Lipid Lowering Drugs

Question 1

Name the 6 drug classes to treat dyslipidemias

Answer 1

1. Omega-3-acid ethyl esters
2. PCSK9 inhibitors
3. Fibrates
4. Resins
5. HMG-CoA reductase inhibitors (Statins)
6. Ezetimibe

Question 2

Name 3 examples of statins

Answer 2

Atorvastatin, pravastatin, simvastatin

Question 3

MOA of statins

Answer 3

1. Competitive inhibitor of HMG-CoA reductase (rate limiting enzyme for endogenous cholesterol synthesis), reduce conversion of HMG-CoA to mevalonic acid, thus overall decreasing cholesterol synthesis
2. Upregulates LDL receptor on cell surface: Decreased intracellular cholesterol causes the cell to increase specific cell-surface LDL receptors that can bind and internalise circulating LDLs

Question 4

2 clinical uses of statins

Answer 4

1. Lower LDL levels in all types of dyslipidemias
2. Reduce the risk of coronary events or mortality in patients with IHD

Question 5

Which time of the day are statins commonly given?

Answer 5

Evening (because dietary cholesterol is low, so body needs to produce more endogenously, thus statins most effective)

Question 6

Give 2 ADRs of statin use

Answer 6

1. Biomedical abnormalities in liver function
2. Muscles: myopathy and rhabdomyolysis (causes tea coloured urine)

Question 7

Statins are contraindicated in (4 types of patients)… because…

Answer 7

1. Pregnancy
2. Nursing mothers
3. Children
4. Teenagers
   Known to affect neurodevelopment in foetus and child

Question 8

State 2 examples of PCSK9 inhibitors

Answer 8

1. Evolocumab
2. Alirocumab

Question 9

MOA of PCSK9 inhibitor

Answer 9

Inhibits PCSK9 which targets LDL receptors for degradation by lysosomes.
Thus reduces degradation of LDL receptors, so increases the number of cell-surface LDL receptors that can bind and internalise circulatory LDL

Question 10

State 2 clinical uses of PCSK9 inhibitors

Answer 10

1. Lower LDL levels in the blood in familial hypercholesterolemia patients especially if they’re intolerant to statins
2. Clinically significant atherosclerotic CVD patients requiring additional LDL lowering therapy after being on diet control and maximally tolerated statin therapy

Question 11

Administration of PCSK9 inhibitors

Answer 11

IV (monoclonal antibody)

Question 12

Advantage of taking PCSK9 in combination with statins

Answer 12

Can lower LDL levels by about 50-60% more than if statins are used alone

Question 13

Give 2 ADRs of PCSK9 inhibitor use

Answer 13

1. Inflammatory reactions at the site of injection
2. Increased incidence of nasopharyngitis and sinusitis

Question 14

PCSK9 inhibitors are contraindicated in patients that develop…

Answer 14

Hypersensitivity reactions

Question 15

Name 2 examples of fibrates / fibric acid derivatives

Answer 15

1. Gemfibrozil
2. Fenofibrate

Question 16

MOA of fibrates

Answer 16

Direct ligand for PPAR-alpha. Interaction with PPAR-alpha increases activity of lipoprotein lipase (LPL).
Effects:
- Increased breakdown of plasma TAG
- Plasma VLDL decreases in part due to decreased secretion by liver
- Plasma HDL rises moderately

Question 17

Clinical use of fibrates

Answer 17

Treatment of hypertriglyceridemia with VLDL elevation, especially in patients with dysbetalipoproteinemia

Question 18

Name 4 ADRs of fibrate use

Answer 18

1. GI effects: nausea
2. Skin rashes
3. Gallstones
4. Myositis

Question 19

Name a omega-3-acid ethyl ester drug

Answer 19

Omacor

Question 20

State the 2 omega-3-acid ethyl ester components in omacor

Answer 20

EPA and DHA

Question 21

MOA of omega-3-acid ethyl esters

Answer 21

1. Reduces TG production and increases TG clearance from VLDLs
2. DHA and EPA are weak substrates for diglyceride acyltransferase enzyme, thus omacor is a functional inhibitor of the enzyme, which reduces TG biosynthesis
3. Increased fatty acid breakdown by beta oxidation

Question 22

2 clinical uses for omega-3-acid ethyl esters

Answer 22

1. Used with dietary measures in hypertriglyceridemia (type IV)
2. Used with statins for familial combined hyperlipidemia (type IIb)

Question 23

2 types of dyslipidemias where omega-3-acid ethyl esters are NOT useful

Answer 23

1. Hyperchylomicronemia (type I)
2. Familial hypercholesterolemia (Type IIa): LDL related issue, thus not effective

Question 24

Omega-3-acid ethyl esters are contraindicated in patients…

Answer 24

Allergic to fish

Question 25

Name 3 possible ADRs of omega-3-acid ethyl esters use

Answer 25

1. GI symptoms: diarrhoea, flatulence, pain, dyspepsia, constipation, abdominal distension 2. Decrease production of thromboxane A2 (thus could increase bleeding time, use in caution with patients on anticoagulants) 3. Potential increase in LDL in some patients due to DHA

Question 26

Use of omega-3-acid ethyl esters should be cautioned in patients on...

Answer 26

Anticoagulants (due to decreased thromboxane A2 production, causing increased bleeding time)

Question 27

Name a bile acid binding resin

Answer 27

Cholestyramine

Question 28

MOA of cholestyramine

Answer 28

Bind to negatively charged bile acids and bile salts in the small intestine. This lowers the bile acid concentration recycled back to the liver, thus liver increases conversion of cholesterol to bile acids, thus intracellular cholesterol concentration decreases. Results in increased hepatic uptake of cholesterol-containing LDL particles, causing a fall in LDL in plasma

Question 29

2 clinical uses of cholestyramine

Answer 29

1. Treat primary hypercholesterolemia (type IIa) 2. With niacin: LDL elevations in familial combined hyperlipidemia (type IIb)

Question 30

Mode of administration of cholestyramine

Answer 30

Oral

Question 31

2 ADRs of cholestyramine use

Answer 31

1. GI symptoms: constipation, nausea, flatulence 2. Decreased absorption of fat soluble vitamins: ADEK

Question 32

MOA of ezetimibe

Answer 32

Inhibitor of NPC1L1 sterol transporter which reduces the intestinal absorption of sterols like cholesterol

Question 33

Clinical use of ezetimibe

Answer 33

To reduce plasma LDL levels *Greater decrease in LDL when used with statins (eg ezetimibe with simvastatin = Vytorin)

Question 34

2 ADRs of ezetimibe use

Answer 34

1. GI effects: diarrhoea, flatulence 2. Rhabdomyolysis (common when used with statins)

Question 35

Ezetimibe use is associated with low incidence of

Answer 35

Hepatotoxicity