Session 3 - Lipid metabolism

Question 1

Outline line the pathophysiology of athersclerosis

Answer 1

1. Endothelial injury due to
   o Raised LDL
   o ‘Toxins’ e.g. cigarette smoke
   o Hypertension
   o Haemodynamic stress
2. Endothelial injury causes
   o Platelet adhesion, PDGF release, smooth muscle cell proliferation and migration
   o Insudation of lipid, LDL oxidation, uptake of lipid by smooth muscle cells and macrophages
   o Migration of monocytes into intima
3. Stimulated SMC produce matrix material
4. Foam cells secrete cytokines causing
   o Further SMC stimulation
   o Recruitment of other inflammatory cells

Question 2

Give four pro-atherogenic effects of oxidate LDL

Answer 2

o Inhibits macrophage motility
o Induces T-cell activation and vascular smooth muscle cell division/differentiation
o Toxic to endothelial cells
o Enhances platelet aggregation

Question 3

What correlates with increased risk of atherosclerosis?

Answer 3

Total and LDL cholesterol concentrations correlate

HDL levels have inverse correlation

Question 4

What are the transport functions of chylomicrons?

Answer 4

Transport dietary triacylglycerols from the intestine to tissues such as adipose tissue.

Question 5

What are the transport functions of VLDL?

Answer 5

Transport of triacylglycerols synthesised in the liver to adipose tissue for storage.

Question 6

What are the transport functions of LDL?

Answer 6

Transport of cholesterol synthesised in the liver to tissues.

Question 7

What are the transport functions HDL?

Answer 7

Transport of excess tissue cholesterol to the liver for disposal as bile salts

Question 8

What is the role of cholesterol in preventing cardiovascular/coronary events

Answer 8

A 10% reduction in total cholesterol results in:
o 15% reduction in Coronary Heart Disease mortality
o 11% reduction in total mortality.
LDL is main target

Question 9

What are the effects of statins (3)

Answer 9

o LDL reduction of between 5-35%,
o HDL raised by ~5%
o Triglycerides reduction of 10-35%

Question 10

What are the mechanisms of action?

Answer 10

The primary pharmacological action of statins is by inhibiting the hepatic enzyme HMG-CoA Reductase, which is involved in cholesterol synthesis. Decrease in hepatic cholesterol concentration stimulates the production of LDL receptors, which increases rate of LDL removal from plasma.

Question 11

What are the three main side effects of statins?

Answer 11

Myalgia, myopathy and rhabdomyolysis

Question 12

Give four types of statins

Answer 12

 Simvastatin
 Atorvastatin
 Rostuvastatin
 Pravastatin

Question 13

What is the route of admin for statins?

Answer 13

oral

Question 14

What are the indications for statins?

Answer 14

 Hyperlipidaemia resistant to dietary control
 Secondary prevention in patients with serum cholesterol greater than 5.5mmol/L (value varies depending on local policy)

Question 15

What are the contraindications for statins?

Answer 15

 Pregnancy, breastfeeding, liver disease

Question 16

What are some adverse drug reactions for statins?

Answer 16

 Increased transaminase levels (Rapidly reversible, no evidence of chronic liver disease)
 Myopathy (diffuse muscle pain, primarily seen when used in combination with cyclosporine and occasionally erythromycin & niacin)
 GI Disturbances
 Arthralgia
 Headaches

Question 17

What induces breakdown of statins?

Answer 17

 CYP450 inducers/inhibitors. Inhibitors significantly increase the risk of myopathies

Question 18

Give a three alternatives to statins?

Answer 18

Fibric Acid Derivatives (Fibrates)
Cholesterol Absorption Inhibitors
Bile Acid Sequestrants

Question 19

What do fibrates do?

Answer 19

Fibrates act as agonists on the Peroxisome Proliferator-Activated Receptor-α (PPAR-α).

Question 20

What do fibrates result in?

Answer 20

o LDL lowering (variable amount)
o HDL increases of 15-25% in hypertriglyceridemia
o Decreases Triglycerides 25-50%

Question 21

Give three examples of fibrates?

