Lipid-Lowering Drugs

Question 1

What is primary hyperlipidaemias?

Answer 1

• Monogenic (severe and rare)
• -> E.g. familial hypercholesterolaemia
• Polygenic (moderate and common)

Question 2

What does secondary hyperlipidaemia involve?

Answer 2

• Very common

- Alcohol, hypothyroidism, diabetes, diet

Question 3

What are the classes of lipid-lowering drugs?

Answer 3

• Statins e.g. simvastatin, atorvastatin
• Fibrates, e.g. clofibrate
• Nicotinic acid
• Drugs that reduce cholesterol absorption from gut
• Others

Question 4

Give examples of drugs that reduce cholesterol absorption from gut

Answer 4

• Anion-exchange resins (e.g. cholestyramine)
• Lipase inhibitor (orlistat)
• Nutraceuticals (phytosterols)
• Cholesterol transporter NPC1L1 inhibitor (ezetimibe)

Question 5

Give examples of other classes of lipid-lowering drugs

Answer 5

• PCSK9 inhibitors

- Maybe fish oils

Question 6

What are the lipoproteins?

Answer 6

• Triglyceride (Structural)
• Phospholipid (structural)
• Cholesterol (structural)
• Apolipoprotein- LP without lipid
• Chylomicron
• VLDL
• LDL
• HDL
• Get smaller and denser

Question 7

Describe triglyceride as a structural component of a lipoprotein

Answer 7

• Glycerol backbone, 3 fatty acids
• Important for energy and are stored in adipose tissue
• Carried in lipoproteins in interior lipoprotein

Question 8

Describe phospholipid as a structural component of lipoprotein

Answer 8

• One fatty acid replaced with phosphate

Question 9

Describe cholesterol as a structural component of a lipoprotein

Answer 9

• Impermeabilise cell membranes

- Without these, water flows through

Question 10

Describe a chylomicron as a lipoprotein

Answer 10

• Takes large amounts of triglycerides form the gut to liver

Question 11

Describe VLDL as a lipoprotein

Answer 11

• Very low-density lipoprotein

- Transports from liver to tissue

Question 12

Describe LDL as a lipoprotein

Answer 12

• Low-density lipoprotein
• Carry from tissue
• Excessive LDL cholesterol with or without triglycerides is known as type 2 hyperlipidaemia- associated with CVD

Question 13

Describe HDL as a lipoprotein

Answer 13

• High-density lipoprotein
• Tissues to liver
• Repeat the cycle

Question 14

What are the risk factors for atheroma/ CAD?

Answer 14

• Raised total cholesterol (>5mmol/l)
• Raised LDL cholesterol (>3mmol/l)
• Reduced HDL (<1mmol/l)
• Raised triglycerdies- acute pancreatitis
• If lipids not effectively handled, deposited in areas of endothelial damage- might be caused by smoking of high BP
• • atheroma–> angina–> MI/ ischaemic stroke

Question 15

How are lipids packaged in the gut following digestion?

Answer 15

• Dietary fat (cholesterol and triglycerides)
• Packaged into chylomicron
• Transports to a liver cell

Question 16

What happens after cholesterol and triglyceride packaged into a chylomicron reach the liver cell?

Answer 16

• They are packages up to VLDLs and sent to the periphery

Question 17

What happens if inadequate amounts of cholesterol are found in the diet?

Answer 17

• Acetyl CoA pathway

- HMG CoA reductase (hydroxymethylglutaryl coenzyme A reductase)

Question 18

What does LDL do with cholesterol and triglycerides after VLDLs?

Answer 18

• Removes fatty acids for burning for energy or muscles or storing in adipose tissue for future use
• Activated by lipoprotein lipase- controlled by insulin

Question 19

What happens to LDL after is deposits fatty acids?

Answer 19

• LDL and HDL return to liver cells where there are LDL receptors
• Vital role in regulating cholesterol in circulation

Question 20

What happens to excess LDL?

Answer 20

• LDL remains too long becomes oxidised and is a risk for atheroma

Question 21

What is the purpose of liver cells?

Answer 21

• Aim to maintain their internal cholesterol

Question 22

How can HMG CoA reductase be inhibited?

