Lipids Flashcards
1
Q
What is normal physiologic role of lipoproteins?
A
- triglycerides are an essential energy source
- cholesterol is necessary for produciton of:
- cell membranes
- bile acids
- steroid hormones
2
Q
What are lipoproteins?
A
- Required for transport of lipids to and from cells in the periphery
- produced via an exogenous pathway (dietary fat, cholesterol, fat soluble vitamines) or endogenous pathways (syntehsis by liver)
- Vary in density:
- chylomicrons- how we carry dietary fat
- very low density lipoproteins- how we carry cholesterol liver produces to rest of body
- intermediate density lipoprotins
- low density lipoproteins- tend to be most problematic
- high density lipoproteins- important with reverse cholesterol transport. bring cholesterol back to liver for elimination. typically want higher HDL and lower LDL
3
Q
Why is hyperlipidemia a problem?
A
- Hypercholesterolemia
- Hypertriglyceridemia
- elevated LDL- main risk in elevation for CV events
- provides more substrate for development of atherosclerotic plaque
4
Q
How do plaques form?
A
- Start with some damage to endothelium layer
- Damage endothelial level express adhesion molecules which recruit monocytes into endothelium then to intima
- macrophages express receptors which can bind to lipoproteins
- lipoproteins become oxidized and turn into macrophage foam cells which get stuck in intma
- foam cell promotes inflammatory response, recruitement cytokines, inflammatory mediates, smooth muscle hypertorphy
- over time with age and high levels LDL substrate, plaques grow and narrow internal diatmer of vessel
- problematic if vessel in coronary, less blood flow through coronary
- in peripheral vessel, less ability for blood flow to skeletal muscle during exercise
- generally, stable condition but issue arises when plaque ruptures.
- PLT aggregate to plaque rupture, form thrombus and occlude vessel
5
Q
What is primary hyperlipidemia?
A
- genetic (or inherited) heterozygous condition resulting in elevated total cholesterol level or triglyceride level
- homozygous= rare, 4x higher cholesterol levels and muhc higher atherosclerosis risk
- total cholesterol usually >200, triglycerides often >500
- have genetic defect in LDL receptors
- often referred to as
- familial hypercholesterolemia
- familial hypertriglyceridemia
6
Q
What is secondary hyperlipidemia?
A
much more common, seen in general population
- diabetes- can also have issues with fat metabolism and have abnormal lipid panel
- hypothyroidism
- obstructive liver disease
- chronic renal failure
- drugs that increase LDL and decrease HDL
- progestins
- corticosteroids
- anabolic steroids
- protease inhibitors
7
Q
What are the varying levels of total cholesterol level?
A
- Desirable <200 mg/dl
- Borderline 200-239 mg/dL
- High >240 mg/dL
8
Q
What are the varying HDL levels?
A
- Low <40
- High >60= desired
9
Q
What are varying LDL cholesterol levels?
A
- optimal <100
- near optimal 100-129
- borderline high 130-159 (where they generally start thinking about adding meds)
- high 160-189
- very high >190
10
Q
Assessing for atherosclerotic CV diseaes?
A
- History of coronary heart disease
- angina
- MI
- Coronary intevention (prca, stent, cabg)
- peripheral arterial disease
- peripheral (Extremity) arterial disease, symptomatic carotid artery dx, abdominal aortic aneurysm
11
Q
What are some risk factors for developing atherosclerotic cardiovascular disease (ASCVD)?
A
- Family hx ASCVD
- Gender
- age
- race
- chornic LDL >160 mg/dL
- everytime you decrease LDL level 39-40, will reduce risk of major CV event by 22%
- HDL- cholesterol
- systolic BP
- Diabetes
- smoker
- renal dx
- metabolic syndrome
- history of pre-eclampsia
12
Q
Intensity of statin therapy is based on:
A
- Risk of clinical ASCVD
- Risk of develping ASCVD
- Presence of diabetes with/without HLD
- Presence of isolated hyperlipidemia (genetic component- ie familial hyperlipidemia)
High, medium and low intensity statin therapy. High the dose, higher the intensity, more risk for s/e
13
Q
What are the parimary prevention suggestions from ACC/AHA? (bowmand said this doesn’t need to be memorized in lecture)
A
- Patient with LDL >190
- high intensity statin therapy to a goal of LDL <100, if necessary adding ezetimbibe and then (if multiple ASCVD risk factors present), possibly a PCSK9 inhibitor
- Patients 40-75 yo with diabetes and LDL >70
- moderate- intesnse statin therapy
- patient with diabetes and LDL >70 who have multiple risk factors or age 70-75 yo
- high intensity statin therapy to reduce LDL >50%
- Patient 40-75 yo without diabetes, LDL >70 and 10 year ASCVD risk> 20%
- high intensity statin therapy to reduce LDL >50%
- Patient >75
- consider risk and benefits
14
Q
What is current recommendation for use of non-statin lipid lowering agents?
