Anti-lipid agents

Question 1

Steps in the pathogenesis of atherosclerosis

Answer 1

LDL accumulates in tunica intima and becomes oxidised.

LDL is taken up into macrophages resulting in foam cells. Smooth muscle proliferates.

Question 2

What are fatty streaks?

Answer 2

These are the initial manifestations of atherosclerotic processes in the intima of large blood vessels. This is a complex picture, however, as not all plaques actually develop at the sites where there were fatty streaks.

Question 3

MOA of Statins

Answer 3

Inhibit HMG-CoA reductase, the rate controlling enzyme in the Mevalonate pathway. This reduces cholesterol production within the cell which has two effects:

a) Less cholesterol is exported in VLDL.
b) Liver cell senses a low [cholesterol] intracellularly and expresses more LDL receptors, promoting more uptake of cholesterol from LDL receptors.

Question 4

Name two commonly prescribed statins

Answer 4

• Atorvastatin

- Simvastatin

Question 5

What effect can statins have on vascular endothelium?

Answer 5

Improved function, with increased levels of NO (Vasodilator) and VEGF. Levels of the Vasoconstrictor endothelin are decreased.

Question 6

What effect do statins have on atherosclerotic plaques?

Answer 6

They stabilise them by decreasing smooth muscle cell proliferation and promoting increased collagen expression.

Question 7

Pharmacokinetics of Statins

Answer 7

Both are prodrugs activated by first pass metabolism. Atorvastatin has a longer half life. Metabolism is by CYP3A4.

Question 8

Adverse effects of Statins…

Answer 8

• Some reversible increase in liver enzyme levels.
• Myalgia (creatine phosphokinase > 10x normal limit).
• A mutation gives some people an increased risk of Rhabdomyolysis.
• GI disruption, nausea and headache also possible.

Question 9

Use of statins in primary prevention…

Answer 9

If 10 year Q risk is > 10% patients should be started on ATORVASTATIN 20mg OD.

Question 10

Use of statins in secondary prevention…

Answer 10

Used in people who have had a cardiovascular episode. ATORVASTATIN 80mg OD. Must be decreased to 20mg in patients with CKD.

Question 11

Grapefruit Juice + Statins

Answer 11

Grapefruit juice is an inhibitor of CYP 3A4. Inhibition of this will lead to an increase in the concentration of statins in the blood and an indication in side effects from this.

Question 12

Give two fibrate drugs…

Answer 12

• Fenofibrate
• Ciprofibrate

Gemfibrozil is another.

Question 13

MOA of Fibrates

Answer 13

Activate the transcription factor PPAR-alpha. This increases the production of lipoprotein lipase, increasing the clearance of triglycerides from lipoproteins, clears LDL (by increasing its affinity for its receptor). HDL Increases, effect on LDL is a minor one.

Question 14

When are fibrates used?

Answer 14

• If statins are contraindicated.
• If the problem is primarily one of increased triglycerides.
• As an adjunct to statins in patients not getting good control on statin monotherapy and who have raised Q-ris scores.

Question 15

Fibrate ADR’s

Answer 15

May cause myositis, gallstones and GI upset. May derange LFT’s and potentiate warfarin: fenofibrate is highly albumin bound.

Do not use (or use carefully) if patient is hepatically or renally impaired.

Question 16

Nicotinic Acid/Niacin

Answer 16

Has some VLDL/LDL lowering effect but its main effect is to raise HDL. This is not used very commonly.

Question 17

Niacin ADR’s

Answer 17

• Headache, Itching and Flushing (low does aspirin 30 mins before can reduce these by decreasing prostaglandin release).
• GI disturbance and hepatotoxicity.

Question 18

Give an example of a cholesterol absorption inhibitor.

Where does it work and how?

Answer 18

Ezetimibe - Acts at the brush border of the small intesting inhibiting a transporter (NCPC 1L1), decreasing cholesterol absorption at the gut by 50%.

Question 19

Ezetimibe Effects.

Answer 19

LDL receptor expression increases, total cholesterol and LDL down by 20%.

Question 20

What is Ezetimibe metabolised into?

Answer 20

Ezetimibe glucoronide. This converts this prodrug into its active form and this passes out into the bile thus entering the enterohepatic circulation. This limits the exposure of the rest of the body to it.

Question 21

ADR’s of Ezetimibe

Answer 21

Headache
Abdominal Pain
Diarrhoea

Typically, however, it is well tolerated - more so than statins.

Question 22

When is Ezetimibe used?

Answer 22

It is used after a few different Statins have not worked or to keep doses low in patients with CKD.

Question 23

Monoclonal Antibody Options. MOA and examples.

Answer 23

Inhibit a protein called PCSK9 that would typically target internalised LDL receptors for degradation within the cells. By preventing this degradation we end up with more LDL receptors to take up this cholesterol and therefore highly significant reductions in LDL.

ALIROCUMAB AND EVOLOCUMAB.

Question 24

Use of Alirocumab and Evolocumab

Answer 24

Very expensive, injection only therapy so used in familial hypercholestrolaemia.

Question 25

Plant Sterols

Answer 25

Put in margarine etc. Competes with cholesterol for uptake. Works with statins but not with Ezetimibe.

Question 26

Fibre

Answer 26

Sequesters cholesterol within the gut lumen.