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CV > 092914 pharm lipid disorders > Flashcards

092914 pharm lipid disorders Flashcards

1
Q

HMG CoA reductase inhibitors/statins. list them

A

atorvastatin
lovastatin
simvastatin

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2
Q

MOA of statins

A

competitive inhibitor for active site on HMG coA reductase (rate limiting step in cholesterol synthesis)

share structural component that is very similar to HMG portion of HMG-CoA

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3
Q

SREBP-what happens to it when sterols are low?

A

normally, SREBP is anchored in ER with SCAP and INSIG

if sterols are low, SCAP and INSIG no longer bind, so SREBP and SCAP move to the Golgi. SCAP is cleaved by site 1 protease and site 2 protease. now get a transcriptionally active SREBP that moves to nucleus to activate transcription of target genes. bind to sterol-responsive element of the LDL receptor gene

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4
Q

pharmacokinetics of statins

A

extensive first pass metabolism by liver–targets liver, the site of action

thereby prevents escape of drug molecules into circulating blood

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5
Q

which are the two statins that are inactive lactones and must be transformed inthe liver to hydroxy acids?

A

simvastatin, lovastatin

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6
Q

how are atorvastatin, lovastatin, simvastatin metablized?

A

CYP3A4

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7
Q

adverse effects of statins in percentage of population that develop them

A

10% of pts develop intolerant symptoms

1-2% develop serious side effects such as myositis or liver enzyme elevations

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8
Q

major adverse effects of statins

A

myopathy-muscle pain, weakness. no or little CK elevation

rhabdomyolysis-marked CK elevation. breakdown of muscle fibers that leads to release of myoglobin into bloodstream, causing kidney damage

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9
Q

myopathy risk factors (when treating with statins)

A

high statin dose

high plasma concentration

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10
Q

genetic variants of what can contribute to statin intolerance?

A

SLCO1B1, which encoes organic anion transporter that regulates hepatic uptake of statins. polymorphism of this is associated with statin induced myopathy

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11
Q

contraindications to statin therapy

A

hypersensitivity
active liver disease
PREGNANT WOMEN or women LACTATING, or likely to become pregnant

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12
Q

statin effect on lipoprotein profile

A

decreases triglycerides
decreases LDL
increases HDL

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13
Q

uses of statins

A

first line for hypercholesterolemia when at risk for MI

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14
Q

what is the only mechanism by which cholesterol is excreted?

A

conversion to bile salts

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15
Q

cholestyramine MOA

A

highly positively charged and binds negatively charged bile acids

b/c of its large size-the resins are not absorbed and the bound bile acids are excreted in the stool

by depleting pool of bild acids, hepatic bile acid synthesis increases (uses up more cholesterol, causing production of LDL receptors, a pathway similar to statins)

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16
Q

what is the dominant mechanism for controlling LDL plasma concentrations

A

regulation of hepatic LDL receptor pathway

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17
Q

how is cholestyramine administered?

A

as a hygroscopic powder administered with water

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18
Q

adverse effects of cholestyramine

A

most common-constipation, bloating
gritty consistency
interferes with absorption of other drugs (not absorbed itself)
modest INCREASE in TG, with time returns to baseline

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19
Q

cholestyramine effect on lipoprotein profile

A

if TG is normal, only transient increase
if TG is greater than 250 mg/dl, get INCREASE

decreases LDL

increases HDL

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20
Q

uses of cholestyramine

A

hypercholesterolemia

not recommended for people with hypercholes and increased TG

usually used as second agents if statin does not lower LDL choles enough

recommended for pts 11-20 yrs old

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21
Q

nicotinic acid is also called

A

niacin

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22
Q

niacin

A

water soluble B complex vitamin–prescription b/c used in much higher doses than vitamin

lipid lowering effect is unrelated to effect as vitamin
MAIN effect is to decrease TG (but does lower cholesterol)

23
Q

MOA of niacin

A

MOA not well understood

in adipose tissue, inhibits free fatty acid mobilization

in liver, decreases VLDL triglyceride production and increases apoB degradation

inhibits uptake of HDL-apoA1 (apoA1 activates LCAT)

24
Q

niacin has what effects

A

decreased serum VLDL

decreased serum LDL (but not through an increase of LDL receptor)

