT, protein C, protein s
  • see decline in 10 min , recheck INR in 30 min

BBW: THROMBOTIC EVENTS RISK

42
Q

Major s/e of warfarin?

A
  • skin necrosis, blue toe(days 3-8)

- limb gangrene in HIT (don’t initiate warfarin until platelets greater than 150)

43
Q

Pregnant women taking warfarin. What to do?

A

-X
- DC! has teratogenic effects!!!!
use heparin instead

D: pregnancy w mechanical heart valves
- in these patients, avoid in the 1st trimester and close to delivery (38 weeks), use LMWH or UFH instead

44
Q

What is the main factor involved in thrombus formation?

A

factor 2a

activates platelets and clotting factors, stabilizes clots, and converts soluble fibrinogen to insoluble.

45
Q

Advantages of direct thrombin inhibitors includes binding___to thrombin, so no antithrombin is needed. DTIs inhibit both ____and___ bound thrombin. There are little interactions with plasma proteins so effects is more___. Is used for ___

A

directly
thrombin and fibrin
predictable
HIT

46
Q

how do DTI’’s work?

A
  • binds directly to the active site and/or exosite to block enzymatic activity.
47
Q

What are the 2 uses or desirudin?

A
  • post op and VTE prophylaxis
  • given SQ, renal adjust less than 30
  • not very popular
48
Q

How does bivalirudin differ from desirudin?

A
  • reversible and bivalent, binding is weaker. reversibility contributes to decreased bleeds and safety
49
Q

What are the main indications for bivalirudin?

A
  • ACS (UA, NSTEMI, STEMI) undergoing PCI
  • HIT

dose IV bolus .75mg/kg then 1.75 mg/kg/hr

50
Q

Onset/offset of bivalirudin?Renally adjust?

A

immediate, and coagulation returns to baseline 1 hour after dc

  • if crcl is less than 30, adjust to .25-1 mg/kg/hr IV inf.
51
Q

What happens when a patient bleeds on bivalirudin? What to monitor?

A
  • hemodialysis, 4 factor PC, and FFP

- monitor aPTT q2 hours

52
Q

How does argatroban bind?

How does it compare to other DTIs?

A
  • reversible, small, univalent that binds to the active site

- lowest affinity for thrombin compared to other DTIs

53
Q

Main indications for argatroban?

  • side effects?
  • CI’s?
A
  • HIT, PCI
  • bleeding, chest pain, dyspnea
  • for bleeding consider 4 factor PCC
  • CI in bleeding
54
Q

Is onset immediate from argatroban? how is the drug metabolized?

A
  • yes, extensively through the liver, therefore use caution when dosing!
55
Q

What is the argatroban dosing for HIT?

A
  • 2mcg/kg/min
    for hepatic issues, 0.2-0.5 mcg/kg/min

no adjustment needed for renal impairment!!

56
Q

How to monitor Argatroban?

A
  • aPTT every 2-4 hours, and check aPTT after every rate change. then check every AM when 2x aPTT goal.
  • CBC, LFT, PT//INR (may increase w argatroban use)
57
Q

How does dabigatran work?

A
  • directly inhibits thrombin, reversibly binds to active site
  • oral, therefore highly lipiphillic and GI absorbable
58
Q

What are the indications for dabigatrin? Dose?

A

nonvalvular a fib, VTE, 150mg BID (not for MI!)

VTE prophylaxis: 110mg 1-4h, maintain at 220mg once daily

59
Q

How is dabigatrin excreted? What is it a substrate of?

A
  • renally
  • Pgp efflux transporter, so avoid use (rifampin, amiodarone, clarithromycin, verapamil, quinidine)

avoid use w CrCl less than 50

60
Q

Common side effects of Dabigatran?

CI

BBW

Reversal agent?

A
  • s/e: GI bleeding, dyspepsia, gastritis
  • BBW: premature d/c increases risk of thrombotic events
  • Epidermal/spinal hematomas in which patients are receiving anesthesia
  • idarucizumab
61
Q

Name the indirect and direct 10a inhibitors

What are these agents approved for?

