blood 2 direct and indirect thrombin inhibitors Flashcards
anticoagulants
inhibit one or more steps in the clotting cascade that lead to fibrin formation…
*They do NOT dissolve clots!
heparin why so acidic?
indirect thrombin inhibitormany carboxyl and sulfate groups are attached (and virtually all critters produce heparin, even ones lacking “traditional blood”, so it’s an ancient molecule on the evolutionary tree.)
Heparin “lives” in
mast cells (basophils)
mast cells produce
histamine
Unfractionated heparin size
5000-30,000 Daltons h2o is 10
heparin is measure in
units
What’s One (1) Unit of Heparin?
The quanTiTy of heparin required to keep 1 milliliter of caT’s blood fluid for 24 hours at 0° C”
“No way!”
• This is ~~0.002 mg of heparin/unit.
porcine intestinal derived heparin better in avoiding
HIT
TWO MAIN SOURCES OF HEPARIN
PORCINE INTESTINE, BOVINE LUNG
heparin always given
parentally
fractionated heparin weight
5500 daltons
fractionated heparin onlt works on___ but
one part of coag. t’s much more uniform, contains less “contaminants” and inactive forms of heparin.
heparin increase at3 activity by
1000
unfractionated heparin accelerates both
AT3 INTERACTION WITH BOTH THROMBIN AND FACTOR Xa
fractionated heparin accelerates
at3 interaction with Xa
only reason we dont use LMWH is
(lovenox) because it is not as efficaious in anticoagulatin
IV half life of heparin
2 hours. 4 hours for LMWH
SETTING OF THERAPY FOR TWO TYPES OF HEPARIN
HOSPITAL. hospital and outpatient for LMWH
MAJOR EFFECT OF BOTH HEPARIN
TOO MUCH BLEEDING AND TOO LITTLE FOR LMWH
BIOAVAILABILITY OF BOTH HEPARIN
20 for unfractionated, 90 for LMWH
PREDCTABILITY OF BOTH HEPARIN
lmwh more predictable
heparin uses
lab samples,orthopedic surgery, pregnancy, flush for cell savers/lines, dialysis machines,circuits
heparin pharmokinetics time to effect:
Time to effect: – Intravenous (IV): a few minutes – Subcutaneous (SQ): 1-2 hours
• Heparin is cleared by binding to macrophages and being depolymerized and desulfonated in the liver…
• …and the metabolites • are excreted in the • urine.
half life of heparin is prolonged
by either renal &/or liver dysfunction. Unfractionated heparin’s half-life is ~1-2 hours (a source of constant controversy amongst perfusionists).
*Fractionated (LMWH) has a much longer half-life (3-7 hours).
Lower doses of heparin are cleared at a
faster rate than higher higher doses (implying that the process is saturable).
- Since it’s a metabolic process, heparin clearance is (naturally) slower at lower temps and accelerated at higher temps.
- Heparin is chemically reversed with Protamine
side effects of heparin
bleeding,HIT,
fondaparinux half life
(arixtra) A synthetic LMWH (a pentasaccharide). • Half-life of ~20 hours and eliminated
unchanged in the urine.
major advantage of fondaparinux
major advantage is the elimination of the risk of “bad” (Type II) HIT.
warfarin what it is and how it works
(coumadin) indirect thrombin inhibitor. widely prescribed orally administered anticoagulant.
* Works by inhibiting Vitamin K (phytonadione/Mephyton) slow acting because you have ton use all vitamin k
warfarin how it inhibits vitamin k
blocks an enzyme (creatively named Vitamin K epoxide reductase)
• Vitamin K epoxide reductase is required to allow the liver to “recycle” spent (oxidized) Vitamin K so eventually stores of Vitamin K are simply depleted.
Warfarin is NOT
Vitamin K antagonist (it doesn’t have antagonist kinetics)…
…so giving the critter Vitamin K readily reverses the effects of warfarin.
liver requires vitamin k to produce
II: Prothrombin VII: Proconvertin
IX: Plasma Thromboplastin Component X: Stuart-Prower Factor
warfarin and protein c +s
(which are also anticoagulants via their ability to block factors Va and VIIIa).
– Consequently, the liver produces incomplete, biologically inactive molecules instead of functioning clotting factors.
akes a while for Warfarin to exert its clinical effect (8-24 hours) since
hose Vitamin K stores have to be depleted.
• Peak effects occur ~2-4 days (once those stores are completely empty)
warfarin half life and duration is
nsanely variable! PLUS it’s highly protein-bound (SO what?)
• Drugs, genetics, foods, spices (!), etc. all effect how long it lasts!
-”Normally” ~ 40 hrs
warfarin used to
prevent pulmonary embolism, VAD,DVT,artificial valves,afib,
warfarin side effects
bleeding#1,Birth/fetal deformities &/or death. • Warfarin necrosis (typical in obese women)
Warfarin Dosing
typical dose is 5-7mg/day with adjustments made after ∽ one week.
warfarin monitoring
Warfarin typically monitored via the prothrombin time (PT).
- So, the PT measures the activity of which factors? intrinsic activity
- ”Normal” PTs vary from lab to lab (due to reagent variability, mostly)
added to warfarin when monitoring
tissue Factor (Factor III) and Calcium (Factor IV) are added to the critter’s plasma.
normal pt range
80-120%
INR
INTERNATIONAL NORMALIZED RATIO. INR = critters PT/LAB NORMAL PT MEAN
lepirudin
(refludon). direct thrombin inhibitor. bivalently and irreversibly to thrombin. no reversible agent
lepirudin cleared
by kidneys
leprrudin half life…..
1 hour but can increase because antibodies can decrease clearance especially in kidney failure
monitoring lepirudin
heir aPTTs and renal functions monitored.
bivalirudin
angiomax. completely synthetic yet chemically smaller
“cousin” of hirudin.
• Like hirudin, it’s also a bivalent direct thrombin inhibitor, operates independent of AT III, and is given parenterally.
Relatively expensive!
bivalirudin clearance
less renal clearance than lepirudin (20%)
bivalirudin half life depending on kidney function
– Mod. renal dysfunction: half-life ~35 minutes – Severe renal dysfunction: half-life ~1 hour – Dialysis patient: half-life ~3.5 hours. can be removed with hemoconcentrators
Bivalirudin
• Very commonly used during PTCAs to prevent
platelet activation.
*Also commonly used for anticoagulation for patients with HIT (we’ll discuss this more later.)
bivalirudin Monitoring
*Ideally, anticoagulation (as on bypass) is measured with the
ecarin clotting time” (ECT)
argatroban half life,clearance, monitoring
parenterally-administered small molecule direct thrombin inhibitor. • Shorthalf-life(~40-50minutes). • Clinical use similar to Angiomax but monitored with aPTTs. • *Eliminated by hepatic clearance
Angiomax vs. Argatroban
Essentially, the choice is made by whether the patient has intact renal or hepatic function (which drug with which condition?)
…and ease of monitoring the anticoagulation
Dabigatran etexilate
pradaxa. An oral anticoagulant cleared by the kidneys that also acts as a direct thrombin inhibitor
– A possible future replacement for oral warfarin (don’t need to test INRs, fewer drug interactions, less variable half- life)
– Currently used for a-fib (why?) cood place for clots
apixiban and rivaroxaban
eliquis, xarelto. Both are oral anticoagulants that directly
inhibit Factor Xa
– Both are cleared renally and used for a-fib
