Atherosclerosis Treatment Flashcards
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
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%
When do results of stain treatment become the most prominent?
years 4-5
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
drugs that lower LDL-C
statins
bile acid sequestrants
niacin
fibrates
omega-3’s
What happens to mean % change from baseline LDL-C every time the dose of statin is doubled?
there will be an extra 6% decrease
non-LDL effects of statins
endothelial function
reduction of inflammatory response
plaque stability
thrombus formation
statins with long half lives
rosuvastatin (19-20 hrs) and atorvastatin (15-30 hrs)
statins with short half lives
fluvastatin, lovastatin, pravastatin, simvastatin
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
statins and diabetes
may raise blood sugar, 1 to 2 excess cases per year per 1000 patients
metabolism of statins
CYP3A4 for lovastatin, simvastatin, and atorvastatin
CYP2C9 for fluvastatin and rosuvastatin
pravastatin has no CYP activty
all statins undergo glucuronidation
lovastatin
fungal derivative
used for over a decade
moderate potency
has similar properties as red yeast rice, which has mevilonin
simvastatin
fungal derivative
at high doses, best at raising HDL-c and Apo A1
very inexpensive
pravastatin
fungal derivative
not metabolized by P450 system, sulfated
inexpensive
fluvastatin
synthetic
not as potent
atorvastatin
synthetic
potent, long half life of 14 hours
cerivastatin
synthetic
removed from market due to myositis risk with high dosages and with gemfibrozil
rosuvastatin
synthetic
most potent due to low lipophilicity and high hepatocyte selectivity because of large polar side chain
19 hour half life
pitavastatin
synthetic
can be used for those who don’t tolerate other statins
GI active drugs
bile acid sequestrants
stanols, sterols
Eztimibe (cholesterol absorbtion inhibitor)
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
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
plant/sterol esters
inhibit micellar cholesterol absorption
not additive to Ezetimibe therapy
efficacy of GI active drugs
sequestrants and Ezetimibe lowers LDL-C about 20%
stanol ester about 10-14%
combinint statin and GI active drugs
same result as 3 doublings of dosage of statins alone
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)
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
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
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)
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
efficacy of fibrates
reduce progression of coronary lesions
reduce major coronary events in primary and secondary prevention trials, bu tnot in trials of diabetics
toxicity of fibrates
cholelithiasis
mild GI symptoms
myositis when combined with HMG CoA reductase inhibitors
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
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%
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
therapies to increase HDL-C
apo A1 milano like IV preparations
CETP inhibitors –Torcetrapib caused increase in CHD and total mortality
