4.2 Hyperlipidaemia Flashcards
how do we obtain cholesterol?
Most cholesterol synthesised in body with contribution (~25%) from diet
what is the function of cholesterol?
Essential for membrane integrity, precursor in production of steroid hormones, bile acids and vitamin D (vitamin C requires cholesterol in epidermis to form vitamin D from sunlight)
why is LDL known as bad cholesterol?
LDL have very long life span and are susceptible to oxidation at damaged endothelium, ROS contributes to endothelial dysfunction increasing adherence of lipid rich deposits and foam cells formed – precursor to
atheromatous plaques
why is HDL known as good cholesterol?
HDL carrier of cholesterol away from circulation to tissues that require it and the liver for disposal in bile
what is the units of cholesterol?
mmol/L
why is cholesterol a target in reducing CVD risk?
As it is a modifiable risk factor
data shows relationship between elevated cholesterol and morbidity and mortality from CHD
what are risk factors for suffering from a significant cardiovascular event?
left ventricular hypertrophy diabetes high cholesterol hypertension male
give some examples of statins
atorvastatin simvastatin fluvastatin pravastatin rosuvastatin lovastatin
what is the mechanism of action of statins?
Competitive inhibition of HMG-CoA reductase – rate controlling enzyme in HMG-
CoA to mevalonate pathway
Low intracellular cholesterol contributes to upregulation of hepatic LDL receptors, increasing the clearance of circulating LDL
low intracellular cholesterol also decreases the secretion of VLDL
what other benefits do statins have aswell as lowering cholesterol?
- Improved vascular endothelial function - ↑NO, vascular endothelial growth factor, ↓endothelin
- Stabilisation of atherosclerotic plaque - ↓smooth muscle cell proliferation ↑collagen
- Improved haemostasis - ↓plasma fibrinogen, platelet aggregation, ↑fibrinolysis
- Anti-inflammatory - ↓proliferation of inflammatory cells into plaque, plasma CRP, adhesion molecules and cytokines
- Antioxidant - ↓superoxide formation
what is the major difference in the pharmacokinetics of simvastatin and atorvastatin?
the half life of simvastatin is 2 hours, and the half life for atorvastatin is 24 hours
what are the adverse drug reactions of statins?
GI disruption, nausea and headache
myalgia – diffuse muscle pain (↑Creatine phosphokinase >5 X normal limit) - dose related)
Rarely – rhabdomyolysis
Increased liver enzymes
what are the contraindications of statins?
renal or hepatic impairment
pregnancy! and breastfeeding
what are the drug interactions of statins?
CYP 3A4 important – amiodarone, diltiazem, macrolides - increases [plasma] statin Remember amlodipine (CCB) also increases [plasma] statin
what is the first line statin?
atorvastatin
what are the common indications of atorvastatin?
used to reduce LDL cholesterol levels
• Primary prevention 20 mg atorvastatin once daily (10 year CVD risk of >10% using QRISK)
• Secondary prevention 80 mg atorvastatin once daily
why is grapefruit juice not advised for patients on statins?
as grapefruit juice inhibits CYP 3A4, a cytochrome responsible for the metabolism of statins
why is it advised that simvastatin is taken at night?
as has relatively short half life and LDL receptor synthesis has a circadian rhythm that primarily happens at night
what is a nocebo effect?
The idea that some patients perceive that they are going to have a side effect and so report that they do have it. this is detrimental as if patient believes that the drug is having side effects then the adherence of the treatment goes down.
give an example of a fibric acid derivate?
fenofibrate
what is the mechanism of action of fenofibrate?
Activation of nuclear transcription factor – PPARα
(peroxisome proliferation-activated receptor)
PPARα regulate expression of genes that control lipoprotein metabolism - increase production of lipoprotein lipase .This results in:
↑triglycerides from lipoprotein in plasma
↑fatty acid uptake by the liver ↑levels of HDL
↑LDL affinity for receptor •
what are the indications for fibric acid derivatives?
co-prescribed in familial hyperlipidaemia
what are the adverse drug reactions of fenofibrate?
cholelithiasis (gall stones), GI upset, myositis (muscle weakness)
what are the contraindications of fenofibrate?
photosensitivity, gall bladder disease
what are the drug interactions of fenofibrate?
warfarin - increases anticoagulation
what drug class is ezetimibe?
cholesterol absorption inhibitor
what is the mechanism of action of ezetimibe?