A
The panel recommends that clinicians treating high-risk patients (those with ASCVD, with LDL ≥190 mg/dL, and those with diabetes age 40 to 75) who have a less-than-anticipated response to statins, who are unable to tolerate a recommended intensity of a statin, or who are completely statin intolerant, may consider the addition of a non-statin cholesterol-lowering therapy. In this situation, this guideline recommends clinicians preferentially prescribe drugs that have been shown in RCTs to provide ASCVD risk-reduction benefits that outweigh the potential for adverse effects and drug–drug interactions
15
Q
What are the secondary treatment goals for lipid lowering agents?
A
- Treat elevated triglycerides
- if triglycerides are >200 and LDL goal has been achieved, add additional treatment for TGs
- treat low HDL <40
- if HDL are <40 and LDL and TG goals have been achieved, add additional treatment for HDLs
16
Q
What are HMG-CoA reductase inhibitors?
A
3-hydroxyl 3- methylglutaryl Coenzyme A Reductase inhibitors
- “statins”- inhibit the enzyme (HMG CoA-Reductase) that catalyzes the rate-limiting step in the formation of cholesterol by the liver
- specifically inhibits the conversion of HMG-CoA to mevalonate
- effect is to 1) decrease cholesterol synthesis in the liver and 2) enhance the LDL receptor expression which increases LDL uptake by the liver
- decreases LDL 20-60%, decrease TG (10-20%) and increase HDL (10%)
17
Q
Examples of HMG-CoA Reducatse Inhibitors?
A
- Lovastatin (Mevacor)
- Rosuvastatin (Crestor)
- Simvastatin (Zocor)
- Pravastatin (Pravachol)
- Atorvastatin (Lipitor)
- Fluvastatin (Lescol)
18
Q
What are benefits to HMG-CoA reductase inhibitors?
A
Beneficial for primary and secondary prevention beyond the normalization of lipids
-
promotes plaque stability
- decrease cardiac M&M with periop admin in high risk pt
- antioxidant, anti-inflammatory, vasodilatory
- atherosclerotic changes is more than just cholesteorl. it’s also inflammatory influence
- RCT show decrease risk for CV events even with normal LDL level
- reduced Heart failure, stroke, MI, hospitilization, peripheral vascular disease, and death
- helpful in diabetic population
- increased bone formation
- may reduce osteoporosis- studies underway
19
Q
HMG COA reductase pharmacokinetics?
A
- Lovastatin and simvastatin are prodrugs
- highly protein bound (except pravastatin)
- extensive CYP 450 metabolism (except pravastatin)
- E1/2T (1-4 hours) except atorvastatin- 14 hours
- clinical effects last for 24 hours though
20
Q
Adverse effects of statin? Pregnancy category?
A
5% of patient in clinical trials demonstrated adverse effects similar to placebo
Common
- HA
- Rash
- GI distrubance
- Myalgias (up to 1/3 pt)
Rare
- hepatotoxicity (0.5-2%)
- peripheral neuropathy
- myopathy/rhabdomyolysis (0.1-0.5%)
- fatal rabhdo in <1 in 1 million
Individuals at risk for myopathy
- pre-existing for myopathy
- age >80
- female
- asian ancestry
- small body frame and frailty- maybe getting relative overdose
- impaired renal or hepatic system
- alcohol abuse
- hypothyroid
- high statin levels
Prenancy category X- need cholesteorl during pregnancy to assure baby developing appropriately
21
Q
Significant drug interactions with statins?
A
- Other drugs known to induce myopathies
- niacin
- gemfibrozil
- cyclosporine increases concentration of all statins and the risk for myopathy
- dabigatran and simvastatin or lovastatin= increase risk of MAJOR hemorrhag e(mechanism is unclear)
- lovastatin and simvastatin (CYP 3A4 inhibitors increase concentration)
- Itraconazole (Sporanox)
- Ketoconazole (Nizoral)
- Erythromycin
- Clarithromycin (Biaxin)
- Grapefruit juice
- Cyclosporine
- HIV protease inhibitors
- Verapamil
- Amiodarone
22
Q
What are bile acid sequestrants/resins?
