Dyslipidaemia Flashcards
Define atherosclerosis
Focal lesions (plaques) on the dinner surface of an artery. Atherosclerosis leads to IHD, peripheral vascular disease (PVD) and cerebrovascular disease.
Atherosclerosis risk factors
Genetic Hypercholesterolaemia (raised LDL, lowered HDL) HTN Smoking Obesity Hyperglycaemia Reduced physical activity Infection - some associated with chronic infections - INVEST trial: dental bacteria correlate with carotid thickening- risk for atherosclerosis
Drug-induced dyslipidaemia, causes
Beta blockers Thiazides Corticosteroids Retinoids (for acne/ psoriasis) - monitor lipid levels Oral contraceptives Anti HIV drugs - some require lipid level monitoring Plasma lipids may be adversely affected by certain drugs.
Hypercholesterolaemia - lipids involved and their roles
LIPOPROTEINS - central core of hydrophobic lipid, encased in phospholipid, cholesterol and apolipoproteins (HDL, LDL, VLDL) CHYLOMICRONS - transport triglycerides and cholesterol from GI tract to the liver. Free FA released and cholesterol is stored, oxidised to bile salts, or released to: VLDL - transports cholesterol and TGs to tissues, where TGs are removed leaving: LDL - large component of cholesterol, taken up by liver and tissues, via endocytoiss via an LDL receptor. HDL - absorbs cholesterol from cell breakdown and readers it to VLDL & LDL.
Hypercholesterolaemia - consequences
Major risk factor for atherosclerosis Ideal cholesterol 6.5mM) Especially important - high LDL/ low HDL Xanthomata - signs of hypercholesterolaemia, yellow lipid deposits on eyelids, cornea and tendons Consult CVS risk tables in rear BNF, can calculate 10year risk
Atherogenesis pathology
Atherogenesis, inflammatory response to injury. Normal healthy endothelium, secrete prostacyclin and NO, vasodilation and prevent platelet aggregation. Endothelial cell also has an LDL receptor which binds LDL and facilitates transport. CVS risk factors (e.g. Smoking/ HTN/ Infection/ Turbulent flow) can lead to endothelial damage. Endothelial damage provokes an inflammatory response. Monocytes/ macrophages go to site of damage. Also production of ROS (reactive oxygen species), leads to the oxidation of LDL, which is damaging to the LDLR. This causes / promotes lipid deposition beneath the endothelium. Beginning of atherosclerosis. Foam cells (cholesterol rich) accumulate beneath endothelium. In time this leads to atherosclerotic plaques - cholesterol rich and may contain connective tissue, and may become calcified.
Atherogeneis process
Damage to blood vessel Inflammatory response Cholesterol- rich deposits form Inflammatory mediators may lead to growth of vascular smooth muscle / connective tissue Plaques form
Managing hypercholesterolaemia
Modifying risk factors Stop smoking Treat HTN/ DM Exercise Drug-induced Low cholesterol diet - but only 25-30% of cholesterol comes from diet and so this only has modest effects
Statins. MOA.
HMG-CoA Reductase inhibitors. Hydroxymethylglutaryl coenzyme A reductase which catalyses: Hydroxymethylglutaryl —> Mevalonate (—> Cholesterol ultimately) HMGCoA reductase is the 1st committed step in cholesterol synthesis.
Statins. Examples and action.
E.g. Simvastatin, pravastatin, atorvastatin, fluvastatin Reduce plasma cholesterol The reduction in hepatic cholesterol synthesis leads to an upregulation of hepatic LDL receptors, promoting LDL uptake. Less effective in patients with homozygous familial hypercholesterolaemia, who cannot make LDL receptor. - but atorvastatin may be effective. Statins are hepatoselective - liver is the main site of cholesterol synthesis, extra hepatic sites synthesise essential cholesterol - 1st pass metabolism: 5% reaches systemic circulation
Statins. Efficacy.
Benefit in types 2a and 2b hyperlipoproteinaemia (high LDL and LDL/VLDL respectively). 4S trial (Scandinavian Simvastatin survival study) - patients treated with simvastatin - 36% reduction in LDL (increased HDL) - 5 years, 30% reduction in mortality, 42% reduction in IHD death Regression of atherosclerosis? - some evidence from statins - lipid depletion may lead to stabilisation of lesions - reduce progression of carotid disease, reduce stroke risk - may lead to improvements in endothelial function WOSCOPS - pravastatin demonstrated of be effective in secondary prevention following initial MI Heart protection study 2002 40mg Simvastatin to high risk patients (IHD, stroke, DM, HTN) 25% reduced MI/ stroke/ revascularisation/ in ALL (even low/normal) 2002 study Atorvastatin trial in HTN patients with normal cholesterol stopped due to substantial MI reduction.
Statins treatment. Key points.
Should be considered for all patients at high risk of cardiovascular disease irrespective of cholesterol Combo: statin + aspirin + beta blocker + ACEI Independently and additively reduce risk in secondary prevention with a 75% reduction in risk.
Clinical selection of patients for statins
Population who may benefit are rationed: 1st choice. Patients following MI or with angina (even w/ normal cholesterol) 2nd choice. Patients with a 30% ten year risk of cardiovascular disease (e.g. HTN/ DM) with total cholesterol >5mM NICE 2006- statins for primary prevention in patients with CV risk > 20% (see BNF)
Statins. Precautions and use.
Taken at night (except atorvastatin), this offsets a nocturnal increase in cholesterol synthesis. Used with care in liver disease, monitor liver function. Statins may cause myopathy leading to rhabdomyolysis - pts should report muscle pains. Risk 1/1000-10000. Risk increased by additional use of fibrates. Statins have a range of interactions (ciclosporin, Fibrates, warfarin, itraconazole) Low dose Simvastatin now available OTC from pharmacies
Bile acid binding resins. Use and action.
COLESTYRAMINE Used in addition to a statin. Binds bile salts in intestine and prevents reabsorption and cycling. Reduced absorption of exogenous cholesterol. Promotes endogenous cholesterol to bile salts. Also increases LDL receptors. 13% fall in plasma cholesterol. 20-25% fall in IHD Reduce absorption of fat soluble vitamins (A,D,K) May prevent absorption or other drugs (inc digoxin, thiazides), thus not given at same time.
Dyslipidaemia treatment pathway
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