Lipid lowering drugs Flashcards
How many sources do lipids come from and which is predominant source of circulating lipids?
- External fatty sources (food)
2. Synthesised in liver - predominant
Targets of lipid lowering drugs
- aiming at preventing absorption of lipids
- increasing uptake of lipids (particularly LDL)
LDL cholesterol 10% link correlates to increased risk of…
CHD by 20%
STRONG ASSOCIATION
What is LDL modified by?
- low HDL
- Smoking
- HTN
- Diabetes
HDL effect of atherosclerosis and CHD
protective effect
Are all forms of HDL protective?
several types, most of which are protective but some of which may not be
HDL association to antherosclerosis and CHD
strong inverse association
lower the HDL cholesterol level, the higher the risk
Impact of high triglycerides on HDL
HDL low
What lowers HDL?
Smoking, obesity and physical inactivity (Atherogenic lifestyle)
Regulation of HDL with drugs?
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
Hypertriglyceridemia association with CHD risk
Increased risk
Not as strong as LDL and weaker when other factors taken into account
Seven countries study
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
10% reduction in total cholesterol results in:
• 15% reduction in CHD mortality
• 11% reduction in total mortality
So it is a modifiable risk factor
Primary target to prevent CHD
LDL
Best efficacy in severe cases of hypercholesterolemia
A combination of two agents
Action of bile acid sequestrants
Stop bile acids being reabsorbed
Bile cannot go on to help maintain LDL
Bile acid is excreted rather than reabsorbed
Problems with bile acid sequestrants
- poor tolerability shown (adverse effects of GI bloating, nausea and constipation)
- using the drugs themselves stimulated more cholesterol synthesis from the liver
Action of ezetemibe
Prevents reabsorption of cholesterol
Most important product of cholesterol synthesis pathway
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
Rate limiting enzyme of cholesterol synthesis pathway
HMG-CoA reductase
- If blocked - reduces circulating levels of cholesterol particularly LDL
What are drugs mipomersen and lomitapide used for
Exclusively in patients with familial hypercholestremia.
Too expensive for wider use
Problem with too low LDL
CNS toxicity
Mechanism by which statins reduce LDL
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
Differences between statins
- Potency - Rosuvastatin (old): low potency. Pravastatin 10 X as potent.
- Cell selectivity
- Variation in half life. - - Max effect on LDL at reasonable non-toxic doses ranges from 30-60%
Are statins interchangeable and why?
Key difference between them: Potency, cell selectivity and variation in half life
Hydrophilicity of statins
The more hydrophilic statins: specific transporters in liver cells (not found elsewhere) Allow entry
Conversely, very lipid soluble drug (simvastatin) can get in everywhere
Cerivastatin story
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
Effect of statins on lipids
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
4S trial
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
effects of statins on stroke:
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
Name of effect of statins not including cholesterol lowering
Pleiotropic effects of statins
Pleiotropic effects of statins and difficulty with concept
Several of these cannot be fully separated from the action of cholesterol.
- Platelet activation
- Plaque stability
Other indisputed effect of statin other than cholesterol lowering
anti-inflammatory, in both the vasculature and in other situations (RA, IBD etc)
Controversy over statins?
Who should have them? Don’t know if they should be given prophylactically yet. Secondary prevention indisputable yes.
ASCOT LLA
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
Side effects of statins
Muscular side effects
Increasing new doubt about diabetes
Fatigue
Sexual dysfunction
Avoiding muscle side effects of statins
Avoid alcohol
Drug interactions
Vit D supplementation
Combination high LDL and low HDL risk
Are HUGELY at increased risk (15-20 fold) compared to those with normal levels
Linear relationship
The lower the HDL the higher the risk
Most negative effect LDL
Increased negative effect of the very small dense LDL - highly atherogenic and easily oxidised
Mechanism of action of fibrates
activation of PPAR alpha
receptors
Problem with study of fibrates
Majority of the trials have been poorly designed, unable to answer questions with any real accuracy
Effect of fibrate and only good trial
HIT: favourable effect of fibrate on CVD evens in CHD patients with isolated low HDL
Action of ezetimibe
Inhibits cholesterol absorption.
Absorbed then activated as glucuronide
Effect of ezetimibe
Shown to work in reducing cholesterol levels Reduces LDL also by 15-20%
Not quite as good as statins but still good
When is ezetimibe useful
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
Nictonic acid effect
Reduces LDL a lot
Increases HDL more than other drug therapies
anti-inflammatory
Problem with nicitonic effect
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)
2 main actions of HDL
- Anti-oxidant - prevents oxidation of LDL (more atherogenic)
- Reverse cholesterol transport - removing cholesterol from foam cells, including VSM foam cells, and back to liver
Problem with HDL system
HDL is converted into LDL via CETP protein
What does blocking CETP protein do
Reduces conversion of HDL to LD but
- INCREASES MORTALITY
→ Off target adverse effect of the drug
Other “rapibs” do not have same effect
PCSK9-inhibitor mechanism of action
PCSK9 is an inactivator of an inhibitor of an LDL receptor
Inhibition of PCSK9 should enhance the effect of stains
Effect of statins on PCSK9
PCSK9 is increased in reposes to statins
At the same time that LDL receptors are upregulated
Opposing effets unfortunately
Current opinion on PCSK9-inhibitor
→ 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
