blood 2 direct and indirect thrombin inhibitors Flashcards Preview

pharmocology > blood 2 direct and indirect thrombin inhibitors > Flashcards

Flashcards in blood 2 direct and indirect thrombin inhibitors Deck (55):
1

anticoagulants

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

2

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.)

3

Heparin “lives” in

mast cells (basophils)

4

mast cells produce

histamine

5

Unfractionated heparin size

5000-30,000 Daltons h2o is 10

6

heparin is measure in

units

7

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.

8

porcine intestinal derived heparin better in avoiding

HIT

9

TWO MAIN SOURCES OF HEPARIN

PORCINE INTESTINE, BOVINE LUNG

10

heparin always given

parentally

11

fractionated heparin weight

5500 daltons

12

fractionated heparin onlt works on___ but

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

13

heparin increase at3 activity by

1000

14

unfractionated heparin accelerates both

AT3 INTERACTION WITH BOTH THROMBIN AND FACTOR Xa

15

fractionated heparin accelerates

at3 interaction with Xa

16

only reason we dont use LMWH is

(lovenox) because it is not as efficaious in anticoagulatin

17

IV half life of heparin

2 hours. 4 hours for LMWH

18

SETTING OF THERAPY FOR TWO TYPES OF HEPARIN

HOSPITAL. hospital and outpatient for LMWH

19

MAJOR EFFECT OF BOTH HEPARIN

TOO MUCH BLEEDING AND TOO LITTLE FOR LMWH

20

BIOAVAILABILITY OF BOTH HEPARIN

20 for unfractionated, 90 for LMWH

21

PREDCTABILITY OF BOTH HEPARIN

lmwh more predictable

22

heparin uses

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

23

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.

24

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).

25

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

26

side effects of heparin

bleeding,HIT,

27

fondaparinux half life

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

28

major advantage of fondaparinux

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

29

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

30

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.

31

Warfarin is NOT

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

32

liver requires vitamin k to produce

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

33

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.

34

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)

35

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

36

warfarin used to

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

37

warfarin side effects

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

38

Warfarin Dosing

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

39

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)

40

added to warfarin when monitoring

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

41

normal pt range

80-120%

42

INR

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

43

lepirudin

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

44

lepirudin cleared

by kidneys

45

leprrudin half life.....

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

46

monitoring lepirudin

heir aPTTs and renal functions monitored.

47

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!

48

bivalirudin clearance

less renal clearance than lepirudin (20%)

49

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

50

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.)

51

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

ecarin clotting time” (ECT)

52

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

53

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

54

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

55

apixiban and rivaroxaban

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