Lipids Flashcards
1
Q
Cholesterol is a steroidal compound with C___
A
27
2
Q
What enzyme is cholsterol synthesized from
A
acetyl coenzyme A
3
Q
How does HMG CoA go to Mevalonic Acid
A
by HMG CoA reductase
4
Q
What molecules are triglycerides formed from
A
glycerol-3-phosphate
5
Q
What are the 4 classifications of major plasma lipoproteins
A
very low density lipoproteins
intermediate-density lipoproteins
low-density lipoproteins
high-density lipoproteins
6
Q
Statins are inhibitors of HMG-CoA reductase and they lower plasma cholesterol levels by what three mechanisms
A
inhibition of cholesterol biosynthesis
enhancement of receptor-mediated LDL uptake
reduction of VLDL precursors
7
Q
What is the pharmacophore of HMG-CoA reductase inhibitors
A
7 ring system dihydroxyheptanoic acid
8
Q
The decalin ring is essential for anchoring the drug to the enzyme _______ _____
A
active site
9
Q
Does a beta hydroxyl group increase or decrease hydrophilicity
A
increase (may improve cellular specificity)
10
Q
What statin is the most hydrophilic and therefore has minimal penetration into lipophilic membrances, better selectivity for hepatic tissues and reduction in side effects
A
Pravastatin
11
Q
All HMGRIs in active form contain a carboxylic acid that is primarily ________ at physiological pH
A
ionized
12
Q
What CYP enzyme metabolizes HMGRIs
A
CYP34A
13
Q
When should statins be administered
A
at night because it counteracts the peak cholesterol synthesis that occurs in the morning
14
Q
Cholesterol Absorption Inhibitor MOA (ezetimbie)
A
-inhibits the absorption of cholesterol at the brush border of the small intestine
-competitively binds to sterol transporter
15
Q
Ezetimibe is selective and does not interfere with the absorption of what molecules
A
triglycerides
lipid soluble vitamines
16
Q
In Cholesterol Absorption Inhibitors the hydrolysis or expansion of the beta-lactam ring produces an ________ compound
A
inactive
17
Q
Why is the secondary alcohol of ezetimibe not as important as the phenolic alcohol
A
The drug can conjugate to become active at the phenolic site
18
Q
Bile Acid Sequestrants act by what MOA
A
binding to major bile acids, glycocholic acid and taurocholic acid, and greatly increase their fecal excretion
19
Q
Bile acid sequestrants do not bind to specific receptors but bind to _______ charged atoms or functional groups on drug molecules
A
negatively
20
Q
Since bile salts contain numerous positive charges they are more likely to bind to ________ compounds or nonelectrolytes
A
acidic
21
Q
Impaired lipolysis by nicotinic acid ________ the mobilization of free fatty acids which reduce their plasma levels and their delivery to the liver
A
decreases
22
Q
Nicotinic acid does not have any effects on what two things
A
cholesterol catabolism or biosynthesis
23
Q
Fibrate MOA
A
-decrease plasma triglyceride levels more than cholesterol levels
-help lipoprotein metabolism by activation of peroxisome proliferator-activated receptors (alpha)
24
Q
Which group in fibrates are essential for activity
A
isobutyric acid and the phenoxy ring
25
The extra space in gemfibrozil enhances _____ solubility which allows the drug to be absorbed through the GI membrane without the need of an ester prodrug
lipid
26
What functional group is important for fibrate binding and activity
carboxylic acid
27
Fenofibrate is a ______ that undergoes rapid hydrolysis to produce fenofibric acid active metabolite
prodrug
28
Dyslipidemia
Levels of lipids or lipoproteins in the blood that are outside or normal boundaries and have adverse effects
29
Hyperlipidemia
elevated levels of lipids or lipoproteins in the blood (mainly family)
30
Hyperlipidemia and ASCVD are associated with a general inflammatory state that contribute to ___________________ disorders
