Antilipemics

Question 1

What are Lipids?

Answer 1

Fat soluble substance present throughout the body, many of which are necessary for normal function
Cholesterol
Fatty Acids/Triglycerides 
Glycerophospholipids
Eicosanoids
Bile salts
Steroid hormones
Fat-soluble vitamins

Question 2

What is cholesterol?

Answer 2

The primary structural compound of cell membranes,

Precursor to bile salts and steroid hormones

Question 3

What are fatty acids/triglycerides?

Answer 3

lipid fuel source

Question 4

What are glycerophospholipids/sphingolipids?

Answer 4

They create the hydrophobic barrier between water and cholesterol, found at the edges of cell membranes

Question 5

What are eicosanoids?

Answer 5

prostaglandin precursors that regulate numerous body processes

Question 6

What is the action of bile salts?

Answer 6

to emulsify dietary fat

Question 7

What are the steroid hormones?

Answer 7

glucocorticoids
mineralocorticoids
sex hormones

Question 8

What are the fat soluble vitamins?

Answer 8

ADEK- important for vision, growth, clotting, prevention of oxidative damage

Question 9

What is the process of triglyceride (triacylglycerol) ingestion?

Answer 9

Fats are ingested => emulsified by bile salts in sm intestine and broken down by lipase => 2 monoacylglycerols and FFA => packaged into micelles and absorbed by intestinal epithelial cells => recombined as TGs =>packaged with proteins and phospholipids into chylomicrons (now water soluble) => chylomicrons ejected into lymphatic system => thoracic duct leads to bloodstream => HDL transfers proteins to chylomicrons (gives purpose and destination) => reaches target tissue and digested in BM by lipoprotein lipase (LPL) => FFAs released to be stored (adipose) or oxidized as energy (muscle) => chylomicron remnants travel back to bind to hepatocyte receptors => degraded and recycled

Question 10

What is the process of cholesterol ingestion?

Answer 10

Similar to TGs: Dietary cholesterol => combines with bile salts in the gut =>bile salt micelles =>micelles absorbed into intestinal epithelial cells =>packaged into chylomicron to travel through plasma =>cholesterol portion of chylomicron travel back to bind to hepatocyte receptors => enter free cholesterol pool =>increase in pool inhibits cholesterol synthesis by liver

Question 11

What is the process of fatty acid synthesis?

Answer 11

Synthesized in liver with dietary glucose as main precursor: Dietary sucrose broken down in gut by alpha glucosidase => glucose and fructose => glycolysis produces pyruvate => converted to TGs => TGs packaged with apoproteins, phospholipids, and cholesterol => VLDL (water soluble) => VLDL secreted into blood stream => proteins transferred from HDL to VLDL => LPL in basement membrane of capillaries digest TGs/FFAs in VLDL => FFAs stored or oxidized

Question 12

What is the process of cholesterol synthesis?

Answer 12

synthesized in most body cells, esp. liver and intestine, Acetyl CoA as precursor: 2 Acetyl CoAs combine with third to form HMG-CoA using HMG-CoA Syntase => HMG-CoA reductase pathway creates cholesterol => cholesterol packaged with TGs and proteins to form VLDL => LPL digests TGs, making VLDL more dense (IDL) => IDLs are unstable and become LDL => LDL returns to liver and take up by hepatocyte LDL receptors => cholesterol is recycled into free cholesterol pool

Question 13

How is the hepatic cholesterol pool maintained?

Answer 13

1. Ingested cholesterol => chylomicron remnant
2. Synthesized cholesterol => LDL- regulated by LDL receptors
3. Intracellular synthesis => HMG-CoA reductase pathway (most important)
   Large cholesterol pool => decreased LDL receptors => increased LDL in circulation=> decreased synthesis of HMG-CoA reductase =>low cholesterol in pool => increased LDL receptors => increased HMG-CoA reductase

Question 14

What is a chylomicron?

Answer 14

water soluble transport for ingested lipids

Question 15

What is VLDL?

Answer 15

water soluble transport for synthesized lipids (esp. TGs)

Question 16

What is IDL?

Answer 16

unstable result of VLDL breakdown

Question 17

What is LDL?

Answer 17

IDL breakdown (fewer TGs)

Question 18

What does HDL do?

Answer 18

From the liver and gut, it is secreted into blood where it interacts with chylomicrons and VLDL, dropping off apoE and apoCII
HDL picks up cholesterol from the cell membrane and transports it to the hepatic cholesterol pool

Question 19

What are Bile Acids?

Answer 19

produced in liver, stored in gall bladder
synthesized from cholesterol
released into gut after a meal to digest dietary lipids (emulsification)
95% of bile acids are reabsorbed and recycled

Question 20

What are lipids role in Atherosclerosis?

