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Medsci305 > Lecture 3: lipoprotein metabolism > Flashcards

Lecture 3: lipoprotein metabolism Flashcards

1
Q

Why does cholesterol have to be esterfied?

A

Cholesterol is only minimally soluble in water. In order to be transported in the blood plasma via carriers, a portion must be esterified

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2
Q

What is cholesterol used for?

A

the cell wall
synthesis of bile acids (for digesting fat)
hormones
metabolism of fat soluble vitamins

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3
Q

Where is the majority of our cholesterol obtained?

A

Not from the diet, but synthesised from Acetyl CoA through the HMG CoA reductase pathway

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4
Q

What is atheromatus disease?

A

This underlies the commonest causes of death which are myocardial infarction and disability (stroke) in industrial societies.

It is a focal disease of the large and medium sized arteries and progresses over many decades.

Results in plague build up in the lining of the arteries causing near blockage as the plaque enlarges

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5
Q

What is a healthy artery made up of?

A 
tunica intima (inner endothelial layer)
tunica media (smooth muscle and elastic fiber)
tunica externa or tunica adventitial (connective tissue and fibroblasts)
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6
Q

what makes up a diseased artery?

A

an accumulation of white blood cells and cholesterol within the intima and media layers (atheroma or plague)

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7
Q

what are the risk factors of atheromatus disease?

A 
raised LDL
reduced HDL
hypertension
diseases e.g. diabetes
cigarette smoking
obesity
physical inactivity
genetics
age
raised coagulation factors
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8
Q

What are the key events and consequences of atherogenesis?

A
  1. compromised endothelial layer
  2. attraction and filtration of monocytes and LDL
  3. LDL oxidised
  4. ox-LDL ingested by monocytes to form macrophage foam cells
  5. Foam cells release more free radicals and growth factors
  6. LDL receptors damaged and accumulation of lipids
  7. Migration of smooth muscle cells
  8. Formation of extracellular matrix (elastic and collagen)
  9. occlusion of artery or rupture of plague
  10. oxygen deficiency or thrombis leading to stroke/MI
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9
Q

What are lipoprotiens?

A

These are the form of lipids like cholesterol and triglyceride when they are transported in the plasma

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10
Q

What are the 4 classes of lipoproteins?

A

chylomicrons
very low density lipoproteins
low density lipoproteins
high density lipoproteins

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11
Q

What are chylomicrons?

A

e.g. ApoB48,E and C2.

These carry cholesterol to the liver

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12
Q

What are VLDLs?

A

very low density lipoproteins
e.g. ApoB100, E and C2
These carry C from the liver

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13
Q

What are LDLs?

A

low density lipoproteins
e.g. ApoB100
These carry cholesterol to the tissue and back to the liver

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14
Q

What are HDLs?

A

high density lipoproteins
e.g. ApoA1
These carry cholesterol from the blood and tissue to the liver

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15
Q

What does an LDL molecule consist of?

A

Cholesterol ester in the core, surrounded by phospholipids and unesterified cholesterol.
ApolipoproteinB100 (LDL or VLDL) surrounds the outside for easy transport through the plasma

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16
Q

What is the exogenous pathway of cholesterol?

A

Cholesterol and triglyceride are absorbed from the GIT, transported in the lymph and plasma as chylomicrons to the capillaries in muscle and adipose tissue.

TG is hydrolysed by lipoprotein lipase, and the free fatty acids are taken up by tissues.

The chylomicron remnant containing the CE pass to the liver, bind to receptors on hepatocytes and undergo endocytosis.

CE is liberated in liver cells

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17
Q

What is the endogenous pathway of cholesterol?

A

CE and TG are transported from the liver as VLDL to the muscle and adipose tissues

TG is hydrolysed by LPL.

the VLDL particles become VLDL remnants, then becoming LDL.

Cells take up LDL by endocytosis via LDL receptors

Cholesterol can also return to the plasma from the tisses in HDL

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18
Q

What is dyslipidemia?

