Lipids Flashcards
Cholesterol is a steroidal compound with C___
27
What enzyme is cholsterol synthesized from
acetyl coenzyme A
How does HMG CoA go to Mevalonic Acid
by HMG CoA reductase
What molecules are triglycerides formed from
glycerol-3-phosphate
What are the 4 classifications of major plasma lipoproteins
very low density lipoproteins
intermediate-density lipoproteins
low-density lipoproteins
high-density lipoproteins
Statins are inhibitors of HMG-CoA reductase and they lower plasma cholesterol levels by what three mechanisms
inhibition of cholesterol biosynthesis
enhancement of receptor-mediated LDL uptake
reduction of VLDL precursors
What is the pharmacophore of HMG-CoA reductase inhibitors
7 ring system dihydroxyheptanoic acid
The decalin ring is essential for anchoring the drug to the enzyme _______ _____
active site
Does a beta hydroxyl group increase or decrease hydrophilicity
increase (may improve cellular specificity)
What statin is the most hydrophilic and therefore has minimal penetration into lipophilic membrances, better selectivity for hepatic tissues and reduction in side effects
Pravastatin
All HMGRIs in active form contain a carboxylic acid that is primarily ________ at physiological pH
ionized
What CYP enzyme metabolizes HMGRIs
CYP34A
When should statins be administered
at night because it counteracts the peak cholesterol synthesis that occurs in the morning
Cholesterol Absorption Inhibitor MOA (ezetimbie)
-inhibits the absorption of cholesterol at the brush border of the small intestine
-competitively binds to sterol transporter
Ezetimibe is selective and does not interfere with the absorption of what molecules
triglycerides
lipid soluble vitamines
In Cholesterol Absorption Inhibitors the hydrolysis or expansion of the beta-lactam ring produces an ________ compound
inactive
Why is the secondary alcohol of ezetimibe not as important as the phenolic alcohol
The drug can conjugate to become active at the phenolic site
Bile Acid Sequestrants act by what MOA
binding to major bile acids, glycocholic acid and taurocholic acid, and greatly increase their fecal excretion
Bile acid sequestrants do not bind to specific receptors but bind to _______ charged atoms or functional groups on drug molecules
negatively
Since bile salts contain numerous positive charges they are more likely to bind to ________ compounds or nonelectrolytes
acidic
Impaired lipolysis by nicotinic acid ________ the mobilization of free fatty acids which reduce their plasma levels and their delivery to the liver
decreases
Nicotinic acid does not have any effects on what two things
cholesterol catabolism or biosynthesis
Fibrate MOA
-decrease plasma triglyceride levels more than cholesterol levels
-help lipoprotein metabolism by activation of peroxisome proliferator-activated receptors (alpha)
Which group in fibrates are essential for activity
isobutyric acid and the phenoxy ring
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
What functional group is important for fibrate binding and activity
carboxylic acid
Fenofibrate is a ______ that undergoes rapid hydrolysis to produce fenofibric acid active metabolite
prodrug
Dyslipidemia
Levels of lipids or lipoproteins in the blood that are outside or normal boundaries and have adverse effects
Hyperlipidemia
elevated levels of lipids or lipoproteins in the blood (mainly family)
Hyperlipidemia and ASCVD are associated with a general inflammatory state that contribute to ___________________ disorders
neurodegenerative
Primary risk factors of hyperlipidemia
reduce clearance that cause overproduction of LDLs or triglycerides
increase clearance that cause underproduction of HDLs
Secondary risk factors of hyperlipidemia
diet
sedentary life
obesity
diabetes
excessive alcohol
CKD
hypothroidism
liver dieases
Risk factors of low HDL
SMOKING
anabolic steroid use
HIV infection
nephrotic syndrome
What are chylomicrons synthesized from
synthesized from dietary triglycerides, cholesterol, and lipid-soluble vitamins in small intestine
Synthesized intestinal cholesterol and plant sterol absorption by what
niemann-pick c1-like protein 1 (NPC1L1)
ATP-binding cassette transporters pump what back into intestinal lumen
plant sterols
What is diagylcerol transferase transferred by
microsomal triglyceride transfer protein (MTP) to newly forming chylomicrons
What is ApoB-48
organizes newly forming chylomicrons
Type 2 isozyme of acyl-coenzyme A; __________ _________ esterifies dietary cholesterol, regulates cholesterol absorption
cholesterol acyltransferase (ACAT2)
________ enter the lymphatic system, pass to circulation via thoracic duct
chylomicrons
Chylomicronemia syndrome is genetic impairment of _____ or _______, impair chylomicron function