Answer 20

1) Some LDLs are oxidized by free radicals
2) macrophages consume oxidized LDLs
3) Macrophages become engorged as ‘foam cell’
4) Foam cells accumulate in blood vessels as fatty streaks
5) Atherosclerotic plaque forms
6) Plaque calcifies, narrowing vessel lumen

Question 21

What is the mechanism of action of HMG-CoA reductase inhibitors?

Answer 21

“Statins” suppress hepatic synthesis of cholesterol, decreasing LDL by up to 60% and modestly decreasing TGs and increasing HDL

1) Inhibit conversion of HMG-CoA to form cholesterol
2) Increases LDL receptor on hepatocytes
3) Increases LDL endocytosis
4) Decreases circulating LDLs

Question 22

What are the adverse effects of statins?

Answer 22

myositistis, myalgia, myopathy (most common)
rhabdomyolisis
dyspepsia, diarrhea, flatulence
headache
Contraindications- Liver disease and pregnancy/lactation

Question 23

What drug interactions are associated with statins?

Answer 23

Potentiates Coumadin
Bile Acid Binders decrease availability of Statins
Ace inhibitors with Statins => Hyperkalemia
Consider CYP450- Simvastatin, Atrovastatin, Lovastatin, Corivastatin (CYP3A4)

Question 24

What Labs should be evaluated with Statins

Answer 24

LFTs @ start of treatment

Question 25

ACC/AHA Guidelines for treatment of blood cholesterol

Answer 25

1) Age 21-75 with ASCVD- high intensity statin;
>75 yrs or not tolerating high intens.- mod. intensity
2) >40 yrs, with LDL >190- high intensity
3) 40-75 yrs with DM- mod. intensity; with ASCVD>7.5%- high
4) 40-75 yrs with 10 yr pooled risk >7.5- mod-high intens.

Question 26

High intensity Statins

Answer 26

> 50% LDL reduction
Atorvastatin 40-80 mg daily
Rosuvastatin 20-40 mg daily

Question 27

Moderate intensity Statins

Answer 27

30-49% LDL reduction
Atorvastatin 10-20 mg daily
Rosuvastatin 10-20 mg daily
Simvastatin 20-40 mg daily
Pravastatin 40-80 mg daily
Lovastatin 40 mg daily

Question 28

Low Intensity Statins

Answer 28

<30% reduction (no role in guidelines for these)
Pravastatin 10-20 mg
Lovastatin 20 mg

Question 29

What benefits do Statins have beyond LDL reduction?

Answer 29

Pleiotropic effects:
improved endothelial cell function
antioxidant properties
stop atheroma development, stabilize plaques
inhibit inflammatory response
antithrombic effects

Question 30

Cholesterol Absorption Inhibitors

Answer 30

Ezetamibe (Zetia)- add if Statin not effective (LDL >70)
Action- Complexes with bile salts and blocks absorption of cholesterol in duodenum => decrease stores in free cholesterol pool => LDL receptors upregulated => plasma clearance of LDL up to 25%

Question 31

PCSK9 Inhibitors

Answer 31

Alirocumab (Prament); Evolocumab (Repatha)
Action- Block PCSK9 protein (which typically interferes with function of LDL receptors to prevent overwork) from binding to LDL receptors => LDL receptors continue to remove LDL from circulation =>additional 50-60% reduction
Very expensive- often only used if on max statins and Zetia
Adverse effects- minor hypersensitivity, URI sx, back pain

Question 32

Omega-3-acid ethyl esters

Answer 32

Icosapent ethyl (Vascepa)
Action- decreases hepatic synthesis of VLDL and enhances LPL to improve VLDL clearance, demonstrates CV risk reduction
Indicated for severe hypertriglyceridemia (>500) or <135 on statins

Question 33

Fibric Acid derivitives

Answer 33

Gemfibrozil (Lopid), Fenofibrate (Tricor), Fenofibric Acid (Trilipix)
Trilipix only one indicated for admin with Statins
Action- Increases activity of LPL and endothelial receptor production of LPL => increased catabolism of VLDL and TGs => decreased TGs; blocks lipolysis of TGs in adipose tissue
Adverse Effects: cholelithiasis, dyspepsia/diarrhea, myositis, LFT abnormalities, HA/dizziness, impotence
Labs: Liver and renal function @ start, may decrease glucose and uric acid

Question 34

Welchol

Answer 34

Bile Acid Sequestrant

• Action- binds bile acids in gut and interrupts reabsorption => more bile acids produced in liver => Increased LDL receptors => increase LDL absorption
• treats hyperlipidemia
• Often also used to treat diarrhea
• Adverse effects: (d/t binding) constipation, GI irritation/bleeding, LFTs abnormal, bile duct obstruction, increase TGs
• Drug interactions- decreases absorption of fat soluble vitamins, oral anticoagulants, digoxin, PCN, theyroid hormone, tetracyclines, iron salts