blood 2 direct and indirect thrombin inhibitors

Question 1

anticoagulants

Answer 1

inhibit one or more steps in the clotting cascade that lead to fibrin formation…
*They do NOT dissolve clots!

Question 2

heparin why so acidic?

Answer 2

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.)

Question 3

Heparin “lives” in

Answer 3

mast cells (basophils)

Question 4

mast cells produce

Answer 4

histamine

Question 5

Unfractionated heparin size

Answer 5

5000-30,000 Daltons h2o is 10

Question 6

heparin is measure in

Answer 6

units

Question 7

What’s One (1) Unit of Heparin?

Answer 7

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.

Question 8

porcine intestinal derived heparin better in avoiding

Answer 8

HIT

Question 9

TWO MAIN SOURCES OF HEPARIN

Answer 9

PORCINE INTESTINE, BOVINE LUNG

Question 10

heparin always given

Answer 10

parentally

Question 11

fractionated heparin weight

Answer 11

5500 daltons

Question 12

fractionated heparin onlt works on___ but

Answer 12

one part of coag. t’s much more uniform, contains less “contaminants” and inactive forms of heparin.

Question 13

heparin increase at3 activity by

Answer 13

1000

Question 14

unfractionated heparin accelerates both

Answer 14

AT3 INTERACTION WITH BOTH THROMBIN AND FACTOR Xa

Question 15

fractionated heparin accelerates

Answer 15

at3 interaction with Xa

Question 16

only reason we dont use LMWH is

Answer 16

(lovenox) because it is not as efficaious in anticoagulatin

Question 17

IV half life of heparin

Answer 17

2 hours. 4 hours for LMWH

Question 18

SETTING OF THERAPY FOR TWO TYPES OF HEPARIN

Answer 18

HOSPITAL. hospital and outpatient for LMWH

Question 19

MAJOR EFFECT OF BOTH HEPARIN

Answer 19

TOO MUCH BLEEDING AND TOO LITTLE FOR LMWH

Question 20

BIOAVAILABILITY OF BOTH HEPARIN

Answer 20

20 for unfractionated, 90 for LMWH

Question 21

PREDCTABILITY OF BOTH HEPARIN

Answer 21

lmwh more predictable

Question 22

heparin uses

Answer 22

lab samples,orthopedic surgery, pregnancy, flush for cell savers/lines, dialysis machines,circuits

Question 23

heparin pharmokinetics time to effect:

Answer 23

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.

Question 24

half life of heparin is prolonged

Answer 24

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).

Question 25

Lower doses of heparin are cleared at a

Answer 25

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

Question 26

side effects of heparin

Answer 26

bleeding,HIT,

Question 27

fondaparinux half life

Answer 27

(arixtra) A synthetic LMWH (a pentasaccharide). • Half-life of ~20 hours and eliminated unchanged in the urine.

Question 28

major advantage of fondaparinux

Answer 28

major advantage is the elimination of the risk of “bad” (Type II) HIT.

Question 29

warfarin what it is and how it works

Answer 29

(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

Question 30

warfarin how it inhibits vitamin k

Answer 30

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.

Question 31

Warfarin is NOT

Answer 31

Vitamin K antagonist (it doesn’t have antagonist kinetics)... ...so giving the critter Vitamin K readily reverses the effects of warfarin.

Question 32

liver requires vitamin k to produce

Answer 32

II: Prothrombin VII: Proconvertin IX: Plasma Thromboplastin Component X: Stuart-Prower Factor

Question 33

warfarin and protein c +s

Answer 33

(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.

Question 34

akes a while for Warfarin to exert its clinical effect (8-24 hours) since

Answer 34

hose Vitamin K stores have to be depleted. | • Peak effects occur ~2-4 days (once those stores are completely empty)

Question 35

warfarin half life and duration is

Answer 35

nsanely variable! PLUS it’s highly protein-bound (SO what?) • Drugs, genetics, foods, spices (!), etc. all effect how long it lasts! -”Normally” ~ 40 hrs

Question 36

warfarin used to

Answer 36

prevent pulmonary embolism, VAD,DVT,artificial valves,afib,

Question 37

warfarin side effects

Answer 37

bleeding#1,Birth/fetal deformities &/or death. • Warfarin necrosis (typical in obese women)

Question 38

Warfarin Dosing

Answer 38

typical dose is 5-7mg/day with adjustments made after ∽ one week.

Question 39

warfarin monitoring

Answer 39

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)

Question 40

added to warfarin when monitoring

Answer 40

tissue Factor (Factor III) and Calcium (Factor IV) are added to the critter’s plasma.

Question 41

normal pt range

Answer 41

80-120%

Question 42

INR

Answer 42

INTERNATIONAL NORMALIZED RATIO. INR = critters PT/LAB NORMAL PT MEAN

Question 43

lepirudin

Answer 43

(refludon). direct thrombin inhibitor. bivalently and irreversibly to thrombin. no reversible agent

Question 44

lepirudin cleared

Answer 44

by kidneys

Question 45

leprrudin half life.....

Answer 45

1 hour but can increase because antibodies can decrease clearance especially in kidney failure

Question 46

monitoring lepirudin

Answer 46

heir aPTTs and renal functions monitored.

Question 47

bivalirudin

Answer 47

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!

Question 48

bivalirudin clearance

Answer 48

less renal clearance than lepirudin (20%)

Question 49

bivalirudin half life depending on kidney function

Answer 49

– 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

Question 50

Bivalirudin | • Very commonly used during PTCAs to prevent

Answer 50

platelet activation. | *Also commonly used for anticoagulation for patients with HIT (we’ll discuss this more later.)

Question 51

bivalirudin Monitoring | *Ideally, anticoagulation (as on bypass) is measured with the

Answer 51

ecarin clotting time” (ECT)

Question 52

argatroban half life,clearance, monitoring

Answer 52

``` parenterally-administered small molecule direct thrombin inhibitor. • Shorthalf-life(~40-50minutes). • Clinical use similar to Angiomax but monitored with aPTTs. • *Eliminated by hepatic clearance ```

Question 53

Angiomax vs. Argatroban

Answer 53

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

Question 54

Dabigatran etexilate

Answer 54

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

Question 55

apixiban and rivaroxaban

Answer 55

eliquis, xarelto. Both are oral anticoagulants that directly inhibit Factor Xa – Both are cleared renally and used for a-fib