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Cardio Renal II Midterm > Med Chem - Hyperlipidemia > Flashcards

Med Chem - Hyperlipidemia Flashcards

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1
Q

Dyslipidemia vs hyperlipidemia

A

dyslipidemia - blood lipid levels are either too high or too low

hyper - lipid levels too high in blood

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2
Q

the term “hyperlipidemia” means that lipid levels are too high WHERE?

A

the blood

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3
Q

what is mixed hyperlipidemia

A

increase in both triglycerides and LDL cholesterol

potential decreases in HDL cholesterol

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4
Q

why is hyperlipidemia bad?

A

it leads to restricted blood flow – and a risk of coronary artery disease (CAD) or coronary heart disease (CHD)

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5
Q

explain what lipoproteins are

(structure and function)

A

particles made of lipids (cholesterol, cholesteryl ester, triglycerides) and apolipoproteins

they transport hydrophobic lipids in the blood (blood is hydrophilic – so lipids need lipoprotein as a carrier)

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6
Q

what is the component of a lipoprotein that recognizes the cell receptor and actually delivers the lipids into the cell?

A

apolipoprotein

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7
Q

name the function of LDL-C vs HDL-C

A

LDL - carries cholesterol from the liver and to the rest of the body (BAD)

HDL - good cholesterol! helps remove excess cholesterol from the bloodstream by bringing it to the liver for disposal

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8
Q

higher HDL-C levels are associated with….

A

a lower risk of heart disease :)

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9
Q

high LDL-C levels can lead to….

A

plaque buildup in the arteries

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10
Q

what is the most common fat in the body

what are they used for?

A

triglycerides

energy storing

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11
Q

why are high levels of triglycerides bad?

what scenario makes high triglycerides worse?

A

bc high TG can contribute to atherosclerosis

it’s worse when combined with high LDL levels or low HDL levels

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12
Q

carriers of lipids through the blood

A

lipoproteins

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13
Q

name the 5 classes of lipoproteins in order of smallest to largest

which has the HIGHEST DENSITY?

A

smallest - HDL
LDL
IDL
VLDL
largest - chylomicrons

HDL has the highest density
chylomicrons have the lowest density

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14
Q

both chylomicrons and VLDL are ____-rich

A

triglyceride

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15
Q

which class of lipoproteins is the main carrier of cholesterol in the blood

A

LDL

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16
Q

explain how high LDL levels cause plaques in the arteries

A

bc LDL is susceptible to oxidation. when this happens, they are taken up by macrophages, which get “fluffed up” and create plaques

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17
Q

which class of lipoproteins plays an essential role in “reverse cholesterol transport” and what does this mean?

A

HDL

they bring cholesterol from the body and to the liver for disposal

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18
Q

name of the core structural apoprotein of chylomicrons

what about VLDL?

A

B48

VLDL - B100

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19
Q

core structural apoprotein of HDL

A

Apo-AI

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20
Q

____ are highly concentrated stores of metabolic energy

A

Triglycerides

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21
Q

within adipose cells, where do triglycerides accumulate?

A

in the cytosol

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22
Q

basic mechanism of statins

A

HMG-CoA reductase inhibitors

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23
Q

basic mechanism of Fibric Acids

A

PPARa agonists

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24
Q

full chemical name of “fibric acids”

