Pharm S2B3 - Cv - Hypolipidemics

Front 1

How are lipids transported in the blood?

Back 1

as macromolecular particles called Lipoproteins

*the main blood lipids cholesterol & triglycerie have to be packaged into lipoprotein balls for transport in blood or they would just float to the top like fat in chicken soup

Front 2

Metabolic disorder with increased levels of Lipoproteins

Back 2

Hyperlipidemia

Front 3

Term that refers to an increased plasma triglyceride level

Back 3

Hyperlipemia

Front 4

List the names of the Lipoproteins that transfer lipids into arterial walls

Back 4

1. LDL
2. IDL = intermediate-density
3. VLDL = very low-density
4. Lipoprotein (a) = Lp(a)

Front 5

Describe the structure of Lipoproteins

Back 5

Lipid membranes = contain free cholesterol & phospholipids arranged in a monolayer

Hydrophobic core:
-Cholesterol esters = cholesterol molecule linked to a fatty acid
-Triglycerides = glycerol molecule linked to 3 FA's

Apolipoproteins = high-molecular weight protein molecules are integrated into the lipid membrane

Front 6

What Lipoproteins contain Apolipoprotein B100?

Back 6

VLDL
IDL
LDL
Lp(a)

**binds to LDL receptor; mediates VLDL secretion

Front 7

What Lipoproteins have Apolipoprotein B48?

Back 7

Chylomicrons = delivers dietary Triglycerides to peripheral tissues & dietary Cholesterol to the Liver

Front 8

Lipoproteins that function as lipid production & transport

Back 8

VLDL
IDL
LDL

Front 9

Lipoprotein that transfers cholesterol & apolipoproteins among different lipoprotein subclasses & to the liver

Back 9

HDL

Front 10

List the Lipoprotein from heaviest (more protein) to lightest (more fat)

Back 10

1. HDL
2. IDL
3. LDL
4. VLDL

Front 11

Describe Chylomicron & Fat Absorption

Back 11

1. Cholesterol esters & Triglycerides are hydrolyzed to form Cholesterol & Fatty Acids
2. Cholesterol & Fatty Acids are solubilized by Bile Salts & Phospholipids are secreted into the Small Intestine
3. Solubilized cholesterol & fatty acids are absorbed by enterocytes in the duodenum & proximal jejunum
4. Long-chain FA's in enterocytes form Chylomicrons
5. Chylomicrons secreted into lymph, thoracic duct, & veins
6. Triglycerides from circulating chylomicrons are hydrolyzed by lipoprotein lipase in adipose & muscle tissues
7. Chylomicron remnants are formed & removed by binding ApoE to hepatic LDL receptor

Front 12

What accounts for 20% of the body's cholesterol? 80%?

Back 12

20% = food

80% = hepatic synthesis

Front 13

Describe what happens after a fatty meal in the liver

Back 13

1. Hepatocytes initiate Triglyceride & cholesterol synthesis
2. Triglycerides & cholesterol fused with Apolipoprotein B100 to form mature VLDL that is secreted into blood
3. Lipoprotein Lipase in muscle/adipose tissues remove Triglyceride core of VLDL to form remnants IDL & LDL
4. LDL is removed by liver & macrophages

Front 14

"bad cholesterol" that makes up 65-75% of total plasma cholesterol

Back 14

LDL

Front 15

What is elevated LDL a major risk for?

Back 15

Atherosclerosis
-LDL that is not taken up by hepatic LDL receptors migrates into vascular INTIMA to be taken up by scavenger receptors on phagocytic cells
-oxidized LDL accumulates in Foam cells

Front 16

Where is HDL synthesized?

Explain how it draws free cholesterol from cholesterol-rich cells

Back 16

Liver & Intestine

1. Cholesterol is esterified by Lecithin:Cholesterol Acyl Transferase (LCAT)
2. forms larger hydrophobic core of Cholesterol Esters in HDL
3. HDL transfers cholesterol esters to VLDL, IDL, LDL & Chylomicrons

*HDL decreases the amount of cholesterol available for tissue deposition by removing it from macrophages & promoting its return to the liver

Front 17

What is the current optimal level of LDL?

Back 17

< 100

Front 18

How are serum lipid levels measured?

Back 18

after 10-hour fast

Front 19

What is the common ending for the HMG-CoA Reductase Inhibitors?

Back 19

"STATINS"
-Atorvastatin
-Fluvastatin
-Lovastatin
-Pravastatin

Front 20

What is the mechanism of all Statins?

