Cholesterol Pharmacology Flashcards
What effect does a 10% reduction in cholesterol have on CHD mortality?
It reduces it by 15%
What effect does a 10% reduction in cholesterol have in total mortality?
11% reduction
What is the primary target to prevent CHD?
LDL cholesterol
What does the intensity of cholesterol intervention depend on?
Total CV risk
What are the pro-atherogenic effects of oxidated LDL?
- Inhibits macrophage motility
- Induces T-cell activation and VSMC divison/differentiation
- Toxic to endothelial cells
- Enhances platelet aggregation
What are the classes of lipid lowering drugs?
- Statins
- Cholesterol lipase inhibitors
- Nicotinic acid
- Fibrates
- Resins
- Omega-3 fatty acids
Give a statin
Simvastatin
Give a cholesterol lipase inhibitor
Ezetimibe
Give a fibrate?
Fenofibrate
Give a resin
Colestyramine
Give an omega-3 fatty acid
Omacor
What are the actions of statins?
- Inhibits cholesterol synthesis in hepatocytes
- Increase clearance of IDL and LDL
- Decreases production of VLDL and LDL
What are the indications for the use of statins?
- CV risk prevention in CVD and diabetes
- Famlial hypercholesterolaemia
What are the potential adverse drug reactions of statins?
- Increased transaminase levels
- Myopathy
- Gastrointestinal complaints
- Arthralgia
- Headaches
What % of patients treated with statins develop increased transaminase levels?
0.1-2.5%
By how much can statins increase transaminase levels?
Can increase >3x the upper normal limit, especially at higher doses
Can increased transaminases due to statin use be reversed?
Yes, rapidly reversible
Does increased transaminase levels due to use of statins cause liver disease?
No
What myopathies can be caused by statins?
- Diffuse muscle pain
- CPK > 10x upper normal limit
When are myopathies due to statin use primarily seen?
When higher doses of statins are used in combination with cyclosporine, gemfibrozil, and occassionally erythromycin and niacin
What are some secondary benefits of statin treatments?
- Anti-inflammatory
- Plaque reduction
- Improved endothelial cell functions
- Reduced thrombotic risk
When is statin therapy recommended?
As part of the management strategy for the primary prevention of CVD for adults who have a 20% or greater risk of developing CVD
How should the level of CVD risk a patient has be calculated?
Using an appropriate risk calculator, or by a clinical assessment for people whom an appropriate risk calculator is not available
What kind of molecules are fibric acid derivatives?
Ampipathic carboxylic acids
How do fibric acid derivatives act to reduce cholesterol?
They are PPAR-alpha agonists, which increase the production of lipoprotein lipase and so reduce triglyceride production
By how much can fibric acid derivatives reduce cholesterol?
10-20%, but variable depending on specific drug
What are the effects of fibric acids?
- Increase fatty acid uptake and oxidation
- Reduces triglyceride levels
- Increases LDL particle size and HDL-C levels
- Direct vascular effects
What are the indications for fibric acid derivatives?
- Hypertriglyceridema
- Combined hyperlipidaemia with low HDL, who do not respond to NA
Is fibric acid derivative therapy used alone, or as an adjuct?
It is an adjuctive therapy to diet
What is the efficacy of fibric acid derivatives?
- Decreases TG by 25-50%
- LDL increases, but variable
- Increases HDL 15-25% in hypertriglycaemia
What are the side effects of fibric acid derivatives?
- GI upset
- Cholelithiasis
- Myositis
- Abnormal LFTs
What are the contraindications for fibric acid derivatives?
- Hepatic or renal dysfunction
- Pre-existing gallbladder disease
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What is the best agent to raise HDL-C?
Nicotinic acid
What is the effect of nicotinic acid?
- Reduces VLDL
- Increases HDL at high doses
How does nicotinic acid have a lipid lowering effect?
By inhibition of lipoprotein (a) synthesis
What effect does nicotonic acid have on the incidence of coronary events?
It reduces the incidence
What are the adverse effects of nicotinic acid?
- Flushing
- Itching
- Headache
- Hepatotoxicity
- GI toxicity
- Activation of peptic ulcer
- Hyperglycaemia and reduced insulin sensitivity
How can the side effects of flushing, itching and headache due to nicotinic acid be reduced?
- Using immediate release Niaspan form
- Using in combination with low dose aspirin
What form of nicotinic acid causes hepatotoxicity and GI toxicity?
Sustained release
What are the contraindications for nicotinic acid?
- Active liver disease
- Unexplained LFT elevations
- Peptic ulcer disease
What is the mechanism of action of ezetimibe?
It selectively inhibits intestinal cholesterol absorption, which;
- Decreases intestinal delivery of cholesterol of the liver
- Increased expression of hepatic LDL receptors
- Decreased cholesterol content of atherogenic particles
What do ezetimibe metabolise to?
An active glucuronide metabolite
How does ezetimibe and its metabolite circulate?
Enterohepatically
What is the result of the enterohepatic circulation of ezetimibe?
It delivers the agent back to the site of action, and limits systemic exposure
What are the adverse drug reactions of ezetimibe?
- Headache
- Diarrhoea
- Abdominal pain
What can statins be used in combination with?
- Fibrate
- Nicotinic acid
- Ezetimibe
- Omega-3 FAs
What should be considered when thinking about giving a patient combination therapy to reduce cholesterol?
- Benefit
- Cost
- ADRs
What is the advantage of combination fibrate and statin therapy?
It may significantly improve triglyceride, LDL-C and HDL-C levels
What is the disadvantage of combination fibrate and statin therapy?
Fibrates plus statins are associated with increased risk of myopathy and rhabdomyolosis
What effect might gemfibrozil have on statins?
May impair glucuronidation of statins, with cervistatin being more susceptible than other statins
Which fibrate seems to have less potential for impairment of statin metabolism?
Fenofibrate
What dietary factors may have a positive effect on statin metabolism?
- Plant sterols
- Fish oils
- Fibre
- Vitamin C/E
- Alcohol (HDL)
What dietary factors may have a negative effect on cholesterol metabolism?
- Dietary cholesterol/fat
- Alcohol (TG)