A

phenoxyisobutyric aicds

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25
general mechanism of ezetimibe
cholesterol absorption inhibitor
26
which class of lipid-lowering agents mediates the clearance of LDL cholesterol by activating LDL receptors?
PCSK9 inhibitors (monoclonal antibodies)
27
general mechanism of niacin as a lipid lowering agent
hydroxycarboxylic acid receptor 2 agonist
28
general mechanism of bempedoic acid (nexletol) as a lipid lowering agent
ATP citrate lyase (ACLY) inhibitor
29
What is the name of the intermediate in the conversion from HMG-CoA to mevalonate? what is important to know about this molecule?
(S)-mevaldyl-CoA this is the TRANSITION STATE and statins mimic this molecle by both the 3 and 5 OH's being Beta (pointing up)
30
TRUE OR FALSE the conversion of HMG-CoA to mevalonate is a 2 step oxidation reaction
FALSE - 2 step reduction
31
in the conversion of HMG-CoA to mevalonate, there is inversion of stereochemistry from __ to ___
(3S) to (3R)
32
**true or false statins mimic HMG-CoA
FALSE - they mimic the transition state - mevaldyl-Coa 1 OH is beta and the other is alpha
33
what is the only natural 1st generation statin
mevastatin
34
*Is the stereochemmistry of mevaldyl-CoA at the 3 position still S? or has it changed to R already?
still S only changes to R when the final product is formed
35
*for which does stereochemistry matter more - 1st generation or 2nd generation statins?
1st generation!!!!! the OH groups on dihydroxyheptaonic acid (or its lactone ring if a prodrug) MUST be 3R, 5R in order to mimic the hydroxy groups of S)-Mevadyl-CoA
36
true or false pravastatin is a LESS active metabolite of mevastatin
true
37
name the 4 1st gen statins
mevastatin lovastatin simvastatin pravastatin
38
true or false all of the 1st gen statins are prodrugs
FALSE - all except pravastatin
39
***CRITICAL pharmacophore for all statins
3R, 5R-dihydroxyheptanoic acid this configuration allows both of the 3 and 5 OH's to be BETA!! mimicking (S)-mevaldyl-CoA
40
what is the general change from 1st gen to 2nd gen statin what was important to keep the same?
VERY important for the 3, 5-dihydroxyheptanoic acid to remain the same (stereochemistry DOES NOT MATTER!!!! AS LONG AS OH POINT SAME WAY AS MEVADYL) however, the didehydrodecalin ring was changed to other hydrophobic groups -- ie - indole, pyrrole, quinoline, pyrrole, etc
41
TRUE OR FALSE 2nd gen statins are more lipophilic than 1st gen statins
true
42
true or false 2nd gen statins have more chiral centers than 1st gen
FALSE 2nd gen statins have less chiral centers
43
**the 2 OH's which are critical for statin activity undergo what kind of binding?
hydrogen bonding
44
*how many different regions of the enzyme (HMG-CoA reductase) do statins bind to? name the interactions
4 different regions the 2 OH's undergo H-bonding COO- undergoes ionic interaction with (+) charged aa hydrophobic interaction protrudes OUTSIDE of the enzyme-ligand binding pocket
45
name the only 2 hydrophilic statins how are they hydrophilic?
pravastatin and rosuvastatin pravastatin already has lactone ring hydrolyzed. (not a prodrug) rosuvastatin has a sulfonamide group at the bottom, making it hydrophilic
46
true or false pravastatin and atorvastatin are the only hydrophilic statins. the rest are lipophilic
FALSE pravastatin and rosuvastatin
47
*which are more of a concern and why - hydrophilic or lipophilic statins?
lipophilic statins are more of a concern bc they are NOT hepato-selective. they can passively diffuse through cell membranes of other tissues besides the liver hydrophilic statins, however, are hepatoselective. they need carrier-mediated uptake into the liver
48
true or false lipophilic statins are hepato-selective
FALSE - hydrophilic are
49
one of the most ____ statins (_____), was withdrawn from the market bc it showed severe myopathy
lipophilic/potent Cerivastatin
50
*name 3 statins metabolized by CYP3A4
SAL simvastatin atorvastatin lovastatin
51
*what CYP metabolizes fluvastatin
2C9
52
*what CYP metabolizes pravastatin and rosuvastatin
NONE - mostly excreted unchanged (hydrophilic)
53
fibric acid drugs are derivatives of....
phenoxyisobutyric acid
54
name 3 fibrates which are prodrugs?
fenofibrate clofibrate gemfibrozil fenofibrate and clofibrate are prodrugs (their COOH is esterified!)
55
which functional group of fibrates is CRITICAL for it to be active
COO- (anion)
56
**explain the MOA of fibrates
they activate PPAR-a the activated PPAR-a forms a heterodimer with RXR this allows the transcription of target genes
57
*what does PPAR-a activation by fibrates do to LDL particle size?
increases LDL particle size. larger LDL is better because it is not susceptible to oxidation and being taken up by macrophages to form a plaque
58
*what does PPAR-a activation by fibrates do to HDL synthesis
increased HDL synthesis
59
**true or false fibrates, through activating PPAR-a, decrease reverse cholesterol transport
FALSE increase reverse cholesterol transport meaning that more cholesterol from the blood is delivered to the liver to be excreted in feces
60
what kind of receptor is PPARa
a nuclear receptor
61
**HOW do fibrates decrease triglycerides
by increasing LPL (lipoprotein lipase) expression this enzyme hydrolyzes triglycerides into free fatty acids in turn, these free fatty acids undergo increased B-oxidation -- and thus TG synthesis is also inhibited
62
*true or false fibrates decrease inflammation
true
63
*true or false larger LDL size is better
TRUE - resistant to oxidation considered anti-atherogenic
64
**through which bonds do fibrates bind to PPAR-a
ALL 4 are hydrogen bonds this is why the free COO- needs to be exposed for activity
65
**explain the metabolism of fenofibrate
fenofibrate is a PRODRUG therefore, the ester is hydrolyzed to its active form this COOH now exposed, will eventually undergo glucuronic acid conjugation
66
which undergoes more extensive metabolism and why - fenofibrate or gemfibrozil?
gemfibrozil bc its more lipophilic
67
**explain the metabolism of gemfibrozil are the metabolites active or inactive
first, hydroxylation through CYP3A4 next, alcohol dehydrogenase converts the OH to the aldehyde version, and then aldehyde dehydrogenase converts to the Carboxylic acid metabolite ALL the metabolites are inactive
68
**explain the MOA of ezetimibe
NPC1L1 antagonist NPC1L1 is a protein on the wall of the intestine which absorbs dietary cholesterol. thus, ezetimibe inhibiting this protein inhibits the absorption of dietary cholesterol
69
*explain the metabolism of ezetimibe (state both the major and minor pathways)
major - phenolic OH is glucuronidated. this metabolite is ACTIVE and undergoes repeated enterohepatic recirculation giving a LONG DURATION OF ACTION minor - aliphatic OH is oxidized to an INACTIVE ketone (major route is active, minor route is inactive)
70
in which organ are bile acids and bile salts synthesized?? where are they stored?
in the liver stored in the gallbladder
71
*explain the function of bile acids and bile salts
they emulsify dietary lipids and fat soluble vitamins -- which helps their absorption through the intestine
72
*what is the RATE DETERMINING ENZYME in the conversion of cholesterol to bile acids and then to bile salts
7a-hydroxylase
73
**name the 2 steps in the conversion of cholesterol to bile acid and then to bile salt
cholesterol -> bile acid -- C-12 hydroxylation and side chain oxidation by rate limiting enzyme (7a-hydroxylase) bile acid -> bile salt - conjugation with glycine
74
***explain how the negative feedback mechanism works in terms of bile salts
when bile salt (glycocholate) is produced, it goes back to the liver and "tells" the liver not to convert any more cholesterol into bile acid (bc there's enough!)
75

Cardio Renal II Midterm (14 decks)

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