CAM201 Lecture Notes - Lecture 4: Hmg-Coa Reductase, Peripheral Artery Disease, Coronary Artery Disease
12 Jun 2018
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Treatet of Hyperlipidaeia
Lipid Levels
Measurements and Target Lipid Levels
• TC < 4.0 mmol/L
• TG < 2.0 mmol/L- fasting TG
• HDL ≥ . mmol/L
• LDL < 2.0 mmol /L
Dyslipidaemia
Types
1. Hypercholesterolaemia- elevated LDL, low or normal HDL, normal TG
2. Hypertriglyceridaemia- normal LDL, low or normal HDL, elevated TG
3. Mixed dyslipidaemia- Elevated LDL, low or normal HDL, elevated
triglycerides
Drug therapy depends on type of dyslipidaemia:
• Drugs that predominantly lower cholesterol levels
− Statins, bile acid binding resins, fibrates, nicotinic acid, ezetimibe
• Drugs that predominantly lower TG levels
− Fibrates, nicotinic acid
Non-Pharmacological Treatment
• Address underlying cause- hypertension, diabetes, alcohol, obesity
• Dietary modification required with drug therapy:
− Reducing saturated and trans fat
− Replacing saturated with mono and polyunsaturated fats
− Increasing soluble fibre
− Introducing plant-sterol enriched milk, margarine, or cheese products-
most effective dietary modification
• Exercising, losing weight, limiting alcohol intake, smoking cessation are
beneficial for lowering lipid levels.
• Increasing exercise and losing weight are the most effective interventions to
lower LDL levels.
• Start treatment to those who have established cardiovascular, cerebrovascular,
or peripheral vascular disease or in those without an established disease but at
high risk
• Consider drug treatment in addition to lifestyle changes if response to 3-6
months of lifestyle modification is inadequate in people at moderate risk
• Statins are first choice for hypercholesterolaemia; they are the most effective
oral LDL lowering agents and are well tolerated.
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• In patients at high risk of cardiovascular disease (with or without coronary
heart disease) statins reduce the risk of MI, stroke, revascularisation
procedures and mortality.
• Other lipid-lowering drugs are an option if statins are contraindicated or not
tolerated.
Statins
• Atorvastatin, fluvastatin, pravastatin, rosuvastatin, simvastatin
• As well as reducing cholesterol, statins reduce risk of coronary artery disease,
stroke and death for people at risk
• Most effective oral cholesterol-reducing agent
• Reduces LDL by 25-55% and TG by 10-20%
• Potent, specific, reversible competitive inhibitors of HMG-CoA reductase (rate
limiting enzyme in cholesterol synthesis).
• Competitively inhibit HMG-CoA reductase, an enzyme in cholesterol synthesis:
HMG-CoA → mevalonic acid → cholesterol
Mechanism of Action
HMG-CoA reductase inhibition
↓
Decreased hepatic cholesterol synthesis
↓
Increased expression of LDL receptors (the body’s attempt to get more cholesterol
into the cells)
↓
Increased clearance of LDL
↓
Reduced plasma concentration of LDL-cholesterol, reduction in triglycerides
• Statins have other potential benefits, as products of the mevalonate pathway
react with proteins- several membrane-bound enzymes are modified this way.
Benefits include:
− Immune suppression
− Protection against sepsis
− Improved endothelial function
− Reduced vascular inflammation
− Reduced platelet aggregation
Pharmacokinetics
• Predominantly cleared by the liver (CYP450), but pravastatin 50% renally
cleared
• Fluvastatin, simvastatin, and pravastatin have short half-lives (1.5-4 hrs), so
they should be taken at night when cholesterol synthesis is at its highest
• Simvastatin and atorvastatin have longer half-lives (20-30 hrs), so they can be
taken at any time of the day
Adverse Effects
• Common: GI disturbances, myalgia
• Rare: rhabdomyolysis (rapid breakdown of skeletal muscle)
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