Answer 21

 Bezafibrate
 Ciprofibrate
 Gemfibrozil

Question 22

When are fibrates used?

Answer 22

Fibrates can be used in conjunction with statins, but typically are only used as first line choices in hypertriglyceridemias. Usually used in  Hyperlipidaemia unresponsive to dietary control

Question 23

What are some contraindications of fibrates?

Answer 23

 Pregnancy, breast feeding, gall bladder disease, severe renal or hepatic impairment, Hypoalbuminaemia

Question 24

Give four adverse reactions to fibrates?

Answer 24

 Gastrointestinal disturbances
 Dermatitis, pruritus, rash
 Impotence
 Headache, dizziness, blurred vision

Question 25

Give some drug drug interactions fibrates?

Answer 25

 Increased change of myalgia and myopathies when taken with statins

Question 26

What are cholesterol absorption inhibitors?

Answer 26

Cholesterol absorption inhibitors inhibit intestinal cholesterol uptake, by blocking the specific cholesterol transport protein NPC1L1 in the brush border. This reduction of dietary cholesterol reaching the liver increases LDL receptor expression, further reducing circulating cholesterol.

Question 27

To what extent do cholesterol absorption inhibitors reduce LDL

Answer 27

A single 10mg dose of a cholesterol absorption inhibitor, Ezetimibe, is enough to reduce LDL levels by 15-20%. It is normally given as monotherapy in statin intolerant patients, however it will reduce LDL by a further 20% when given in combination with a statin. This is a better reduction than is gained by doubling statin dose and also reduces the risk of statin ADRs.

Question 28

What increases half life of cholesterol absorption inhibitors?

Answer 28

Ezetimibe also undergoes enterohepatic circulation, increasing its half-life.

Question 29

Give an indication for a cholesterol absorption inhibitor

Answer 29

 Hyperlipidaemia resistant to dietary control, in statin intolerant patients
 Given in combination with a statin

Question 30

Give a contraindication for route cholesterol absorption inhibitor

Answer 30

Breastfeeding

Question 31

What is mech of action of cholesterol absorption inhibitor

Answer 31

 Hyperlipidaemia resistant to dietary control, in statin intolerant patients
 Given in combination with a statin

Question 32

Give two adverse drug reactions of ezetimibe

Answer 32

 Gastrointestinal disturbances (Diarrhoea, pain)

 Headache

Question 33

Give two bile acid sequsterants

Answer 33

 Colestyramine

 Colestipol

Question 34

What is an indication for bile acid sequesterants

Answer 34

o Elevated cholesterol resulting from a high LDL concentration

Question 35

What is a contraindiction for bile acid sequestration

Answer 35

Billiary obstruction

Question 36

Give a mechanism of action for bile acid sequesterants

Answer 36

o Bind to bile acids in the intestine. This prevents their reabsorption and subsequent conversion of hepatic cholesterol into bile acids. Lower levels of hepatic cholesterol leads to increased LDL receptor expression and lowered plasma cholesterol concentration.

Question 37

Give an adverse drug reaction of bile acid sequesterants

Answer 37

o GI disturbances – Nausea, vomiting, constipation, abdominal pain, flatulence, heart burn
o Very few systemic side effects as they are not absorbed

Question 38

Give a couple of physiological processes which effect ADME of statins

Answer 38

o Intestinal absorption varies between 30 – 85%
o Hepatic first pass uptake is extensive
 May occur either by diffusion or active transport by OATP2
 Systemic availability may fall to 5 – 30% of administered dose
o Hepatic elimination includes CYP3A4 for some statins, whilst others are only metabolised by Phase 2 pathways
o Exhibit Non-Linear Pharmacokinetics
 Doubling of dose results in ~6% reduction in LDL

Question 39

Give a short acting statin

Answer 39

Simvastatin

Question 40

Give a long acting statin

Answer 40

 Atorvastatin
 Rostuvastatin
 Half-life ~20 hours. Given any time of day.