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Adv. Pharm Test 2 > Lipids > Flashcards

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
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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
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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
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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
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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
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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
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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
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8
Q

What are the varying HDL levels?

A
  • Low <40
  • High >60= desired
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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
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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
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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
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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

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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
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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

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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
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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%)
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17
Q

Examples of HMG-CoA Reducatse Inhibitors?

A
  • ­Lovastatin (Mevacor)
  • Rosuvastatin (Crestor)
  • ­Simvastatin (Zocor)
  • Pravastatin (Pravachol)
  • ­Atorvastatin (Lipitor)
  • Fluvastatin (Lescol)
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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

Adv. Pharm Test 2 (6 decks)

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