Lipid & Cholesterol Metabolism

Question 1

Describe the pathophysiology of atherosclerosis

Answer 1

Endothelial dysfunction 
Increased LDL/lipids in intima
Monocytes --> macrophages --> foam cells (LDL oxidation) 
Pro-inflammatory changes 
Fibrous cap/lipid core
Rupture of plaque
Thrombus forms, platelets aggregate

Question 2

Describe the WHO/Frederickson Classification of Lipid Disorders

Answer 2

Type I - elevated chylomicrons (lipoprotein lipase deficiency)
Type IIa - elevated LDL (familial hypercholesterolaemia, familial combined hyperlipidaemia)
Type IIb - elevated LDL, vLDL (familial combined hyperlipidaemia)
Type III - elevated IDL (dysbetalipoproteinaemia)
Type IV - elevated vLDL (familial hypertriglyceridaemia, familial combined hyperlipidaemia, diabetes)
Type V - elevated chylomicrons, vLDL (diabetes)

Question 3

Describe the method of action and ADRs of statins

Answer 3

MOA - inhibit HMG-CoA reductase –> decrease intracellular cholesterol
ADRs - myopathy, rhabdomyolysis, myalgia, increased plasma hepatic enzymes
DDIs - grapefruit juice, verapamil, rifampicin, St. John’s wort

Question 4

Describe the method of action and ADRs of cholesterol absorption inhibitors

Answer 4

E.g. Ezetimibe
MOA - selectively inhibits absorption of dietary and biliary cholesterol in small intestine –> decreased cholesterol to liver
ADRs - headache, abdominal pain, diarrhoea

Question 5

Describe the method of action and ADRs of fibric acid derivatives

Answer 5

E.g. Fenofibrate
MOA - PPAR-a agonist –> increase production of lipoprotein lipase –> increase fatty acid uptake
ADRs - GI upset, cholelithiasis, myositis, abnormal LFTs, impair absorption of fat soluble vitamins (ADEK)

Question 6

Describe the method of action and ADRs of niacin (nicotinic acid)

Answer 6

MOA - strongly inhibits lipolysis in adipose –> lower free fatty acids, TAGs
ADRs - flushing, itching, headache, GI upset, hyperuricaemia/gout, hepatotoxicity, decreased glucose tolerance, peptic ulcer activation

Question 7

Describe the method of action and ADRs of bile acid sequestrants

Answer 7

E.g. Resins
MOA - anion-exchange resins bind negatively charged bile acids/salts in small intestine –> excreted in faeces
ADRs - GI upset, impair absorption of fat soluble vitamins (ADEK)

Question 8

Describe the method of action and ADRs of omega 3 fatty acids

Answer 8

E.g. Tuna, salmon, fish oil tablets

MOA - inhibit vLDL and triglyceride synthesis in liver

Question 9

What combination therapy has an increased risk of rhabdomyolysis?

Answer 9

Statin + fibrate

Question 10

Define the normal total cholesterol and fasting LDL/HDL levels

Answer 10

Total cholesterol = 5.0 mmol/L
Fasting LDL = 3 mmol/L
Fasting HDL = 1.2 mmol/L