Term
| What is the primary aim of any hyperlipidaemia treatment and which two approaches are taken to do so? |
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Definition
the aim is to reduce plasma cholesterol
- control of dietary intake of cholesterol and other fats
- direct pharmacological intervect
both are usually used |
|
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Term
| How is diet controlled to treat hyperlipidaemia? |
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Definition
- consumption of cholesterol is limited to less than 20mg/day
- maintenance of total fat intake should be less than 30% of total daily intake
- 30% of this fat should be mono/polysaturated fat. |
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Term
| What are the main sources of dietary LDL? |
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Definition
| saturated fats and cholesterol |
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Term
| When is drug treatment required? |
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Definition
- if a patient suffers from CAD or is thought to be at risk of doing so
- primary hyperlipidaemics |
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Term
| What are the main drugs used in treatment of hyperlipidaemia? |
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Definition
- HMG CoA reductase inhibitors
- Fibrates (fibric acid)
- Bile acid binding resins |
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Term
| What are HMG CoA reductase inhibitors known as? Give examples |
|
Definition
- statins
- inhibit cholesterol synthesis via the endogenous pathway (de novo)
- atorvastatin, simvastatin and pravastatin |
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Term
|
Definition
| mainly used for high LDL levels and high LDL/VLDL levels |
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Term
| Describe the mechanism of HMG CoA reductase inhibitors |
|
Definition
- rate limiting step in endogenous production of cholesterol involves HMG CoA reductase inhibitors
- statins competitively inhibit HMG CoA reductase inhibitors
- mevalonate production rate decreased
- cholesterol production reduced |
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Term
| How do hepatocytes respond to reduced liver cholesterol? |
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Definition
- detection
- synthesise new LDL receptors
- increased LDL clearance and reduction in blood LDL levels |
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Term
| How effective is this mechanism at reducing blood LDL levels? |
|
Definition
- LDL plasma levels are reduced by 20-40%
- TG levels decrease by around 25%
- HDL CH content increases by 13% |
|
|
Term
| What is the fate of the extra cholesterol? |
|
Definition
- recycled
- goes to HDLs (endogenous pathway)
- see an increase in cholesterol content of 13% |
|
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Term
| What are the unwanted effects of HMG CoA reductase inhibitors? |
|
Definition
- altered liver function
- GIT effects such as abdominal pain, nausea and although considered rare,
- may cause muscle pain or weakness, which should be reported by the patient |
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Term
| What are other reported benefits of statins? |
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Definition
1. improved endothelial function
2. reduced platelet aggregability
3. increased neovascularisation of ischaemic tissure
4. antithrombotic actions
5. atherosclerotic plaque stabilisation
6. immune suppression |
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Term
| What are the issues with statins and liver disease |
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Definition
- use with caution if a patient has a history of liver disease (may need to use liver function tests)
- contraindicated in active liver disease
- use with caution with high alcohol intake |
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Term
| What are the issues with statins and pregnancy? |
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Definition
1. contraindicated in pregnancy - use adequate contraception for a month after treatment - germ cell migration by HMG CoA reductase
2. contraindicated for breast feeding mothers |
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Term
| What are the most common used fibrates? |
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Definition
|
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Term
| What are fibrates and what are they used against? |
|
Definition
- high levels of VLDLs
- agonists at PPAR-alpha |
|
|
Term
|
Definition
- a transcription factor and a major regulator of lipid metabolism in the liver
- activated under conditions of energy deprivation |
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|
Term
| What does PPAR-alpha activation promote? |
|
Definition
uptake, utilisation and catabolism of fatty acids by up-regulation of genes involved in:
- fatty acid transport
- fatty acid binding and activation
- peroxisomal and mitochondrial fatty acid beta-oxidation |
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|
Term
| Describe the mechanism of action for fibrates |
|
Definition
- complex
- increases activity of lipoprotein lipase which increases the catabolism of TG-rich VLDLs and IDLs, thus decreasing the secretion of VLDLs by hepatocytes |
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Term
