5.1 Hyperlipidemias

Question 1

What vitamin is cholesterol important in the production of ?

Answer 1

Vitamin D, steroid hormone, bile acids

Question 2

How do you get a fatty streak?what is the pathology?

Answer 2

• Accumulation of LDL at the intima
• Oxidation by local endothelial cell products
• Modified LDL and additional oxidation gives you an oxidized LDL
• Recruited monocyte uptake oxidized LDL via scavenger receptors (SR-A)
• Foam cells formed building up in intima/endothelial space
• Proliferation of smooth muscle cells
• Fatty streaks develop
• Chronic inflammation and accumulation of disrupted vascular smooth muscle cells

Question 3

When do you get fatty streaks?

Answer 3

Dependant in cholesterol levels, doesn’t really link to age

Question 4

What are statins?

Answer 4

Competitive inhibition of HMG-CoA reductase – (rate controlling step) enzyme in mevalonate pathway

This up-regulates hepatic LDL receptors

So, get increased clearance of circulating LDLs = helps prevent against cardiovascular disease

Question 5

Name some statins

Answer 5

Atorvastatin

Simvastatin

Question 6

What are the additional benefits of statins?

Answer 6

CVD reduction

Improved vascular endothelial function (increased NO and VEGF, decreased endothelin)

stabilisation of atherosclerotic place (decreased SMC proliferation and increased collagen)

improved haemostasis (decreased plasma fibrinogen, platelet aggregation and increased fibrinolysis)

anti-inflammatory (decreased proliferation of inflammatory cells into plaque, plasma CRP, adhesion molecules and cytokines)

antioxidant (decreased superoxide formation)

Question 7

how are statins activated?

Answer 7

simvastatin

• activated by first pass metabolism
• half life 2 hrs

atorvastatin

• first pass metabolism
• half life of 30hrs

Question 8

what are the ADR of statins?

Answer 8

• raised ALT and AST
• myalgia
• rarely get rhabdomuoloysis
• GI disruption, nausea and headache

Question 9

what are the NICE guidelines for statin prescription?

Answer 9

primary prevention
- 20 mg of atorvastatin once daily to all those who have CVD risk of over 10%

secondary prevention
- 80 mg atorvastatin once daily

check lipid profile including HDL, non HDL and TG before prescribing

Question 10

what are fibrates?

Answer 10

fibric acid derivatives e.g fenofibrate and ciprofribrate

activate nuclear transcription factor (PPARa) which regulates expression of genes that control lipoprotein metabolism (increase production of lipoprotein lipase)

they enhance the clearance of triglycerides from lipoprotein plasma and increase fatty acid uptake by the liver

they also increase LDL affinity for its receptor

Question 11

name two fibrates

Answer 11

fenofibrate

ciprofribrate

Question 12

what are the ADRs of fibrates?

Answer 12

GI upset
cholelithiasis (gall stones)
myositis

Question 13

what are nicotinic acids?

Answer 13

an antilipolytic = reduces fatty acid supply = reduced triglyceride synthesis

e.g niacin

Question 14

what are the ADRs of nicotinic acids?

Answer 14

flushing 
heachache
itching (reduced by low dose of aspirin 30mins prior)
hepatoxicity 
GI disturbance

Question 15

give an example of a nicotinic acid

Answer 15

niacin

Question 16

what are cholesterol absorption inhibitors?

Answer 16

act at the brush border of the small intestine of the mucosa and reduce cholesterol absorption = hepatic LDL receptor expression increases = decreases total cholesterol and LDLs

A pro drug that stays in the enterohepatic circulation (= less systemic exposure)

e.g ezetimibe

Question 17

what are the ADRs of cholesterol absorption inhibitors?

Answer 17

headache
abdominal pain
diarrhoea

Question 18

give an example of a cholesterol absorption inhibitor

Answer 18

ezetimibe

Question 19

what combination of drugs can be used against CVD?

Answer 19

statins e.g atorvostatin and a cholesterol absorption inhibitor e.g ezetimbine

Question 20

what can you use if statins aren’t working at reducing LDL levels, and how do they work?

Answer 20

Alirocumab
Evolocumab

when LDL attaches to LDL receptor, it is internalised and receptor is degraded and I recycled in the cell
PCSK9 is a protein that directs the degradation of internalised LDL receptors

these drugs are PCSK9 inhibitors, so prevent internal LDL receptor degredation = more receptors = more LDLs can be taken into cells

Question 21

what other suggestions can be made to a patient to reduce risk of CVD?

Answer 21

eat more

• fish oils
• fibre
• vit C/E
• alcohol = increases HDL cholesterol but increase triglycerides

effective, especially in low risk patients maintaining low risk