Back 20

Inhibit HMG-CoA Reductase to:
1. reduce hepatic formation of Cholesterol
2. increase high affinity LDL receptors in liver cells & lower plasma LDL
3. decrease plasma Triglycerides
4. increase HDL

Front 21

Which STATINS are prodrugs?

Which ones are active congeners?

Back 21

Lovastatin & Simvastatin

Atorvastatin, Fluvastatin, & Pravastatin = FAP

"LS = Latent Statins"

Front 22

GI absorption is almost complete for ______ & varies from 40-75% for the other STATINS; all have high 1st-pass hepatic extraction & mostly excreted in ______

Back 22

Fluvastatin

Bile

Front 23

What does HMG CoA Reductase do?

Back 23

converts HMG CoA -> Mevalonate
-leads to formation of Cholesterol

Front 24

Explain the step-wise mechanism of action of the STATINS

Back 24

1. Competitive inhibition of HMG CoA Reductase which catalyzes Cholesterol synthesis
2. decreased Cholesterol in Hepatocytes causes cleavage of sterol regulatory element binding protein (SREBP), a cytoplasmic transcription factor
3. SREBP diffuses into the nucleus to bind to Sterol Response Elements (SRE) & cause up-regulation of the LDL receptor
4. increased LDL-R results in increased plasma LDL clearance & reduced circulating LDL levels

Front 25

List the 4 Pleiotropic Statin effects

Back 25

-

Front 26

What is the 1st line therapy for elevated LDL levels?

Back 26

Statins

Front 27

At what time of day are administration of STATINS most likely to be effective?

What enhances absorption?

Back 27

Night when most of cholesterol synthesis occurs

When taken with food

Front 28

What do STATINS significantly reduce the mortality from?

Back 28

MI & Cardiovascular Disease patients

Front 29

What indicates STATIN toxicity?

Back 29

serum Aminotransaminase = Hepatotoxic = increased LFT's

Front 30

How is Statin heptatic toxicity manifested?

Back 30

Malaise

Anorexia

precipitous fall in LDL

*more pronounced in patients with liver disease or alcoholism

Front 31

Which Statins are mainly catabolized by CYP-3A4?

Back 31

Atorvastatin
Lovastatin
Simvastatin

*SAL - Charles Barkley (3a4)

Front 32

What drugs inhibit CYP-3A4 and can increase the concentration of Atorvastatin, Lovastatin, & Simvastatin?

Back 32

Macrolides = Erythromycin
Cyclosporine
Ketoconazole
Fibrates
Grapefruit juice

Front 33

Which drugs can inhibit CYP-2C9 & increase levels of Fluvastatin & Rosuvastatin

Back 33

Ketoconazole
Metronidazole
Sulfinpyrazone
Amiodarone
Cimetidine

MASCK the effects of 2C9

Front 34

Which Statin is not metabolized by P450 & is preferred whenever concurrent treatment with other drugs is required?

Back 34

Pravastatin

*PRivileged-statin

Front 35

What are the toxicities of the Statins?

Back 35

Hepatotoxicity

Myositis/Rhabdomyolysis = increased Creatine Kinase activity
-skeletal muscle pain, tenderness, or weakness

Front 36

What serum tests should be done before treatment & every 6-12 months thereafter when taking STATINS?

Back 36

1. Aminotransferase = hepatotoxicity

2. Creatine Kinase = rhabdomyolysis

Front 37

What is Niacin?

Back 37

Water soluble vitamin (B3) that is converted to the Amide, incorporated into Niacinamide Adenine Dinucleotide (NAD) & excreted in urine

Front 38

What is currently the most effective drug for elevating HDL?

Back 38

Niacin

Front 39

List the effects of Niacin administration

Back 39

1. decreases lipase activity in adipose tissue
-reduces free FA flux to liver
-decreases hepatic synthesis of Triglycerides & VLDL
-LOWER plasma LDL & TG's

2. increases ApoAI to elevate plasma HDL

Front 40

What are the therapeutic uses of Niacin?