25
Q

adverse effects of niacin

A

skin flushing, pruritis–mediated by vasodilatory prostaglandins (can use NSAIDs to block effect). tolerance to flushing occurs with continued use

less frequent:
GI
elevated liver enzymes-no liver toxicity BUT MAJOR CONCERN if combined w statins
hyperuricemia (contradindicated for gout)
increases fasting glucose levels

26
Q

drug interaction of niacin

A

combined use with statin increases risk of myopathy

27
Q

niacin effect on lipoprotein profile

A

decreases TG
decreases LDL
increases HDL
decreases Lp(a)

28
Q

uses of niacin

A

hypercholesterolemia, hypertriglyceridemia

typically not first line therapy for hypercholesterolemia (side effects)

ONLY lipid lowering drug that decreases Lp (a)

29
Q

ezetimibe MOA

A

binds to NPC1L1 and inhibits cholesterol absorption by enterocyte. lowered cholesterol causes increase in LDL receptor expression.

cholesterol absorption inhibitor

30
Q

side effects of ezetimibe

A

well tolerated

side effects increase if combined with other drugs like statins

31
Q

ezetimibe effect on lipoprotein profile

A

decreases TG 5%
decreases LDL
increases HDL 1-2%

32
Q

uses of ezetimibe

A

primary hypercholesterolemia

combined with statins (efficacy questioned)

33
Q

fibric acid/fibrate/PPAR activators

A

gemfibrozil, fenofibrate

primarily lower TG-rich lipoproteins

34
Q

MOA of fibrates

A

bind to PPARalpha (expressed primarily in liver and brown adipose tissue). PPAR binds with retinoid X receptor to form heterodimer. they bind to specific genetic response elements. effect is to reduce TGs, increase reverse cholesterol transport

35
Q

what is an ex of a gene regulated by PPARalpha

A

lipoprotein lipase

36
Q

adverse effects of fibrates

A

generally well tolerated

GI symptoms-most common
increased risk of gallstones
less common-hematological or hepatic abnormalities

if also using statin, increases creatine kinase, leading to renal failure

37
Q

gemfibrozil side effect

A

can increase systemic statin concentrations by blocking tansporter in liver

38
Q

fibrates are contraindicated in which pts

A

renal impairment pts

39
Q

fibrates’ effect on lipoprotein profile

A

decreases TG
decreases LDL (highly variable)
increases HDL

40
Q

uses of fibrates

A

pts with high TGs and low HDL associated with metabolic syndrome or type 2 diabetes

41
Q

drugs of choice for hypercholesterolemia

A

statins-lifetime tx

bile acid resins (long term safety, younger pt, add on to statins)

ezetimibe (safety as monotherapy vs maybe add on to statins)

niacin (both elevated TG and cholesterol, low HDL)

42
Q

drugs of choice for hypertriglyceridemia

A

gemfibrozil/fenofibrate-1st choice
niacin
omega 3 fatty acids

43
Q

which drug has greatest effect at raising HDL?

A

niacin

44
Q

side effect comparisons of drugs

A

see slide 90 and 91

45
Q

effects of omega 3s

A

reduces rate of secretion of VLDL

reduce arrhythmia risk
stabilizes plaques
reduces HR
improves endothelial fxn

46
Q

side effects of omega 3s

A

fish allergy
may increase LDL
may increase liver enzymes
may prolong bleeding time

47
Q

use of omega 3s

A

adjunct in tx of hyperTG

48
Q

PCSK9 inhibitors

A

antibodies that prevent PCSK9 binding to LDLR-LDL complex

49
Q

MTP

A

microsomal triglyceride transfer protein–if you inhibit, prevents assembly of apo-B containing lipoproteins in enterocytes and hepatocytes, reducing chylomicrons, VLDL, LDL-C

50
Q

side effects of MTP inhibitors

A

GI

hepatotoxicity

51
Q

uses of MTP inhibitors

A

pts with homozygous familial hypercholesterolemia

52
Q

apoB-100 inhibitor MOA

A

antisense oligonucleotide hybridizes with coding region of apoB-100 mRNA. activates RNaseH

53
Q

side effects of apo-B inhibitors

A

injection site rxns
flu like symptoms
headache
elevation of liver enzymes

54
Q

use of apo-B inhibitors

A

homozygous familial hypercholesterolemia

adjunct ot dietary therapy and other lipid lowering treatments

CV (34 decks)

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