neurodegenerative
31
Primary risk factors of hyperlipidemia
reduce clearance that cause overproduction of LDLs or triglycerides
increase clearance that cause underproduction of HDLs
32
Secondary risk factors of hyperlipidemia
diet
sedentary life
obesity
diabetes
excessive alcohol
CKD
hypothroidism
liver dieases
33
Risk factors of low HDL
SMOKING
anabolic steroid use
HIV infection
nephrotic syndrome
34
What are chylomicrons synthesized from
synthesized from dietary triglycerides, cholesterol, and lipid-soluble vitamins in small intestine
35
Synthesized intestinal cholesterol and plant sterol absorption by what
niemann-pick c1-like protein 1 (NPC1L1)
36
ATP-binding cassette transporters pump what back into intestinal lumen
plant sterols
37
What is diagylcerol transferase transferred by
microsomal triglyceride transfer protein (MTP) to newly forming chylomicrons
38
What is ApoB-48
organizes newly forming chylomicrons
39
Type 2 isozyme of acyl-coenzyme A; __________ _________ esterifies dietary cholesterol, regulates cholesterol absorption
cholesterol acyltransferase (ACAT2)
40
________ enter the lymphatic system, pass to circulation via thoracic duct
chylomicrons
41
Chylomicronemia syndrome is genetic impairment of _____ or _______, impair chylomicron function
LPL
apoC-II
(cause severe hypertriglyceridemia, pancreatitis)
42
Chylomicron remanants are remanants after __________ from chylomicrons
triglycerides
43
What are the different chylomicron remanants
endothelial fenestres
ApoE
Hepatic lipase (HL)
LDL receptor or LDL receptor-related protein
44
What is LDL
-produced in liver, large, can cause plasma turbidity
-production is stimulated by triglycerides released from chylomicrons
45
What is IDL
triglycerides in VLDL metabolized by LPL to form IDL
released from capillary beds into circulation
46
How is LDL cleared
ApoB100/LDL receptor interaction in hepatocytes
47
Atherosclerosis is a syndrome in which atherosclerotic _________ develop in arteries, producing narrowing of the arterial passage and thickening of the arterial wall
plaques
48
How are plaques formed in atherosclerosis
oxidized LDL is taken up by macrophages
49
HDL is produced by liver and intestine and form chylomicron ___________ and VLDL
remnants
50
Pre-beta1 HDL primarily mediates transport of __________ to and from other cells
cholesterol
51
Lecithin is cholesterol acetyltransferase that esterifies cholesterol in what
pre beta1 HDL
HDL
HDL2
HDL3
52
In reverse cholesterol transport ____ absorb cholesterol from peripheral cells/macrophages
HDL
53
HDL2 and HDL1 exchanges cholesterol in liver excreted in bile _____ with bile _______
ducts
salts
54
In exogenous lipid transport ____ hydrolyzes triglycerides; free fatty acids absorbed by tissues
LPL
55
In exogenous lipid transport LPL releases free fatty acids to form _____
IDL
56
Cholesterol synthesis: long metabolic pathway, begins with transport of _________ from mitochondrial stores
acetyl-coA
57
3-hydroxy-3-methylgutaryl-CoA synthesized from acetyl-CoA and acetoacetyl-CoA by what
HMG-CoA reductase
58
Drugs that treat hypercholesterolemia
statins
ezetimibe
bile acid-binding agents
PsK9 inhibitors
59
Drugs that treat hypertriglyceridemia
fibrates
omega-3 fatty acids
niacin
60
What is the rate limiting step in cholesterol synthesis
HMG-CoA reductase
61
Statin inhibit HMG-CoA reductase which reduce endogenous ________ _________
cholesterol synthesis
62
What are the two natural statins
mevastatin
lovastatin
63
What are the two synthetic statins
pravastatin
simvastatin
fluvastatin
atorvastatin
rosivastatin
pitavastatin
64
All statins contain a _______ acid side chain that is a structural analog of an HMG-CoA intermediate
heptanoic
65
