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
Adverse drug reactions for bil acid sequestrants?
* 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
What is Nicotinic acid?
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 outcome**s "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
Agents for niacin?
Nicotinic acid (immediate relase, extended release and sustained release or Niaspan
28
Drug interaction with niacin
Statin and niacin increased risk of hepatic dysfunction
29
Advese effects of niacin?
* 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
Dosing of niacin?
* ASA 30 min prior to administration
* caution: contains yellow dye #5
31
PCSK9 inhibitors: mechanism and efficacy?
* 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
Adverse effects and interactions with PCSK9 inhibitors?
* 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
What are fibric acid derivatives? MOA? agents?
(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
A/E of fibric acid derivatives?
* 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
What are fibric acid derivatives combined with potentially?
Statin and Fibric Acid Derivatives
* Primarily assist in decreasing triglycerides
* Increased risk of myopathies
* Contraindicated with severe hepatic disease
36
What is Ezetimibe?
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
Ezetimibe drug interactions?
* 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
What happesn when simvastatin and ezetimibe used together?
* 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
Summary of MOA of lipid lowering agents?
40
LIpid lowering agents to avoid in pregnancy?
* Statin
* ezetimibe
* niacin
* fibric acid derivative
BIle acid-bindign resins are currently the only lipid-lowering medication safe to use during pregnancy
41
What are apoplipoproteins?
* 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 activit**y, 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
How are apolipoprotines used to lower risk for atherosclerotic events?
* 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
What is mipomersen?
* 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
What is lopitamide?
* 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