A

An abnormal ratio of lipoprotein particles.

These can be primary or secondary to some generalised diseases

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19
Q

How is dyslipidemia classified?

A

according to which lipoprotein is raised

The higher the plasma concentration of LDL, the lower the concentration of HDL cholesterol and therefore the higher the risk of ischaemic heart disease

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20
Q

What are the ideal cholesterol levels as quoted by the NZ heart foundation?

A 
Total cholesterol < 4mmol/L
LDL cholesterl < 2.0mmol/L
HDL cholesterol > 1mmol/L
TC/HDL ratio < 4.0
triglycerides < 1.7mmol/L
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21
Q

What are the main drug classes to prevent atheromatous disease?

A

statis
fibrates
bile acid binding resins

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22
Q

Who are statins recommended for?

A

Patients with high LDL and multiple risk factors (5-40mg/day)

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23
Q

What type of drugs are statins?

A

specific, competitive reversible HMG CoA reductase inhibitors

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24
Q

What are examples of statins?

A 
Lovostatin (naturally occuring)
Simvastatin (lipex, double the potency of lovostatin)
pravastatin
rosuvastatin
atorvastatin
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25
Q

What are statins thought to also decrease?

A

macrophage activation and plague rupture
hepatic cholesterol synthesis
plasma triglyceride levels

26
Q

What do statins increase?

A

synthesis of LDL receptors –> increased clearance of LDL

HDL cholesterol

27
Q

Which statins are prodrugs?

A

lovastatin and simvastatin. These are given in the lactone form and are activated in the GIT

28
Q

Why are liver function tests given to patients before initiation of therapy?

A

There is high FPM of statins in the liver by the enzymes 3A4 and 2C9

29
Q

Why is short acting simvastatin given at night?

A

to reduce cholesterol synthesis which peaks when fasting

30
Q

what are the side effects of statins?

A 
impaired cognition
abdominal pain, nausea, headaches
myalgia
myopathy and rhabdomylosis
increased serum Aminotransferase
contraindicated in pregnancy due to potential teratogenecity
31
Q

What is the key pharmacological outcome of giving statins?

A

decreased cholesterol synthesis

32
Q

What are fibrates?

A

fibric acid derivatives which stimulate the b-oxidative degradation of fatty acids.
These are peroxisome proliferator activated receptor a agonists

33
Q

What is the mechanism of action of fibrates?

A

stimulates transcription of genes for LPL activity. This increases the hydrolysis of TG in chylomicrons and VLDL to liberate free fatty acids.

This results in a shift in the density of LDL particles to larger buoyant partiles resutling in less oxidation and more affinity to the LDL receptor for clearance.

34
Q

What are examples of fibrates?

A

bezafibrate
ciprofibrate (also some effect on HMGCoA reductase. Has produced significant reductions in plasma fibrinogen. Increases fibrinolytic activity)

35
Q

What are the effects of fibrates?

A

reduced hepatic VLDL secretion
increased hepatic LDL uptake via LDL receptors
Marked reduction in circulating VLDL and TG with a modest reduction in LDL and an increase in HDL

Improve glucose tolerance and inhibit VSM inflammation

36
Q

What are the side effects of fibrates?

A

nausea and headaches (2-5%)
assoc. with increases in plasma creatinine and urea (kidney damage?)
Possible liver damage
gallstones due to high cholesterol saturation in bile (but not with ciprofibrate)

37
Q

What are bile acid binding resins?

A

These are anion exchange resins. They are taken orally, but not absorbed.

38
Q

Who should take bile acid binding resins?

A

patients with moderate LDL elevation

39
Q

What are examples of bile acid binding resins?

A

cholestyramine, colestipol

40
Q

What is the mechanism of action of bile acid binding resins?

A

binds to bile acids in the intestine

forms complex which is excreted in the faeces

41
Q

What is the result of bile acid binding resins?