Membrane-bound (sterol regulatory element bring protein) is cleaved by a protease and SRE translocates to the ______
nucleus
66
SRE increases expression of ______ gene
LDLR
67
Statins increase the removal of LDL from the blood __________ LDL-C
lowering
68
Where are statins absorbed
small intestine
69
Where are statins distributed
most in liver
low levels in plasma
mostly protein-bound
70
How are statins metabolized/excreted
metabolized in liver and excreted in feces
71
What is rhabdomyolysis
toxic muscle protein products in serum
72
Carriers of PCSK9 cause a loss of function allele which _____ MI
decreases
73
Fibrates are what kind of agonist
peroxisome proliferator-activated receptor alpha (PPARalpha)
74
Fibrates reduce triglyceride levels by how much percent
30-50%
75
What are the two main fibrate drugs
gemfibrozil
fenofibrate
76
Omega 3 fatty acids are peroxisome proliferator-activated receptor _____ and ______
alpha
gamma
77
Cholesterol uptake inhibitor drug
ezetimibe (zetia)
78
Ezetimibe inhibit luminal cholesterol absorption via ________ by jejunal enterocytes
NPC1L1
79
NPC1L1 recruits free cholesterol creating a ___________ mechanism
raft-like
80
Ezetimibe is metabolized by ___________ (intestinal wall)
glucuronidation
81
Ezetimibe absorption limited to enterohepatic circulation which causes a limited ________ exposure
systemic
82
Dual therapy with ezetimibe cause exacerbated ______ associated adverse effects
statin
83
Primary bile acid synthesized by ________ from cholesterol
hepatocytes
84
Secondary bile acids are synthesized in ___ by bacteria
gut
85
What are bile salts
they are bile acids conjugated with taurine or glycine secreted into bile ducts
86
Bile salts reduce ____ globules to smaller emulsified droplets
fat
87
Bile salts increase effectiveness of _________ _________ freeing more fatty acids for absorption
pancreatic lipase
88
What is niacin
water soluble B complex vitamin
source of NAD or NADP
improves all lipid parameters
89
Niacin acts at ______ and senses energy metabolites in adipose tissues
HCA2 (hydroxycarboxylic acid receptor 2)
90
In the liver Niacin inhibits __________ which decreases triglyceride synthesis/triglyceride esterification
diacylglycerol acyltransferase-2
91
Adverse side effects of Niacin
Dyspepsia
Hepatic Toxicity
Flushing/pruritus
92
Niacin exacerbates statin-induced _______
myopathy
93
Cholesterol absorption and transportation
-cholesterol from food and bile enters the intestine
-micelles bind cholesterol and transport to enterocyte
-fatty acids synthesized to TGs
-TF and cholesterol esters from chylomicrons
-chylomicrons released into lymphatic system then transport to liver
94
ILDL can promote growth of ______
atheroma (ASCVD risk)
95
What is the main component of atheromatous plaque (ASCVD risk)
LDL
96
How to calculate LDL-C
TC - (TG/5) - HDL
97
If TG are greater then 400 mg/dL what happens
do not use equation and cannot calculate
98
The equation is not as accurate if LDL is very low. What level is considered low
<70 mg/dL
99
Is fasting needed to collect a lipid pannel
no
100
What are the 4 ASCVD risks
coronary artery disease
stroke
aortic aneurysm
peripheral vascular disease
101
What is CAD
Angina
MI (revascularization)
-stent or balloon
-CAD
102
Carotid artery stenosis is a common cause of what
strokes
103
Is this primary or secondary ASCVD:
genetic defects
-hypertiglyceridemia
-homozygous familial hypercholesterolemia
-heterozygous familial hypwecholesterolemia
primary (familial)
104
Is this primary or secondary ASCVD:
-diet/lifestyle
-drugs
-disorders/defects
-diseases/comorbidities
secondary (acquired)
105
What are the diet etiology
excessive alcohol intake
anorexia or weight gains
excessive carb intake
106
What are the drugs etiology
atypical antipsychotics
beta-blockers/diuretics
glucorticoids
estrogen
