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LCRS Pharma > Atherosclerosis & Lipid-lowering Drugs > Flashcards

Atherosclerosis & Lipid-lowering Drugs Flashcards

1
Q

what defines the type of lipoprotein?

A

the apoproteins present

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2
Q

what are the differences in apoprotein in HDL and LDL?

A

HDL- apoprotein A-1

LDL- apoprotein B

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3
Q

what is the exogenous pathway for lipid metabolism?

A

food is broke down into chylomicrons (large)

these a further broken down into FFAs and chylomicrons remnants (taken by the liver)

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4
Q

what is the relevance of chylomicron remnants?

A

these deposit in vessels and become atheroma

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5
Q

which pathway do most HDL/LDL originate from?

A

the endogenous pathway

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6
Q

what does the endogenous pathway of lipid metabolism involve?

A

acetyl CoA (liver)–> cholesterol–> VLD (TG+chol)

VLDL–>IDL–>LDL

  • this conversion involves progressive release of TG by Lipoprotein lipase
  • LDL is concentrated in cholesterol (low TG content)
  • LDL can be removed from circulation by the liver, LDL receptors located on the liver
  • LDL can be used by peripheral tissue for use of cholesterol

Hepatic lipase in metabolism

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7
Q

which lipoproteins are usually deposited in atheroma formation?

A

IDL and LDL

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8
Q

what is reverse cholesterol transport?

A

the removal of cholesterol from vessel walls back to the liver by HDL

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9
Q

what is the detailed process of atherosclerosis?

A
  1. LDL enters endothelium (into tunica intima)
  2. LDLs are oxidised by macrophages and VSMCs.
  3. Release of growth factors and cytokines.
  4. Additional monocytes/macrophages recruited.
  5. Foam cell accumulation.
  6. VSMC (in the media) migration.
  7. VSMC proliferation.
  8. Plaque growth.
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10
Q

what endothelial dysfunctions occur as a result of atherosclerosis?

A
  • Increased endothelial permeability.
  • Upregulation of adhesion molecules.
  • Leucocyte adhesion.
  • Migration of leucocytes into artery wall.
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11
Q

what causes the formation of the fatty streak in atherosclerosis?

A
  • Migration of VSMCs.
  • Activation of T-cells.
  • Adherence & activation of platelets.
  • Formation of foam cells.
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12
Q

what leads to the formation of the complicated plaque in atherosclerosis?

A
  • Formation of fibrous cap.
  • Accumulation of macrophages.
  • Formation of necrotic core
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13
Q

what are the stages of the atherosclerotic lesion over time? [6]

A
  1. Lesion-prone location – Adaptive thickening.
  2. Type 2 lesion – foam cells.
  3. Type 3 lesion (preatheroma) – extracellular lipid.
  4. Type 4 lesion (atheroma) – bigger core of extracellular lipid.
  5. Type 5 lesion (fibroatheroma) – fibrous thickening.
  6. Type 6 lesion (complicated lesion) – fissure & haematoma.
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14
Q

what lipids are considered as remnants? what do remnants do?

A

VLDL, chylomicron remnants and IDL

these can infiltrate the endothelial wall easily, play a more important role than LDL alone

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15
Q

why do remnants have a very important role in atherosclerosis?

A

the inflammatory component of atherosclerosis is caused by the remnants rather than LDLs by its self

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16
Q

what is the difference between a stable and unstable plaque?

A

stable plaque: thick fibrous cap. Prognosis is better

unstable plaque: thin fibrous cap, rich core of lipids and macrophages, less VSMC proliferation

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17
Q

what are the effects of LDL on disease?

A

strongly associated with atherosclerosis & CHD events

10% increase LDL –> 20% increase in CHD events.

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18
Q

what modifies the risk associated with LDL?

A

smoking
low HDL
hypertension
diabetes

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19
Q

what are the effects of HDL on disease?

A

protective effect for atherosclerosis & CHD events

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20
Q

what levels are HDL when Triglycerides are high?

A

HDLs are low

high TG promotes LDL

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21
Q

what lowers HDL levels?

A

smoking
obesity
physical inactivity

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22
Q

which drug is no longer used? why?

