Cholesterol

Question 1

What are the proathrogenic effects of ox-LDL

Answer 1

Inhibits macrophage motility
Induces T cell activation and VSMC division/differentiation
Toxic to endothelial cells
Enhances platelet aggregation

Question 2

How do statins work?

Answer 2

They inhibit cholesterol synthesis in hepatocytes.
Reduced cholesterol causes an increase in LDL receptors
Therefore more LDL removed
They also decrease production of VLDL and LDL

BLOCK HMG CoA REDUCTASE

Question 3

What is cholesterol synthesised from?

Answer 3

Acetyl CoA

Question 4

When is statin treatment indicated?

Answer 4

CV risk prevention (CVD and DM)

Familial hypercholesterolaemia

Question 5

What are statin ADRs?

Answer 5

Increased liver transaminases (quickly reversible stopping rx)
Myopathies
GI upset, arthralgia and headaches

Question 6

What are the secondary benefits of statins?

Answer 6

Anti-inflammatory
Plaque reduction
Improved endothelial cell function
Reduced thrombotic risk

Question 7

What is lipoprotein lipase?

Answer 7

A water soluble enzyme that hydrolyses triglycerides in lipoproteins such as those found in chylomicrons and VLDL into two free fatty acids and one monoacylglycerl molecule.

Question 8

What does using a fabric acid derivative do?

Answer 8

PPAR alpha (peroxisome proliferator activated receptor) agonist -
Increases production of lipoprotein lipase
Reduces triglyceride production +++

Some reduction in LDL (10-20%) but variable depending on specific drug.

Question 9

How does the PPAR work?

Answer 9

Increases fatty acid uptake and oxidation
Reduces triglyceride levels
Increases LDL particles size and HDL-C levels
Direct vascular effect

Question 10

when would you use a fabric acid derivative ?

Answer 10

Hypertriglyceridemia
Adjunctive therapy to diet
Combined hyperlipidemia with low HDL who do not respond to NA

Question 11

What are the side effects of fibric acid derivatives?

Answer 11

GI upset (8%)
Cholelithiasis - gall stones
Myositis - inflammation of muscles
Abnormal LFTs

Question 12

When are fibric acid derivatives contraindicated?

Answer 12

Hepatic or renal dysfunction

Pre-existing gallbladder disease

Question 13

What does nicotinic acid do?

Answer 13

Reduces VLDL and increases HDL at high doses

Lipid lowering effect by inhibition of lipoprotein a synthesis

Question 14

With combination therapy what could you combine a statin with?

Answer 14

Fibrate
Nicotinic acid
Ezetimibe
Omega-3 FAs 
(Resins)

Question 15

What is a problem with fibrates and statins?

Answer 15

May improve triglyceride, reduce LDL and increase HDL
But
Fibrates and statins are associated with increased risk for myopathy and rhabdomyolosis

Question 16

How does ezetimibe work?

Answer 16

It selectively inhibits intestinal cholesterol absorption

Question 17

What are the effects of ezetimibe?

Answer 17

Reduced delivery of cholesterol to the liver
Increased expression of hepatic LDL receptor
Reduced cholesterol content of atherogenic particles

Question 18

What are some ADRs with ezetimibe?

Answer 18

Headache
Abdominal pain
Diarrhoea

Question 19

Quick overview of each drug and how it works:

Statin

Nicotinic acid

Fibric acid derivative

Ezetimibe

Answer 19

Statin: HMG CoA reductase: reduce production of cholesterol

Nicotinic acid: prevents formation of VLDL in the liver and increases HDL at higher doses

Fibric acid derivative:
PPAR agonist- increased production of lipoprotein lipase - reduces triglyceride pduction by 10-20% in LDL
Increases fatty acid uptake and oxidation

Ezetimibe- prevents intestinal absorption of cholesterol