107
What are the diseases etiology
renal failure
pregnancy
hypothyroidism
uncontrolled diabetes
108
Symptoms related to ASCVD events
chest pain
palpitations
sweating
anxiety
SOB
loss of consciousness
difficulty speaking/moving
109
Signs of ASCVD
pancreatitis
eruptive xanthomas
peripheral neuropathy
110
Labs of ASCVD
elevated: TC, LDL, TG, CRP, Apo-B
decreased: HDL, Apo-A
111
What are the 4 diagnostics of ASCVD
carotid ultrasound (carotid artery stenosis)
coronary calcium score (CAD/stroke)
Ankle-brachial index (PVD)
Left heart catheterization (CAD)
112
Primary prevention of ASCVD
before an ASCVD event occurs
No active disease
Prevent dyslipidemia or future ASCVD event
113
Secondary prevention of ASCVD
after an ASCVD event occurs
Active disease
prevent another future ASCVD event
114
ASCVD risk stratification:
Low
Borderline
Intermediate
High
Low: <5%
Borderline: 5-7.4%
Intermediate: 7.5-19.9%
High: >20%
115
What are premature ASCVD for males and females
male: <55
female: <65
116
What age to start screening for ASCVD
20 yo
117
Ages 0-39 are generally low risk but what are the exceptions
familial hypercholesterolemia
premature ASCVD in family and LDL >160 mg/dL
LDL > 190mg/dL
118
Ages 4-75 yo: risk varies
who benefits from statin
LDL >190 mg/dL
DM
119
ASCVD risk enhancers
family history
LDL >160 mg/dL
CKD
metabolic syndrome
women preeclampsia, premature menopause
inflammatory diseases (arthritis, HIV)
Ethnicity (African American)
120
What are the 5 indicators in metabolic syndrome and how many do you need to be considered to have it
3/5
-HTN
-waist >40 male, >35 females
-blood glucose >100 mg/dL
-TG >175 mg/dL
-Low HDL <40 male, <50 female
121
What is CAC
computed tomography (CT) scan
provides imaging of calcium deposits in coronary arteries
122
CAC Agatston score
0: low risk
1-10 low risk <10% ASCVD
11-100: low risk, consider meds if >55 yo
101-400: moderate plaque, high risk, start statin
>400: large plaque, very high risk, start statin
123
What are the 4 statin benefit groups
clinical ASCVD
LDL >190 mg/dL
Age 40-75 yo & DM
40-75 with ASCVD >7.5%
124
Following a low-cholesterol diet can lead to how much of a reduction in LDL
20-30%
125
How long can you trial a lifestyle change in patients to lower their LDL
12 weeks
126
Comorbidities of dyslipidemia
hypothyroidism
obstructive liver disease
renal disease
DM
pregnancy
127
Statins
HMG-CoA reductase inhibitors
block conversion of HMG-CoA to mevalonic acid
rate-limiting step in cholesterol production
mainstay of LDL-lowering therapies
most effective oral medication for lowering LDL levels
128
Why should some statins be taken at night
Medications with short half-lives should be taken at night because that is when cholesterol is the highest
129
What are the three statins that should be taken at night
lovastatin
fluvastatin
simvastatin
130
What are the two hydrophilic statins
rosuvastatin
pravastatin
131
Drug interactions with gemfibrozil
all statins
increased risk of rhabdo
132
Drug interactions with amiodarone
inhibit 3A4 and 2C9
max simvastatin 20 mg
max lovastatin 40 mg
133
Drug interactions with amlodipine
inhibit 3A4
max simvastatin 20 mg
134
Drug interactions with diltiazem
inhibit 3A4
max simvastatin 10 mg
max lovastatin 20 mg
135
Drug interactions with fenofibrates
all statins
increased risk of rhabdo
136
Common ADRs with statins
diarrhea
arthralgias
nasopharyngitis
nausea
137
SAMS: myalgias
muscle pain
no CK elevation
138
SAMS: myopathy
muscle pain
CK >10x ULN
139
SAMS: rhabdomyolsis
muscle pain
CK >40x ULN
often with acute renal failure
140
SAMS: immune-mediated necrotizing myopathy (IMNM)
muscle pain
elevated CK
HMG-CoA antibodies
141
Non-modifiable risk factors of SAMS
first year of therapy
>75 yo
hypothyroidism
preexisting muscle disease
