Lipid Lowering Drugs

Question 1

Type I hyperlipoproteinaemia

Answer 1

Familial hyperchylomicronemia.
Deficiency in LPL results in elevated CM levels.
Cholesterol (+) and TG (+++)

Question 2

Type IIa hyperlipoproteinaemia

Answer 2

Familial hypercholesterolemia.
Decreased LDL-R levels results in elevated LDL.
Cholesterol (++)

Question 3

Type IIb hyperlipoproteinaemia

Answer 3

Familial combined (mixed) hyperlipidemia.
Overproduction of VLDL by the liver. Elevated VLDL and LDL.
Cholesterol (++) and TG (++)

Question 4

Type III hyperlipoproteinaemia

Answer 4

Familial dysbetalipoproteinemia.
Overproduction or underutilisation of IDL resulting in elevated beta VLDL (IDL) and CM remnants.
Cholesterol (++) and TG (++)

Question 5

Type IV hyperlipoproteinaemia

Answer 5

Familial hypertriglyceridemia.
Overproduction and/or decreased removal of VLDL triacylglycerol; elevated VLDL.
Cholesterol (+) and TG (++)

Question 6

Type V hyperlipoproteinaemia

Answer 6

Familial mixed hypertriglyceridemia.
Increased production or decreased clearance of VLDL and CM; elevated VLDL and CM.
Cholesterol (+) and TG (++)

Question 7

Name the 7 classes of drugs used in hyperlipidemias.

Answer 7

1. Omega-3 acid ethyl esthers
2. PCSK9 inhibitors
3. Niacin
4. Fibrates
5. Resins
6. HMG-CoA reductase inhibitors (“statins”)
7. Ezetimibe

Question 8

MOA of statins

Answer 8

1. Inhibits HMG-CoA reductase, the rate-limiting step in de novo cholesterol synthesis
2. Upregulates LDL receptors on the cell surface due to depletion of intraceullar cholesterol

Question 9

Two clinical uses of statins

Answer 9

1. Reduce plasma LDL-C levels in all types of hyperlipidaemias
2. Reduce risk of coronary events and mortality in patients with ischaemic heart disease

Question 10

How are statins administered?

Answer 10

Orally; in the evening

Question 11

Why are statins administered in the evening?

Answer 11

Inhibits de novo synthesis of cholesterol when its rate is the highest due to the lack of dietary intake of cholesterol.

Question 12

Three adverse effects of statins

Answer 12

1. Biomedical abnormalities in liver function
2. Myopathy and rhabdomyolysis
3. CI: pregnancy, nursing mothers, children and teenagers (affects neurodevelopment of fetus and child)

Question 13

Name the two PCSK9 inhibitors.

Answer 13

Evolocumab, alirocumab

Question 14

MOA of PCSK9 inhibitors

Answer 14

1. Inhibition of hepatic PCSK9 which targets LDL receptors for degradation in lysosomes
2. More LDL-R on the cell surface that can bind and internalise LDL-C in circulation

Question 15

Two clinical uses of PCSK9 inhibitors

Answer 15

1. Lowering of LDL-C in familial hypercholesterolaemia, esp. if intolerant to statins
2. In patients with clinically significant atherosclerotic CVD requiring additional LDL-C lowering even after diet control and maximally tolerated statin therapy

Question 16

How are PCSK9 inhibitors administered?

Answer 16

Injection, max. serum conc. after 3 or more days, dosing every 2-4 weeks

Question 17

Three adverse effects of PCSK9 inhibitors

Answer 17

1. Hypersensitivity reactions e.g. vasculitis or serious allergies
2. Injection site inflammatory reactions (erythema, itchiness, swelling, pain, tenderness)
3. Nasopharyngitis and sinusitis
   (Also expensive, and difficult to store and transport)

Question 18

Name the two fibrates.

Answer 18

Gemfibrozil, Fenofibrate

Question 19

MOA of fibrates

Answer 19

1. Ligands for PPAR-alpha, increasing activity of LPL (alters gene exp, slow onset)
2. Decrease in plasma TG levels
3. Decrease plasma VLDL due to decreased secretion by the liver
4. Rise in HDL levels

Question 20

Clinical use of fibrates

Answer 20

Treat hypertriglyceridaemias with elevated VLDL esp. dysbetalipoproteinaemia

Question 21

Name 4 adverse effects of fibrates

Answer 21

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

Question 22

MOA of omega-3-acid ethyl esters (Omacor)

Answer 22

1. Reduces hepatic TG production and increases TG clearance from VLDL
2. FUNCTIONAL inhibition of diglyceride acyltransferase (TG biosynthesis) as EPA and DHA are poor substrates
3. Increase free fatty acid breakdown (beta-ox)
4. Increases LPL activity

Question 23

Name two clinical uses of Omacor.

Answer 23

1. Hypertriglyceridaemia (Type IV) monotherapy
2. Familial combined hyperlipidaemia (Type IIb) in combination with statins

Question 24

How is Omacor administered?

Answer 24

Orally (2-4g or more) with food

Question 25

Name three adverse effects of Omacor.

Answer 25

1. GI symptoms (abdominal distension, pain, constipation, diarrhoea, dyspepsia, flatulence) 2. DHA may increase LDL-C 3. Reduces production of TXA2, may lead to increased bleeding time (esp. if patients on aspirin and warfarin) 4. CI: fish allergy

Question 26

MOA of niacin (Vit B3)

Answer 26

1. Increases HDL-cholesterol 2. Strongly inhibits lipolysis in adipose tissue, decreasing plasma TG (in VLDL) and cholesterol (in VLDL and LDL) 3. Decreases circulating fibrinogen and increases tPA, reverses thrombosis associated with atherosclerosis

Question 27

Clinical uses of niacin

Answer 27

Treatment of Type IIb and Type IV hyperlipoproteinemia

Question 28

How is niacin administered?

Answer 28

Orally, converted to nicotinamide in the body.

Question 29

Name two adverse effects of niacin.

Answer 29

1. Intense cutaneous flush and pruritus 2. Hyperuricemia and gout

Question 30

MOA of bile acid binding resins (cholestyramine)

Answer 30

1. Bind negatively charged bile acids and bile salts in the small intestine, prevents recycling of bile acids 2. Lowering bile acid concentration causes hepatocytes to increase conversion of cholesterol to bile acids, decreasing intracellular concentration of cholesterol 3. Activates increased hepatic uptake of LDL-cholesterol, decreasing plasma LDL 4. May increase VLDL

Question 31

Clinical uses of cholestyramine

Answer 31

1. Primary hypercholesterolaemia (Type IIa) 2. In conjunction with niacin for LDL elevations in combined hyperlipidaemia (Type IIb)

Question 32

How is cholestyramine administered?

Answer 32

Orally

Question 33

Name two adverse effects of cholestyramine.

Answer 33

1. GI effects: constipation, nausea and flatulence 2. Impaired absorption of fat-soluble vitamins: A, D, E, K

Question 34

What is ezetimibe?

Answer 34

Selective inhibitor of cholesterol transport protein, NPC1L1, thus reducing intestinal sterol absorption

Question 35

Clinical uses of ezetimibe

Answer 35

Reduction of LDL, may be used in conjunction with simvastatin (Vytorin)

Question 36

How is ezetimibe administered?

Answer 36

Orally

Question 37

Name one adverse effect of ezetimibe.

Answer 37

Reversible impaired hepatic function