| What does increased breakdown of VLDLs and IDLs lead to? |
|
Definition
an increase in the amount of cholesterol in HDLs
- cholesterol (from HDLs) -> VLDL
- VLDL -> LDL (TG is removed via action of lipoprotein lipase) |
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|
Term
| What happened to cholesterol levels in lipoproteins when VLDL levels are reduced? |
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Definition
- cholesterol from HDLs cannot be exchanged
- reduction in the amount of cholesterol contained in LDLs |
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|
Term
| Describe the mechanism of fibrates once more |
|
Definition
1. VLDLs are hydrolysed in tissues
2. converted into LDLs via cell-mediated endocytosis
3. tissue breakdown
4. HDL picks up CH
5. HDL can't exchange CH so can't gve any to VLDLs
6. Reduction in CH contained in LDLs |
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Term
| How effective is Gemfibrozil? |
|
Definition
- reduced TG and CH levels
- total CH reduced by 11%
- LDL-CH by 10%
- TG reduced by 43%
- increases HDL-CH by 10% |
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|
Term
| What are the unwanted effects of Gemfibrozil? |
|
Definition
- generally well tolerated so unwanted effects quite rare
- may cause muscular damage - rhybdomyolysis which can cause kidney damage (acute renal failure)
- therefore should not be used if the patient has a history of renal failure |
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|
Term
| Name some examples of bile acid binding resins |
|
Definition
|
|
Term
| Describe bile acid binding resins |
|
Definition
- large polymers
- hydrophilic
- used against high LDL levels
- often used alongside a statin
- we do not absorb them |
|
|
Term
| Describe bile acid binding resins mechanism of action |
|
Definition
they act as ion exchange resins
1. bind to bile acids
2. cholesterol is converted to bile acids
3. high concentration of bile acids inhibits the enzyme controlling this process via a negative feedback mechanism, thus reducing the amount bile acids formed |
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Term
| Why is a reduction in bile acids formed help lower cholesterol level? |
|
Definition
- bile acids are needed for the absorption of cholesterol
- removal of bile salts due to binding means less cholesterol absorbed
- liver responds by increased HMG CoA reductase activity and increased synthesis and expression of LDL receptors
- liver cholesterol is maintained by overall loss of cholesterol in the body is experienced |
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|
Term
| Unwanted effects of bile acid binding resins |
|
Definition
- not absorbed so low toxicity (yay)
- can cause nausea, constipation, diarrhoea and severe flatulence
- can reduce absorption of fat-soluble vitamins such as vitamin K, folic acid and other drugs |
|
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Term
| What should bile acid binding resins patients be cautious of? |
|
Definition
| If they are CAD patients also, they may be on other coagulant drugs. |
|
|
Term
| What works as a replacement to bile acid binding resins? |
|
Definition
Ezetimibe
- azetidinone cholesterol absorption inhibitor
- adjunction to statins and diet |
|
|
Term
|
Definition
- acts by blocking CH absorption by binding to NPC1L1 in brush border of enterocytes
- no effect on vit K absorption
- well tolerated - low dose 10mg, compared to BARBs |
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|
Term
| What are nicotinic acid and acipimox used for? |
|
Definition
- vitamin derivatives
- reduces VLDL levels and to some extent IDL and LDL levels |
|
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Term
| How do nicotinic acid and acipimox reduce VLDL levels and to some extent IDL and LDL levels? |
|
Definition
1. decreased TG and VLDL secretion by liver
2. increased lipoprotein lipase activity (breaks down VLDL), which increases HDL levels
usually used in combination with resins |
|
|
Term
| What are the adverse effects of nicotinic acid and acipimox? |
|
Definition
GIT
liver function
palpatations
PGD2
acipimox (nicotinic derivative) less unwanted effects but less effective |
|
|
Term
|
Definition
- used to reduce TG if patient is judged to be of special risk of ischaemic heart disease - poorly understood
e.g. -3 marine TG (unknown mechanism) |
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|
Term
| What are the unwanted effects of fish oils? |
|
Definition
problem tends to cause an increases in LDL
unwanted effects are nausea and flatulence
NOT DRUGS |
|
|
Term
| How are plant sterols used? |
|
Definition
beta-sitosterol and sitostanol (benecol)
- poorly absorbed
- inhibits absorption of dietary and endogenous CH
- competes for micelle space
- reduces total and LDL cholesterol in plasma
NOT DRUGS |
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Term
| What are the main drug effects of statins? |
|
Definition
inhibits CH synthesis in liver
increases LDL receptors
increases LDL clearance and levels |
|
|
Term
| What are the main drug effects of fibrates? |
|
Definition
alter levels of different lipoproteins
increase activity of lipoprotein lipase
decrease hepatic VLDL and ultimately LDL |
|
|
Term
| What are the main drug effects of BABR? |
|
Definition
sequester bile acids from the GI tract
reduced exogenous cholesterol absorption
increases endogenous cholesterol metabolism |
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