Cholesterol

Question 1

What is the impact of high cholesterol/LDLs on the body?

Answer 1

They are major risk factors for MI, CHD and stroke due to atherosclerosis involvement (see MoD/CVS notes)

Question 2

What study showed a link between cholesterol/LDL and coronary atherosclerosis?

Answer 2

Framingham study

Question 3

What are the normal total cholesterol, fasting LDL and HDL levels?

Answer 3

Total cholesterol - 5mmol/L or less

Fasting LDLs - 3mmol/L or less

HDLs - 1.2mmol/L or less

Question 4

What foods are good for tackling high cholesterol?

Answer 4

Fish oils, fibre, vitamin C/E, alcohol (HDLs)

Question 5

What foods are bad for cholesterol?

Answer 5

Dietary cholesterol/fat, alcohol (triglycerides)

Question 6

Describe the mechanism of action for statins

Answer 6

Hepatocytes - inhibit HMG-CoA reductase which is required for the synthesis of cholesterol from acetyl-CoA. This leads to a reduction in plasma cholesterol and this increases LDL receptors (less internalised) and reduces plasma cholesterol further.

LDL levels fall, triglyceride levels fall, HDL levels increase

Question 7

Describe the pharmacokinetics of statins stating some of the differences

Answer 7

Absorption varies and there is excessive hepatic first pass uptake so that only 5-30% reaches

Some metabolised by CYP3A4, others only phase II reactions

Simvastatin - half life of 1-4 hours, taken at night to match peak cholesterol production in the early morning

Atorvastatin and rosuvastatin - half life of 20 hours taken at any time of day

Question 8

Are stating linear or non-linear?

Answer 8

Non-linear

Question 9

What are the ADRs for statins?

Answer 9

Usually well tolerated

Increase in transminase levels

Myopathies and rhabdomyolysis - test CPK

Question 10

What are the DDIs for statins?

Answer 10

CYP450 inducers decrease effect and inhibitors increase risk of ADR

Question 11

What monitor is required for statin treatment?

Answer 11

LFTs, LDLs

Question 12

What study showed reduced mortality taking statins?

Answer 12

4S Total Mortality

Question 13

Name some other studies concerning statins

Answer 13

WOSCOPS - less non-fatal MI and CHD death
CARE - less non-fatal MI and CHD death
LIPID - reduced cumulative death from CHD
AFCAPS/TexCAPS - less non-fatal MI, sudden cardiac death and unstable angina

Question 14

Name a cholesterol absorption inhibitor and when would it be used?

Answer 14

Ezetimibe - statin intolerance, or with statin can further reduce LDLs (better than increasing statin which increases risk of ADR)

Question 15

What is the mechanism for cholesterol uptake inhibitors?

Answer 15

Block cholesterol transport protein NPC1L1 in the brush border thus reduces uptake of dietary cholesterol. This in turn increases LDL receptors and further reduces plasma cholesterol.

It circulates enterohepatically so can be recycled and limits systemic exposure.

Question 16

What are the main ADRs of cholesterol uptake inhibitors?

Answer 16

Headache, abdominal pain, diarrhoea

Question 17

What are the indications and contraindications for the use of fibrates?

Answer 17

Mainly used for hypertryglyceraemias but can be used in addition to statins (increased risk of myopathy and rhabdomyolysis)

Not to be used in renal dysfunction and gall bladder disease

Question 18

What is the mechanism of fibrate drugs?

Answer 18

They stimulate PPAR-a which increases lipoprotein lipase which increases the uptake of fatty acids and reduces triglyceride production. Also lowers LDLs and raises HDLs.

Question 19

What are the main ADRs of fibrates?

Answer 19

GI upset, gallstones, myositis, abnormal LFTs

Question 20

What two studies looked at fibrate usage? What did they conclude?

Answer 20

BIP- reduced LDLs, triglycerides, increased LDLs, less non-fatal MI/CHD death in secondary prevention.

Helsinki heart study - less non-fatal MI/CHD death in primary prevention.

Question 21

What are the contraindications for nicotinic acid? What is its mechanism of action? What are the main ADRs?

Answer 21

Contraindications - liver disease, unexplained raised LFTs, peptic ulcer.

Mechanism - inhibits lipoprotein a synthesis, reduces VLDL and increases HDL to reduce CHD.

ADRs - hepatotoxic, activation of peptic ulcer, hyperglycaemia, flushing, itching.

Question 22

What are the 4 classes of drugs used to treat hyperlipidaemia?

Answer 22

Statins

Cholesterol uptake inhibitors

Fibrates

Nicotinic acid