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Therapeutics II > Anti-hyperlipidemic drugs > Flashcards

Anti-hyperlipidemic drugs Flashcards

1
Q

Importance of cholesterol metabolism to public health

A

-Brown and Goldstein
-cholesterol metabolism
-59% decline in death rate from CHD from 1950-1999

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2
Q

Major lipids

A

-cholesterol
-triglyceride

-transported in blood as lipoproteins bc very hydrophobic

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3
Q

Cholesterol

A

-essential component of cell membranes
-precursor to sterols and steroids
-STRUCTURE

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4
Q

Triglyceride (triacylglycerol)

A

-storage form of fuel to support generation of high energy compounds
-component of structural lipids
-STRUCTURE

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5
Q

Lipoprotein

A

-transport cholesterol and tgs in blood
-spherical particles w phospholipid, free cholesterol and protein making up surface
-core made of tg and cholesterol ester
-apoproteins on surface critical in regulating transport and metabolism
-lipoprotein lipase system

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6
Q

Lipoprotein lipase systems

A

-release free fatty acids from lipoproteins

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7
Q

Lipoprotein structure

A

-apoprotein on surface (regulation)
-surface: phopholipid, protein, and cholesterol
-core: tg and cholesterol esters

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8
Q

Classes of lipoproteins (largest to smallest)

A

-Chylomicrons
-VLDL
-IDL
-LDL
-HDL

-based on density, composition and electrophoretic mobility

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9
Q

Chylomicrons

A

-transport dietary lipids from gut to liver and adipose tissue
-formed in intestine
-too big to absorb into capillaries, enter lymph node
-mostly tg structure

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10
Q

VLDL

A

-very-low
-secreted by liver into blood as source of tgs
-mostly tgs

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11
Q

IDL

A

-intermediate
-tg-depleted VLDLs

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12
Q

LDL

A

-low
-main cholesterol form in blood
-mostly cholesterol

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13
Q

HDL

A

-high
-secreted by liver and acquire cholesterol from peripheral tissues and atheromas (reverse cholesterol transport)
-bring cholesterol from tissue back into liver
-ApoA-I

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14
Q

Centrifugation

A

-HDL densest at bottom with ApoA1
-VLDL and chylomicron remnants at top with ApoB

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15
Q

important apoliproteins

A

-ApoA-I
-ApoB-100
-ApoE
-ApoCII

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16
Q

ApoA-I

A

-structural in HDL
-ligand of ABCA1 receptor
-mediates reverse cholesterol transport! (also how HDLs are formed)
-produced in liver and intestine

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17
Q

ApoB-100

A

-structural in VLDL, IDL, LDL
-LDL receptor ligand
-produced in liver

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18
Q

ApoB-48

A

-structural in chylomicrons
-production of chylomicrons and transport reminants to liver
-produced in intestine!

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19
Q

ApoE

A

-ligand for LDL remnant receptor
-reverse cholesterol transport w HDL!
-produced in liver and other tissues

20
Q

ApoCII

A

-chylomicrons and VLDL
-binds to llipoprotein lipase to enhance tg hydrolysis to fatty acids

21
Q

Lipid absorption and transport

A

-exogenous path (intestine)
-endogenous path (liver)

22
Q

Exogenous pathway

A

-dietary fat and cholesterol absorbed in intestine
-packaged into chylomicrons by bile acids from liver
-LPL breaks down tgs of chylomicron to FFAs that go to adipose tissue or peripheral tissue
-free FFAs from liver go to adipose tissue
-chylomicron reminants go to remnant receptors with help of LPL, HL, APOE

23
Q

Endogenous pathway of lipid transport

A

-VLDL from liver to IDL and FFA by LPL
-FFA go to adipose or peripheral tissues
-IDL either goes back to liver w ApoE help or turns into LDL by LPL and HL
-LDL either goes to peripheral tissues to distribute cholesterol or back to liver (LDL receptors) ApoB mediated

24
Q

Lipoprotein lipase (LPL) found in

A

-capillaries of fat
-cardiac and skeletal muscle

25
Q

Hepatic lipase (HL) found in

A

-produced in liver
-convert IDL to LDL!!

