CPT9 - Hyperlipidaemias

Question 1

5 features of using statins to reduce cholesterol levels

Drug Names x2
Drug Differences x2
Mechanism x2
Side Effects x3
Contraindications/Caution x3

Answer 1

1. ) Drug Names - atorvastatin and simvastatin
   - others: fluvastatin, pravastatin, rosuvastatin, lovastatin
2. ) Drug Differences
   - simvastatin is a prodrug and has a short half-life (2h)
   - atorvastatin is newer, has a much longer half-life (30h)
3. ) Mechanism - inhibition of HMG-CoA reductase
   - ↓intracellular cholesterol → synthesis of LDL receptors
   - promotes uptake/clearance of circulating LDLs
   - ↓intracellular cholesterol also ↓ secretion of VLDLs
4. ) Side-Effects
   - GI upset, nausea and headache
   - asthenia: physical weakness or lack of energy
   - myalgia (CPK > 10x normal) and rhabdomyolysis
   - development of diabetes
5. ) Contraindications/Caution
   - liver impairment: measure LFTs before tx and 3 + 12 mths after treatment, only stop statins of LFT is >3x upper limit of normal
   - stop statins if CK >5x upper limit of normal, can recontinue at a LOWER dose if sx resolve and CK returns to normal
   - renal impairment
   - pregnancy/breastfeeding (3mths before conceiving)
   - CYP3A4 inhibitors: macrolides e.g. clarithromycin, diltiazem, amiodarone, amlodipine, grapefruit, St John’s Wort

Question 2

5 additional benefits of statin therapy which reduces the risk of cardiovascular disease

Vascular Endothelial Function x2
Atherosclerotic Plaques x2
Haemostasis x3
Anti-Inflammatory
Antioxidant

Answer 2

1. ) Improved Vascular Endothelial Function
   - reduction in vasoconstriction (↑NO and ↓endothelin)
   - improved angiogenesis (↑VEGF)
2. ) Stabilisation of Atherosclerotic Plaques - due to:
   - decrease in SMC proliferation and increase in collagen
3. ) Improved Haemostasis
   - ↓fibrinogen, ↓platelet aggregation, ↑fibrinolysis
4. ) Anti-Inflammatory - reduced proliferation of inflammatory cells into atherosclerotic plaques
   - ↓cytokines, ↓CRP, ↓adhesion molecules

5.) Antioxidant - reduced superoxide (O2-) formation

Question 3

4 features of prescribing statins

Primary Prevention
Secondary Prevention
Time Taken
Target x2

Answer 3

1. ) Primary Prevention - QRISK of >10%
   - atorvastatin (20mg) once daily
2. ) Secondary Prevention - had major CHD
   - HDL:LDL ratio is most important in determining
   - atorvastatin (80mg) once daily
3. ) Time Taken - taken at night
   - LDL receptor activity/synthesis increases at night
   - short half-life of simvastatin

4.) Target - < 2mM of LDL, <4mM of total cholesterol

Question 4

5 features of using fibrates (fibric acid derivatives) to reduce cholesterol levels

Drug Name
Mechanism
Usage
Side-Effects x2
Caution x1

Answer 4

1.) Drug Name - fenofibrate

2. ) Mechanism - ↑production of lipoprotein lipase (LPL)
   - activation of nuclear transcription factor (PPAR-alpha) which regulates expression of genes producing LPL
   - ↑TG and FA uptake from plasma
   - ↑HDL and ↑LDL affinity for the receptor
3. ) Usage - co-prescribed with statins
   - can be given alone if statins contra-indicated
4. ) Side-Effects
   - gall stones (choletihiasis), myositis
5. ) Caution
   - warfarin (↑ effects of warfarin)

Question 5

6 features of using cholesterol absorption inhibitors to reduce cholesterol levels

Drug Name
Mechanism
Drug Features x2
Usage
Side Effects x2
Contra-indications x1

Answer 5

1.) Drug Name - ezetimibe

2. ) Mechanism - ↓gut absorption of cholesterol (by 50%)
   - inhibits NPC1L1 transporter which increases expression of the hepatic LDL receptor
3. ) Drug Features
   - pro-drug: enterohepatic circulation ↓systemic effects
   - secreted by bile: good tolerability
4. ) Usage - co-prescribed with statins
   - often given in familial hypercholesterolemia
   - also if patients can only tolerate low dose statins
5. ) Side Effects - abdominal pain and GI upset
6. ) Contra-indications - hepatic failure

Question 6

3 features of using monoclonal antibodies to reduce cholesterol levels

Drug Name
Mechanism
Usage

Answer 6

1. ) Drug Names - alirocumab
   - other: evolocumab
2. ) Mechanism - ↑LDL receptors on liver cells (↑uptake)
   - PCSK9 inhibitors prevent PCSK9 from binding to the internalised LDL receptor, preventing degradation
3. ) Usage - co-presribed with a statin
   - for resistant familial hypercholesterolaemia and some high risk secondary prevention patients
   - requires lifetime injections and very expensive (x100)

Question 7

2 other options to improve cholesterol levels

Plant Sterols
Alcohol

Answer 7

1. ) Plant Sterols - ↓LDL cholesterol (0.8mM)
   - competes w/ absorption of cholesterol
   - works with statins but not w/ ezetimibe
   - fish oils, fibre, whole grains, vitamin C/E

2.) Alcohol - ↑HDL-C but also ↑triglycerides

Question 8

Hypercholesterolaemia

Causes
Investigations
Management

Answer 8

1. ) Causes
   - familial hyperlipidaemia
   - obesity, alcohol excess, Anorexia Nervosa
   - chronic renal failure, uncontrolled hypothyroidism
   - medication: thiazide diuretics, ciclosporin
2. ) Investigations
   - lipid profile (requires fasting for >12hrs): TC >5mM
   - U+Es, LFTs: renal/hepatic impairment can be a cause
   - TFTs: hypothyroidism can increase cholesterol
   - fasting glucose: poorly controlled diabetes
3. ) Management
   - lifelong medication: atorvastatin or ezetimibe
   - total fat intake <30% of total energy intake
   - stop smoking, exercise 5 times a week