Anti-Coagulants And Plasma Lipids

Front 1

what is antithrombin-III?

Back 1

a specific protease inhibitor that cleaves factors IIa, VII, IV, and X

heparin binds ATIII and accelerates it's action

Front 2

how does heparin reduce clot growth?

Back 2

binds ATIII via pentasaccharide sequence

accelerates it's action against clotting factor proteases

Front 3

how is heparin administered?

Back 3

IV or subcutaneously

IM will induce a hematoma, and it isn't absorped PO

Front 4

heparin metabolism

Back 4

not protein bound

rapid zero-order initial reaction

1st order renal clearance

Front 5

anticoagulant indications

Back 5

DVT pulmonary thrombosis

arterial and heart valve emboli

venous stasis

unstable angina & post-MI

DIC

Front 6

heparin toxicity

Back 6

hemmorrhage and 25% get thrombocytopenia (increases clotting time)

hypersensitivity, anaphylaxis, fever

Front 7

protamine

Back 7

highly positive protein, binds/neutralizes heparin if given too much

Front 8

heparin dosing

Back 8

less for inhibition of thrombus formation (does not affect clotting time or cause adverse effects)

more for slowing growth of existing thrombus

Front 9

LMWH

Back 9

recombinant/fractionated kind: enoxaparin, dalteparin, tinzaparin

synthetic pentasaccharide

selects for factor Xa

depends on ATIII, but no longer binds thrombin (greater anti-Xa activity than anti-IIa)

protamine: ineffective

Front 10

LMWH pharmacokinetics

Back 10

more bioavailable and longer lasting

clearance is dose INDEPENDANT

easier to predict/control response

give in mg's instead of units

lower toxicity, but use for the same problems

Front 11

oral anticoagulants

Back 11

resemble vit-K structure:
- derivatives of 4-hydroxycoumadin
warfarin - still used alot in US
indan-1,3-diones - not seen much in US (more toxic)

Front 12

oral anti-coagulants mechanism

Back 12

inhibit epoxide reductase reaction (req. for vit-K recycling)
--> inhibition of biosynthesis of active vit-k dependant factors (II, VII, IX, X, proteins C & S)

these factors require gamma-carboxylation of glutamic acid to complex with Ca2+

w/o Ca2+ complex formation

Front 13

warfarin pharmacology

Back 13

inpatient and outpatient; delayed onset of action (even IV)

Front 14

how do you monitor warfarin efficacy?

Back 14

factor VII turns over the fastest, so watch the prothrombin time

Front 15

warfarin pharmacokinetics

Back 15

over 95% of it is bound in circulation

can be displaced by aspirin --> bleeding

Front 16

warfarin toxicity

Back 16

hemorrhage

can't give antidote, but can discontinue usage, give vitamin-K1 (pytonadione) for resynthesis of the factors

give plasma that has the factors in it already (for emergencies)

Front 17

warfarin contraindications

Back 17

don't give to people with bleeding disorders, ulcers, visceral carcinoma

don't give to pregnant women!

Front 18

direct thrombin inhibitors

Back 18

-rudins (lepirudin, bivalirudin, desirudin)

use when thrombocytopenia is present

cut directly at FIIa

argatroban - synthetic antithrombi --> useful for dealing if thrombocytopenia is present

Front 19

antiplatelet drugs:
- classes
- indications

Back 19

aspirin, dipyridamole, platelet ADP receptors; glycoprotein IIa/IIIb inhibitors

prevent thrombi in arterial blood
- prosthetic heart valves
- MI (prophylaxis & prevention of rethrombosis)
- Percutaneous translumenal angioplasty (PCTA): balloon and stent

Front 20

aspirin

Back 20

COX inhibitor (irrev.)
- prevents TxA2 formation in platelets
so can't be released for aggregation
platelets can't synthesize new COX (b/c... no nucleus)

- blocks PGI2 formation in endothelial cells
blocks platelet aggregation to endothelium
endothelial cells can still make new COX
==> end result: COX inhibited selectively in platelets

NSAIDS compete for binding/catalytic site of COX

Front 21

dipyridamole

Back 21

inhibits platelet PDE, increasing cAMP, inhibiting aggregation and release

not effective alone, so usually combined with warfarin or aspirin

Front 22

platelet ADP receptor inhibitors

Back 22

function: prophylaxis

Ticlopidine (aspirin alternative)
for preventing/Tx'ing thrombotic stroke

oral absorption and binds to plasma proteins; metabolized in liver

GI disturbances and potential neutropenia/blood dyscrasias

effect STARTS at 4 days (req. bioactivation)


