Lipid Lowering Therapies

Question 1

What level of LDL is considered indication for lipid-lowering therapies?

Answer 1

160mg/dL

Question 2

What non-pharmacological treatments can be used in hypercholesterolaemia?
How effective are these?

Answer 2

Diet
Exercise
Weight Reduction
Modest reduction in LDL and increase in HDL

Question 3

What is the first line treatment for hyperlipidaemia?

Answer 3

HMG CoA reductase inhibitors

aka statins

Question 4

What is the mechanism of action of statins?

Answer 4

Statins are analogues of HMG. They have a strong affinity for the enzyme and bind effectively to inhibit HMG CoA reductase. This reduces intracellular supplies and upregulates expression of LDL receptors. This reduces serum cholesterol.

Question 5

Give some examples of statins:

Answer 5

Lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastin.

Question 6

Rank the statins in order of potency. 1 being most potent.

Answer 6

1. Pitavastatin
2. Rosuvastatin
3. Atorvastatin
4. Simvastatin
5. Pravastatin
6. Lovastatin
7. Fluvastatin.

Question 7

What are the indications for statin therapy?

Answer 7

All types of hyperlipidaemia except familial hypercholesteraemia as lack of LDL receptor means that mechanism is not effective at reducing serum cholesterol.

Question 8

Describe the PK’s of statins:

Answer 8

Prava- and Fluvastatin are almost completely absorbed after oral administration and are active as such. Lovastatin and atorvastatin are 30-50% absorbed and are hydrolysed to active form. Excretion is primarily by bile and faeces however some renal excretion can occur. Simvastatin half life 5 hours, others much longer.

Question 9

What are the ADR’s of statins?

Answer 9

Liver problems - monitoring required.

Myopathy/Rhabdomyolysis - RARE - more common in HRH

Question 10

DDI’s/Contraindications of statins?

Answer 10

May increase warfarin levels - monitor INR frequently

Not to be used in pregnant and nursing mothers, children or teenagers.

Question 11

What is second line treatment for hypercholesteraemia?

Answer 11

Ezetimibe

Question 12

What is the mechanism of action of Ezetimibe?

Answer 12

Selectively inhibits absorption of dietary and biliary cholesterol in the small intestine. This reduction in intracellular hepatic stores prompts clearance of cholesterol from the serum.

Question 13

What are the PKs of Ezetimibe?

Answer 13

Metabolised in the liver and small intestine and excreted by bile and renal excretion. Half life 22 hours.

Question 14

How effective are statins?

Answer 14

Very effective at reducing LDL
Modestly effective at increasing HDL
Slightly effective at decreasing triglyceride

Question 15

How effective is niacin?

Answer 15

Slightly effective at reducing LDL
Very effective at increasing HDL
Effective at reducing triglycerides

Question 16

How effective are fibrates?

Answer 16

Slightly effective at reducing LDL.

Effective at increasing HSL. Very effective at decreasing triglycerides.

Question 17

Describe the mechanism of action of Niacin:

Answer 17

Inhibits lipolysis in adipose tissues. Reduction in VLDL and LDL levels and triglycerides.

Question 18

Indications for niacin?

Answer 18

Familial hyperlipidaemias
Severe hypercholesteraemia
Best agent at increasing HDL.

Question 19

What are the PK’s of niacin?

Answer 19

Administered orally, converted to nicotinamide in the body. Niacin and its metabolites are excreted in the urine.

Question 20

ADR’s of Niacin?

Answer 20

Intense Cutaneous flush and pruritus (can be avoided when administered with aspirin or given as sustained release)
Nausea and abdo. pain
Hyperuricaemia and gout.
Impaired glucose tolerance
Hepatotoxicity.

Question 21

Gives some examples of Fibrates:

Answer 21

Fenofibrate - more effective

Gemfibrozil

Question 22

What is the mechanism of action of fibrates?

Answer 22

PPARS (Perioxisome Proliferator activated receptors) are activated by fibrates. This leads to a decreased production of apoproteins and increased expression of lipoprotein lipase. Reduced triacylglyceride concentration.
increases expression of apoplipoproteins for HDL

Question 23

What are the PKs of fibrates?

Answer 23

Completely absorbed after oral dose. Distributed widely bound to albumin. Extensive biotransformation. Excreted in urine.

Question 24

ADR’s of fibrates?

Answer 24

GI effects - mild which lessen as therapy continues.
Lithiasis - increase biliary cholesterol excretion so increased predisposition to gallstone formation.
Myositis - Patients with renal insufficiency may be at risk.

Question 25

DDIs and contraindications of fibrates?

Answer 25

Competition for binding sites on binding proteins with coumarin anticoagulants - monitor INR - May elevate levels of sulfonylureas. - Not known in pregnancy and lactating women. Not to be used in those with severe hepatic and renal dysfunction or those with pre-existing gallbladder disease.

Question 26

Give some examples of Bile-acid binding resins:

Answer 26

Cholestryamine Colestipol Colesevalam

Question 27

Describe the mechanism of action of bile-acid binding resins.

Answer 27

They are anion exchange resins that bind negatively to bile acids and bile salts in the small intestines. This resin/bile acid complex is excreted in the faeces thus preventing them from returning via the enterohepatic circulation to the liver. This causes the liver to increase synthesis of bile acids from cholesterol reducing intracellular cholesterol. This causes up regulation of LDL receptors and reduction in serum cholesterol.

Question 28

What are the therapeutic uses of bile-acid binding resins?

Answer 28

Type IIA Type IIB hyperlipaemias Cholestryamine can also relieve pruritus caused by bile acid accumulation in patients with biliary obstruction.

Question 29

What are the PK's of Bile acid-binding resins?

Answer 29

Taken orally - insoluble so they are neither absorbed or metabolically altered by the intestine. Totally excreted in faeces.

Question 30

What are the ADR's of Bile acid-binding resins

Answer 30

GI effects - constipation, nausea and flatulence Impaired absorption - at high doses impairs with absorption of fat soluble vitamins Drug interactions - interfere with the intestinal absorption of many drugs - therefore they should be taken 1-2hrs before or 4-6hrs after.