A

bile acid sequestrants

poor compliance

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23
Q

what is the effect of nicotinic acid?

A

increases HDL well but has side effects

not used often

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24
Q

what is the first line of treatment for raised dyslipidaemia?

A

statins (HMG-CoA reductase inhibitor):

  • blocks cholesterol production
  • upregulates LDL receptors in liver
  • highly effective at lowering LDL
  • good compliance
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25
Q

what are statins?

A

HMG-CoA reductase inhibitors
e.g. atorvastatin, simvastatin, pravastatin

metabolism by CYP3A4 (pravastatin is not metabolised)

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26
Q

what is the role of HMG-CoA reductase?

A

conversion of HMG-CoA to mevalonic acid, therefore halts the cholesterol pathway

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27
Q

what is the significance of inhibiting the HMG-CoA reductase enzyme?

A

the rate-limiting step is being targeted

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28
Q

what is the effect of statins in halting the cholesterol synthesis pathway?

A
  • Reduces the modification of proteins involved in modifying gene translation to create LDL
  • has the effect of UP-REGULATING the LDL receptors expressed on hepatocytes in the liver
  • so more LDL being removed from the blood as the liver is starved of cholesterol

blood HDL is also increased
Liver is depleted of cholesterol as synthesis has stopped, so LDL receptors increase to replenish cholesterol

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29
Q

how does selectivity ratio affect binding of statins?

A

the higher the selectivity ratio, the greater the chance of it being concentrated in the hepatocyte.

oSimvastatin gets into many cells as it’s very lipid soluble. Pravastatin is mainly hepatocytes.

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30
Q

how does potency number affect the usefulness of the statin?

A

the lower the number, the more powerful the drug is as an inhibitor of the enzyme.

31
Q

what are the effects of rosuvastatin?

A

has the greatest effect in reducing LDL and raising HDL

however, just a modest effect in reducing TG.

32
Q

what is the “Rule of 6” in statin therapy?

A

doubling the dose ONLY makes a 6% extra reduction.

33
Q

when do CHD risk patients benefit from statin therapy? what was side effect of reducing LDL too much?

A

when there is a 30% risk reduction

but too little LDL resulted in problems in the CNS and memory

34
Q

what kind of effect does statin have, which is both good and bad at the same time?

A

pleiotropic effect

N.B has other effects outside effects on cholesterol e.g. anti-inflammatory action

35
Q

what are the drug therapies used in reducing cholesterol?

A
  • HMG-CoA reductase inhibition i.e. statins
  • fibrates e.g. gemofibrozil (PPAR-alpha receptor agonist–> reduce plasma TGs)
  • nicotinic acid
  • ezetimibe (cholesterol absorption inhibitor in small intestine)
  • CETP inhibitor e.g. torcetrapib (can have off target activation of aldosterone synthase causing increased BP)
36
Q

what are fibrates? e.g. gemfibrozil

A

PPAR-alpha receptor agonist.

PPAR= Peroxisome Proliferator Activated Receptors
- act on the liver to reduce plasma TG and fatty acid levels

37
Q

what do fibrates do?

A

Decrease FFAs and TGs.

Increases HDL very effectively

but LDL doesn’t change a lot

38
Q

what should fibrates not be confused with?

A

Thiazolidinediones – PPAR-GAMMA receptor agonists.

These act on adipose.

39
Q

what is ezetimibe?

A

Inhibits cholesterol absorption in the small intestine to reduce LDL levels

40
Q

how does ezetimibe become activated?

A

converted to glucuronide in the intestines

41
Q

how can the “rule of 6” be avoided in ezetimibe administration?

A

co-administer with statins to have a greater reduction in LDL

42
Q

what are CETP inhibitors?
give an example
why is it discontinued?

A

CETP= Cholesterol Ester Transfer Protein

e. g. Torcetrapib
- inhibits LDL increase due to reduced TG transfer towards LDL
- leads to unexpected deaths
- off target activation of aldosterone synthase increases BP

43
Q

what does CETP do?