Clopidogrel: like ticlopidine, but safer

Front 23

glycoprotein IIa/IIIb inhibitors

Back 23

for acute MI, PCA, & Prinzmetal
(give IV)

Abciximab (monoclonal Ab): blocks fibrinogen a vWF binding to GPIIb/IIIa complex --> inhibits platelet aggregation; use for PCI; noncompetitive inhibitor

eptifibadine
cyclic heptapeptide that competitively inhibits

tirofiban: non-peptide; competitive inhibitor

Front 24

fibrinlysis: how's it work, normally?

Back 24

t-PA released from endothelium
binds to fibrin and complex forms b/w t-PA, fibrin, and plasminogen

plasminogen --> plasmin and dices that clot up like it was sushi (also destroys clotting factors) --> releases fibrin degradation products

plasmin deactivated by alpha-2-antitrypsin

Front 25

fibrinolytic drugs:
action
generations

Back 25

plasminogen activators

1st: streptokinase & urokinase
- hits fibrin and fibrinogen

2nd: alteplase (basically, t-PA)
binds fibrin
less systemic fibrinolysis
doesn't eat up fibrinogen as much

3rd: reteplase, tenecteplase
improves fibrin specificity and kinetics

Front 26

indications for fibrinolytic drugs

Back 26

pulmonary embolism, DVT, arterial thrombosis

MI: establish re-canalization
minimizes damage
give with anti-coags to prevent rethrombosis

ischemic stroke

Front 27

streptokinase

Back 27

not an enzyme
binds to plasminogen --> exposes site that activates more plasmin

from group-A-strep (antigenic)

IV - limited by antigenicity
IC - gets around this problem & allows delivery to site of need

Front 28

urokinase

Back 28

enzyme that activates plasmin directly

from recombinant human kidney cells, so no antigenicity

Front 29

alteplase

Back 29

recombinant t-PA
single chain that turns into t-PA dimer when it meets fibrin

30 minute half-life

more effective than streptokinase

Front 30

anistreplase

Back 30

noncovalent streptokinase:t-PA-protease-domain complex

inert at first, but metabolized to give active plasminogen

==> time required for this gives longer effect

Front 31

reteplase

Back 31

alteplase (rt-PA) derivative --> has domain for binding fibrin and protease domain of t-PA

faster onset & more potent

Front 32

tenecteplase

Back 32

amino acid substitutions

more specific

longer half-life than alteplase

Front 33

antifibrinolytic drugs

Back 33

aminocaproic acid: inhibits plasminogen activation and plasmin action
- activates all the plasminogen --> depletion of factors
- blocks the lysine binding sites required by plasminogen/plasmin for binding to fibrin
--> inhibits plasmin

see in dental procedures

Front 34

VLDL

Back 34

originate in liver with cholesterol from de novo and dietary sources

Front 35

LDL

Back 35

come from VLDL that's had triglycerides taken out of it

usually removed by receptor mediated uptake in liver and other tissues

Front 36

HDL

Back 36

precursors produced in liver and sent out to pick up cholesterol to bring back to liver

Front 37

type I hyperlipidemia

Back 37

see hyperchylomicronemia on fasting, even with normal fat intake

deficiency of lipoprotein lipase or normal apolipoprotein CII

NOT associated w/ increased CAD

Tx: low fat diet; no drug Tx required

Front 38

type IIA hyperlipidemia

Back 38

elevated LDL and normal VLDL b/c can't degrade LDL

from decrease in LDL receptors

GREATLY accelerates ischemic heart disease

Tx: low cholesterol/fat diet; give cholestyramine and/or statin (heterozygote
for homozygote, do the same and add niacin

Front 39

type IIB hyperlipidemia

Back 39

same as IIA, but w/ VLDL increased

from overproduction of VLDL in liver --> rel. common

Tx - dietary restriction of cholesterol, fat, and EtOH; give same drugs as with homozygous IIA

Front 40

type III hyperlipidemia

Back 40

See increased IDL

overproduce/underuse LDL (mutant apolipoprotein E)

xanthomas and accelerated vascular disease by middle age

Tx: reduce wt. restrict diet; give niacin and gemfibrozil or statin

Front 41

type IV

Back 41

VLDL increased, normal LDL, and MUCH increased TG's

overproduction/decreased removal of VLDL

assoc. w/ ischemic heart disease

pts are usually obese, diabetic, and hyperuricemic

E2-Tx also can do this (or 3rd trimester of pregnancy)