A
- second line drugs brought in when statins don’t work
- Non-absorbable resin that binds bile acids and other substances in the GI tract preventing absorption and promoting GI excretion
- results in liver using hepatic cholesterol to produce more bile acids and increased LDL receptor expression on hepatocytes
- effect is to decrease LDL and increase HDL (little effec ton TG- may actually increase in susceptible patients)
-
agents:
- cholestyramine (questran)
- colestipol
- colesevelam
23
Q
Dosing for bil acid sequestrants?
A
- Fomrulated as a powder mixed with liquid
- 30 min before, during or 30 minute after meal
- tht’s when bile acids are secreted and when this drug will be most effective
24
Q
Drug interactions with bile acid sequestrants?
A
- Can interfere with absorption and/or form compelxes with many PO meds
- synthroid,
- oral contraceptions,
- sulfonylurea antibiotics,
- phenytoin,
- thiazide diuretic,
- fat soluble vitamins
25
Q
Adverse drug reactions for bil acid sequestrants?
A
- GI- severe constipation (encourage high fiber diet and adeuqate hydration)
- flatulence, nausea, vomtiing
- use stool softener
- reduced folate levels with long term use
- cholestyramine (chloride)- hyperchloremic acidosis (young/small patient)
26
Q
What is Nicotinic acid?
A
Niacin
- just lost FDA approval for lowering LDL. lowers LDL but outcomes don’t reflect reduction
- mechanism of action unclear
- niacin acts on the liver and adipose tissue to inhibit TG production but HDL change remains a mystery
- drug of choice in patients at risk for pancreatitis (TG levels)
- decreaes hepatic synthesis of VLDL by severeal potential mechanisms (decrease release of FAs) and this leads to a decrease in LDL and TG
-
Increase HDL levels more effectively than any other drugs
- HDL breakdown is also decreased and levels increase by 20-30 mg/L
- niacin does little to improve long term outcomes “reduction in risk factors does not translate to reduciton in actual risk”
- works by reducing produciton of VLDLs, effect is to reduce LDL 15-35%, reduce TG and increase HDL
27
Q
Agents for niacin?
A
Nicotinic acid (immediate relase, extended release and sustained release or Niaspan
28
Q
Drug interaction with niacin
A
Statin and niacin increased risk of hepatic dysfunction
29
Q
Advese effects of niacin?
A
- SKin (intense flushing, itching)
- intense flushing initially, can pretreat with ASA 30 min before dose
- decreased with suatained release version niacin
- GI (exacerbation of peptic ulcers)
- visual changes
- hepatotoxiicty
- assess liver fxn regularly. severe liver damag ehas been reported
- hyperglycemia- caution in DM!!
- gouty arthritis
- can raise blood levels of uric acid (check kidney function, encourage 2-3 l/day water intake
30
Q
Dosing of niacin?
A
- ASA 30 min prior to administration
- caution: contains yellow dye #5
31
Q
PCSK9 inhibitors: mechanism and efficacy?
A
- proprotein convertase subtilisin/kexin type 9 *PCSK9” is an enzyme that binds to LDL receptors and promotes lysosomal degradaitonof the receptos
- Alirocumab (praluent) and evolucumab (repatha) are monoclonal antibodies that bind to PCSK9, preventing subsequent binding of PCSK9 to LDL receptors
- end restul- high cocentration of LDL receptors and enhanced clearance of LDL-C
- Foureir clinical trial (n=27,564 with ASCVD)
- evolucumab reduced median LDL-C from 92-30
- lower risk of MI, CV death, stroke, unstable angina, PCI
- Odyssey clinical trial (n=18,924 with recent acute coronary syndrome)
- when added to statins, reduces death from CV causes (9.5% to 11.1%)
32
Q
Adverse effects and interactions with PCSK9 inhibitors?
A
- Appear well tolerated with no significant interactions
- muscle aches, rash, uticaria, mild injeciton site reaction
- abnormalyl low LDL-C <25 does not appear to be problematic based on current info
- may cuase neural tube defect- unclear at time
33
Q
What are fibric acid derivatives? MOA? agents?
