CVS 5 - Lipids Flashcards
Lipoproteins
- Cardiovascular disease is a major killer in western world
- Elevated LDL leading to atherosclerosis major contributor
Hydrophobic core: •cholesterol–fatty acid ester •triacylglycerol
Surface monolayer of phopholipid
•amphipathic nature allows transport in blood
•Apolipoprotein – amphipathic surface proteins -ligands for lipoprotein receptors
Pathophysiology
• Clear link between cardiovascular disease and elevated LDL & decreased HDL (HDL is protective)
• Lowering LDL/HDL ratio slows arthrosclerosis
• Hyperlipidemia’s:
– Hypercholesterolemia
– Hypertriglyceridemia
– Mixed hyperlipidemia
• Hyperlipidemia’s may be
– familial (genetic component) eg LDL-R mutations – diet
good and bad cholesterol
HDL = good cholesterol
Management of hyperlipidemias
• Multiple causes of atherosclerosis – should consider all of these
• Risk factors:
– Smoking 2x↑ coronary artery disease
– Diet & obesity ↑ risk MI & physical activity ↓ risk MI
– hypertension & diabetes→ risk ↑ MI treat these!
• Lifestyle changes before pharmacological intervention –can reduce LDL
• Pharmacological treatment
– Primary prevention versus secondary prevention
» Primary: treatment before clinical evidence of disease
– measure serum cholesterol in patients with family history of arterial disease, obesity, diabetes, hypertension
» Secondary: treatment after clinical evidence of vascular disease – significantly decreased risk of MI
Statins
– reduce mortality after myocardial infarction
– reduce mortality in absence of obvious cardiovascular disease
Statins indications and mechanism
• Indications
– occlusive arterial disorders (eg stroke) coronary heart disease (angina, MI)
– Patients at risk of arthrosclerosis even if asymptomatic eg
» diabetic patients>40 (increased risk of cv disease)
» familial hypercholesterolaemia • Mechanism
– Inhibit synthesis of cholesterol
– ↓liver cholesterol →active SREBP→↑ expression of LDL receptor →↑LDL uptake→ ↓plasma cholesterol
– Some reduction in triglyceride concentration – increased clearance VLDL, but fibrates often preferred
Statins drugs and effect
• Drugs – Lovastatin - first statin approved, isolated from aspergillus fungus – Simvastatin - prodrug activated by cyp3A4; short t1⁄2 ~2hr – Pravastatin –short t1/2~2hr – Fluvastatin –short t1/2~2hr – Atorvastatin - long t1/2~14h – Rosuvastatin- long t1/2~14h – Pitavastatin – coming soon? t1/2~11 h
• Effect
– Up to 60% reduction LDL cholesterol (20-40% more typical)
– Combinations with other drugs if necessary
what determines what time of day to take statin
Short t1⁄2 - hepatic metabolism. Take at night – when cholesterol synthesis occurs
Longer t1⁄2 - can take during day
Statins PK, ADR, caution, contraindication and interaction
• PK
– most subject to high first pass metabolism (dominant site of therapy = liver)
– differences in metabolism affect drug-drug interactions » metabolised by Cyp3A4: simvastatin, atorvastatin » metabolized by Cyp2C9: fluvastatin
» not metabolised by Cyps: pravastatin, rosuvastatin (renal elimination)
• ADR
– generally well tolerated
– myopathy (esp at high dose). Mechanism unclear
» muscle pain, stiffness & can progress to rhabdomyolysis
» monitor by measuring serum creatine kinase level if necessary
» risk increased by renal insufficiency, co-treatment with fibrates or ciclosporin
• Cautions
– patients at risk of myopathy (eg muscular dystrophy)
• Contraindications
– liver disease
– pregnancy (avoid pregnancy 1 month after stopping drug)
– breastfeeding
• Interactions
– Significant! Drugs affecting Cyp P450
» eg warfarin –potential increase in level
define rhabdomyolysis
breakdown of muscle tissue
Drug -> metabolite ( by Cyp P450)
Co-administration of Cyp substrate with:
•Cyp inducer may lead to increased metabolism, potential treatment failure
•Cyp inhibitor may lead to reduced metabolism, potential ADR
•Cyp substrate may lead to reduced metabolism, potential ADR
Statins have a risk of
myopathy (muscle disease)
Bile acid binding resins
• Positively charged resin that binds negatively charged bile acid & excreted:
– ↓decreased re-absorbtion bile (enterohepatic recirc.)→↑excretion
– ↑bile synthesis → ↓liver cholesterol →↑LDL receptor expression → ↓plasma cholesterol
• Drugs
– Cholestyramine
– Colestipol
• Indications
– patients in which statins are insufficient on own or contraindicated (eg pregnant women)
– Take before meal so present during bile acid secretion
– Decreases LDL cholesterol up to 30%
• PK
– insoluble in water – not absorbed
– inconvenient to take & gram doses
• ADR
– limited because not absorbed
– GI : constipation, bloating, flatulence
• Caution
– may also bind
» vitamin A, D,K - supplements may be necessary
» certain drugs (warfarin, digoxin, some statins, thiazides, aspirin ), reducing their bioavailability
– take other drug 1 hour before or 4 hr after resin
Inhibitors of cholesterol absorption
• Ezetimibe
– Inhibits transport of cholesterol across
intestinal brush border
– decreased cholesterol in chylomicrons, liver, VLDL and hence LDL
– upregulation of LDL receptor further reduces plasma cholesterol
• Indications
– hypercholesterolemia
– used with statin or on own if statin not appropriate
• PK
– is absorbed and undergoes repeated enterohepatic recirculation giving long t1/2~22h
– hence majority drug excreted in faeces • Caution
– hepatic impairment
• contraindication
– breast feeding
• ADR
– GI disturbances (diarrhoea, abdominal pain)
• Interactions
– plasma concentration increased with fibrates
Plant sterol
- Similar structure to cholesterol
- Displace cholesterol from micelles, so excreted not absorbed
- Large quantities needed (g)
