Dyslipidaemia

Question 1

Where does cholesterol come from and what is its role?

Answer 1

Cholesterol comes from dietary sources and from hepatocytes at night. Its an essential component of cell membranes and manufacture of steroid hormones, bile acid and vitamin D.

Question 2

How are lipids transported and what is the function of lipoproteins?

Answer 2

Lipoproteins are a water-soluble complex. The protein part of the complex is called an apoprotein. The function of lipoproteins is absorption and transport of dietary lipids by the small intestine, transport of lipids from liver to peripheral tissues. Transport of lipids from peripheral tissues to the liver and intestine.

Question 3

What is the consequence of high lipid states?

Answer 3

Increased levels of TGs –> acute pancreatitis. Increased levels of lipoproteins in plasma –> atherosclerosis.

Question 4

How does an inflammatory response result from the pathogenesis of atherosclerosis?

Answer 4

Activation of T-lymphocytes, macrophages and smooth muscle cells. Growth factor secretion, procoagulation and proinflammatory cytokines.

Question 5

What is the pathogenesis of atherosclerosis?

Answer 5

The endothelial lining becomes dysfunctional. LDL then cross this lining and accumulate in the intima. The LDL is then oxidised by enzymes derived from inflammatory cells. Monocytes bind to the endothelium and take up oxidized LDL to form foam cells. T-cells activate macrophages and causes smooth muscle cells to multiply. These cells produce collagen, take up LDL and form foam cells. Immune cells infiltrate into the intima and the plaque develops. Endothelial cells cover the plaque, but may become damaged causing platelets to form. Blood clots may break off and block an entire artery.

Question 6

What is the composition of an atherosclerotic plaque

Answer 6

Foam cells (originate from macrophages), collagen, fibrin, calcium and smooth muscle cells.

Question 7

What is the MoA of Statins?

Answer 7

They target the endogenous pathway of cholesterol production. They competitively inhibit the activity of HMG-CoA reductase. This means less cholesterol is produced and less VLDL and LDL is produced.

Question 8

What are some other benefits of statins other than decreasing LDL

Answer 8

It increases endothelial production of nitric oxide. It also improves plaque stability. Statins also decrease levels of CRP. They also reduce platelet aggregation and reduce the deposition of platelet thrombi.

Question 9

What are some adverse effects of statins?

Answer 9

GIT discomfort - minimized by taking with food
Myalgia - muscle stiffness, pain or weakness.
Rhabdomyolysis - Creatinine protein precipitation in the kidney, leading to renal failure. Contraindicated in pregnancy and lactation.

Question 10

What are some monitoring recommendations of statins?

Answer 10

Transaminase levels - baseline alanine transaminase. Myopathy - monitor creatine kinases level

Question 11

List 4 drug interactions of statins.

Answer 11

Inhibit CYP3A4 - macrolides, ketoconazole, PIs, fibrates, grapefruit juice.
Induce CYP3A4 - pheytoin, rifampicin, barbiturates.

Question 12

List some contra-indications to statin use.

Answer 12

Hepatic disease, concomitant use of CYP3A4 inhibitors, severe renal failure and use with gemfibrozil.

Question 13

What is the MoA of Nicotinic Acid?

Answer 13

Adipose tissue - inhibits adeylyl cyclase, which inhibits lipolysis, which decreases generation of FFA. Less FFA to liver for hepatic synthesis of TG.
Liver - reduced TG synthesis, decreases VLDL production.
In circulation - LDL levels decrease, TG decrease, increase HDL by decreasing its catabolism

Question 14

What are some adverse effects of nicotinic acid?

Answer 14

Flushing (take aspirin 30 min before), dry skin, GIT (take after meals), hepatotoxicity, diabetogenic.

Question 15

What are some drug interactions of nicotinic acid?

Answer 15

HMG-CoA RIs (Increased risk of rhabdomyolysis), antihypertensives (potentiates hypotension), warfarin (increased prothrombin time)

Question 16

What is the MoA of Fibrates?

Answer 16

They act as agonists for PPAR-alpha for gene transcription. They increase hepatic LDL receptors, increase oxidation of fatty acids in liver, increase lipolysis of TGs, increase HDL because of increased expression of apo A-1 and A-11.

Question 17

What are some PK of fibrates?

Answer 17

Well absorbed, if taken after a meal, except gemfibrozil, taken 30 min before food. No CYP involvement, dosage adjustment in renal impairment.

Question 18

What are some adverse effects of fibrates?

Answer 18

GIT disturbances, myalgia, arrhythmias, insomnia, alopecia, pruritus, impotence.

Question 19

What are some drug interactions of fibrates?

Answer 19

Warfarin (increase anticoagulant effect, reduce warfarin dose by half). Statins (risk of additive muscle effects and rhabdomyolysis). Sulphonylureas (hypoglycaemia), cholestyramine.

Question 20

What is the MoA of Bile Acid Sequestrants?

Answer 20

They bind to bile acids and are cleared faecally with bound bile acids. This prevents EHR, stimulating hepatic synthesis of bile acid, using hepatic Ch, decrease in hepatic Ch results in upregulation of LDL-receptors

Question 21

What are some bile acid sequestrants side effects?

Answer 21

GIT: constipation (increase fluid intake and psyllium), dyspepsia, bloating, may increase TG levels. Decrease absorption of fat-soluble vitamins.

Question 22

What is the MoA of Ezetimibe?

Answer 22

Inhibits intestinal absorption of phytosterols and dietary cholesterol, this leads to decreased hepatic cholesterol, which increased upregulation of LDL receptors, which reduce LDL levels.