Session 5: Hyperlipidaemias Flashcards
Broad functions of cholesterol.
Membrane integrity (both fluidity and rigidity)
Precursor of steroid hormones
Bile acids
Also important for vitamin D production in dermis.
What is LDL?
Lipoprotein carrying cholesterol.
It is susceptible to oxidation at damaged endothelium by necrotic tissue and ROS leading to atherosclerosis.
This is because LDL has a higher half-life.
Function of HDL.
Carries cholesterol away from circulation to the liver for recycling.
Healthy level of:
Total cholesterol
LDL
Non-HDL
HDL
TAGs
<5 mmol/l
<3 mmol/l
<4 mmol/l
>1 mmol/l
<2.3 mmol/l
Briefly explain the formation of atheroma by LDL.
Accumulation of LDL will be oxidised by local endothelial cells.
Recruited monocytes will phagocytose the oxidised LDL via scavenger receptors.
Foam cells form and build up in the intima.
Proliferation of smooth muscle cells and a fatty streak develops.
When do fatty streaks start to form?
Early on in life.
1/3 in 20-29 year olds have fatty streaks and just increase in prevalence with age meaning it can start early.
Explain the action of statins.
Competitive inhibition of HMG-CoA reductase.
This leads to lower levels of cholesterol as that is the rate-controlling enzyme in the mevalonate pathway.
The low levels of intracellular cholesterol leads to stimulation of hepatic LDL receptors.
This promotes uptake of LDL from blood.
Low intracellular cholesterol also decreases the secretion of VLDL.
Examples of statins.
Atorvastatin
Simvastatin
Fluvastatin
Pravastatin
Rosuvastatin
Lovastatin
Give additional benefits of statin therapy.
Improved vascular endothelial function (More NO and less endothelin)
Stabilisation of atherosclerotic plaque
Improved haemostasis (less plasmafibrinogen and more fibrinolysis)
Anti-inflammatory - less proliferation of inflammatory cells into the plaque
Anti-oxidant
Explain activation of simvastatin.
A prodrug that is activated by first pass metabolism.
Explain the activation of atorvastatin.
Active as it is, but also metabolised and have active derivatives. The active derivates is what accounts for most of the action.
Half-life of simvastatin.
2 hrs
Half-life of atorvastatin.
>30 hrs
Side-effects of statins.
GI disruptions, nausea, and headache
Myalgia with diffuse muscle pain where creatine phosphokinase/creatine kinase levels are 10 times above normal limit.
Rhabdomyolysis can occur on very rare occassions.
When should you not take statins?
When renally impaired
When pregnant
When breastfeeding
When taking amiodarone, diltiazem, macrolides and amlodipine.
Also don’t give statins short term
Why would you not give statins when pregnant?
Because cholesterol is needed in the developing foetus.
Why should you not give statins with amiodarone, diltiazem, macrolides or amlodipine?
Because they are CYP3A4 inhibitors which would cause a build up of statins because CYP3A4 is supposed to degrade it.
This leads to an increased risk of side effects.
What drives the choice of statin given?
Cost and severity of side effects.
This explains why rosuvastatin isn’t prescribed as much anymore since it has side-effects.
Which statin is primary prevention in hyperlipidaemia?
20 mg atorvastatin once daily.
When do you start to give statin?
When QRISK >10%
Secondary prevention of hyperlipidaemia.
80 mg atorvastatin once daily.
When can you not give secondary prevention (80 mg atorvastatin)?
When ADRs show
When they have chronic kidney disease
What is needed to be done before prescribing a statin?
A full lipid profile including HDL, non-HDL + TGs.
What is the goal of a statin?
A reduction of over 40% in non HDL-C at three months time.
What non-medical is not to be taken when on a statin?
Grapefruit juice (CYP3A4 inhibitor) or whole grapefruits.
At what time a day is the statin to be taken?
At night due to the circadian rhythm of the LDL receptor synthesis and activity
Explain the mechanism of fibric acid derivatives aka Fibrates.
Activation of nuclear transcription factor PPARalpha.
This receptor regulates the expression of genes that control lipoprotein metabolism.