LPL
apoC-II
(cause severe hypertriglyceridemia, pancreatitis)
Chylomicron remanants are remanants after __________ from chylomicrons
triglycerides
What are the different chylomicron remanants
endothelial fenestres
ApoE
Hepatic lipase (HL)
LDL receptor or LDL receptor-related protein
What is LDL
-produced in liver, large, can cause plasma turbidity
-production is stimulated by triglycerides released from chylomicrons
What is IDL
triglycerides in VLDL metabolized by LPL to form IDL
released from capillary beds into circulation
How is LDL cleared
ApoB100/LDL receptor interaction in hepatocytes
Atherosclerosis is a syndrome in which atherosclerotic _________ develop in arteries, producing narrowing of the arterial passage and thickening of the arterial wall
plaques
How are plaques formed in atherosclerosis
oxidized LDL is taken up by macrophages
HDL is produced by liver and intestine and form chylomicron ___________ and VLDL
remnants
Pre-beta1 HDL primarily mediates transport of __________ to and from other cells
cholesterol
Lecithin is cholesterol acetyltransferase that esterifies cholesterol in what
pre beta1 HDL
HDL
HDL2
HDL3
In reverse cholesterol transport ____ absorb cholesterol from peripheral cells/macrophages
HDL
HDL2 and HDL1 exchanges cholesterol in liver excreted in bile _____ with bile _______
ducts
salts
In exogenous lipid transport ____ hydrolyzes triglycerides; free fatty acids absorbed by tissues
LPL
In exogenous lipid transport LPL releases free fatty acids to form _____
IDL
Cholesterol synthesis: long metabolic pathway, begins with transport of _________ from mitochondrial stores
acetyl-coA
3-hydroxy-3-methylgutaryl-CoA synthesized from acetyl-CoA and acetoacetyl-CoA by what
HMG-CoA reductase
Drugs that treat hypercholesterolemia
statins
ezetimibe
bile acid-binding agents
PsK9 inhibitors
Drugs that treat hypertriglyceridemia
fibrates
omega-3 fatty acids
niacin
What is the rate limiting step in cholesterol synthesis
HMG-CoA reductase
Statin inhibit HMG-CoA reductase which reduce endogenous ________ _________
cholesterol synthesis
What are the two natural statins
mevastatin
lovastatin
What are the two synthetic statins
pravastatin
simvastatin
fluvastatin
atorvastatin
rosivastatin
pitavastatin
All statins contain a _______ acid side chain that is a structural analog of an HMG-CoA intermediate
heptanoic
Membrane-bound (sterol regulatory element bring protein) is cleaved by a protease and SRE translocates to the ______
nucleus
SRE increases expression of ______ gene
LDLR
Statins increase the removal of LDL from the blood __________ LDL-C
lowering
Where are statins absorbed
small intestine
Where are statins distributed
most in liver
low levels in plasma
mostly protein-bound
How are statins metabolized/excreted
metabolized in liver and excreted in feces
What is rhabdomyolysis
toxic muscle protein products in serum
Carriers of PCSK9 cause a loss of function allele which _____ MI
decreases
Fibrates are what kind of agonist
peroxisome proliferator-activated receptor alpha (PPARalpha)
Fibrates reduce triglyceride levels by how much percent
30-50%
What are the two main fibrate drugs
gemfibrozil
fenofibrate
Omega 3 fatty acids are peroxisome proliferator-activated receptor _____ and ______
alpha
gamma
Cholesterol uptake inhibitor drug
ezetimibe (zetia)
Ezetimibe inhibit luminal cholesterol absorption via ________ by jejunal enterocytes
NPC1L1
NPC1L1 recruits free cholesterol creating a ___________ mechanism
raft-like
Ezetimibe is metabolized by ___________ (intestinal wall)
glucuronidation
Ezetimibe absorption limited to enterohepatic circulation which causes a limited ________ exposure
systemic
Dual therapy with ezetimibe cause exacerbated ______ associated adverse effects
statin
Primary bile acid synthesized by ________ from cholesterol
hepatocytes
Secondary bile acids are synthesized in ___ by bacteria
gut
What are bile salts
they are bile acids conjugated with taurine or glycine secreted into bile ducts
Bile salts reduce ____ globules to smaller emulsified droplets
fat
Bile salts increase effectiveness of _________ _________ freeing more fatty acids for absorption
pancreatic lipase
What is niacin
water soluble B complex vitamin
source of NAD or NADP
improves all lipid parameters
Niacin acts at ______ and senses energy metabolites in adipose tissues
HCA2 (hydroxycarboxylic acid receptor 2)
In the liver Niacin inhibits __________ which decreases triglyceride synthesis/triglyceride esterification
diacylglycerol acyltransferase-2
Adverse side effects of Niacin
Dyspepsia
Hepatic Toxicity
Flushing/pruritus
Niacin exacerbates statin-induced _______
myopathy
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
