Cholesterol Lowering Drugs

Question 1

What forms the central core of a hydrophobic lipid?

Answer 1

Lipoproteins

Question 2

Provide an example of a hydrophobic lipid in which lipoproteins form a core

Answer 2

– triglycerides or cholesterol esters

Question 3

What role do lipoproteins play in polar substances?

Answer 3

Hydrophilic coat of polar substances 
– phospholipids
– free cholesterol
– associated proteins
    • apoproteins or apolipoproteins

Question 4

What features are used to classify lipoproteins?

Answer 4

– core lipids
– apoproteins
– size
– density

Question 5

What are the five main classes of lipoproteins?

Answer 5

1) High density lipoproteins (HDL)
2) Intermediate density lipoproteins (IDL)
3) Low density lipoproteins (LDL)
4) Very low density lipoproteins (VLDL)
5) Chylomicrons

Question 6

What do chylomicrons do?

Answer 6

Chylomicrons transport TG (triglycerides) and cholesterol esters from the GI to tissues
– Split by lipoprotein lipase to release free fatty acids (FFAs)
– FFAs taken up by muscle and adipose tissue

Question 7

What happens to chylomicron remnants?

Answer 7

Chylomicron remnants taken up in the liver

– Cholesterol stored, oxidised to bile acids or released to VLDL

Question 8

What does VLDL do?

Answer 8

VLDL transport cholesterol and newly synthesised TG to tissues
– TGs removed from VLDL leaving LDL with a high cholesterol (taken up by cells or liver)

Question 9

What does HDL do?

Answer 9

HDL absorbs cholesterol from cell breakdown and transfer it to VLDL and LDL

Question 10

Describe lipoprotein metabolism’s impact on health

Answer 10

↑ plasma cholesterol associated with ↑ LDL is a risk factor for atheromatous disease
– may lead to atherosclerosis, ischaemic heart disease, myocardial infarction & cerebral vascular accidents

An increase in the plasma concentration of lipids is called hyperlipidaemia

Question 11

What is an increase in the plasma concentration of lipids called?

Answer 11

hyperlipidaemia

Question 12

What is associated with a high plasma conc. of total and LDL cholesterol?

Answer 12

↑ risk of atherosclerosis and CHD associated

Question 13

Where in the artery wall do plaques form?

Answer 13

The intima

Question 14

What is the average total cholesterol level in the UK?

Answer 14

5.7mmol/l

Question 15

What is the ideal total cholesterol level?

Answer 15

< 5mmol/l

Question 16

What are the ranges of considered cholesterol severity?

Answer 16

Ideal level (< 5mmol/l)

Mildly high cholesterol level (5 to 6.4mmol/l)

Moderately high cholesterol level (6.5 to 7.8mmol/l)

Very high cholesterol level (> 7.8mmol/l)

Question 17

Other than total cholesterol level what factors have to be taken into account in assessing someones risk presented by cholesterol level?

Answer 17

– the ratio between “good” (HDL) and “bad” (LDL) cholesterol
– other risk factors for cardiovascular disease,
• e.g. smoking, diabetes, high blood pressure

Question 18

What is the aim of lipid lowering drugs?

Answer 18

Aim is to reduce plasma cholesterol
– Lifestyle modification (i.e. diet and exercise) is first step
– Drug therapy should be secondary

Question 19

How do lipid lowering drugs work?

Answer 19

Work either by reducing production of lipoproteins or by increasing their removal from the blood

Question 20

How does the body accumulate cholesterol?

Answer 20

Cholesterol is derived from 3 sources
– De novo synthesis in liver
– Uptake form circulating LDLs
– Uptake of chylomicron remnants

Question 21

What actions may drugs take to lower cholesterol?

Answer 21

Sequester bile acids in the intestine/Decrease hepatic stores of cholesterol
– e.g. colestyramine

Inhibit transport protein for cholesterol in the brush border of enterocytes in the duodenum
– e.g. ezetimibe

Alter the levels of plasma lipoproteins
– e.g. fenofibrate, bezafibrate, gemfibrozil & nicotinic acid

Inhibit the synthesis of cholesterol in the liver
– e.g. simvastatin, pravastatin, atorvastatin, rosuvastatin

Question 22

What is colestyramine?

