cholesterol

are triglycerides or phospholipids more polar?

• phospholipids = more polar

is cholesterol or cholesterol ester more polar?

• cholesterol = more polar

• cholesterol ester = more lipophilic

structure of a chylomicron

• outside = cholesterol + phospholipid 

• inside = cholesterol ester + triglycerides 

  • usually more TG> CE 

SATA: which of the following are inside the chylomicron

a) cholesterol

b) cholesterol ester

c) triglyceride

d) phospholipids

b) cholesterol ester

c) triglyceride

SATA: which of the following are outside the chylomicron

a) cholesterol

b) cholesterol ester

c) triglyceride

d) phospholipids

a) cholesterol

d) phospholipids

what happens after the chylomicron enters the circulation?

• hydrolysis in tissues by lipases

  • most of the TG in the core → fatty acids for energy (ATP) 

• chylomicron core = more CE > TG = remnant chylomicrons 

remnant chylomicrons vs chylomicrons

• remnant chylomicrons = CE > TG 

  • smaller size 

• chylomicrons = TG > CE 

  • bigger size 

what happens to the remnant chylomicrons after they are formed?

• liver 

  • digested by lysosomes into free cholesterol 

    • can become CE by esterification (storage) 

    • or metabolized into bile acids 

what does the liver make from recombining the 4 components of the chylomicrons? 

• VLDL particles 

  • same orientation (TG + CE = inside, C, PL = outside) 

  • TG = very high 

what is the purpose of the apo-protein

• helps chylomicrons move through circulation 

• helps with recognition of certain tissues 

liver makes a small particle from remnant chylomicron that is mostly of TG

a) low density lipoprotein (LDL) 

b) high density lipoprotein (HDL)

c) intermediate density lipoprotein (IDL) 

d) very low density lipoprotein (VLDL) 

d) very low density lipoprotein (VLDL) 

liver makes a small particle from remnant chylomicron that is more CE > TG (after adipose tissue)

a) low density lipoprotein (LDL) 

b) high density lipoprotein (HDL)

c) intermediate density lipoprotein (IDL) 

d) very low density lipoprotein (VLDL) 

c) intermediate density lipoprotein (IDL) 

liver makes a small particle from remnant chylomicron that is mostly just CE inside globule. dangerous because of its apo-proteins 

a) low density lipoprotein (LDL) 

b) high density lipoprotein (HDL)

c) intermediate density lipoprotein (IDL) 

d) very low density lipoprotein (VLDL) 

a) low density lipoprotein (LDL) 

liver makes a small particle from remnant chylomicron that lost all of its TG. 

a) low density lipoprotein (LDL) 

b) high density lipoprotein (HDL)

c) intermediate density lipoprotein (IDL) 

d) very low density lipoprotein (VLDL) 

b) high density lipoprotein (HDL)

list the cholesterol lowering agents or antihyperlipoprotein drugs

1. nicotinic acid

2. gemfibrozil 

3. statins 

4. bile 

5. cholesterol transport inhibitors 

what is the most commonly used class of cholesterol lowering agents 

• statins 

what is the most effective cholesterol lowering agent

• nicotinic acid 

what is this drug?

• nicotinic acid

what is the difference between nicotinic acid and nicotine

• replaced pyrrolidine ring in nicotine with COOH 

Nicotinic acid is also known as ______

• vitamin B3 (niacin) 

how is nicotinic acid absorbed? how is it metabolized

• good oral absorption 

  • possibly active transport because it is small and polar

  • poor lipophilicity 

• metabolized in liver → nicotinamide

what is a side effect of nicotinic acid? why?

• flushing 

  • peripheral vasodilator effects as well 

effects of nicotinic acid

• effective in lowering LDL + raising HDL levels

what type of drug is this? 

• aryloxyisobutyric acid derivative 

  • gemfibrozil 

how is gemfibrozil metabolized? 

• aliphatic hydroxylation → conjugation 

gemfibrozil effects 

• lowers both cholesterol and triglycerides 

gemfibrozil absorption + administration 

• orally 

  • high PPB 

smaller particle lipid cycle order

• VLDL → IDL → LDL → HDL 

what type of drug is this? 

• aryloxyisobutyric acid derivative 

  • fenofibrate

fenofibrate MOA 

• enhances catabolism of TG-rich particles + reduces secretion of VLDL → hypotriglyceridemic effects 

statin MOA

• HMG CoA reductase inhibitors

  • block rate-limiting step (HMG CoA → mevalonic acid) = blocks production of cholesterol 

T/F: statins decrease endogenous and exogenous cholesterol levels 

• false 

  • statins only inhibit endogenous cholesterol biosynthesis in the liver (decreases LDL) 

  • does not affect dietary cholesterol 

cholesterol synthesis steps

1. acetyl CoA 

2. HMG CoA (3 acetyl CoA together + acetyl cos)

(HMG CoA reductase)

3. mevalonic acid 

(20 steps)

4. cholesterol 

how many carbons are in acetyl CoA?

• 2 carbons

how many carbons are in HMG CoA

• 6 carbons (3 acetyl CoA combined)

how many carbons are in mevalonic acid?