A

reduces the absorption of exogenous cholesterol
increases metabolism of endogenous cholesterol into bile acids

Increased expression of LDL receptors on hepatic cells
increased removal of LDL and reduced concentration of LDL cholesterol in plasma

42
Q

What would cause cholesterol 7-alpha-hydroxylase to synthesise more bile acids?

A

interruption of the enterohepatic bile acid recirculation. This results in a reduction of intrahepatic cholesterol stores

43
Q

Why are bile acid binding resins not recommended when elevated triglycerides are the primary dyslipidaemia?

A

bile acid binding resins may slightly increase triglyceride levels.

44
Q

What are the side effects of bile acid binding resins?

A

constipation
bad taste - low compliance
may delay/reduce absorption of other concomitant oral medications
may interfere with normal fat digestion and absorption of fat soluble vitamins A, D, E and K

45
Q

What is the major limitation to long term cholestyramine therapy?

A

patient acceptability and tolerance to GI adverse effects

46
Q

What are the 3 main types of newer therapies?

A

Ezetimibe- cholesterol absorption inhibitor
Nicotinic acid- Niacin, a form of vitamin B3
Cholesterylester transfer protein (CETP) inhibitors

47
Q

What is Ezetimibe?

A

These are cholesterol specific transport protein blockers. so do not affect absorption of fat soluble vitamins, TG, or bile acids

These inhibit Niemann-Pick C1-like 1 transport proteins in the brush border of enterocytes

48
Q

What are the effects of ezetimibe?

A

decreases intestinal cholesterol absorption by up to 54%

49
Q

Why are binding resins and statins used in conjunction with ezetimibe?

A

ezetimibe has a different mechanism of action to the other drug groups so can be used concomitantly to achieve a better outcome

e.g. Vytorin 10/20mg which is a combination of ezetimibe/statin recently approved

50
Q

What are the side effects of ezetimibe?

A

it is generally well tolerated but there may be some GI disturbances, headache and rash

51
Q

What are the pharmacokinetic parameters of ezetimibe?

A

oral
rapidly absorbed, conjugated,

Cmax of conjugate occurs in 1-2 hours

52
Q

What is nicotinic acid used for?

A

adjunct therapy for high chylomicrons, LDLs and VLDLs (if statins cant be used)

53
Q

What is the mechanism of action of nicotinic acid?

A

inhibits ApoB-100 containing lipoproteins, promoting lipoprotein lipase activity.

54
Q

What is the effect of nicotinic acid?

A

Changes the way body breaks down fat by binding to adipose nicotinic acid receptors.
This downregulates free fatty acid mobilisation thus decreasing TG levels

Increases fecal output of sterols
Also effective at raising HDL and promotes hepatic apoA-I production

55
Q

What are the side effects of nicotinic acid?

A

vasodilation effect causing skin flushing via prostaglandin D2

56
Q

What are the doses of nicotinic acid given?

A

Prescriptions for oral >500mg required

dietary forms are < 250mg

57
Q

What are cholesterylester transfer protein inhibitors?

A

These inhibit the Cholester transfer proteins

Increases HDL and lower LDL

58
Q

what are the examples of CETP inhibitors?

A

Torcetrapib
Dalcetrapib
Anacetrapib
evacetrapib

59
Q

What was a limitation of torcetrapib

A

this was the first CETP inhibitor. Its limitations included raised BP and serum aldosterol levels. There was also an increase in CV events and mortality

60
Q

Why was dalcetrapib terminated?

A

this was the second CETP inhibitor drug.
Its termination was due to its ineffectiveness and side effects. It failed to decrease LDL, but increased BP and inflammation

61
Q

How are anacetrapib and evacetrapib progressing?

A

these are currently undergoing evaluation in pahse III clinical trials.

So far, both have shown beneficial effects by increasing HDL cholesterol and decreasing LDL cholesterol concentrations.

Their successes remain to be confirmed.

Medsci305 (17 decks)

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