MT2_6_Anticoagulant Pharma Flashcards
Red thrombus is made of
White thrombus is made of
fibrin and RBCs
platelets
Arterial thromboses develop in an ____that usually develops on top of an _______ and causes a __
artery
arthersclerotic plaque
Myocardial infarct
Describe the mechanism of blood coagulation (primary vs secondary)
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
In the coagulation cascade, what is the goal?
to make thrombin (factor 2A) which converts soluble fibrinogen to insoluble fibrin (to make a stable thrombus)
What are the three pathways of the cascade?
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
Indirect Anticoags
Direct Coags
Indirect: heparin, fonda, warfarin (activates antithrombin for anticaog. activity)
Direct: desirudin, bivalirudin, argatroban, dabigatran
Direct 10a: rivaroxaban apixaban, edoxaban, betrixaban
What is heparin dependent on, and does it have fibrinolytic activity?
- dependent on AT
- does not have fibrinolytic activity..will prevent clots from forming but not break them down
How is anticoagulation achieved with heparin?
Long chain inhibits…and short chain inhibits…
- binding of UFH + AT = complex catalyzing inactivation of factor 2a (thrombin) and 10a
2a, 10a
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)
quick short kidney safe in renally impaired patients liver/reticuloendothelium system pregnant women
What is the dose for treating acute coronary syndrome?
DVT/PE?
Prophylaxis VTE?
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
What is used to monitor heparin? (two things) When to measure?
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
What is CI in the use of heparin? (3)
Side effects?
- CI: hypersensitivity to pork, bleeding, severe thrombocytopenia
- bleeding
- heparin induced thrombocytopenia
- osteoporosis, vertebral fractures, alopecia, priapism purple toe syndrome
In type 2 HIT (heparin induced thrombocytopenia), When does it occur, what happens, and the most common complication?
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
• _ 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
PF4, coagulation
IgG, heparin bound platelet
platelet activation
Major presentations of HITII?
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.)
HIT II Diagnosis? (4Ts)
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.)
So, what to give patients with type I HIT? DC and give DIRECT thrombin inhibitors
- 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
What happens if a patient bleeds on heparin?
due to short half life, a reversal agent is not needed, so just stop the infusion.
Protamine sulfate is usually used in a bleed
Why would I use heparin? Why not?
- 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
Why would low molecular weight heparins be preferred? (4)
reduced binding to plasma proteins gives more predictability regarding dose response
also, less monitoring, less HIT, SQ (so can be used outpatient)
Similar to UFH, LMWH requires___
The shorter chain allows for more ____
Antithrombin
selectivity to 10a (not 2a)
LMWH half life?
Renal excretion?
Protein Binding
Protamine Reversal
4 hours (longer than UFH)
Renally excreted therefore adjust
does not bind to heparin binding proteins
partial reversal
For enoxaparin (LMWH) what are the main indications?(4)
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
When a patient is on a LMWH, what do you monitor?
- Hgb, Hct, platelets, bleeding
- anti 10 a sometimes…only if patient is obese, renal insufficiency, pregnant.
Enox CI
- pork allergy, bleeding
BBW for Enox
epidermal or spinal hematomas in patients getting LMWH + anesthesia…can result in paralysis
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 ______
- vitaminK
C1…VKORC1
7, 9, 10, 2 (SNTT)
What are the main indications for warfarin?
- all purpose anticoag
- VTE
A fib, a flutter - thrombus
- prosthetic heart valves
- Thrombophilia antiphospholipid syndrome
The onset of anticoagulation for warfarin is ___
Peak effect is ___
INR may increase in ___
- 1-3 days
- 5-7 days
- 36-72 hours
basically, it has a long onset
warfarin has R and S enantiomers. S has more anticoagulant effect, but more DDIs. How is it metabolized?
Through CYP2C9
- 2*: decrease by 30%
- 3* decrease by 80%
- therefore decrease the dose of warfarin
R is through 3A4, 1A2
What are the variables that contribute to warfarin dose response variations?
- DDIs
- dietary vitamin K
- genetic polymorphisms for CYP2C9, VKORC1 (AA phenotype)
- hepatic congestion, impairment
What are some of the drugs that will potentiate warfarin’s effect (therefore more bleeding?)
- thyroid supplements
- antibiotics/fungals
- amiodarone
- cimetidine, allopurinol, fluoxetine, apap, alcohol
What are some of the drugs that will decrease warfarin’s effect?
rifampin
CBZ
barbituates
ethanol
When counseling a patient about vit K and diet, what do you say?
- consistency with diet
- foods that contain high vitamin k include greens, cauliflower, soybeans
What to monitor for with warfarin?
- PT/INR
- Hbg/Hct, platelets
- LFT, urinalysis, stool, pregnancy
monitor INR daily then reduce over time
What is the most common INR goal?
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
starting dose for warfarin?
less than 5mg/day in the first 1-2 days then titrate based on INR
Dr. wants rapid anticoagulation. What to recommend?
- UFH/LMWH bridge
- overlap with parental anticoag for 5 days, target INR higher than 2 for 2 days before dc the parental heparin
How long does it take for warfarin to achieve full anticoag effect?
- 4-5 days due to the half lives of all the clotting factors
When do bleeds usually occur on warfarin (INR?) what to do if there is a bleed?
- 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.
When is PCC4 (Kcentra) used?
BBW?
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
Major s/e of warfarin?