A
(used before statins came around)
MOA
- Interact with receptor (PPAR alpha) which increases synthesis of lipoprotein lipase (LPL) and decrease an apolipoprotien that inhibits LPL- more LPL (inhibits the inhibitor of lipoprotein)
- Increase lipolysis of triglycerides (decrease VLDL levels)
- Most effective drugs available for decreaseing TG elvel (40-50)
- can increae HDL cholesterol by about 15-25%
- very little decrease in LDLs
three drugs in US
- Gebfibrozil (lopid)- only fibrate associated with beneficial CV outcomes
34
Q
A/E of fibric acid derivatives?
A
- Rashes (common)
- Gastrointestinal disturbances (common)
- Headache
- Rhabdomyolysis & myopathy –avoid use with statins
- Gallstones (D/C if this occurs and avoid use with ezetimibe)
- Liver injury (hepatotoxic- LTFs)
- Can potentiate oral anti-hyperglyemic drugs
- Can increase serum concentration of statins
- Displaces warfarin from plasma albumin
- Can increase the risk for bleeding in patients on warfarin
- Measure INR frequently
35
Q
What are fibric acid derivatives combined with potentially?
A
Statin and Fibric Acid Derivatives
- Primarily assist in decreasing triglycerides
- Increased risk of myopathies
- Contraindicated with severe hepatic disease
36
Q
What is Ezetimibe?
A
ZETIA
- works by inhibiting cholesterol and phytosterol absortpion from the brush border of the intestine (disrupts compelx b/w annexin 2 and cavolin 1 proteins)
- increases expression of LDL receptos
- no effect on absorption of fat soluble vitamine (A,D,E,K)
- No apparent effect on CYP450 enzymes
- intended for use in combo with a statin
37
Q
Ezetimibe drug interactions?
A
- May increase bleeding with warfarin
- is increased by and will increase concentraiton of cyclosporin
- when used with gemfibrozil, increased r/f gallstones (combo contraindicated)
- absorption inhibited by bile acid sequestrants
38
Q
What happesn when simvastatin and ezetimibe used together?
A
- More effective than simvastatin alone
- IMPROVE-IT trial added ezetimibe to simvasatin and reduced LDL by 24$
- also demonstrated 2% reducitonin primary composite end point of CV death, major coronary events or nonfatal CVA
- Unclear if this is based on voerall lowering of LDL or the addition of the ezetimibe, but undercuts the idea that only statins provide a mortality benefit
39
Q
Summary of MOA of lipid lowering agents?
A
40
Q
LIpid lowering agents to avoid in pregnancy?
A
- Statin
- ezetimibe
- niacin
- fibric acid derivative
BIle acid-bindign resins are currently the only lipid-lowering medication safe to use during pregnancy
41
Q
What are apoplipoproteins?
A
- The atherogenic lipoprotein particle (LDL, IDL, VLDL, chylomicrons, lipoprotein A) is composed of a core of cholesterol and triglycerides surrounded by the phospholipid membrane with apolipoproteins imbedded within
- Apolipoproteins necessary for the assembly of lipoproteins, provide structural integrity, act as co-activators of enzyme activity, and as receptor ligands for cellular uptake
- These apolipoprotein particles bind with the arterial wall and begin an oxidative and inflammatory process that encourages atherogenesis
42
Q
How are apolipoprotines used to lower risk for atherosclerotic events?
A
- Evidence suggests that atherogenesis tracks more closely with apolipoprotein B (located on VLDL, IDL, and LDL) numbers than with LDL or non-HDL numbers
- Evidence from multiple RCTs shows that, just as with decreases in LDLs, decreases in apolipoprotein B result in lower cardiovascular disease risk
- Monitoring of apolipoprotein B can be useful as an additional means of monitoring the efficacy of a given treatment regimen
43
Q
What is mipomersen?
A
- Antisense oligonucleotide targeted to human mRNA for apolipoprotine B-100
- hybridization of mipomersen to the apoB mRNA results in degradation and loss of translation of apoB protein
- FDA approved for hx familial hyperlipidemia
- adverse effects include hepatic dysfunction, and steatosis/hepatotoxicty, flu-like symptoms, nausea, and HA
44
Q
What is lopitamide?
A
- microsomal triglyceride transfer protein inhibitor, resides in endoplasmic reticulum, prevents assembly of apoB containing lipoproteins in enterocytes and hepatocytes
- inhibits the synthesis of chylomicrons and VLDL in the liver
- up to 50% reduciton in plasma LDL
- major adverse effect is hepatic steatosis