Back 40

1. DOC for pts with elevated LDL & lowered HDL
2. normalizes LDL when combined with Resin or Statin for treatment of Heterozygous Familial Hypercho-cholesterolemia & other Hypercholesterolemias
3. Familial combined Hyper-lipoproteinemia
4. Familial Dysbetalipoproteinemia

Front 41

DOC for patients with elevated LDL & lowered HDL

Back 41

Niacin (B3)

Front 42

What are the manifestations of Niacin toxicity? (5)

Back 42

1. MC is CUTANEOUS VASODILATION with WARM SENSATION
2. pruritis, rashes, dry skin, nausea, abdominal discomfort
3. may elevate Aminotransferases but true Hepatotoxicity is rare
4. glucose tolerance may be impaired
5. may cause Hyperuricemia & Gout

Front 43

List the Fibric Acid derivatives used as lipid-lowering agents

Back 43

Fenofibrate
Gemfibrozil
Clofibrate
Benzafibrate

Front 44

List the mechanism of action of the Fibrates

Back 44

act as ligands for the nuclear transcription factor PPAR-alpha in hepatocytes

activation of hepatic PPAR-alpha DECREASES PLASMA TRIGLYCERIDES, VLDL, & LDL; increases HDL

**greatest effect is on decreasing Triglycerides

Front 45

What are the Fibrates used for the treatment of?

Back 45

Hypertriglyceridemia = hepatic overproduction of VLDL

Dysbetalipoproteinemia = deficiency of Apolipoprotein E
-increased remnants = VLDL, IDL, & Chylomicrons

Front 46

What are the toxic effects of the Fibrates?

Back 46

Rare but:
-skin rashes
-GI symptoms
-myopathy
-arrhythmias
-hypokalemia
-increases Aminotransferases or Alk Phos
-decreases in WBC's or hematocrit
-rarely Rhabdomyolysis
-increased incidence of Gallstones

Front 47

What drugs do the Fibrates potentiate?

Back 47

Anticoagulants
-Indanedione
-Coumarin (Warfarin)

Front 48

List 3 Bile Acid-binding Resins used as Lipid-lowering agents

Back 48

1. Colestipol

2. Cholestyramine

3. Colesevelam

**C(h)oles

Front 49

Describe the Bile Acid resins

Back 49

large cationic exchange resins, insoluble in water, that bind bile acids to prevent their intestinal absorption & increase excretion
1. upregulates 7-alpha hydroxylase = hepatic enzyme that catalyzes synthesis of bile acids from cholesterol
2. increased bile acid synthesis reduces the amount of hepatic cholesterol
3. reduction in hepatic cholesterol increases LDL recpetors
4. enhances removal of LDL from circulation
5. lowers plasma LDL & elevates plasma HDL

Front 50

What are the Bile Acid Resins used therapeutically for?

Back 50

1. Primary Hypercholesterolemia

2. Digoxin toxicity = bind digoxin

Front 51

What is the toxicity of Bile Acid Resins? (6)

Back 51

1. no significant systemic effects b/c they are not absorbed
2. Unpleasant sandy & gritty quality
3. occasional heartburn & diarrhea
4. Bloating & constipation occur due to decreased fat absorption
5. Hypoprothrombinemia due to Vitamin K malabsorption
6. Steatorrhea in pts with Bowel Disease or Cholestasis
7. Gallstone formation is enhanced in Obese pts

Front 52

What drugs do Bile Acid Resins impair the absorption of?

Back 52

1. Digoxin
2. Thiazides
3. Tetracycline
4. Fluvastatin
5. Thyroxine
6. Aspirin

DAFTTT

Front 53

What is the name of the Cholesterol absorption blocker?

Back 53

Ezetimibe

**"Easy time" at blocking cholesterol absorption

Front 54

What effects does Ezetimibe possess?

Back 54

1. inhibits intestinal absorption of Cholesterol & Phytosterols
2. reduces plasma LDL with minimal HDL increase
3. effective even when there is no dietary cholesterol b/c it inhibits absorption of cholesterol excreted in bile

Front 55

What are the therapeutic used of Ezetimibe?

Back 55

1. Primary Hypercholesterolemia

2. single daily dose of 10 mg reduces LDL by 18%

Front 56

What is the low incidence toxicity associated with Ezetimibe?

Back 56

reversible hepatic impairment = increased LFT's

Front 57

When are drug combinations useful?

Back 57

1. When VLDL levels increase during Resin therapy of Hypercholesterolemia

2. when VLDL & LDL are both elevated

3. when VLDL or LDL levels are not normalized by a single drug

4. when elevated Lp(a) or HDL deficiency occurs with other hyperlipidemias

Front 58

Niacin + Lovastatin = ?

Back 58

Advicor

Front 59

Ezetimibe + Simvastatin = ?

Back 59

Vytorin

Front 60

-

Back 60

-