- Inhibit NPC1L1 transporter at brush border of the small intestine
- Reduces absorption of cholesterol by the gut ~50%
- Hepatic LDL receptor expression increases
- ↓total cholesterol ~ 15%, LDL ~ 20%
what are the pharmacokinetics of ezetimibe?
Pro-drug
hepatic metabolism -> enterohepatic circulation -> limits systemic exposure as stays in GI
secreted by bile
what are the indications for ezetimibe?
Adjunct to statin (or if not tolerated?) for homozygous familial hypercholesterolemia
what are the adverse effects of ezetimibe?
abdominal pain
GI upset
what are the contraindications of ezetimibe
hepatic failure
what is the target cholsterol for secondary prevention?
2.0 mmol/L LDL cholesterol is a target → ~ 4.0 mmol/L total
why is ezetimibe used in multiple target therapy?
Combination of ezetimibe with statin benefit in CKD and in some for secondary CVD prevention. evidence shows decrease in major CV event
what drug class is alirocumab?
PCSK9 inhibitor (monoclonal antibody)
what is the mechanism of action of alirocumab?
inhibits PCSK9 protein.
When LDL attaches to LDL receptor, receptor is internalised. LDL catabolised and receptor degraded or recycled in cell
PCSK9 – protein that binds internalised LDL-R – directing for degradation
PCSK9 inhibitors demonstrated highly significant reduction in LDL cholesterol over placebo (statin +/- ezetimibe)
what are the disadvantages of PCSK9 inhibitors?
Long term effects on cholesterol lowering and CVD risk remain to be determined
Lifetime injections - could affect adherence
very expensive
what are the indications of alirocumab?
currently recommend for primary and secondary prevention in resistant familial
hypercholesterolemia and some high risk secondary prevention patients
Other than medication, what can patients do to reduce cholesterol?
Exercise
Plant sterols provide some LDL cholesterol lowering effects
Naturally occurring in grains, legumes etc. structurally similar to cholesterol – competing for
absorption
• Work with statins but not with ezetimibe
• Yes to….
Fish oils/oily fish
Fibre, whole grains
Vitamin C/E
• Alcohol – increases HDL cholesterol BUT also increases triglycerides
Which statin is offered as a first line option to patients in the UK and why?
Atorvastatin - has high efficacy compared to other statins such as simvastatin. Has lowest number needed to treat of statins. The Number Needed to Treat (NNT) is the number of patients you need to treat to prevent one additional bad outcome (death, stroke, etc.).
How does ezetimibe reduce circulating cholesterol?
Ezetimibe inhibits NPC1L1 in the small intestine to prevent cholesterol absorption. As absorption is decreased there is less circulating cholesterol. It also increases the heptic expression of the LDL receptor to remove LDL from circulation
How do PCSK9 inhibitors work?
inhibit the PCSK9 protein which marks the LDL receptor for degredation once it has bound to LDL. Inhibiting this protein stops the receptor from being degraded and increases its expression, effectivelt reducing the amount of circulating LDL.
Why may it be appropriate to prescribe a statin and ezetimibe together, comment on their
mechanisms?
statin reduces the amount of intracellular cholesterol produced by competitively inhibiting the HMG-CoA reductase to reduce the HMG-CoA to mevalonic acid.
ezetimib reduces the cholesterol absorption from the small inestine and increases the removal of LDL from circulation
As their mechanisms focus on different pathways, they can be effectively used together in multiple target therapy to reduce the risk of a CV event
What considerations should be made when prescribing a statin for primary CVD prevention?
individual patient risk/benefit
Full lipid profile including HDL, and non-HDL + triglycerides before prescribing
What action of other drugs is important to consider when prescribing a statin which may influence the dose of the statin prescribed?
amlodipine interacts with simvastatin
The metabolism of statins is reduced by cytochrome P450 interactions inhibitors, such as amiodarone, diltiazem, itraconazole, macrolides and protease inhibitors. This leads to accumulation of the statin in the body, which may put patients at increased risk of adverse effects.
Amlodipine has a similar interaction although the mechanism is less clear. To reduce this risk you may need to reduce the dose of the statin or, if the other drug is being used for a short period only (e.g. a course of clarithromycin therapy), withhold the statin.
