Atherosclerosis and lipid lowering drugs

Question 1

what do the apoproteins define?

Answer 1

the type of lipoprotein
A-1: HDL
B: LDL

Question 2

describe the exogenous pathway of lipid metabolism

Answer 2

• when we eat food, it is broken down into chylomicrons (large)
• which are broken down into FFAs and chylomicron remnants
• remnants deposit in vessels
• atheroma

Question 3

describe the endogenous pathway

Answer 3

• most LDL/HDL comes from this
• lipoprotein lipase and hepatic lipase metabolise most
• HDLs and LDLs are deposited in vessels to form atheromas

Question 4

what is reverse cholesterol transport?

Answer 4

removal of cholesterol from vessel walls back to liver by HDL

Question 5

define atherosclerosis

Answer 5

inflammatory fibro-proliferative disorder

Question 6

describe the steps to atherosclerosis

Answer 6

1. LDL enters endothelium into tunica intima
2. LDLs are oxisided by macrophages and VSMCs
3. release of GF and cytokines
4. additional monocytes/macrophages recruited
5. Foam cell accumulation
6. VSMC migration
7. VSMC proliferation
8. plaque growth

Question 7

what is in the tunica media?

Answer 7

VSMCs

Question 8

describe the endothelial dysfunction in atherosclerosis

Answer 8

• inc. endothelial permeability
• upregulation of adhesion molecules
• leucocyte adhesion
• migration of leucocytes into artery wall

Question 9

describe the fatty streak formation

Answer 9

• migration of VSMCs
• activation of T cells
• adherence and activation of platelets
• formation of foam cells

Question 10

describe complicated plaque formation

Answer 10

• formation of fibrous cap
• accumulation of macrophages
• formation of necrotic core

Question 11

describe what is seen in the different lesions in atherosclerosis

Answer 11

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 and haematoma

Question 12

what are the remnant lipids?

Answer 12

chylomicron remnants that are very good at infiltrating endothelial wall
remnants include:
- VLDL
- CM remnants
- IDL

Question 13

what is the inflammatory part of atherosclerosis caused by?

Answer 13

lipid remnants

Question 14

describe a stable plauque

Answer 14

• thick fibrous cap
• thinner lumen
• less likely to rupture

Question 15

describe an unstable plaque

Answer 15

• thin fibrous cap
• rich core of lipids and macrophages
• less evidence of VSMC proliferation

Question 16

what are LDLs associated with? what are these events modified by?

Answer 16

associated w/ atherosclerosis and CHD events
10% inc. in LDL –> 20% inc. in CHD events
events modified by: smoking, low HDL, hypertension, diabetes

Question 17

what is HDL? what is HDL lowered by?

Answer 17

• protective effect for atherosclerosis and CHD events
• HDL tends to be low when TG are high
• HDL lowered by smoking, obesity, physical inactivity

Question 18

what are the 3 different drug therapies used in the past?

Answer 18

• bile acid sequestrants - poor compliance
• nicotinic acid (inc. HDL well but SEs)
• statins (1st line treatment for dyslipidaemia, highly effective at lowering LDL)

Question 19

what is the MoA of statins?

Answer 19

HMG-CoA reductase inhibitors

• halts cholesterol synthesis pathway at RLS
• reduces modification of proteins involved in modifying gene translation to create LDL

Question 20

what effect do statins have on the LDL receptors?

Answer 20

• up regulate the LDL receptors expressed on hepatocytes in liver
• results in more LDL being removed from blood
• results in more HDL levels

Question 21

what is the selectivity ratio?

Answer 21

• higher selectivity ratio, greater the chance of it being concentrated in hepatocyte
  e.g. Simvastatin = 0.54, Pravastatin = 3.3
  simvastatin gets into many cells as is very lipid soluble, pravastatin mainly hepatocytes

Question 22

what is potency?

Answer 22

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

Question 23

which statin has the greatest effect in reducing LDL and raising HDL?

Answer 23

Rosuvastatin

but just has a modest effect in reducing TG

Question 24

what is the rule of 6?

Answer 24

doubling the dose ONLY makes a 6% extra reduction

Question 25

what happens when LDLs are lowered too much?

Answer 25

problems in CNS and memory

Question 26

what is the MoA of fibrates?

Answer 26

PPAR-alpha receptor agonist
PPAR (peroxisome proliferator activated receptors)
act on liver
dec. FFAs and TGs
inc. HDL very well but LDL doesn’t change a lot

Question 27

what does Ezetimibe do?

Answer 27

• inhibits cholesterol absorption

- ezetimibe –> glucuronide in intestines = ACTIVATED

Question 28

what can Ezetimibe be coadministered with?

Answer 28

statins to avoid rule of 6

statins have more dramatic effect at lowering LDL

Question 29

what do cholesterol ester transfer protein (CETP) inhibitors do?

Answer 29

• CETP converts HDL into LDL
• inhibiting it causes inc. HDL
• but their use lead to a lot of unexpected deaths so use discontinued

Question 30

What is PCSK9?

Answer 30

• inhibitor of LDL receptor
• monoclonal anti-PCSK9 antibodies inactivate PCSK9 so more LDL can be absorbed by lower
• people with familial hypercholesterolemia benefit well