Lipid and Cholesterol Metabolism

Question 1

What is the healthy target for cholesterol levels

Answer 1

• Ideally total cholesterol levels < 5mmol/L

- Non HDL-cholesterol < 4mmol/L

Question 2

State the main drug groups used in reducing LDL cholesterol

Answer 2

• Statins
• Fibrates
• Cholesterol lipase inhibitors
• Nicotinic acid/niacin
• Bile acid sequestrants
• PCSK9 inhibitors

Question 3

Describe the mechanism of statins

Answer 3

• Eg. Simvastatin, pravastatin, fluvastatin, atorvastatin
• Mechanism
  
  • Inhibit HMG-CoA reductase to inhibit cholesterol synthesis in hepatocytes
  • Lower cholesterol levels in liver stimulate transcription and synthesis of LDL receptors which further decreases serum LDL cholesterol
  • Increase clearance of IDL and LDL
  • Decrease production of VLDL and LDL

Question 4

Describe the ADRs and contraindications of statins

Answer 4

• Adverse drug reactions of statins
  
  • Increased transaminase levels - monitor liver function
  • Myopathy - muscle (myalgia), joint pain - monitor serum CK levels
  • GI problems
  • Headaches
• Contraindications
  
  • Patients with poor liver function
  • Alcoholic patients
  • Warfarin - interactions with cytochromes in liver
• Low chance of contraindications therefore statins commonly given to patients
  - Given to patients after heart treatment as prevention of CVD

Question 5

Describe the mechanism of fibrates

Answer 5

• Eg fenofibrate, benzafibrate
• Mechanism
  
  • Increases production of lipoprotein lipase
  • Increases fatty acid uptake and oxidation, thus reducing triglyceride levels as it becomes stored in adipose tissue
  • Increases HDL levels
    
    • Little effect on LDL

Question 6

Describe the ADRs and contraindications of fibrates

Answer 6

• Adverse drug reactions
  
  • GI upset, myositis
  • Abnormal liver function tests
• Contraindications
  
  • Hepatic or renal dysfunction
  • Pre-existing gallbladder disease
  • Fibrates + statins are associated with increased risk of myopathy and rhabdomyolysis
    
    • Fenofibrate appears to have less potential for impairment of statin metabolism, therefore more used than gemfibrozil

Question 7

Describe the mechanism of cholesterol lipase inhibitors

Answer 7

• Selectively inhibits intestinal cholesterol absorption
  
  • Decreases intestinal delivery of cholesterol to the liver
  • Increases expression of hepatic LDL receptors and lowers LDL levels
  • Decreases cholesterol content of atherogenic particles
• Ezetimibe and its active glucuronide metabolite circulate enterohepatically
  
  • Delivers agent back to the site of action
    
    • Limits systemic exposure

Question 8

Describe the ADRs of cholesterol lipase inhibitors

Answer 8

• Headache, abdominal pain, diarrhoea

- May have risk of myopathy when given with statins

Question 9

Describe the mechanism of nicotinic acid/niacin

Answer 9

• Reduces VLDL and increases HDL at high doses
• Reduces apolipoprotein B, which is the major lipoprotein in VLDL and LDL
• Reduces triglyceride levels in the blood

Question 10

Describe the ADRs and contraindications of niacin

Answer 10

• Adverse effects
  
  • Flushing, itching, headache
  • Hepatotoxicity, GI
  • Activation of peptic ulcer
  • Hyperglycaemia and reduced insulin sensitivity
• Contraindications
  
  • Active liver disease or unexplained LFT elevations
    
    • Peptic ulcer disease

Question 11

Describe the mechanism of bile acid sequestrants

Answer 11

• Eg. Cholestyramine
• Binds bile in the digestive tract to prevent its reabsorption and thus is excreted in the faeces
• Causes liver to produce more bile, thus using up cholesterol levels

Question 12

Describe the mechanism and uses of PCSK9 inhibitors

Answer 12

• Block PCSK9 protein to make it easier for the body to remove LDL from blood
• Used in people who cannot manage their cholesterol through lifestyle and statin treatments

Question 13

Describe non-drug dietary approaches to lipid lowering

Answer 13

• Plant sterols - beans, peas, lentils, nuts, seeds
• Fish oils
• Vitamin C/E
• Reduce intake of fat
• Omega-3 fatty acid - cold water fish

Question 14

Describe how to undertake a CV risk assessment

Answer 14

• Qrisk2 assessment takes into account different parameters to determine the risk of someone having a heart attack or stroke over the next 10 years
• In the new guideline, atorvastatin 20mg should be given for patients with a 10% or greater 10-year risk of developing CVD
• Start statin treatment in people with CVD with atorvastatin 80 mg
  
  • Give reduced dose is potential drug interactions, high risk of adverse effects, patient preference