females
surgery
Asians
Renal/hepatic dysfunction
142
Modifiable risk factors of SAMS
drug interactions
low body mass index
heavy exercise
higher doses of statins
lipophilic statins
143
Management of SAMS
assess for history of current muscle pains
obtain a baseline CK levels
assess for muscle complaints at every patient encounter
assess for any non-statin causes of muscle pain
144
Management of SAMS if discontinue statin and symptoms resolve within 2 weeks
not statin
resume as same or reduced dose
145
Management of SAMS if discontinue statin and symptoms resolve 2-4 weeks
statin related
resume at reduced dose or change statin
146
Management of SAMS if discontinue statin and symptoms do not resolve >4 weeks
not statin
hold until aches resolve, resume at same dose or reduced dose
147
Other statin strategies
change to hydrophilic statin
every other day dosing
M, W, F dosing
once weekly dosing
148
Should you use Coenzyme Q10 to help with SAMS
no
there is no evidence
149
Statin contraindications
active liver failure
decompensated cirrhosis
lactation
150
Baseline labs for statins
lipid pannel
AST/ALT
CK
151
Follow-up labs for statins
repeat lipid pannel in 4-12 weeks and then every 12 months after LDL at goal
152
Cholesterol reuptake inhibitors MOA
-inhibit absorption of cholesterol at brush border of small intestine
-block sterol transporter (NPC1L1)
-leads to decreased delivery of cholesterol to the liver
153
Adverse effects and contraindications of ezetimibe
AE: increase serum transaminase, myalgias, myopathy, rhabdo
Contra: pregnancy and breastfeeding
154
Bile acid sequstrants MOA
-binds biles acids in the intestinal lumen
-interrupts enterohepatic circulation of bile acids
-increased excretion of acidic steroids in the feces
-increased conversion of hepatic cholesterol into bile acids occurs to replenish the bile acid supply
155
BAS medications are to avoid if TG are above what
300 mg/dL
156
When to place someone on a BAS
-consider when patients are unable to take statins
-can add in patients who do not have >50% LDL-C reduction on a statin and ezetimibe
-safe in pregnancy since no systemic absorption
157
BAS adverse effects
GI upset
Constipation
Contraindications
Decreased vitamin absorption
158
When taking BAS they should be taken __ hours before or __ hours after other meds with drug interactions
1
4
159
BAS monitoring
baseline lipid pannel (repeat 4-12 wks)
Monitor triglyceride levels
160
PCSK9 inhibitors MOA
-MABs
-inhibition of PCSK9 leads to LDL-R recycling to cell surface
-increases LDL clearance from circulation
161
ADE of PCSK9 inhibitors
injection site reactions
angioedemia
headache
flu-like symptoms
162
Adenosine Triphosphate-Citrate Lyase Inhibitors (ACL) MOA
-ACL is an enzyme responsible for generating acetyl CoA
-Acetyl CoA is needed for synthesis of fatty acids and cholesterol in the liver
-ACL inhibitors prevent cholesterol production upstreams of statins
163
Adverse side effects of ACLs
gout
hyperuricemia
ab distress
tendon rupture
164
Fredrickson Classification of hyperlipdemia
-Primarily for research / genetic screening
-Blood sample is centrifuged
-NMR spectroscopy performed for lipoprotein subfraction analysis
165
What is the Associated Clinical Disorder and genetic defect for LDLs
ACD: Familial hypercholesterolemia, familial combined hyperlipidemia
Genetic: LDL receptor deficiency
166
What is the Associated Clinical Disorder and genetic defect for LDL, VLDL
ACD: Familial combined hyperlipidemia
genetic:LDL receptor deficiency
167
What is the Associated Clinical Disorder and genetic defect for VLDL
ACD: familial hypertriglyceridemia and familial combined hyperlipidemia
genetic: Increased VLDL production/synthesis
168
What is the Associated Clinical Disorder and genetic defect in chylomicrons and VLDL
