Hypercholesterolemia and Atherosclerosis Flashcards
What is Hypercholesterolaemia? (definition)
Elevated plasma cholesterol, this leads to Atherosclerosis
What is Atherosclerosis?
Focal lesions (Plaques) on the inner surface of an artery
What are risk factors for atherosclerosis?
- Genetic
- Hypercholesterolaemia(raised LDL-c or lowered HDL-c)
- Hypertension–
- Smoking–
- Obesity–
- Hyperglycaemia–
- Red physical activity–
What is cholesterol?
- Primary component of cell membranes
- Substrate for synthesis of bile acids, steroid hormones and vitamin D
- Dietary cholsterol-little influence on blood cholesterol
- Type of fat inf blood cholesterol
- Dietary sources-liver, fish, shellfish/
What is Hypercholesterolaemia? (explanation)
- Major risk factors for atherosclerosis
- Total plasma cholesterol >6.5mmol/l
- Ideal cholesterol < 5.2mmol/l
- 25-30% middle aged pop have hypercholesterolaemia
- Especially important in high LDL-C component or low HDL-c
Explain lipid transport?
Cholesterol and TAGs transported around the body as lipoproteins:
* VIDL-TAG rich, transports TAG to adipose/muscles
* LDL-cholesterol rich. Transports cholesterol from liver to cells
* HDL-removal of excess cholesterol from peripheral tissues
Raised LDL-cholesterol associated with CVD
HDL-cholesterol-inversely related to CVD
How do you manage Atherosclerosis?
Modify risk factors:
* Stop smoking
* Treat HT/DM
* Excercise
Reduce saturated and trans fats:
* NB only 25-30% of cholesterol comes from diet
Whay are plaques bad?
- Over time they build up and start to impede on lumen of blood vessel
- Changes blood flow
Explain how a plaque forms?
What are the statins? (1)
HMG-CoA Reductase inhibitors
* Hydroxymethylglutaryl coenzyme A reductase which catalyses:
- Hydroxymethylglutaryl–>Mevalonate–>Cholesterol
- HMG-CoA reductase is the 1st commited step in cholesterol synthesis
What are the statins? (2)
- E.g. simvastatin, pravastatin, atorvastatin, fluvastatin
- Red plasma cholesterol
- Cholesterol synth–>^^Hepatic LDL receptors, promoting LDL-C uptake
- Statins are hepatoselective
1. Liver is the main site of cholesterol synth
2. First pass metabolism:5% reaches systemic circulation - Cholesterol synthesis greater at night therefore statins taken at night
What is a pro-dug?
- Are metabolised to form active compound
- This allows better uptake into cells and therefore a more effective drug.
- E.g. STATINS
What are the effects of statins?
- 4S trial (scandanavia Simvastatin Survival Study)
- Over 5 years, 30% reduction in mortality, 42% reduction in death from CAD
- Some evidence that Statins may lead to regression of atherosclerosis
- Treatment for 2 years with 40mg rosuvastatin per day caused a reduction in size of atheroma in 75% of patients.
What are adverse effects of statins?
- Cautions: Use with care in liver disease, monitor liver function
- May cause Rhabdomyolysis-Risk 1 in 1,000-10,000
- Cervastatin withdrawn Aug 2001 because of reports of fatal rhabdomyolysis
- Possibly due to inhibition of mitochondrial function
What are Non-cholesterol effects of statins?
- Inv in post-translational modification (and activation) of proteins
- Inhib of signalling pathwyas independent of effects on cholesterol
