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BSc module 3 > Lipid lowering drugs > Flashcards

Lipid lowering drugs Flashcards

1
Q

How many sources do lipids come from and which is predominant source of circulating lipids?

A
  1. External fatty sources (food)

2. Synthesised in liver - predominant

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2
Q

Targets of lipid lowering drugs

A
  • aiming at preventing absorption of lipids

- increasing uptake of lipids (particularly LDL)

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3
Q

LDL cholesterol 10% link correlates to increased risk of…

A

CHD by 20%

STRONG ASSOCIATION

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4
Q

What is LDL modified by?

A
  • low HDL
  • Smoking
  • HTN
  • Diabetes
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5
Q

HDL effect of atherosclerosis and CHD

A

protective effect

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6
Q

Are all forms of HDL protective?

A

several types, most of which are protective but some of which may not be

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7
Q

HDL association to antherosclerosis and CHD

A

strong inverse association

lower the HDL cholesterol level, the higher the risk

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8
Q

Impact of high triglycerides on HDL

A

HDL low

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9
Q

What lowers HDL?

A

Smoking, obesity and physical inactivity (Atherogenic lifestyle)

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10
Q

Regulation of HDL with drugs?

A

Not well regulated with drugs
Not easy to increase with drugs
The easiest ways to raise levels are by not smoking, by losing weight and by increased physical active

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11
Q

Hypertriglyceridemia association with CHD risk

A

Increased risk

Not as strong as LDL and weaker when other factors taken into account

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12
Q

Seven countries study

A

Northern Europe and US - steep relationship between level of total cholesterol and CV risk
In Southern Europe and Japan - the slope is barely noticeable
However, the large between-country difference in CHD mortality rates at a given cholesterol level indicates that other factors, such as diet, also play a role in the development of CHD

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13
Q

10% reduction in total cholesterol results in:

A

• 15% reduction in CHD mortality
• 11% reduction in total mortality
So it is a modifiable risk factor

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14
Q

Primary target to prevent CHD

A

LDL

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15
Q

Best efficacy in severe cases of hypercholesterolemia

A

A combination of two agents

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16
Q

Action of bile acid sequestrants

A

Stop bile acids being reabsorbed
Bile cannot go on to help maintain LDL
Bile acid is excreted rather than reabsorbed

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17
Q

Problems with bile acid sequestrants

A
  • poor tolerability shown (adverse effects of GI bloating, nausea and constipation)
  • using the drugs themselves stimulated more cholesterol synthesis from the liver
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18
Q

Action of ezetemibe

A

Prevents reabsorption of cholesterol

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19
Q

Most important product of cholesterol synthesis pathway

A

Small lipids involved in post translational modification of various growth factors, motility factors, etc. Without the modification, these proteins do not work
These can only be made by body whereas cholesterol can be got from outside world

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20
Q

Rate limiting enzyme of cholesterol synthesis pathway

A

HMG-CoA reductase

- If blocked - reduces circulating levels of cholesterol particularly LDL

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21
Q

What are drugs mipomersen and lomitapide used for

A

Exclusively in patients with familial hypercholestremia.

Too expensive for wider use

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22
Q

Problem with too low LDL

A

CNS toxicity

23
Q

Mechanism by which statins reduce LDL

A

Reduction in cholesterol synthesis in the hepatocyte Stimulated the cell to ↑expression of LDL receptors on its surface
These receptors then bind LDL, internalised it And it is then broken down
V SIMPLIFIED

24
Q

Differences between statins

A
  1. Potency - Rosuvastatin (old): low potency. Pravastatin 10 X as potent.
  2. Cell selectivity
  3. Variation in half life. - - Max effect on LDL at reasonable non-toxic doses ranges from 30-60%
25
Q

Are statins interchangeable and why?

A

Key difference between them: Potency, cell selectivity and variation in half life

26
Q

Hydrophilicity of statins

A

The more hydrophilic statins: specific transporters in liver cells (not found elsewhere) Allow entry

Conversely, very lipid soluble drug (simvastatin) can get in everywhere

27
Q

Cerivastatin story

A

Drug given to the wrong people at the wrong dose Extremely potent, given at high dose to elderly people Hundreds of cases of rhabdomyolysis -Released of myoglobin and K+ from damaged cells. Rhabdomyolysis can be seen with all statins but RARELY. Myoglobin obstructs renal tubules → reduced renal function
K+ normally cleared but the kidney isn’t functioning properly
Hence many deaths as a consequence of arrhythmias associated with rhabdomyolysis

