8 - Hyperlipidaemia Drugs Flashcards
What are the pro-atherogenic effects of oxidised LDL?
- Inhibits macrophage motility
- Induces T-cell activation and VSMC division / differentiation
- Toxic to endothelial cells
- Enhances platelet aggregation
How do atheromas form?
- Endothelial injury e.g hypertension, smoking, hyperlipidaemia
- LDL deposits in the intima of blood vessels
- LDL gets oxidised and then phagocytosed by macrophages forming foam cells
- Smooth muscle cells start to proliferate forming a fatty streak
- Fibrous cap forms of the top
- Centre of the plaque dies and necrosis develops, dead cells release cholesterol so cholesterol clefts are seen
What is the mechanism of action of statins and what are the two main ones prescribed?
- Atorvastatin and Simvastatin
- Inhibit HMG CoA Reductase in the rate limiting pathway so inhibits cholesterol synthesis in hepatocytes
- Upregulates hepatic LDL receptors so increased clearance of circulating LDL
- Decreased LDL and VLDL production so less cholesterol
What other actions do statins have to lower CVD risk, apart from lowering cholesterol?
- Anti-inflammatory
- Plaque reduction/stabilisation
- Improved endothelial cell function e.g increased NO production
- Reduced thrombotic risk due to improved haemostasis
- Antioxidant
What are some adverse effects of statins?
- GI disruption
- Nausea
- Headaches
- Myalgia (raised CPK>10x normal limit)
- Rhabdomyolysis (rare and in high doses for long period of time)
- Renal impairment from muscle breakdown
- Hepatocyte injury so raised ALT
What are some contraindications for statin use (should not be used)?
- Renal impairment
- Pregnancy and breastfeeding as cholesterol needed for fetus
- Drugs that inhibit CYP3A4: amiodarone, diltiazem, macrolides, amlodipine (stop statins shortly when taking antibiotics)
How are statins administered, and what’s the half life of the two main ones given
- Orally and they are prodrugs until first pass metabolism
- Simvastatin has short half life of 2 hours so take at night
- Atorvastatin has long half life of 30 hours
When are statins prescribed ?
- 10 year CVD risk >10% using QRISK
- Familial Hypercholesterolaemia
- Post MI
Primary prevention: Low dose 20mg atorvastatin OD
Secondary prevention: High dose 80mg if tolerated and no drug interactions. Done as low NNT
What advice should be given to a patient taking statins and what is the aim when prescribing these?
- Do not eat/drink grapefruit
- Take at night as LDL receptor synthesis follows circadian rhythm and short half life of simvastatin
- Take full lipid profile before inc HDL and TG
- Want >40% reduction in non-HDL-C at three months
Grapefruit juice can block the action of intestinal CYP3A4, so instead of being metabolized, more of the drug enters the blood and stays in the body longer.
What is the mechanism of action of fibric acid derivatives (fibrates) and what is the name of the drug from this class prescribed?
- PPARα (transcription factor) agonist – increases production of lipoprotein lipase which allows chylomicrons to release their TAG into muscle and liver cells lowering TAG in blood
- Reduces triglyceride production
- Increase HDL levels
- Fenofibrate: usually co-prescribed with a statin and good diet
What are the possible adverse effects of fibric acid derivatives?
- Cholelithiasis (Gall stones)
- GI upset
- Myositis/Rhabdo when given with statins
- Hepatic, renal and gall bladder issues
What are the contraindications for fibric acid derivatives?
- Patient taking warfarin as high risk of bleeding
- Hepatic or renal dysfunction
- Pre-existing gallbladder disease
When are fibrates used?
- Adjunctive therapy to diet if statin not tolerated or contraindicated
- Hypertriglyceridemia (high TAG)
- Combined hyperlipidemia with low HDL
How does ezetimibe work as a lipid lowering drug?
- Cholesterol absorption inhibitor (lowers cholesterol+LDL)
- ↓ intestinal absorption* by inhibiting NPC1L1 transporter
- ↑ expression of hepatic LDL receptors
- ↓ cholesterol content of atherogenic particles
What are the possible adverse effects of ezetimibe and what are some contraindications for its use?
- Headache
- Abdominal pain
- Diarrhoea
When is ezetimibe prescribed?
- Adjunct to statin instead of resins and bile salt sequesterants as better tolerability/less side effects
- Used if statins not tolerated
- Familial hypercholesterolaemia
- No dose escalation, always 10mg
Describe how lipid lowering drugs can be used in combination therapy and what should one consider when assessing the use combination therapy of lipid lowering drugs?
- Benefit (CV risk reduction)
- Cost
- ADRs
Complete the table by indicating whether the drug increases/decreases or does not affect the listed lipid parameter
How does alirocumab work as a lipid lowering drug?
- Monoclonal antibody that inhibts PCSK9 enzyme
- PCSK9 normal degrades LDL receptors so less internalised but this drug stops this so increased expression of LDL receptors with this drug
- Big reduction in LDL but very expensive!!!
How is alirocumab administered and why is it not used much in practice?
- Biweekly subcut injections
- Too expensive: weekly cost of £100 over £1 with statins
- Given when primary hypercholesterolaemia has not responded to anything else
Apart from lipid lowering drugs, what can be done by a patient to lower their cholesterol?
- Eat plant sterols as they compete with cholesterol for absorption, found in grains and legumes. (not as helpful with ezetimibe as this is inhibiting cholesterol absorption too)
- Eat fish oils, fibre, vitamin C and E
- Alcohol increases HDL but also increases TAG so be careful
USE THIS METHOD IF STATINS NOT TOLERATED
How is a persons 10 year CVD risk calculated?
- QRISK score
- Takes into account age, smoke, diabetes etc and helps to decide how to manage, e.g change diet or statins
How do bile acid sequesterants work and why are they not used so much anymore?
Which statin is the best at lowering the lipid profiles?
NOT ALL THE SAME
What are some of the factors taken into consideration on the QRISK score?