26
Q

Atherosclerotic plaque from endogenous pathway

A

-LDL oxidized
-scavenger receptors on macrophages
-turn into foam cells

27
Q

oh boy

A

slide 13

28
Q

HDL formation

A

-ApoA1 takes cholesterol from tissues to make HDL
-HDL to IDL by LCAT and CETP
-or HDL to liver, steroid-secreting cells

29
Q

LCAT

A

-lethicin-cholesterol acyltransferase
-on LDL and HDL
-HDL to IDL

30
Q

CETP

A

cholesterol ester transfer protein in blood
-HDL to IDL

31
Q

Cholesterol synthesis

A

-liver most critical to total body burden
-de novo is major source
-acetoacetyl CoA + acetylCoA to cholesterol

32
Q

Cholesterol synthesis steps

A
  1. acetoacetyl CoA + acetyl CoA
    -HMG-CoA synthase
  2. hydroxymethylglutaryl-CoA
    -HMG-CoA reductase + 2 NADPH
  3. Mevalonate
  4. IPP + DMAPP
  5. GPP + IPP
  6. FPP + squalene
  7. Lanosterol
    -19steps
  8. cholesterol

-IPP=isopentenyl pyrophosphate
-DMAP=dimethylallyl pyrophophate
-GPP=geranyl
-FPP= farnesyl

33
Q

Diseases from lipoprotein disorders

A

-hyperlipoproteinemia
-hypertriglyceridemia

34
Q

Hyperlipoproteinemia

A

-artherosclerosis (accumulation of cholesterol in vascular smooth muscle)
-premature CAD
-stroke

35
Q

Hypertriglyceridemia

A

-pancreatitis
-xanthomas
-inc risk of CHD

36
Q

Deadly duo

A

-artherosclerotic plaque + thrombosis
-plaque rupture

37
Q

Artherosclerosis patho

A
  1. fatty streak
  2. accumulated plaques

-oxidation +/- endothelial damage (sheer stress)

38
Q

LDL oxidation in artherosclerosis

A

-cigarette smoking
-taken up by macrophages
-oxidized LDLs activates T cells to convert monocytes to macrophages via cytokines also inc chemotaxis into intima
-T cells stimulate proliferation of smooth muscle cells = hypertrophy = smooth muscle cells move into intima
-all leads to accumulation of LDL, macrophages, and smooth muscles
-

39
Q

Sheer stress

A

-flow of blood damaging endothelium
-HTN inc risk of artherosclerosis bc more sheer stress

40
Q

Damage of endothelium in artherosclerosis

A

-damage causes monocytes to flow in
-upregulation of adhesion molecules that let monocytes from outside stick to endothelium and enter intima where they turn into macrophages

41
Q

Accumulation of LDL, macrophages, smooth muscle in intima (Artherosclerosis)

A

-macrophages and smooth muscle take up LDL cholesterol
-take up so much and covert to cholesterol ester = foam cells
-foam cells die and deposit cholesterol ester in blood vessel

42
Q

Subendothelial uptake of cholesterol by macrophages

A

-initiated by LDL accumulation
-influx and efflux pathway
-2 fates

43
Q

influx pathway of cholesterol uptake by macrophage

A

–influx and efflux pathway
-LDL enter macrophage by pinocytosis or LDLR
-mLDL enters by SR-A or CD36
-both to lysosome

44
Q

efflux pathway of cholesterol uptake by macrophage

A
  1. esterification by ACAT1
  2. back to free cholesterol by CEH and freed by ApoA1 and HDL
    -Apo1 binds ABCA1 to free cholesterol
    -SR-BI = HDl +FC
    -HDL binds ABCG1 to free cholesterol
45
Q

ACAT1

A

-acylCoA cholesterol acyltransferase
-esterifies cholesterol in macrophage
-tried to inhibit this but didnt work that well

46
Q

CEH

A

-cholesterol ester hydrolase
-de-esterifies cholesterol in macrophage

Therapeutics II (55 decks)

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