Lipid Metabolism & Pharmacology

Question 1

Familial Hyperchylomicronemia

Answer 1

Caused by defect in removing Chylomicrons (apoCII and/or LPL defects)

*Manifests as elevated Triglycerides w/ resulting Pancreatitis

Question 2

Familial Hypertriglyceridemia

Answer 2

Caused by less severe defects in LPL and ApoCII, or by from elevated ApoCIII (which inhibits LPL)

• Manifests as:
• Moderately elevated triglycerides, usually just VLDL

Question 3

Familial Dysbetalipoproteinemia

Answer 3

Caused by defective removal of remnant particles (IDL) due to loss of function mutations in ApoE alleles (E2/E2)
(I.e. ApoE can’t bind LDL receptors on liver cells)

• Manifests as:
• elevated VLDL and IDL
• Cholesterol and TG elevated at a 1:1 ratio
• premature athersclerosis
• poor response to statins

Question 4

Familial combined Hyperlipodemia (FCH)

Answer 4

Due to overproduction of apoB100 (the primary structural protein of VLDL)

• Variable phenotype: Elevated VLDL, LDL, or both
• Autosomal Dominant
• Associated with Premature Atherosclerosis

Question 5

Familial Hypercholesterolemia

Answer 5

Cause by inherited (AD) defects in LDL receptor and ApoB

*LDL increased w/ premature athersclerosis (lipid profile stable otherwise)

• Xanthelasma may appear in 3rd decade
• Coronary Disease occurs prematurely
• Tendon Xanthomas often present

Question 6

Secondary causes of Hyperlipidemia

Answer 6

• Excess caloric intake
• Hypothyroidism
• Kidney & Liver disease
• Medications
• excess in take of simple sugars (Pop & Alcohol)
• Genetic

Question 7

Current recommendations for dietary management of hyperlipoproteinemia?

Answer 7

• limit cholesterol, Saturated fats, and trans-fats (Red meat, diary, backed goods)
• Limit excess simple sugars, carbohydrates, alcohol. (these lead to increased synth and secretion of VLDL
• use poly or mono-unsaturated fats

Question 8

MOA for Statin drugs

Answer 8

Competitively Inhibit the rate limiting step of cholesterol biosynthesis (HMG-CoA reductase enzyme) resulting in increased expression of LDL-receptors and therefore lower LDL plasma

Question 9

MOA for Bile Acid Resins

Answer 9

Bind to bile acids and prevent their reabsorption and re-use of bile cholesterol

• Modest effect on HDL
• Does NOT decrease TGs
• GI side effects can limit use

Question 10

What are the intermediately potent and efficient Statin drugs?

Answer 10

Lovastatin and Simvastatin

• CYP3A4 metabolized

Question 11

What are the potent and highly efficient Statin drugs?

Answer 11

Atrovastatin and Rosuvastatin

• Synthetic versions with longer plasma half-lives

Question 12

What is the advantage of using Pravastatin?

Answer 12

It does NOT have any CYP interactions

Question 13

CYP drugs that commonly cause drug interactions with statins

Answer 13

• Macrolide Antibiotics (Erythromycin, Clarithromycin)
• Azole antifungals
• Calcium channel blockers (verapamil, diltiazem)
• Grapefruit juice
• HIV PIs (“Navirs”)
• Immunosuppresants (Cyclosporine)

Question 14

Drugs, other than CYP and P-gp drugs, that inhibit statin metabolism?

Answer 14

Gemfibrozil

- glucuronyltransferase-1

Question 15

Name 3 Bile Acid Sequesters

Answer 15

• Colestipol (powder or tab)
• Cholestyramine (powder)
• Colesevelam (tab)

Question 16

Adverse affects and contraindications of Bile Acid Sequestrants

Answer 16

GI: Bloating, Nausea, flatulence, constipation
*Take w/ water!

• Drug-interactions: Beta-Blockers, coumadin
• take hours before or after bile acid seq.
• Contraindications: Hypertriglyceridemia, complex drug regimens, and hx of constipation
• May increase TGs

Question 17

Ezetimibe

Answer 17

Cholesterol absorption Inhibitor

• prevents the direct uptake of cholesterol itself from the the intestines (lowers intake and also upregulates LDL-receptors)
• normally given in conjunction with statins or when they cannot be used

Question 18

Gemfibrozil

Answer 18

Fibric acid derivative

• MOA: competitive inhibitors of PPAR-alpha nuclear receptor (lipid metabolism receptor)
• > reduces TGs (~50%) and Increases HDL
• drug-drug interaction with STATINS
• *can be safely given to those w/ renal disease

Question 19

Fenofibrate

Answer 19

Fibric acid derivative

• MOA: competitive inhibitors of PPAR-alpha nuclear receptor (lipid metabolism receptor)
• > reduces TGs (~50%) and Increases HDL
• *does NOT interact w/ statins
• not recomended for advance renal disease due to accumulations

Question 20

Fenofibric Acid

Answer 20

Fibric acid derivative

• MOA: competitive inhibitors of PPAR-alpha nuclear receptor (lipid metabolism receptor)
• > reduces TGs (~50%) and Increases HDL

Question 21

Niacin (MOA

Answer 21

MOA: Inhibits mobilization of free FA from adiopocytes resulting in:

• reduced hepatic TG synthesis
• reduced VLDL syn and secretion (ApoB)
• Enhances reverse cholesterol transport via HDL
• Enhances LPL conversion of VLDL to LDL

Question 22

Adverse affects of Niacin

Answer 22

Cutaneous Flushing

- give asprin and start w/ low dose then increase slowly

Question 23

When are high efficacy statins recommended to be used?

Answer 23

for patients with atherosclerotic vascular disease and/or a previous MI