Lecture 13: Hyperlipoproteinemia

Question 1

Function of lipoprotein

Answer 1

transport cholesterol, triglycerides and phospholipids in plasma

Question 2

Apolipoproteins

Answer 2

function as ligands
recognized by cellular lipoprotein receptors
induce internalization of lipoproteins

Question 3

Apo CII and CIII

Answer 3

CII activates lipoprotein lipase

CIII inhibits lipoprotein lipase

Question 4

Atherosclerosis

Answer 4

hardening of arteries

high plasma LDL, low HDL

narrowed blood vessel lumen

reduce blood flow and plaque breaking off leads to embolus, and the infarct

Question 5

Foam cells

Answer 5

oxidized LDL and macrophages form foam cells

foam cells cannot be taken up by liver which leads to cell necrosis

Question 6

Lipoprotein A Lp(a)

Answer 6

strong correlation between elevate Lp(a) to risk of atherosclerosis

competitively inhibits tissue plasminogen activator which breaks down blood clots

promotes thrombus formation, atherogenic

Question 7

HMg-CoA reductase

Answer 7

HMg-Coa to mevalonic acid to cholesterol

rate limiting enzyme in cholesterol synthesis

hepatic cholesterol level exerts feedback inhibition of HMg-CoA activity, decrease LDL receptor

Question 8

Statins

Answer 8

structural analogs for HMg-CoA
competitive inhibition

depletes sterol pools

increase LDL receptor expression, LDL uptake

decrease plasma LDL concentration

Question 9

Atorvastatin and Rosuvastatin

Answer 9

statins

useful for most hyperlipoproteinemias but not for genetic LDL receptor deficiency

acts synergistically with bile acid binding resins (colestipol & cholestyramine) and Ca blockers

Question 10

Adverse effect of statins

Answer 10

well tolerated

elevated liver transaminase

NOT TO BE USED IN PREGNANCY (cholesterol important in fetal development)

P450 inhibitors (ketoconazole) can increase statin concentration

myositis and rhabdomyolysis (most common)

Question 11

Cholestyramine and Colestipol

Answer 11

inhibit cholesterol absorption

cationic bile acid binding resins

lead to decrease in bile acid production

increase HMg-CoA reductase activity
decrease cholesterol
increase LDL receptors
increase HDL

USED WITH STATINS can increase efficacy markedly

Question 12

Adverse effect for cholestyramine and colestipol

Answer 12

few side effect because not absorbed from intestine

might impair intestinal absorption of other drugs

Steatorrhea - excess fat in stools, chronic diarrhea and weight loss, due to impaired absorption of dietary fat

Question 13

Neomycin

Answer 13

aminoglycoside antibiotic

interferes with absorption of bile acids

similar to cholestyramine and colestipol

Question 14

Ezetimibe and adverse effect

Answer 14

blocks absorption of dietary and biliary cholesterol at small intestine

block NPC1L protein transporter

used in combination with STATINS but can be used in monotherapy

adverse effect: GALLSTONES

Question 15

Nicotinic Acid (Niacin)

Answer 15

inhibit release of free fatty acid

decrease VLDL production in liver

decrease IDL and LDL in plasma

ONLY LIPID LOWERING DRUG CURRENTLY TO LOWER Lp(a) levels

synergistic effect with bile acid binding resins

Question 16

adverse effects of niacin

Answer 16

hyperglycemia
flushing
GI upset
serious liver dysfunction

Question 17

Clofibrate, Fenofibrate and Gemfibrozil

Answer 17

stimulate PPARa (gene associated with lipid metabolism)

increase lipoprotein lipase expression, promote VLDL conversion to IDL and LDL

LDL levels rise initially but fall due to VLDL and triglycerides depletion

increase HDL levels

decrease ApoCIII (inhibitor of LPL) activity
decrease fatty acid synthesis and increase fatty acid oxidation

Antithrombotic effect: inhibit coagulation and enhance fibrinolysis

can produce gallstones

DO NOT USE WITH STATINS

Question 18

PCSK9 inhibitors (Evolocumab)

Answer 18

monoclonal antibody targeting PCSK9

PCSK9 binds to LDL receptor and increases degradation of LDL receptor after internalization

increases LDL receptor recycling

increase removal of LDL