Cholesterol lowering agents

What are the biochemical classes of lipids?

1. prostaglandins

2. triglycerides

   1. unsaturated (oil)

   2. saturated (fats)

   3. phospholipids → very polar

3. steroids

   1. cholesterol

   2. cholesterol esters (CE) → more lipophilic than C

What are cholesterol esters?

• fatty acids esterifying C3 hydroxyl

• more lipophilic than cholesterol

What are the ingested lipids?

• TGs

• phospholipids

• cholesterol

• CE

What is the 1st step of the lipid cycle?

• ingested lipids form big micelle structures → chylomicrons

  • outer: cholesterol + phospholipids

  • inner: TG + CE

• combined via the hydrophobic effect to allow globule movement

What is the structure of chylomicrons? How do they move through the aqueous system?

• outer: cholesterol and phospholipids

  • aqueous components

• inner: TGs and CE

  • lipophilic components

• hydrophobic effect allows movement through the aqueous system

  • aqueous parts cover the lipophilic ones

What is the 2nd step in the lipid cycle?

• chylomicrons undergo hydrolysis by lipases 

  • loses most of its TGs

• new particle = remnant chylomicron

  • inner: CE>TG

  • much smaller than chylomicron

What is the 3rd step in the lipid cycle?

• remnant chylomicrons go to the liver and are digested by lysosomes

  • product: free cholesterol

    • stored by esterification into CE

    • metabolized into bile acids

What is the 4th step of the lipid cycle?

• liver recombines the 4 componenets into very small particles with the same inner and outer orientation

  • TG content = very high

    • very low density (VLDL)

  • coated with apo-lipoproteins (direct the globule into a specific tissue)

What is the apo-lipoprotein that is selective to the coronary arteries?

apo-B100

What happens to the chylomicron when it is traveling in the lymph?

• picked up by adipose tissue and skeletal muscle

• both tissues extract FAs from TGs via lipolipase to use for energy

• deposited in adipose tissue

What is VLDL?

• very low density lipoprotein

• high TG content

What is IDL?

• intermediate density lipoprotein

• CE>TG content

What is LDL?

• low density lipoprotein

• mostly just CE

• loss of all TG

• dangerous because apo-B100 will bind to coronary arteries

• goes to other tissues where CEs are hydrolyzed to make free cholesterol

  • increases density of globule

What is HDL?

• returns to liver for recycle

What is the correct name for cholesterol lowering agents?

antihyperlipoprotein drugs

Nicotinic acid (Niaspan)

• vitamin B3 (niacin)

• pyridine group

• COOH group

• effective in lowering LDL and raising HDL

• good oral absorption → active transport because it is small + polar

  • poor lipophilicity

• adverse effect: flushing

  • due to peripheral vasodilatory effects

• metabolized in liver → nicotinamide

What is the MOA of nicotinic acid?

• unknown

• may enhance lipoproteinase

  • breaks down chylomicrons → increases catabolism of LDL

• may interfere w/ apo-protein synthesis

Why does nicotinic acid have an ADR of flushing?

because it is also a peripheral vasodilator

Gemfibrozil (Lopid)

• aryloxyisobutyric acid derivative

• isobutyric acid group

• lowers both cholesterol + TGs

• used PO

• >99% PPB

• metabolized aliphatic hydroxylation then conjugated

• unknown MOA

What is the dose of gemfibrozil?

600 mg BID

How is Lopid metabolized?

• aliphatic hydroxylation

• conjugation

fenofibrate

• enhances catabolism of TG rich particles

• reduces secretion of VLDL

  • leads to hypotriglyceridemic effects

What are statins?

• HMG CoA reductase inhibitors

• effectively block conversion of HMG-CoA → mevalonic acid

What are the effects of statins?

• inhibits HMG-CoA reductase

• inhibits endogenous cholesterol biosynthesis in liver

• decreases LDL

T/F: statins decrease dietary cholesterol

FALSE

• no effect on dietary cholesterol

What is process of cholesterol synthesis?

1. acetyl CoA

2. 3 hydroxy-3-methyl Gluteryl CoA

   1. HMG CoA reductase

3. mevalonic acid

4. cholesterol

What are the key features of statins?

• 5 C backbone w/ hydroxyl + carboxyl groups

• coenzyme A structure replaced w/ highly lipophilic area connected to mevalonic acid

What are the properties of statins?

• good absorption from stomach and GI

• PPB is high

  • OH = polar but hydrophilicity is outnumbered by the lipophilcity

• similar potency = 20-40 mg

  • rosuvastatin is dosed 5-10 mg due to the resistance to metabolism from the sulfonamide group

Describe how statins are metabolized.

• high 1st pass, low bioavailability

• undergoes phase II conjugation

• undergoes further hydroxylation

lovastatin (Mevacor)

• napthalene ring

• very carbon rich = lipophilic

• similar to HMG CoA structure

• PRODRUG

pravastatin (Pravachol)

• more hydrophilic than others

simvastatin (Zocor)

• PRODRUG

atorvastatin (Lipitor)

• very large lipophilic area

  • off sets hydroxyl groups

fluvastatin (Lescol)

rosuvastatin (Crestor)

• has sulfonamide group

  • resistant to liver metabolism

  • lower dose: 5-10 mg

What are bile acids?

• metabolites of cholesterol

  • liver breaks down cholesterol to bile acids

• excreted into GIT to emulsify lipids

• approximately 97% of bile acids are reabsorbed into liver via enterohepatic circulation

What happens is bile acids become sequestered (trapped) in the GIT?

• liver cholesterol will be depleted

• sequestration (adsorption) prevents reabsorption into liver

What are the chemical properties of bile acid sequestrants?

• positively charged N

  • quaternary = no absorption

  • needs to stay in GIT and work locally

  • reacts with COOH

• polymeric lipophilic area

  • reacts with bile acid lipophilic backbone

cholestyramine Cl (Questran)

• bile acid sequestrant

• polymer of styrene

• quaternary ammonium

• adverse effect: severe constipation

  • drug absorbs water alone with bile acid

• nonselective

Why is the nonselectivity of cholestyramine a problem?

• will sequester anything that is highly lipophilic

• can lead to DDIs

  • contraceptives (lipophilic + acidic)

  • vitamin K (lipophilic + acidic)

    • causes problems with clotting

    • may decrease absorption of all nonwater soluble vits (KADE)

colestipol HCl (Colestid)

• bile acid sequestrant

• polymer of tetraethylenepentamine

• non-quaternary ammonium

  • but protonated in GIT

• secondary + tertiary amines

• constipation side effect

How do cholestyramine and colestipol lower plasma LDL levels?

by indirectly increasing the rate at which LDL is cleared from the bloodstream

What are cholesterol transporter inhibitors (CTI)?

• lowers plasma cholesterol levels by inhibiting transport and absorption of cholesterol at the brush border of the SI 

  • binds to specific cholesterol transport protein

• inhibits exogenous cholesterol absorption from food

How does the body compensate for the decreased absorption of cholesterol from the GIT?

• upregulates LDL receptors + produces more HMG-CoA reductase to try to make more cholesterol

  • given in combo drugs like Vytorin (simvastatin + ezetimibe)

ezetimibe (Zetia)

• CTI

• very lipophilic

• very poor dissolution rate

• conjugated in phase II w/ glucuronic acid → goes back to GIT + interacts with transporter

Which statins are prodrugs?

• lovastatin (Mevacor)

• simvastatin (Zocor)