This means that activation of PPARalpha will cause increased production of lipoprotein lipase.
Give an example of a fibrate.
Fenofibrate
Beneficial effects of fibrates.
Increase in triglycerides from lipoprotein in plasma
Increased uptake of fatty acid uptake by the liver
Increased levels of HDL
Increased LDL affinity for receptor.
When are fibrates given?
They are rarely given alone and commonly co-prescribed with a statin in the case of statin not being effective enough.
Side-effects of fibrates.
Cholelithiasis
Myositis
When should you not take fibrates?
When on warfarin.
Why should you not take fibrates when on warfarin?
Because it will potentiate the effect of warfarin by competing for the binding.
This leads to a greater effect of the warfarin and bleeding.
Explain the mechanism of cholesterol absorption inhibitors.
Inhibit NPC1L1 transporter. This leads to a reduction in the absorption of cholesterol by the gut (around 50%).
Also hepatic LDL receptor expression increases.
All of this leads to a reduction in total cholesterol by around 15% and reduction of LDL by around 20%.
Give an example of a cholesterol absorption inhibitor.
Ezetimibe
Explain the pharmacokinetics of ezetimibe.
A pro-drug that is activated by hepatic metabolism. It is activated in Phase II where the active metabolite is a conjugate with glucuronide.
It is involved in the enterohepatic circulation which limits systemic exposure.
Secreted by bile and then into faeces mainly. Some renal excretion.
When is ezetimibe given?
Adjunct to statin
In familial hypercholesterolaemia.
ADRs of ezetimibe.
Abdo pain
GI upset e.g. diarrhoea
When not to take ezetimibe.
Hepatic failure
Ezetimibe has a no dose escalation, what does this mean?
That you only give one dose. Giving a larger dose will not have any bigger effect.
When is ezetimibe co-prescribed with a statin?
Beneficial in CKD to give a desired effect (since ezetimibe is mainly excreted via faeces).
Secondary CVD prevention
Those that can only tolerate a low dose statin.
When are fibrates or nicotinic acid co-prescribed with a statin?
Specialist advice in familial hypercholesterolaemia
Not given as primary or secondary prevention.
What does synergistic mean?
That two drugs will together have greater effect than the sum of them.
What is the target for LDL levels and total cholesterol levels in secondary prevention?
- 0 mmol/l LDL
- 0 mmol/l total
Explain the mechanism of PCSK9 inhibitors.
When LDL attaches to the LDL receptor the receptor will be internalised by receptor-mediated endocytosis.
The LDL is then catabolised and the receptor is degraded or recycled.
PCSK9 is a protein that binds internalised LDL receptor and directs the receptor for degradation.
PCSK9 inhibitors will inhibit the degradation of the receptor.
This means more LDL is taken up by the hepatocyte.
Give examples of PCSK9 inhibitors.
Alirocumab
Evolocumab
Explain why or why not PCSK9 inhibitors could become a replacement for statins.
It is very effective in lowering cholesterol however long term effects on cholesterol lowering and CVD risk remain to be determined.
It also requires lifetime injections
The current cost is also that of 100x statins
When are PCSK9 inhibitors given?
Currently recommended for primary and secondary prevention of resistant familial hypercholesterolaemia.
Also in some high risk secondary prevention patients.
Give other non-medical options of lowering cholesterol.
Plant sterols that will provide LDL cholesterol lowering effects.
Fish oils/oily fish
Fibres
Whole grains
Vitamin C/E
Where will you find plant sterols?
Grains
Legumes
Mechanism of plant sterols.
Structurally similar to cholesterol meaning it will compete for absorption.
What does plant sterols work with?
Statins but not with ezetimibe
Why is the cost of statins so low?
They are off patent meaning anyone can make a statin.
How do you assess CVD risk?
Manchester tables
Or more commonly now:
QRISK
When do you start giving statins?
When QRISK gives a chance of CVD at >10%
Which statin is offered as a first line option to patients and why?
Atorvastatin at 20mg daily dose.
This is to reduce cholesterol (especially LDL) and to minimise the risk of CVD.