Answer 22

• Statins

Question 23

How might the liver prevent excess circulating LDL?

Answer 23

• By inducing expression of LDL receptors

Question 24

Give some examples of statins

Answer 24

• Simvastatin
• Pravastatin
• Fluvastatin
• Atorvastatin

Question 25

What do Statins do?

Answer 25

- Inhibit HMG CoA reductase - Compensatory increase in hepatic LDL receptors clears plasma LDL cholesterol (20-50%) - Decrease triglycerides (25%) - Increase HDL (15%)

Question 26

What do statins treat?

Answer 26

- First line for hypercholesterolaemia to reduce progression of atherosclerosis - Primary prevention of MI and stroke - Secondary prevention of MI and stroke

Question 27

What are some other effects of statins?

Answer 27

- Reduced vascular inflammation and thrombosis - Improved endothelial function and plaque stability\ - Reduced cancer deaths (prostate and colorectal cancers)

Question 28

What are some unwanted effects of statins?

Answer 28

- Myalgia (<5%) - Rhabdomyolysis (muscle breakdown --> acute renal failure) - More common, and 10x higher with a fibrate)

Question 29

What do fibrates do?

Answer 29

- Activate and enhance activity of lipoprotein lipase - May also reduce release of VLDL - Reduce amount of cholesterol going through cycle - Reduce risk of excess LDL

Question 30

Give examples of fibrates

Answer 30

- Clofibrate | - Fenofibrate

Question 31

What is the mechanism of fibrates?

Answer 31

- Activate PPAR alpha (peroxisome proliferator-activated receptor α) - Decreases synthesis of VLDL - Activates lipoprotein lipase - Redues plasma triglycerides by 20-50% - LDL decreased and HDL increased

Question 32

What are fibrates?

Answer 32

- First line drugs for hyper-TG (Reduces pancreatitis - Effects on CAD are variable (gemfibrozil best) - Can be combined with statins

Question 33

What are the side effects of fibrates?

Answer 33

- NVD - Myositis/flu - Gall stones

Question 34

What does nicotinic acid do?

Answer 34

- Inhibits diacylglycerol acyltransferase-2 (DGAT2) - -> Prevents cholesterol and TG combination to produce VLDLs - Reduces TG synthesis and release from liver - Lowers plasma TF by 20-50% and LDL by 10-20% - Combines with fibrates for hypertriglyceridemia

Question 35

What are the side effects of nicotinic acid?

Answer 35

- Flushing (prostaglandins) - Itching - Dizziness - Palpitations - Hyperglycaemia - Gout - Poorly tolerated - Acipimox better tolerated by less effective

Question 36

How do ion exchange resins affect bile acids?

Answer 36

- Bile acids normally emulsify fats in gut for better absorption - Ion exchange resin forms complex with bile acids, so dietary lipids are not emulsified but excreted - Not absorbed in the gut - Also clear plasma LDL cholesterol

Question 37

Give examples of anion exchange resins

Answer 37

- Cholestyramine | - Colestipol

Question 38

How are ion exchange resins administered?

Answer 38

- Combination therapy for severe hyperlipidaemia | - Side effects- gut only (bloating, NVD, decreased fat-soluble vitamin absorption)

Question 39

What are lipase inhibitors?

Answer 39

- E.g. orlistat | - Blocks breakdown of TG to fatty acids within the gut

Question 40

What are nutraceuticals?

Answer 40

- E.g. plant sterols - Reduce gut absorption of cholesterol - But no by much and rather expensive

Question 41

What is ezetimibe and what does it do?

Answer 41

- Inhibits intestinal cholesterol transport (NPC1L1) - Halves cholesterol absorption and reduced plasma LDL-C by 15% - Used as adjunct to diet and statins in hypercholesterolaemia

Question 42

What are PCSK9 inhibitors and give examples?

Answer 42

- E.g. alirocumab and evolocumab - Monoclonal Abs block pro protein converts subtilisin/kexin type 9 - Reduces degradation of LDL receptors on hepatocytes by PCSK9 - Reduces plasma LDL-C by 45-70% - Given subcutaneously every 2 wks for resistant primary hypercholesterolaemia (combined with statins and other drugs)