A
  • indirect: fonda (SQ)
  • direct (rivaroxaban, apixaban, edoxaban, betrixaban PO)
  • both indirect and direct are approved for VTE, direct NOT of ischemic heart disease
62
Q

How does Fonda work? Indications?
Excretion?
CI?

A
  • with antithrombin, it irreversibly binds to antithrombin, neutralizing it
  • VTE prophylaxis, treatment, and ACS
  • renal
  • CrCl less than 30
  • anti10a can be monitored, but mainly only in peds, obese, pregnant, renal failure
63
Q

BBW of fonda

CI

A

epidermal/spinal hematomas + anesthesia

CI: severe renal impairment less than 30

  • body weight less than 50kg
  • active major bleeding, bacterial endocarditis, thrombocytopenia
64
Q

Main indications for rivaroxaban? Must take with…

A
  • nonvalvular fib, VTE treatment and prophylaxis

- FOOD to increase BA

65
Q

How is rivaroxaban metabolized?Excreted

Avoid use when..

A
  • liver, excreted in urine

avoid use if CrCl is less than 15-30,mod/severe hepatic impairment (B, C) and strong 3A4 inducers/inhibitors

66
Q

SE of rivaroxaban

BBW?

A
  • bleeding (reversal agent: adexanet alfa), 4factor PCC
  • premature dc increase risk of thrombotic events
  • epidermal/spinal hematoma
67
Q

Indications for apixaban?

Metabolism? Excretion

A
  • nonvalvular fib, VTE treatment and prophylaxis
  • cyp 3A4/5 PGP (avoid in inhibitors–cins, roles)
  • excreted in urine
68
Q

SE
CI
BBW
for apixaban

A
  • bleeding, reversal (andexanet)
  • severe bleeding
  • premature DC/epidermal, spinal hematomoas
69
Q

Indications for edoxaban?

A
  • valvular fib, VTE TREATMENT ONLY no prphylaxis (given at least 5 days after with IV anticoag)
70
Q

Edoxaban is
Metabolized by…
Excreted in ….
Dialysis?

A
  • cyp 3A4, pgp
  • renally excreted
  • only one where dialysis is not effective in removing from blood….less protein binding
71
Q

For nonvalvular afib, edoxaban should not be used when CrCL is…

A

greater than 95 or less than 15 (for fear of underexposure to the drug, resulting in increased risk of ischemic stroke)

72
Q

Edoxaban SE, CI, and BBW?

A
  • SE: bleeding
  • CI: Bleeding
  • BBW: premature dc, epidermal/spinal hematomas
73
Q

Indications for Betrixaban? (BED)
How long does it last?
Avoid use in…

A

VTE prophylaxis in hospitalized patients

anticoag effect may persist more than 73 hours after discontinuing

avoid use in hepatic impairment

74
Q

S/E of betrixaban?
CI?
BBW

A
  • bleeding
  • CI in bleeding
  • premature discontinuation increases the risk of thrombotic events, and the anticoag effect may persist for at least 72 hours
  • BB: epidermal or spinal hematomas
75
Q

What are the monitoring parameters for rivaroxaban, apixaban, edoxaban, betrixaban?

A
  • PT and aPTT can detect the drug in the plasma, anti 10a, to see the accumulation of the drug, not used for dose adjustments
76
Q

What is the reversal agent for factor 10a?

A
  • andexanet

- only rivaroxban and apixaban are approved for reversal

77
Q

What are the advantages of direct oral anticoags?

A

rapid onset/offset
fewer DDI than warfarin
predictable PK
lack of regular monitoring

78
Q

Disadvantages of DOACs?

  • warfarin is the __
  • med __
  • Uncertainty in __
  • Avoided in
  • DDIs
  • $$
A
  • warfarin is the standard of care
  • adherence concerns
  • uncertainty about dosing (renal dysfunction, extremes in body weight)
  • avoided in dialysis patients
  • DDI’s Pgp transport utilized and extensive hepatic metabolism

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