ILDL can promote growth of ______
atheroma (ASCVD risk)
What is the main component of atheromatous plaque (ASCVD risk)
LDL
How to calculate LDL-C
TC - (TG/5) - HDL
If TG are greater then 400 mg/dL what happens
do not use equation and cannot calculate
The equation is not as accurate if LDL is very low. What level is considered low
<70 mg/dL
Is fasting needed to collect a lipid pannel
no
What are the 4 ASCVD risks
coronary artery disease
stroke
aortic aneurysm
peripheral vascular disease
What is CAD
Angina
MI (revascularization)
-stent or balloon
-CAD
Carotid artery stenosis is a common cause of what
strokes
Is this primary or secondary ASCVD:
genetic defects
-hypertiglyceridemia
-homozygous familial hypercholesterolemia
-heterozygous familial hypwecholesterolemia
primary (familial)
Is this primary or secondary ASCVD:
-diet/lifestyle
-drugs
-disorders/defects
-diseases/comorbidities
secondary (acquired)
What are the diet etiology
excessive alcohol intake
anorexia or weight gains
excessive carb intake
What are the drugs etiology
atypical antipsychotics
beta-blockers/diuretics
glucorticoids
estrogen
What are the diseases etiology
renal failure
pregnancy
hypothyroidism
uncontrolled diabetes
Symptoms related to ASCVD events
chest pain
palpitations
sweating
anxiety
SOB
loss of consciousness
difficulty speaking/moving
Signs of ASCVD
pancreatitis
eruptive xanthomas
peripheral neuropathy
Labs of ASCVD
elevated: TC, LDL, TG, CRP, Apo-B
decreased: HDL, Apo-A
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)
Primary prevention of ASCVD
before an ASCVD event occurs
No active disease
Prevent dyslipidemia or future ASCVD event
Secondary prevention of ASCVD
after an ASCVD event occurs
Active disease
prevent another future ASCVD event
ASCVD risk stratification:
Low
Borderline
Intermediate
High
Low: <5%
Borderline: 5-7.4%
Intermediate: 7.5-19.9%
High: >20%
What are premature ASCVD for males and females
male: <55
female: <65
What age to start screening for ASCVD
20 yo
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
Ages 4-75 yo: risk varies
who benefits from statin
LDL >190 mg/dL
DM
ASCVD risk enhancers
family history
LDL >160 mg/dL
CKD
metabolic syndrome
women preeclampsia, premature menopause
inflammatory diseases (arthritis, HIV)
Ethnicity (African American)
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
What is CAC
computed tomography (CT) scan
provides imaging of calcium deposits in coronary arteries
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
What are the 4 statin benefit groups
clinical ASCVD
LDL >190 mg/dL
Age 40-75 yo & DM
40-75 with ASCVD >7.5%
Following a low-cholesterol diet can lead to how much of a reduction in LDL
20-30%
How long can you trial a lifestyle change in patients to lower their LDL
12 weeks
Comorbidities of dyslipidemia
hypothyroidism
obstructive liver disease
renal disease
DM
pregnancy
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
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
What are the three statins that should be taken at night
lovastatin
fluvastatin
simvastatin
What are the two hydrophilic statins
rosuvastatin
pravastatin
Drug interactions with gemfibrozil
all statins
increased risk of rhabdo
Drug interactions with amiodarone
inhibit 3A4 and 2C9
max simvastatin 20 mg
max lovastatin 40 mg
Drug interactions with amlodipine
inhibit 3A4
max simvastatin 20 mg
Drug interactions with diltiazem
inhibit 3A4
max simvastatin 10 mg
max lovastatin 20 mg
Drug interactions with fenofibrates
all statins
increased risk of rhabdo
Common ADRs with statins
diarrhea
arthralgias
nasopharyngitis
nausea
SAMS: myalgias
muscle pain
no CK elevation
SAMS: myopathy
muscle pain
CK >10x ULN
SAMS: rhabdomyolsis
muscle pain
CK >40x ULN
often with acute renal failure
SAMS: immune-mediated necrotizing myopathy (IMNM)
muscle pain
elevated CK
HMG-CoA antibodies
Non-modifiable risk factors of SAMS
first year of therapy
>75 yo
hypothyroidism
preexisting muscle disease
females
surgery
Asians
Renal/hepatic dysfunction
Modifiable risk factors of SAMS
drug interactions
low body mass index
heavy exercise
higher doses of statins
lipophilic statins
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
Management of SAMS if discontinue statin and symptoms resolve within 2 weeks
not statin
resume as same or reduced dose
Management of SAMS if discontinue statin and symptoms resolve 2-4 weeks
statin related
resume at reduced dose or change statin
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
Other statin strategies
change to hydrophilic statin
every other day dosing
M, W, F dosing
once weekly dosing
Should you use Coenzyme Q10 to help with SAMS
no
there is no evidence
Statin contraindications
