Lipid Lowering Drugs

Question 1

Where specifically in the blood vessels to atherosclerotic plaques develop?

Answer 1

In the intima [of large and medium sized arteries).

Question 2

What is the first clinical appearance of a plaque?

Answer 2

Stable (exertional angina).

Question 3

What biochemical increases with plaque development?

Answer 3

C-reactive protein (not very specific)

Question 4

What BMI does the WHO consider overweight?

Answer 4

20

Question 5

What three things are in the outer coat of lipoproteins?

Answer 5

cholesterol, phospholipids, apolipoproteins

Question 6

What two things are in the core of lipoproteins?

Answer 6

cholesterol esters, triglycerides.

Question 7

Because lipid-lowering drugs are expensive, they have the most benefit to patients with…

Answer 7

…high risk of CV events, or high cholesterol.

ALWAYS treated in conjunction with reduction of modifiable risk factors.

Question 8

List eight modifiable risk factors for plaques

as always just say diabetes at least

Answer 8

lipid profile,
diabetes,
weight, 
tobacco intake, 
alcohol intake, 
diet (salt/fat), 
exercise, 
hypertension.

Question 9

List four non-modifiable risk factors

Answer 9

ethnicity
age
sex (male)
family history

Question 10

In what way do fibrates sorta influence reverse cholesterol transport?

Answer 10

Lower VLDL secretion, meaning lower future CETP-mediated redistribution of cholesterol via ApoB-48 lipoproteins to the periphery. More delivered straight back to the liver.

Question 11

What are the first-line lipid-lowering drugs?

Answer 11

Statins

Question 12

What does HMG-CoA reductase catalyse?

Answer 12

HMG-CoA → mevalonic acid

Question 13

What is the hepatic cholesterol synthesis rate-limiting enzyme that statins competitively, reversibly inhibit?

Answer 13

HMG-CoA reductase.

Question 14

What is the net effect of statins?

Answer 14

20-50% reduction in LDL.

Question 15

Statins, resins and fibrates’ mechanisms aren’t related to LDLr, but as the diagram points out, they increase LRLr-mediated uptake of LDLs. Explain.

Same resins.

Answer 15

It’s a net effect brought on by cholesterol starvation in the liver. Hepatocytes avoid cholesterol starvation by increasing LDLr expression, promoting accumulation in the hepatic compartment by uptake of LDLs (and chylomicron remnants). IOW they promote clearance of LDL from circulation.

Same with resins.

Question 16

What are the second-in-line drugs when LDL is elevated?

Answer 16

Bile-acid-binding resins.

Cholestyramine, colestipol.

Question 17

What are the two resins?
Both have the fat in their name. What should mum have used on the floor? What do MAOIs increase that we with they wouldn’t?

Answer 17

Colestipol, cholestyramine

Question 18

What are the two resins? (no prompts)

Answer 18

Colestipol, cholestyramine

Question 19

Why isn’t the reduction in circulating cholesterol as low as we’d predict in resin therapy?

Answer 19

Reduction in cholesterol form bile reabsorption results in increased cholesterol synthesis.
The net reduction is due to reduction in the overall cholesterol economy and increased LRLr expression.

Question 20

What are the two downsides to resins?

Answer 20

GI complaints (indigestion, bloating, constipation). 
Can bind other drugs in the GI tract. But avoidable if taken in 3-4 hours isolation.

Question 21

Fibrates are a first-line therapy to control cholesterol. T or F?

Answer 21

FALSE - they are a first line therapy, but for triglycerides (not cholesterol).

Question 22

What four things do we need to know about the mechanism of fibrates?

Answer 22

1. Involves fatty acid oxidation
2. Involves PPARs
3. Increases LRLr LDL uptake
4. Inhibits cholesterol and bile synthesis - enhances cholesterol secretion in the bile.

Question 23

What are two big risks of fibrate therapy?

Answer 23

Gallstones (increase bile cholesterol content)

Myopathy (with CPK elevation)

Question 24

What are the poorly tolerated (not unsafe) effects of fibrates?
The bald man made a rash decision to get out of bed too quickly with a tummy upset.

Answer 24

Mainly tummy upset, also rash fatigue and hair loss.

Question 25

What are the poorly tolerated (not unsafe) effects of fibrates?
No prompts

Answer 25

Mainly tummy upset, also rash fatigue and hair loss.

Question 26

In the liver, niacin inhibits X. In adipose tissue, it inhibits Y.
It can even Z if very low.

Answer 26

Liver: triglyceride synthesis.
Adipose: lipolysis.
It can even elevate HDL if it’s very low.

Question 27

Niacin is cheap and effective but patient compliance is poor. Aside from myopathy and hepatotoxicity (same as fibrates), what four things are overtly bothersome?

Answer 27

Gastric irritation, gout, flushing, impaired glucose tolerance.

Question 28

Eww there’s a zit in my bowl.

What’s that cholesterol absorption inhibitor called?

Answer 28

Ezitimibe.

Question 29

Where does ezitimibe block cholesterol absorption?

Answer 29

Enterocytes in the duodenum.

Question 30

What are the adverse effects of ezitimibe?

Imagine shitting uncontrollably for hours on the toilet. How would that feel?

Answer 30

Abdominal pain, diarrhoea, headache

Question 31

How can you decrease LDL cholesterol with plant sterols? What can you expect?

Answer 31

Eat about 2-3g a day, leading to around a 10% decrease in LDL cholesterol.
You may need to compensate for carotenoids.