- skin necrosis, blue toe(days 3-8)
- limb gangrene in HIT (don’t initiate warfarin until platelets greater than 150)
Pregnant women taking warfarin. What to do?
-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
What is the main factor involved in thrombus formation?
factor 2a
activates platelets and clotting factors, stabilizes clots, and converts soluble fibrinogen to insoluble.
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 ___
directly
thrombin and fibrin
predictable
HIT
how do DTI’’s work?
- binds directly to the active site and/or exosite to block enzymatic activity.
What are the 2 uses or desirudin?
- post op and VTE prophylaxis
- given SQ, renal adjust less than 30
- not very popular
How does bivalirudin differ from desirudin?
- reversible and bivalent, binding is weaker. reversibility contributes to decreased bleeds and safety
What are the main indications for bivalirudin?
- ACS (UA, NSTEMI, STEMI) undergoing PCI
- HIT
dose IV bolus .75mg/kg then 1.75 mg/kg/hr
Onset/offset of bivalirudin?Renally adjust?
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.
What happens when a patient bleeds on bivalirudin? What to monitor?
- hemodialysis, 4 factor PC, and FFP
- monitor aPTT q2 hours
How does argatroban bind?
How does it compare to other DTIs?
- reversible, small, univalent that binds to the active site
- lowest affinity for thrombin compared to other DTIs
Main indications for argatroban?
- side effects?
- CI’s?
- HIT, PCI
- bleeding, chest pain, dyspnea
- for bleeding consider 4 factor PCC
- CI in bleeding
Is onset immediate from argatroban? how is the drug metabolized?
- yes, extensively through the liver, therefore use caution when dosing!
What is the argatroban dosing for HIT?
- 2mcg/kg/min
for hepatic issues, 0.2-0.5 mcg/kg/min
no adjustment needed for renal impairment!!
How to monitor Argatroban?
- 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)
How does dabigatran work?
- directly inhibits thrombin, reversibly binds to active site
- oral, therefore highly lipiphillic and GI absorbable
What are the indications for dabigatrin? Dose?
nonvalvular a fib, VTE, 150mg BID (not for MI!)
VTE prophylaxis: 110mg 1-4h, maintain at 220mg once daily
How is dabigatrin excreted? What is it a substrate of?
- renally
- Pgp efflux transporter, so avoid use (rifampin, amiodarone, clarithromycin, verapamil, quinidine)
avoid use w CrCl less than 50
Common side effects of Dabigatran?
CI
BBW
Reversal agent?
- 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
Name the indirect and direct 10a inhibitors
What are these agents approved for?
- indirect: fonda (SQ)
- direct (rivaroxaban, apixaban, edoxaban, betrixaban PO)
- both indirect and direct are approved for VTE, direct NOT of ischemic heart disease
How does Fonda work? Indications?
Excretion?
CI?
- 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
BBW of fonda
CI
epidermal/spinal hematomas + anesthesia
CI: severe renal impairment less than 30
- body weight less than 50kg
- active major bleeding, bacterial endocarditis, thrombocytopenia
Main indications for rivaroxaban? Must take with…
- nonvalvular fib, VTE treatment and prophylaxis
- FOOD to increase BA
How is rivaroxaban metabolized?Excreted
Avoid use when..
- liver, excreted in urine
avoid use if CrCl is less than 15-30,mod/severe hepatic impairment (B, C) and strong 3A4 inducers/inhibitors
SE of rivaroxaban
BBW?
- bleeding (reversal agent: adexanet alfa), 4factor PCC
- premature dc increase risk of thrombotic events
- epidermal/spinal hematoma
Indications for apixaban?
Metabolism? Excretion
- nonvalvular fib, VTE treatment and prophylaxis
- cyp 3A4/5 PGP (avoid in inhibitors–cins, roles)
- excreted in urine
SE
CI
BBW
for apixaban
- bleeding, reversal (andexanet)
- severe bleeding
- premature DC/epidermal, spinal hematomoas
Indications for edoxaban?
- valvular fib, VTE TREATMENT ONLY no prphylaxis (given at least 5 days after with IV anticoag)
Edoxaban is
Metabolized by…
Excreted in ….
Dialysis?
- cyp 3A4, pgp
- renally excreted
- only one where dialysis is not effective in removing from blood….less protein binding
For nonvalvular afib, edoxaban should not be used when CrCL is…
greater than 95 or less than 15 (for fear of underexposure to the drug, resulting in increased risk of ischemic stroke)
Edoxaban SE, CI, and BBW?
- SE: bleeding
- CI: Bleeding
- BBW: premature dc, epidermal/spinal hematomas
Indications for Betrixaban? (BED)
How long does it last?
Avoid use in…
VTE prophylaxis in hospitalized patients
anticoag effect may persist more than 73 hours after discontinuing
avoid use in hepatic impairment
S/E of betrixaban?
CI?
BBW
- 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
What are the monitoring parameters for rivaroxaban, apixaban, edoxaban, betrixaban?
- PT and aPTT can detect the drug in the plasma, anti 10a, to see the accumulation of the drug, not used for dose adjustments
What is the reversal agent for factor 10a?
- andexanet
- only rivaroxban and apixaban are approved for reversal
What are the advantages of direct oral anticoags?
rapid onset/offset
fewer DDI than warfarin
predictable PK
lack of regular monitoring
Disadvantages of DOACs?
- warfarin is the __
- med __
- Uncertainty in __
- Avoided in
- DDIs
- $$
- 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