28
Q

Effect of statins on lipids

A

20-50% reduction
Rule of 6: Double the dose but only 6% reduction in LDL
(Yet to be properly explained)
So you increase your rate of toxicity faster than you increase the rate of efficacy
→ Efficacy is less dose-responsive than the toxicity

29
Q

4S trial

A

Looked at high risk pts (with angina or previous MI, high level of LDL - double the average level)
Significant reduction in rate of CV events -
was a benefit in these people Up to 30% reduction in risk. Particularly heart attacks and CV deaths
→ Proof of the efficacy of statins
→ Minimal side effects: proved safety

30
Q

effects of statins on stroke:

A

Similar picture as CHD risk but not quite so convincing:

- Haemorrhagic strokes, loweing cholesterol doesn’t make a difference but in ischaemic stroeks it doe

31
Q

Name of effect of statins not including cholesterol lowering

A

Pleiotropic effects of statins

32
Q

Pleiotropic effects of statins and difficulty with concept

A

Several of these cannot be fully separated from the action of cholesterol.

  • Platelet activation
  • Plaque stability
33
Q

Other indisputed effect of statin other than cholesterol lowering

A

anti-inflammatory, in both the vasculature and in other situations (RA, IBD etc)

34
Q

Controversy over statins?

A

Who should have them? Don’t know if they should be given prophylactically yet. Secondary prevention indisputable yes.

35
Q

ASCOT LLA

A

Continued advantage in pt survival for pts taking stains. Interestingly most of which is not cardiovascular. Main change has been seen in respiratory disease - fewer respiratory infection. May be anti-inflammatory etc

36
Q

Side effects of statins

A

Muscular side effects
Increasing new doubt about diabetes
Fatigue
Sexual dysfunction

37
Q

Avoiding muscle side effects of statins

A

Avoid alcohol
Drug interactions
Vit D supplementation

38
Q

Combination high LDL and low HDL risk

A

Are HUGELY at increased risk (15-20 fold) compared to those with normal levels
Linear relationship
The lower the HDL the higher the risk

39
Q

Most negative effect LDL

A

Increased negative effect of the very small dense LDL - highly atherogenic and easily oxidised

40
Q

Mechanism of action of fibrates

A

activation of PPAR alpha

receptors

41
Q

Problem with study of fibrates

A

Majority of the trials have been poorly designed, unable to answer questions with any real accuracy

42
Q

Effect of fibrate and only good trial

A

HIT: favourable effect of fibrate on CVD evens in CHD patients with isolated low HDL

43
Q

Action of ezetimibe

A

Inhibits cholesterol absorption.

Absorbed then activated as glucuronide

44
Q

Effect of ezetimibe

A

Shown to work in reducing cholesterol levels Reduces LDL also by 15-20%
Not quite as good as statins but still good

45
Q

When is ezetimibe useful

A

Helps to overcome the Rule of 6
Addition of ezetimibe to simvastatin/atorvastatin to give greater efficacy without the effect of increased toxicity
BUT lack of hard evidence and IMPROVE-IT trial:
→ Benefit was rather small
2% reduction in risk over 7 years

46
Q

Nictonic acid effect

A

Reduces LDL a lot
Increases HDL more than other drug therapies
anti-inflammatory

47
Q

Problem with nicitonic effect

A

AIM-HIGH trial
Of extended release niacin stopped because of futility (it was not working)
Now very rarely used (occasionally in pts unresponsive to other options)

48
Q

2 main actions of HDL

A
  1. Anti-oxidant - prevents oxidation of LDL (more atherogenic)
  2. Reverse cholesterol transport - removing cholesterol from foam cells, including VSM foam cells, and back to liver
49
Q

Problem with HDL system

A

HDL is converted into LDL via CETP protein

50
Q

What does blocking CETP protein do

A

Reduces conversion of HDL to LD but
- INCREASES MORTALITY
→ Off target adverse effect of the drug
Other “rapibs” do not have same effect

51
Q

PCSK9-inhibitor mechanism of action

A

PCSK9 is an inactivator of an inhibitor of an LDL receptor

Inhibition of PCSK9 should enhance the effect of stains

52
Q

Effect of statins on PCSK9

A

PCSK9 is increased in reposes to statins
At the same time that LDL receptors are upregulated
Opposing effets unfortunately

53
Q

Current opinion on PCSK9-inhibitor

A

→ Currently approved in UK (£4000 a year) and USA ($14000 a year)
But this is a long term therapy and could be for many years Hence very expensive choice
Must decide who exactly should get this drug

BSc module 3 (10 decks)

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