Atherosclerosis - 3

Question 1

Fibrates - why are they not used much any more? When are they commonly used?

Answer 1

Only really used when statins not tolerated

Used in combo with other lipid lowering drugs in patients w severe treatment-resistant dyslipidaemia

Question 2

Fibrates mechanism of action?

Answer 2

Activate PAR recep –> switches on lipid metabolising enzymes
Decreases circulating LDL
Metabolised by cytochrome p450 found in the liver and intestine
Enzyme oxidises small foreign organic molecules eg drugs and toxins so that they can be removed from the body
Reduce non fatal MIs

Question 3

Effects of fibrates?

Answer 3

Decreases circulating LDL
Reduce non fatal MIs
Decrease circulating VLDLs, moderate decrease in LDL and modest increase in HDLs (10% and 10% respectively)

Question 4

Adverse side effects - fibrates?

Answer 4

Stomach upset
Neuropathy
Muscle damage and inflammation
Kidney disease

Question 5

Cholesterol absorption inhibitors - example? How do they work and

Answer 5

EZETIMIBE - stops production of chylomicrons to prevent exogenous pathway
Blocks absorption in the intestine by blocking transport protein in enterocyte brush borders
Generally given to patients who get side effects from statins

Question 6

EZETIMIBE - why useful?

Answer 6

Doesn’t impact fat soluble vitamins, triglycerides or bile acids
High potency (10 mg/day causes 17-19% reduction in LDL) - can conveniently be taken once a day therefore
Taken in combo with statin to increase to around 25% reduction
Taken orally with long half life - 80% each dose actively metabolised
Low potential to interact with other meds

Question 7

EZETIMIBE - side effects?

Answer 7

Mild - diarrhoea, abdom pain, headache, rashes, oedema, NOT TO BE USED IN PREGNANCY
EXPENSIVE!!!!!

Question 8

Resins - mechanism of action?

Answer 8

Target bile acids by preventing their absorption of them into the bloodstream
Liver compensates by increasing production of LDLrs, increasing clearance of LDLs and decreasing concentration of LDL in the plasma therefore

Question 9

Resins - adverse effects

Answer 9

Negatively impact the gut and cannot be taken with other meds due to high number of interactions
Intolerance - must be taken 1-6 hours before other meds

Question 10

Plant sterols/stanols - derived from? Used to make? Mechanism?

Answer 10

Isolated from wood pulp, used to make yogurts and margarine
Structurally similar to cholesterol – less cholest absorbed into bloodstream as chylomicrons as chylomicrons are carrying plant stanol rather than cholesterol –> reduced serum LDL concentration

Need to be taken as part of a meal for optimal efficacy and to retain their efficacy long term

Question 11

PCSK9 inhibitors - what are they? Mechanism

Answer 11

EVOLOCUMAB
PCSK9 = negative regulator of LDLr, binds to receptor and complex is internalised
Receptor they undergoes lysosomal degradation and LDL continues to circulate
These drugs aim to prevent this mechanism increasing LDL clearance and lowering circulating LDL levels

Question 12

PCSK9 –|s and STATINS – taken in combo with statins

Answer 12

Causes large reduction in circulating cholesterol
Sub cutaneous injection
+ Good diet
Treatment for familiar hypercholesterolaemia / CVD where an additional lowering of LDL-C is needed

Question 13

Adverse effects of PCSK9 –|s

Answer 13

Nasopharyngitis
Upper respire tract influenza
Back pain
Injection site reaction
Hypersensitivity reactions