Tx: reduce weight first! give niacin and/or gemfibrozil or statin if drug tx required

Front 42

type V

Back 42

VLDL & chylomicrons elevated; LDL normal

pretty much the same thing as type IV in terms of presentation and Tx

Front 43

HMG CoA Reductase inhibitors

Back 43

Statins
inhibit the rate limiting step of cholesterol biosynthesis --> depend on dietary cholesterol
may also stabilize/reduce atherosclerosis

reduce MI and stroke

forcing reliance on dietary cholesterol upregulates LDL receptors, clearing the blood quicker

Front 44

HMG CoA Reductase inhibitors:
side effects

Back 44

damage to muscle may occur --> inflammation --> acute renal failure; oncurrent use with gemfibrozil increases risk of myopathy

increase serum liver enzymes - asymptomatic and trasient

bloating & diarrhea

other side effects may occur and long term use unknown

don't use w/ pregnant or breastfeeding: don't know what it'll do to the kid

first pass metabolism by liver

Front 45

bile acid binding products

Back 45

- cholestyramine, colestipol
- ion X-change prevents reabsorption of bile acids --> must metabolize cholesterol to make bile salts
- decreases cholesterol and fatal MI by 20%

Front 46

bile acid binders:

- side effects

- latest addition

Back 46

these drugs can cause constipation/diarrhea, steatorrhea, and can inhibit fat-soluble vitamin absorption
reduces acidic drug absorption

coleselvelam - new product, a hydrogel polymer; doesn't have as much GI and drug-binding problems as resins

Front 47

ezetimibe

Back 47

inhibits chosesterol uptake in lumen with NOT effect on other sterols of lipid soluble vitamins

acts at the brush border

no significant drug interaction noted

now combined with a statin in a pill for two mechanisms of lowering cholesterol

Front 48

CEPT inhibitor

Back 48

investigational drug

cholesterol-ester-transfer-protein mediates transfer of neutral lipids b/w lipoproteins
high levels correlate with low HDL levels

CEPT inhibitor increases HDL and decreases LDL (at least in one study)

one drug increased mortality and CV deaths

Front 49

synthetic HDL

Back 49

investigational drug used IV after MI or major coronary events

HDL is antiatherogenic & may reduce risk of thrombosis

synthetic variant that's better at binding cholesterol

Front 50

LXRalpha agonists
&
PPARalpha agonists

Back 50

liver receptor alpha

peroxisome proliferator activator receptor alpha

conceptual at this stage

Front 51

clofibrate

Back 51

decreases plasma triglycerides (w/ slight cholesterol[VLDL] increase)

stimulates lipoprotein lipase to breakdown plasma tri-G from lipoproteins

side effects: increased Rx of gallstones; increased mortality; protein-binding drug interaction (potentiates anti-coagulants)

DRUG OF LAST CHOICE (for this class)

Front 52

gemfibrozil

Back 52

stimulates lipoprotein lipase --> decreases plasma TG's

modest hyperchol. activity:
inhibits apoB synthesis --> decreases VLDL, LDL, and increases LDL uptake in liver

use for hyper-TG involving marked elevatio of VLDL

Front 53

fenofibrate

Back 53

latest anti-TG drug

like gemfibrozil, but more effective with LDL reduction

inhibits Acetyl CoA carboxylase; decreases FA synthesis; increases LDL liver uptake

effective w/ reducing CAD in diabetes-II

Front 54

niacin

Back 54

decreases adipose tissue TG-breakdown --> less free FA for TG & VLDL synth in liver

this also lowers LDL & increases HDL

flushing and itching, hepatotoxicity, and GI disturbances associated with this

Niaspan: extended release

Adicor - niacin and statin in one pill

Front 55

hypo-TG drugs (4)

Back 55

clofibrate
gemfibrozil
fenofibrate
omacor

drugs decrease plasma TG and slightly decrease cholesterol by inhibiting VLDL release in liver

Front 56

omacor

Back 56

omega-3 FA preparation --> reduces plasma TG and increases post-MI survival

Front 57

new drugs under development (3)

Back 57

CEPT inhibitor

synthetic HDL

LXR-alpha & PPAR-alpha

Front 58

cholesterol absorption inhibitor (1)

Back 58

ezetimibe

Front 59

bile acid binding drugs (3)

Back 59

cholestryamine

colestipol

colesevelam