active liver failure
decompensated cirrhosis
lactation
Baseline labs for statins
lipid pannel
AST/ALT
CK
Follow-up labs for statins
repeat lipid pannel in 4-12 weeks and then every 12 months after LDL at goal
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
Adverse effects and contraindications of ezetimibe
AE: increase serum transaminase, myalgias, myopathy, rhabdo
Contra: pregnancy and breastfeeding
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
BAS medications are to avoid if TG are above what
300 mg/dL
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
BAS adverse effects
GI upset
Constipation
Contraindications
Decreased vitamin absorption
When taking BAS they should be taken __ hours before or __ hours after other meds with drug interactions
1
4
BAS monitoring
baseline lipid pannel (repeat 4-12 wks)
Monitor triglyceride levels
PCSK9 inhibitors MOA
-MABs
-inhibition of PCSK9 leads to LDL-R recycling to cell surface
-increases LDL clearance from circulation
ADE of PCSK9 inhibitors
injection site reactions
angioedemia
headache
flu-like symptoms
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
Adverse side effects of ACLs
gout
hyperuricemia
ab distress
tendon rupture
Fredrickson Classification of hyperlipdemia
-Primarily for research / genetic screening
-Blood sample is centrifuged
-NMR spectroscopy performed for lipoproteinsubfraction analysis
What is the Associated Clinical Disorder and genetic defect for LDLs
ACD: Familial hypercholesterolemia, familial combined hyperlipidemia
Genetic: LDL receptor deficiency
What is the Associated Clinical Disorder and genetic defect for LDL, VLDL
ACD: Familial combined hyperlipidemia
genetic:LDL receptor deficiency
What is the Associated Clinical Disorder and genetic defect for VLDL
ACD: familial hypertriglyceridemia and familial combined hyperlipidemia
genetic: Increased VLDL production/synthesis
What is the Associated Clinical Disorder and genetic defect in chylomicrons and VLDL
ACD: Familial combined hyperlipidemia
genetic: Increased VLDL production and decreased LPL
Atherosclerosis is “ramped up” = ________ risk of premature ASCVD
higher
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
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
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
Xanthomas
Foam cells (plaque) build up in tendons/organs
Atheromas
Foam cells (plaque) build up in arteries
Familial HypercholesterolemiaTreatment
-Usually requires a lipid specialist
-Multiple lipid lowering agents required (statin, ezetimibe, PCSK9i, bempedoic acid)
-LDL apheresis
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
Hypertriglycerdemia treatment if level is 150-499
Lifestyle modifications
Address secondary causes
Hypertriglyceridemia treatment if level is over 500
Consider adding statin first if ASCVD risk is >7.5
Hypertriglycerdemia treatment if level is above 500 and ASCVD is below 7.5%
Add omega 3 polyunsaturated fatty acid and then fibrate if necessary
What is acute pancreatitis
-Most clinically relevant complication of hypertriglyceridemia
>500 risk may be increased
>1000 increased risk in all patients
>2000 medical emergency
What are the disease states the acute pancreatitis can lead to
pseudocyst
pancreatic necrosis
infection
sepsis/death
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
What are the two fibric acid derivatives
fenofibrate (cause renal dysfunction)
gemfibrozil (dont use with statin)
When TG >500 mg/dL to reduce risk of acute pancreatitis what medicine is used
fibric acid
ADE of fibric acids
GI discomfort
increase risk for gallstones
elevations in transaminase levels
myalgias
increase serum statin concentrations
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%
Lovaza
Omega-3-polyunsaturated fatty acids
4 g qd or 2 g bid
generic
Lcosapent ethyl/vascepa
2 g bid
EPA only
not generic
ADEs of omega-3-PUFA
GI
ab pain
fishy burps (refrigerate capsules)
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
ADE niacin
flushing
itching
elevate LFT
hyperuricemia
hyperglycemia
Contraindication of niacin
acute liver disease
gout flare
active peptic ulcer disease
Low HDL cholesterol treatment
Men <40mg/dL
Women <50 mg/dL
No HDL raising goals
Recommendations is smoking cessation, physical activity, diet
Dietary supplements: fiber
-increase soluble fiber intake through bran, pectins, psyllium products
-decrease LDL only
-decrease absorption of cholesterol
Dietary supplements: fish oils
decrease ASCVD and CV deaths
reduce TG and VLDL
need high doses
Dietary supplements: phytosterols
reduce LDL levels
2 g qd
decrease cholesterol uptake
Avoid in sitosterolemia
Dietary supplements: red yeast rice
identical to lovastatin
NO recommendations