• 6 carbons

how many carbons are in cholesterol?

27 carbons

what is the full name for HMG CoA

• 3 hydroxy-3-methyl gluteryl CoA

what is a common structure in statins

• 5 carbon backbone with hydroxyl + carboxyl groups 

  • similar structure to HMG

T/F: statins have coenzyme A part replaced with highly lipophilic area connected to mevalonic acid

describe the absorption of statins

• absorbed well (good oral absorption) 

• high PPB 

  • lipophilicity > hydrophilicity 

• all have similar potency 

how are statins metabolized?

• high FPM = low bioavailability 

• phase 2 conjugation 

• further hydroxylation 

what type of drug is this?

• Statin 

  • lovastatin 

what type of ring does lovastatin have?

• naphthalene ring 

which statins are prodrugs?

• lovastatin 

• simvastatin 

which statin is more hydrophilic than the others?

a) lovastatin

b) rosuvastatin

c) pravastatin 

d) simvastatin 

c) pravastatin 

what type of drug is this? 

• statin 

  • pravastatin 

what type of drug is this?

• statin 

  • simvastatin 

what type of drug is this?

• statin 

  • atorvastatin 

what type of drug is this?

• statin 

  • fluvastatin 

what type of drug is this? 

• statin 

  • rosuvastatin

what structure in rosuvastatin makes its metabolism a little different? how does it affect its dose?

• sulfonamide group 

  • liver does not like sulfonamide 

  • lower dose than other because of liver metabolism resistance 

what are bile acids

• metabolites of cholesterol 

what happens when bile acids are sequestered in the GIT?

• liver cholesterol will be depleted 

common structure in bile acid sequestrants

• positively charged N 

  • decrease absorption in GIT = localized action 

• polymeric lipophilic area 

  • polymers = not absorbable = localized action 

what structure in bile acid sequestrants react with the carboxylic group?

• quaternary nitrogen 

what structure in bile acid sequestrants react with the bile acid lipophilic backbone ?

• polymer lipophilic area 

what type of drug is this?

• bile acid sequestrant 

  • cholestyramine chloride 

what is an ADE of cholestyramine chloride? why? 

• severe constipation 

  • quaternary ammonium loves water = absorbs water in GIT = severe constipation 

why might cholestyramine have problems with drug-drug interactions?

• nonselectivity → sequesters anything highly lipophilic

what specific drugs can cholestyramine have drug-drug interactions with ?

• anything highly lipophilic 

  • contraceptives (steroid hormone supplement) → ineffective

  • vitamin K → clotting

    • decrease absorption of all non-water soluble vitamins (ADEK) 

what type of drug is this?

• bile acid sequestrant 

  • colestipol HCl 

describe the structure of colestipol 

• polymer of tetraethylenepentamine 

• non-quaternary (2 + 3 amines) 

  • but is protonated in GIT

side effects + concerns of colestipol 

• constipation (less than cholestyramine) 

what type of drug is this? 

• cholesterol transport inhibitors (CTI) 

  • ezetimibe 

MOA of ezetimibe

• cholesterol transporter-inhibitors 

  • inhibits absorption of cholesterol at the brush border of the small intestine in the GIT 

  • inhibits EXOGENOUS cholesterol absorption 

compensatory mechanism of cholesterol transporter-inhibitors (CTI)

• compensation mechanism to increase cholesterol 

  • upregulates LDL receptors 

  • increases HMG-reductase 

T/F: cholesterol transporter-inhibitors are often given in combination  

• true 

  • prevent compensatory mechanisms

what is in Vytorin combination drug

• simvastatin

• ezetimibe 

describe the absorption of ezetimibe

• very lipophilic = poor dissolution

  • conjugated in phase 2 → goes back to GIT → interact with transporter 

ADE of cholesterol transporter inhibitors 

• affects muscle buildup 

• sexual impetus 

  • sperm needs lipids 

which of the following drugs inhibits exogenous cholesterol absorption?

a) ezetimibe 

b) cholestyramine chloride 

c) rosuvastatin 

d) fenofibrate 

a) ezetimibe 

which of the following drugs inhibits endogenous cholesterol biosynthesis?

a) ezetimibe 

b) cholestyramine chloride 

c) rosuvastatin 

d) fenofibrate 

c) rosuvastatin

which of the following drugs is effective in lowering LDL and raising HDL levels?

a) nicotinic acid 

b) cholestyramine chloride 

c) rosuvastatin 

d) fenofibrate 

a) nicotinic acid 

which of the following drugs is effective in lowering cholesterol and triglycerides?

a) nicotinic acid 

b) cholestyramine chloride 

c) gemfibrozil 

d) fenofibrate 

c) gemfibrozil 

which of the following drugs is effective in lowering trglyceride-rich particles and secretion of VLDL?

a) nicotinic acid 

b) cholestyramine chloride 

c) gemfibrozil 

d) fenofibrate 

d) fenofibrate

which aryloxyisobutyric acid derivative has the isobutyric acid given as an ester form?

• fenofibrate