ACD: Familial combined hyperlipidemia
genetic: Increased VLDL production and decreased LPL
169
Atherosclerosis is “ramped up” = ________ risk of premature ASCVD
higher
170
Familial Hypercholesterolemia
Deficit of LDL-receptors
Elevation of LDL due to lack of LDL degradation
24X higher risk of an MI before the age of 40 yo
171
HoFH is MORE severe form
Early appearance of xanthomas
Essentially no LDL receptors
TC: 650-1000 mg/dL
Fatal CV event before 20 years old
172
HeFH is LESS severe form
Later appearance of xanthomas
Half the normal number of LDL receptors
TC: 300-600 mg/dL
CV events in 30 and 40 years of age
173
Xanthomas
Foam cells (plaque) build up in tendons/organs
174
Atheromas
Foam cells (plaque) build up in arteries
175
Familial Hypercholesterolemia Treatment
-Usually requires a lipid specialist
-Multiple lipid lowering agents required (statin, ezetimibe, PCSK9i, bempedoic acid)
-LDL apheresis
176
Familial Hypertriglyceridemia
TGs elevated: 200-500 mg/dL (can be >1000)
Fasting TG >500 mg/dL is usually due to a genetic defect (not just lifestyle/comorbidities) Elevated TG can cause eruptive xanthomas
can cause pancreatitis
177
Hypertriglycerdemia treatment if level is 150-499
Lifestyle modifications
Address secondary causes
178
Hypertriglyceridemia treatment if level is over 500
Consider adding statin first if ASCVD risk is >7.5
179
Hypertriglycerdemia treatment if level is above 500 and ASCVD is below 7.5%
Add omega 3 polyunsaturated fatty acid and then fibrate if necessary
180
What is acute pancreatitis
-Most clinically relevant complication of hypertriglyceridemia
>500 risk may be increased
>1000 increased risk in all patients
>2000 medical emergency
181
What are the disease states the acute pancreatitis can lead to
pseudocyst
pancreatic necrosis
infection
sepsis/death
182
Fibric Acid Derivatives MOA
-Activated peroxisome proliferator-activated receptor type alpha (PPARalpa)
-Increase lipolysis and elimination of trig-rich particles
-Increase synthesis of apoproteins A1 and A2
-decrease VLDL, LDL, increase HDL
183
What are the two fibric acid derivatives
fenofibrate (cause renal dysfunction)
gemfibrozil (dont use with statin)
184
When TG >500 mg/dL to reduce risk of acute pancreatitis what medicine is used
fibric acid
184
ADE of fibric acids
GI discomfort
increase risk for gallstones
elevations in transaminase levels
myalgias
increase serum statin concentrations
185
Omega-3-polyunsaturated fatty acids MOA
EPA prevents LDL oxidation and promotes LDL clearance
High doses needed (2-4 g/d) to reduce TG and VLDL by 20-50%
186
Lovaza
Omega-3-polyunsaturated fatty acids
4 g qd or 2 g bid
generic
187
Lcosapent ethyl/vascepa
2 g bid
EPA only
not generic
188
ADEs of omega-3-PUFA
GI
ab pain
fishy burps (refrigerate capsules)
189
Niacin MOA
-increase HDL
-decrease TG/LDL
-inhibit lipolysis, decrease FFA in plasma and decrease hepatic esterification of TG
-reduce HDL catabolism and decrease hepatic removal
-reduce synthesis of VLDL
190
ADE niacin
flushing
itching
elevate LFT
hyperuricemia
hyperglycemia
191
Contraindication of niacin
acute liver disease
gout flare
active peptic ulcer disease
192
Low HDL cholesterol treatment
Men <40mg/dL
Women <50 mg/dL
No HDL raising goals
Recommendations is smoking cessation, physical activity, diet
193
Dietary supplements: fiber
-increase soluble fiber intake through bran, pectins, psyllium products
-decrease LDL only
-decrease absorption of cholesterol
194
Dietary supplements: fish oils
decrease ASCVD and CV deaths
reduce TG and VLDL
need high doses
195
Dietary supplements: phytosterols
reduce LDL levels
2 g qd
decrease cholesterol uptake
Avoid in sitosterolemia
196
Dietary supplements: red yeast rice
identical to lovastatin
NO recommendations