A

converts HDL into LDL
- responsible for moving cholesterol esters and triglycerides between VLDL, LDL, and HDL

  • Lower CETP levels promote HDL formation, thereforte aim to inhibit e.g torcetrapib
44
Q

what is PCSK9?

A

inhibitor of the LDL receptor.

45
Q

how can PCSK9 be targeted to increase LDL absorption in the liver?

A

Monoclonal anti-PCSK9 antibodies have been made to inactivate PCSK9 and so more LDL can be absorbed by the liver

46
Q

in which patients are PCSK9 antibodies particularly useful?

A

Familial Hypercholesterolemia

47
Q

what transfers TGs from VLDL to LDL?

where does it take TGs from?

A

Cholesterol Ester Transport Protein

VLDLs
Chylomicrons
HDL

48
Q

how is cholesterol created endogenously?

A

by the liver using acetyl CoA

can use TGs and cholesterol from diet

49
Q

what does cholesterol in the liver release during fasting?

A

VLDL

made of TGs and cholesterol

50
Q

what happens to VLDL when released?

A

becomes IDL then LDL via lipoprotein lipases

51
Q

how does VLDL become LDL?

A

via lipoprotein lipase

this releases TGs from the VLDL to concentrate the cholesterol into a small dense LDL particle via the IDL form

before this TGs must be transferred to LDL via CETP

52
Q

how are chylomicron remnants taken up by the liver in the exogenous pathway?

A

via remnant receptors on the liver

53
Q

what is the role of HDL?

A

removes cholesterol from tissues

54
Q

where can LDL produced from VLDL go next [2]?

A
  • either into the liver again via LDL receptor

- into peripheral tissues to provide cholesterol

55
Q

how does HDL dump cholesterol into the liver?

A

via scavenger receptors

56
Q

why does HDL dump cholesterol from other cells into the liver?

A

for later use or excretion

57
Q

which subendothelial layer of arteries do LDLs enter?

A

tunica intima

58
Q

what are LDLs oxidised by?

A

free radicals

59
Q

how does the macrophage endocytose the oxidised LDL?

A

via scavenger receptor

N.B that scavenger receptors are also on the liver for HDL to dump its cholesterol

60
Q

what do macrophages become when they endocytose the oxidised LDL?

A

foam cells

61
Q

what do foam cells stimulate?

A

chronic inflammation: vicious cycle of

  • lipoprotein oxidation
  • monocyte/macrophage recruitment
  • phagocytosis/endocytosis
62
Q

what do the present macrophages stimulate?

A

proliferation of smooth muscles and increased collagen synthesis

wound healing

63
Q

what cells leads to the formation of the fibrous cap around the foam cells?

A

macrophages

64
Q

how is the fibrous cap formed?

A

macrophages stimulateproliferation of smooth muscles and increased collagen synthesis

65
Q

what is the fatty streak?

A

fibrous cap around foam cell mass

66
Q

what how can a fatty streak lead to thrombosis?

A

rupture though the cap and endothelium

67
Q

which lipoproteins are atherogenic?

what kind of fat contribute these lipoproteins?

A

LDLs, IDL
small dense LDLs

saturated fat

VLDLs are the least atherogenic (low cholesterol concentration)

68
Q

what effect will the inhibition of HMG-CoA reductase have?

what effect does it have on the liver itself?

A
  • blockage of cholesterol production in liver

- up regulation of LDL receptors on liver to increase LDL uptake

69
Q

what metabolises statins?

A

CYP3A4

70
Q

which statin is not metabolised?

A

pravastatin

71
Q

what is the effect of doubling the statin dosage?

A

6% reduction in LDLs

72
Q

what is PPAR-alpha?

A
  • transcription factor active during starvation
  • allows concentration of fatty acids which are ligands to PPAR
  • expression of genes involved in fatty acid uptake and metabolism
  • fibrates are ligands of PPAR, mimicking fatty acids
73
Q

what is torcetrapib?mechanism of action

A

CETP inhibitor

reduced the formation of LDLs as the transfer for TGs is reduced

74
Q

why is torcetrapib discontinued?

A

off target activation of things like aldosterone synthase

leads to increased BP

LCRS Pharma (32 decks)

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