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Flashcards in Atherosclerosis Treatment Deck (37):
1

reasons for using statins over other cholesterol lowering therapies

Proven effective based on large number (21) of randomized clinical trials (RCTS)

More intensive statin therapy reduces rates of CHD, stroke and death more than less intensive therapy (5 RCTs)

Inexpensive (5 of 7 generic)

Safe when given as directed

2

statin benefit groups

clinical ASCVD

LDL-C >/= 190 mg/dL without secondar ycause

primary prevention/diabetes - ages 40-75, LDL-C 70-189 mg/dL

primary prevention/no diabetes - ages 40-75, LDL-C 70-189 mg/dL, ASCVD risk >/= 7.5%

3

When do results of stain treatment become the most prominent?

years 4-5

4

mechanism of action of statins

structurally similar to HMG-CoA and act as a competitive inhibitor of HMG-CoA reductase, thereby reducing synthesis of cholesterol

leads to increased LDL receptors

small elevations in HDL-c is also seen

5

drugs that lower LDL-C

statins

bile acid sequestrants

niacin

fibrates

omega-3's

6

What happens to mean % change from baseline LDL-C every time the dose of statin is doubled?

there will be an extra 6% decrease

7

non-LDL effects of statins

endothelial function

reduction of inflammatory response

plaque stability

thrombus formation

8

statins with long half lives

rosuvastatin (19-20 hrs) and atorvastatin (15-30 hrs)

9

statins with short half lives

fluvastatin, lovastatin, pravastatin, simvastatin

10

toxicity of statins

liver enzyme rises (transaminases)

muscle myositis

interacts with cyclosporine, gemfibrozil (glucuronidation affected), grapefruit juice (P450), erythromycin

decrease in ischemic stroke but slight increase in hemorrhagic stroke

11

statins and diabetes

may raise blood sugar, 1 to 2 excess cases per year per 1000 patients

12

metabolism of statins

CYP3A4 for lovastatin, simvastatin, and atorvastatin

CYP2C9 for fluvastatin and rosuvastatin

pravastatin has no CYP activty

all statins undergo glucuronidation

13

lovastatin

fungal derivative

used for over a decade

moderate potency

has similar properties as red yeast rice, which has mevilonin

14

simvastatin

fungal derivative

at high doses, best at raising HDL-c and Apo A1

very inexpensive

15

pravastatin

fungal derivative

not metabolized by P450 system, sulfated

inexpensive

16

fluvastatin

synthetic

not as potent

17

atorvastatin

synthetic

potent, long half life of 14 hours

18

cerivastatin

synthetic

removed from market due to myositis risk with high dosages and with gemfibrozil

19

rosuvastatin

synthetic

most potent due to low lipophilicity and high hepatocyte selectivity because of large polar side chain

19 hour half life

20

pitavastatin

synthetic

can be used for those who don't tolerate other statins

21

GI active drugs

bile acid sequestrants

stanols, sterols

Eztimibe (cholesterol absorbtion inhibitor)

22

bile acid sequestrants

cholestyramine and colestipol - resins

colesevelam - gel

binds bile acids in the gut and causes depletion of hepatic cholesterol pools

increased production of more LDL receptors

non-systemic, not absorbed

23

Ezetimibe

cholesterol absorption inhibitor

hepatic glucuronidation and then intestinal villi

decreased absorption of biliary and dietary cholesterol

acts at brush borders of small intestins

helpful in sitosterolemia

only one year of SHARP trial data for safety and additive effect with statins

24

plant/sterol esters

inhibit micellar cholesterol absorption

not additive to  Ezetimibe therapy

25

efficacy of GI active drugs

sequestrants and Ezetimibe lowers LDL-C about 20%

stanol ester about 10-14%

26

combinint statin and GI active drugs

same result as 3 doublings of dosage of statins alone

27

niacin (vitamin B3) mode of action

a. Potent inhibitor of adipose tissue lipolysis  (G-coupled receptor) - Suppression of lipolysis in adipocytes by niacin activating its receptor GPR109A

b. Decreases flux of FFA used by liver for VLDL production

c. Inhibits VLDL synthesis; see decrease in large TG rich VLDL

d. Decrease in assembly of apo B containing lipoproteins

e. See decreased small dense LDL

f. See increased HDL Apo A-1 (prolongs half-life) - Inhibits hepatic removal, best drug for raising HDL-C

g.  Reduces Lp(a)  (only lipid drug to do this) 

28

clinical usage of niacin

Patients with high cholesterol and high triglyceride and low HDL-c

Raises HDL at low dose; less potent in lowering LDL c at low dose than statins

29

niacin toxicity

1)  Cutaneous vasodilation and flushing due to effects of receptors in the dermis

2) Hepatotoxicity; more prominent with Niacin than it is with statins.

3) Niacin raises blood sugar; increases hepatic glucose output-use carefully in diabetics

4) Elevates uric acid--can lead to gouty arthritis

5) Exacerbates peptic ulcer disease

30

forms of niacin

sustained release (more GI side effects, hepatic toxicity)

intermediate release (bed time only, linear kinetics, best balance between flushing and liver concerns)

immediate release (cheapest, most flushing)

31

fibrates - Gemfibrozil and Fenofibrate mechanism of action

Triglyceride rich lipoproteins – major effect on lowering TG levels, done through PPAR alpha effects on ApoCII (decrease) and LPL (increase)

LDL:  Differing effects depending on LDL and TG levels - best LDL lowering if high LDL alone, paradoxical increases in LDL-C if LDL is not elevated

fenifibrate lowers LDL-C more thatn Gemfibrozil

HDL: increase if baseline levels are low, increase in ApoAI and AII

Fenofibrate lowers uric acid and raises homocystein

32

efficacy of fibrates

reduce progression of coronary lesions

reduce major coronary events in primary and secondary prevention trials, bu tnot in trials of diabetics

33

toxicity of fibrates

cholelithiasis

mild GI symptoms

myositis when combined with HMG CoA reductase inhibitors

34

omega 3 fatty acids mode of action

Lower TG in a dose –related fashion (lipid reason to use omega 3 fatty acids)

Don’t use to lower LDL-c

Can see slight increase in HDL-c

Reduced CHD death in survivors of MI 

35

efficacy of omega 3 fatty acids

In those with very high TG; can lower TG up to 50%

In those with mild-moderate TG, can lower TG about 25%

36

side effects of omega 3 fatty acids

well tolerated

can raise LDL-C if combined with hyperlipidemia

see increasing bruising

can be used in combined hyperlipidemia with statins

37

therapies to increase HDL-C

apo A1 milano like  IV preparations

CETP inhibitors –Torcetrapib caused increase in CHD and total mortality