Lipid-Lowering Therapy

Question 1

What features of the clinical assessment are important for determining need for lipid lowering therapy? history/exam/investigations?

Answer 1

1. History - if end-organ damage
2. Exam - BP (risk factors), xanthoma (fatty deposits beneath skin), xanthelasma (yellow plaques surrounding eyes)
3. Investigations - U&Es, glucose, fasting TC/HDL/LDL/TGs, ECG

Question 2

What are the drug targets for TC/LDL/TG?

Answer 2

TC <4mmol/L
LDL <1.8mmol/L
TG <1.7mmol/L

Question 3

STATINS -

• dose
• most effective
• primary indications
• secondary indications
• MoA

Answer 3

Simvastatin (nocte) + atorvostatin 10-80mg
Most effective = rosuvastatin
primary = high CV risk, diabetic, familial hyperlipidaemia
secondary = previous MI, angina, CVA, TIA, PVD
Inhibits HMG-CoA Reductase which a) reduces cholesterol synthesis + b) up regulates hepatic LDL receptors to reduce circulating levels

Question 4

What is the “pleiotropic effect” of statins?

Answer 4

due to reduction in isoprenoid synthesis
Isoprenoids are involved in inflammation, cell proliferation/differentiation/signalling, cytoskeletal functions and apoptosis
Benefit has been shown in COPD/MS

Question 5

What are the side effects of statins?

Answer 5

1. Myalgia = common + in elderly may just be old age
2. Myositis = stop if CK x10
3. Rhabdomyolysis - severe inflammation + muscle breakdown releasing myoglobin which is nephrotoxic (stop if ALT x3)
4. Teratogenic - cholesterol required for fatal development

Question 6

What causes increased risk of myopathy

Answer 6

1 in 10,000 have

increased risk with reduced activity SLCO1B1 gene - which codes for OATP1B1 that takes up statins into hepatocytes

Question 7

What drug interactions occur?

Answer 7

metabolised by CYP3A4 system + inhibitors of CYP3A4 will increase levels + SEs
- inhibitors = amiodarone, cyclosporine, diltiazem, verapamil, erythromycin

Question 8

BEZAFIBRATE

• Dose?
• % reduction?
• Indications (2)
• MoA? 4 effects?
• SEs

Answer 8

200-400mg od
reduces TGs 30-50%
Indications = isolated high TGs (with lifestyle changes), resistant hyperlipidaemia (combination with statin)
PPAR-alpha agonist = DNA receptor mediating 2nd messenger systems involved in TG synthesis
- reduces VLDL synthesis + increases CL
- Increases skeletal muscle FA storage
- Activates lipoprotein lips + breaks down TGs
- Anti-proliferative + anti-inflammatory
SEs = myositis (high with statin), GI upsets (nausea, diarrhoea), deranged LFTs

Question 9

EZETIMIBE

• MoA? 3 effects?
• SEs (2)

Answer 9

inhibits NPC1L1 receptor in intestine 
- reduces cholesterol absorption
- reduces intestinal delivery to liver (via chylomicrons)
- up regulates LDL receptor expression
SEs = abdo pain, diarrhoea/steatorrhoea

Question 10

NICOTINIC ACID/NIACIN

• Dose?
• Combination?
• MoA (3)
• SEs (3)

Answer 10

25-500mg od
combination therapy with fibrates/statins
MoA = decreases FA mobilisation from periphery, HDL degradation, TG/VLDL production
SE’s = GI intolerance, flushing, dry skin

Question 11

BA-BINDING RESINS/CHOLESTYRAMINE

• Dosing?
• MoA + 3 effects
• SEs = GI, vits, drug absorption

Answer 11

3xd oral dosing
binds bile acids + stops enterohepatic circulation
- Reduces exogenous absorption
- increased endogenous conversion to BAs
- increased hepatic LDL receptor expression
SEs = lots
- GI = nausea, bloating, diarrhoea/vomiting
- impair fat-soluble vit absorption e.g. A,D,E,K
- interfere with drug absorption e.g. digoxin, warfarin, thiazides, T4