hypercholestrolaemia

Question 1

Atherosclerosis and hypercholesterolemia definition and risk factors.

Answer 1

Hypercholesterolemia: elevated blood [cholesterol]. when total [cholesterol] > 6.5mmol/L. LDL:HDL ratio important

Focal plaque on the inner surface of an artery

Genetics, hypercholesterolemia, hypertension, smoking, obesity, hyperglycemia, reduced physical activity.

Question 2

Cholesterol endogenous roles and factors that influence conc

Answer 2

primary compontent of plasma membrane

Substrate for synthesis of bile, steroid hormones (test), and vit D.

Types of fats ingested influences blood cholesterol. dietary intake of cholesterol has small role

Question 3

Lipid and cholesterol transport

Answer 3

VLDL transports triacylglycerols to adipose and muscles.

LDL transports cholesterol from liver to cells, but also for uptake into the liver

HDL removes excess cholesterol from peripheral tissues.

LDL associated with CVD. opposite for HDL

Question 4

Non-pharmacolgoical managements

Answer 4

stop smoking.

Treating other diseases that may contribute, e.g., diabetes

Exercise.

Reduce saturated and trans fats intake.

Question 5

Atherogenesis and plaque formation

Answer 5

Damage to vascular endothelium (by smoking, hypertension, etc…) leads to monocytes and macrophages to respond.

The release of reactive oxygen species by monocytes oxidises LDL, to produce a worse form. This form will be taken up by receptors on the endothelium and in the macrophages.

The macrophages fill with cholesterol, eventually becoming cholesterol rich foam cells that accumulate in the space between the endothelium and the vascular SM. This continues to grow, until the foam cells begin to interfere with blood flow.

If the plaques rupture, platelet aggregation occurs, forming a clot in the blood vessel which can lead to complete occlusion (blockage)

Question 6

Statins

Answer 6

e.g., simvastatin (pro-drug for better bioavailability), pravastatin, atorvastatin

inhibit the enzyme HMG-CoA reductase, which catalyses the production of mevalonate, which is an intermediate in the synthesis of cholesterol.

they are hepatoselective

They also lead to an increase in hepatic LDL receptors, which are responsible for uptake of the bad LDL-cholesterol.

May lead to regression of atherosclerosis.

Monitor liver function. Rarely can cause rhabdomyolysis (destruction of muscle cells.

Question 7

Statins DDIs

Answer 7

simvastatin metabolised by CYP3A4.

amlodipine and other CYP3A4 inhibitors (like grapefruit) increase [simvastatin]

Question 8

Cholesterol absorption inhibiors

Answer 8

ezetimibe inhibits NPC1L1, an intestinal sterol transporter. Prevents absorption of dietary cholesterol. Can be used in conjunction with simvastatin

Question 9

Bind acid binding resins

Answer 9

colesytramine binds to bile salts in the intestine and prevents the reabsorption of cholesterol.

Also sees an increase in LDL receptors.

Question 10

PCSK9 inhibiors

Answer 10

e.g., alirocumab and evolocumab

Monoclonal antibodies for PCSK9, which breaks down LDL receptors in liver. Ultimately increases LDL-receptor concentrations, leading to higher uptake into the liver.

Inclisiran is an siRNA that also targets and inhibits PCSK9

Question 11

Fibrates

Answer 11

bezafibrate, gemofibrazil

activate PPAR-a, to promote breakdown of VLDL via the increased transcription of lipoprotein lipase, which metabolises triacylglycerols in the blood.

Also increases HDL, while decreasing LDL