Cholesterol Flashcards
What does oxidation of LDLs cause?
Inhibition of macrophage motility
T cell activation and vascular smooth muscle cell division and differentiation
Enhanced platelet aggregation
What are the main drug classes used for lowering lipids?
Statins Cholesterol lipase inhibitors Nicotinic acid/niacin Fibrates Resins Omega-3 fatty acids Plant sterols
How do statins work?
Inhibit HMG-reductase, inhibiting synthesis of cholesterol in hepatocytes
Increased clearance of IDL and LDL
Decrease production of VLDL and LDL
Increase LDL receptors/expression of lipoprotein lipase
How is cholesterol produced?
From acetyl CoA
Requires enzymes
-HMG-CoA reductase
-HMG-CoA synthetase
Function of LDLs and VLDLs?
LDLs transport cholesterol from the liver to tissues
VLDLs transport TAGs synthesised in the liver to adipose tissue
Indications for statins?
- People with a 10% or greater 10 year risk of developing CVD
- Familial hypercholesteroaemia
- Diabetes mellitus
- Chronic kidney disease
- Over 85 years
What are some adverse drug reactions to statins?
Increased transaminase levels - reversible
Myopathy - diffuse muscle pain and raised creatinine phosphokinase
GI complaints
Arthralgias
Headaches
What can increase myopathy in statin use?
When higher doses are used in combination with
- cyclosporine
- gemfibrozil
- erythromycin
- niacin
Name some secondary benefits of statins
Anti-inflammatory
Plaque reduction
Improved endothelial cell function
Reduced thrombotic risk
What are fibric acid derivatives?
They are carboxylic acids which are PPARα agonists
-increase the production of lipoprotein lipase
How does atherosclerosis develop?
Endothelial injury
Platelet adhesion and PDGF released affecting smooth muscle cells
Macrophages, lymphocytes, smooth muscle cells and LDLs accumulate
Macrophages phagocytose LDLs and become foam cells
Foam cells die and release contents, producing a lipid core
Macrophages release cytokines and growth factors, leading to proliferation of of smooth muscle towards the lipid core and into the media
Inflammatory response causes fibrosis
Small blood vessels grow into the plaque
Actions of fibric acid derivatives?
Increase lipoprotein lipase
- increased fatty acid uptake and oxidation
- reduced triglyceride levels
- increased LDL particle side and HDL-C levels
- direct vascular effects
What are some indications for fibric acid derivatives?
Adjunctive therapy to diet
Hypertriglycerdemia
Combined hyperlipidaemia with low HDL who do not response to nicotinic acid
What is the efficacy of fibric acid derivatives?
Decreases TG by 25-50%
LDL decreases are variable
Increased HDL by 15-25% in hypertriglyceridemia
Side effects of fibric acids?
GI upset
Cholelithiasis (gall stones)
Myositis (muscle ache)
Contraindications for fibric acid derivatives?
Hepatic or renal dysfunction
Pre-existing gall bladder disease
Action of nicotinic acid?
Reduces VLDL and increases HDL at higher doses
-by inhibiting lipoprotein synthesis
Shown to reduce coronary events
Adverse effects of nicotinic acid?
Flushing Itching Headache Hepatotoxicity GI Activation of peptic ulcer Hyperglycaemia and reduced insulin sensitivity
Contraindications for nicotinic acid?
Active liver disease or unexplained LFT elevations
Peptic ulcer disease
Give an example of a cholesterol lipase inhibitor
Ezetimibe
Mechanism of action of cholesterol lipase inhibitors (Ezetimibe)
Selectively inhibit intestinal cholesterol absorption
Decrease intestinal delivery of cholesterol to the liver
Increase expression of hepatic LDL receptors
Decrease cholesterol content in atherogenic particles
Adverse drug reactions of Ezetimibe?
Headache
Abdominal pain
Diarrhoea
What can statins be combined with?
Fibrates (not gemfibrozil) Nicotinic acid Ezetimibe Omega-3 FAs Resins
How can pharmacodynamics between statins vary?
Intestinal absorption varies between 30-85%
Hepatic first pass uptake may occur via diffusion of active transport (by OATP2)
Some require activation
Therefore systemic availability can fall to 5-30% of administered dose
How are statins eliminated?
Undergo hepatic elimination
Either by CYP3A4 or phase II pathways
Why is simvastatin given at night?
Has a short half life of 1-4 hours
Given to coincide with peak cholesterol production in early morning
Why can atorvastatin and rosuvastatin be given at any time?
Have half-lives of around 20 hours
What kind of pharmacokinetics (linear or non-linear) do statins exhibit?
Non-linear
Which drug is best for raising HDL-C?
Nicotinic acid
What are the effects of HDL and LDL levels on CVS risks?
HDL reduce CHD risk
LDL increase risk
What are target levels of
- total cholesterol
- LDL
- HDL
Total - 5 mmol/L
LDL - 3 mmol/L
HDL - above 1.2 mmol/L
What are the other two main factors increasing CHD risk?
Smoking
Hypertension
DDIs of statins?
Those metabolised by phase I are affected by CYP inducers and inhibitors - inhibitors increase risk of myopathy and other effects
Inducers decrease levels
What monitoring should be done on patients on high levels of statins
Regular LFTs
Constant LDL level monitoring
How do cholesterol absorption inhibitors work?
Block the cholesterol transport protein NPC1L1 in the brush border
Reduces cholesterol absorption and that reaching the liver
Causes a secondary upregulation of LDL transporter expression
Lowers circulating cholesterol level
Why is there low systemic exposure with ezetimibe?
Ezetimibe and its active glucuronide metabolite circulate enterohepatically so delivers agent back to the site of action