Answer 22

Is a basic anion exchange resin

Question 23

What does colestyramine do?

Answer 23

– sequesters bile acids to prevent enterohepatic recirculation
– Therefore ↑the metabolism of endogenous cholesterol into bile acids
– ↑ LDL receptor numbers in the liver resulting in the removal of LDLs from the blood

Question 24

How effective are bile-sequestering drugs?

Answer 24

Bile-sequestering drugs plus inhibitors of cholesterol biosynthesis can lower blood cholesterol by 50%

Question 25

What are fibrates?

Answer 25

activators of lipoprotein lipase

Question 26

Name some fibrates

Answer 26

Fenofibrate, gemfibrozol

Question 27

What do fibrates do?

Answer 27

– ↓plasma triglycerides and, to a lesser extent, cholesterol
– Particularly ↓ elevated concentrations of VLDL

– Main action is stimulation of lipoprotein lipase which ↓ the triglyceride content of VLDL

– Clearance of LDL by the liver is also stimulated
– ↑ HDL production and reverse cholesterol transport

Question 28

In what clinical situations may fibrates be used?

Answer 28

Mixed dyslipidaemia (i.e. raised serum triglyceride as well as cholesterol)

In patients with low HDL and high risk of atheromatous disease (e.g. Type 2 diabetes)

Combined with other lipid-lowering drugs in patients with severe treatment resistant dyslipidaemia

Question 29

What is nicotinic acid?

Answer 29

(niacin)

Vitamin with lipid-lowering properties

Question 30

What does nicotinic acid (niacin) do?

Answer 30

– ↓ VLDL production which leads to a ↓ in LDL – Also activates lipoprotein lipase

Question 31

What does ezetimibe do?

Answer 31

Specifically reduces intestinal cholesterol absorption

– Inhibits a sterol carrier protein in the brush border of the enterocytes

Question 32

What are statins?

Answer 32

Hydroxymethlglutamyl-coenzyme A reductase (HMG-CoA reductase) inhibitors

Question 33

What is HMG-CoA reductase?

Answer 33

– Major rate-limiting step in cholesterol synthesis

– Converts HMG-CoA to mevalonic acid (MVA)

Question 34

What are simvastatin, pravastatin, atorvastatin and rosuvastatin?

Answer 34

– long-lasting HMG-CoA reductase inhibitors

Question 35

What is the mevalonate pathway?

Answer 35

One half = cholesterol synthesis

Other half = protein prenylation

Question 36

What is protein prenylation?

Answer 36

Addition of lipid tails to small GTPase signaling molecules
Ensures they are localised correctly
(Ras and Rho)

Question 37

What are the clinical uses of statins?

Answer 37

Secondary prevention of myocardial infarction and stroke in those who have atherosclerotic diseases

Primary prevention of arterial disease in patients with high serum cholesterol

Atorvastatin lowers serum cholesterol in familial hypercholesterolaemia

Question 38

What are the side effects of statins?

Answer 38

Statins can cause myositis, angio-oedema, GI disturbances, insomnia, rash

Question 39

What are the side effects of fibrates?

Answer 39

Fibrates can cause myositis (esp. in patients with renal impairment), GI disturbances

Question 40

What are the side effects of colestyramine + ezetimibe?

Answer 40

Colestyramine, ezetimibe can cause GI symptoms (nausea, abdominal bloating, constipation, diarrhoea)

Question 41

What are the side effects of nicotinic acid (niacin)?

Answer 41

Nicotinic acid can cause flushing, palpitations, GI disturbances

Question 42

Name some PCSK9 inhibitors

Answer 42

Alirocumab and evolcumab

Question 43

What do PCSK9 inhibitors do?

Answer 43

PCSK9 is an enzyme that mediates the degradation of LDL receptors on surface of liver cells.
Inhibiting this enzyme increases the amount of LDL bound and removed by the liver.