Hyperlipidemia - Sinal 3 Flashcards
Chylomicrons
Least dense
Mostly triglycerides
Important in energy storage and transport
Produced in intestine form dietary lipids
Fatty acids are released using lipoprotein lipase mediated lipolysis
Remnant is taken up by liver by receptor mediated endocytosis
LDL
Low density lipoproteins
Mainly cholesterol
Retain most of cholesterol originally presented in VLDL
Majority of circulating cholesterol
Primary means of delivery of cholesterol to peripheral tissues
Uptake achieved by LDL receptor mediated endocytosis
Bad cholesterol
HDL
High density lipoprotein
Almost half protein
Secreted by liver as immature
Mature by requiring lipid (primarily cholesterol) from VLDL and chylomicrons and acquiring cholesterol from peripheral tissues
Can transport cholesterol back to the liver via scavenger receptor BI mediated uptake
Good cholesterol
Lipoprotein lipase
Enzyme that converts parts of chylomicrons into FAs
Cholesterol biosynthesis
Multiple steps HMG-CoA reductase is rate limiting Major site is liver Cholesterol is precursor for the biosynthesis of several essential commands Acetyl CoA -> HMG-CoA -> Cholesterol
Cholesterol catabolism
End product are bile acids
Major site is liver
Bile acid biosynthesis is important means of cholesterol removal from the liver and body
Emulsifies chylomicrons and bile is reabsorbed and retired to the liver
VLDL
Very low density lipoproteins
Triglyceride rich
Second lower density lipoprotein
Secreted by liver to transport lipids to other tissues
Hydrolyzed by LPL on capillary surface of peripheral tissues to release fatty acids
Remnant can be converted to LDL in blood by removal of some apolipoproteins and lipolysis of the remaining triglyceride
Type IIa hyperlipoproteinemias
LDL
Increased cholesterol
Familial, polygenic or sporadic
Decreased LDL receptor expression/function
Type IIb hyperlipopoetinemias
LDL and VLDL
Increased cholesterol and triglycerides
Familial, combined and sporadic
Decreased LDL receptor expression/function and/or increased VLDL secretion
Athersclerosis
Reduction in blood flow leading to increased risk for CVD, stroke, kidney failure and other clinical events
Consequent of aging
Risk factors: hypertension, elevated blood lipids, smoking, hyperglycaemia, obesity, infection and inflammation
Macrophage foam cell formation
Critical early event in pathology of atherosclerosis
Initiated by injury to vessel endothelial layer
Allows LDL penetration to vessel anima, where it is oxidized
Inflammatory cells are recruited to site of injury, macrophages take up the oxidized LDL
Cholesterol from the LDL is stored inside the macrophage as cholesterol esters, which can be removed by efflux to HDL (ABCA1 transporter mediated)
Excessive cholesterol ester accumulation in macrophages can lead to foam cell formation
Foam cell death
Release of cholesterol esters into intimate
Release of pro-inflammatory cytokines
Propagation and amplification of inflammatory response
Formation of necrotic core, fibrosis, plaque formation and obstruction of blood vessel (advanced)
Risk of atherosclerosis
Positive with LDL, total cholesterol, and LDL:HDL
Negative with HDL
Therapeutic lifestyle changes
TLCs
Diet, exercise, stop smoking, stop alcohol
Statins
Drug of choice for patients with LDL
Competitive inhibitors of HMG CoA reductase
Increases hepatocyte LDL receptor levels, increasing uptake of LDL in liver (indirect effect of inhibiting cholesterol biosynthesis)
Anti-inflammatory, anti-coagulant
Reduce risk of death
Limited benefit for Type IIa familial (due to LDL receptor mutation)
Adverse effects of statins
Reversible liver toxicity
Cardiomyopathy
Drug interactions
Niacin
Water soluble vitamin, B3
Inhibits lipolysis in adipose tissue causing reduction of circulating FA-reduced hepatic triglyceride biosynthesis, reduced hepatic VLDL synthesis/secretion, reduced serum LDL
Reduced plasma LDL cholesterol, and total plasma, effective in combination with other drugs
Clinical use is limited by requirement for high doses and adverse effects
Adverse effects of niacin
Flushing, hot flashes, GIT irritation, hepatotoxicity
Bile-acid binding resins
Anion exchange resins that bind bile acids in the small intestine
Complex is excreted in the feces
Reduced bile acid reabsorption from intestine/return to liver, intracellular bile acid levels leading to increased bile acid synthesis and reduction of cholesterol stores
Increased expression of LDL receptors, hepatic LDL uptake
Lower LDL blood levels
Safe and effective
Do not interfere with absorption of dietary lipids/lipid soluble vitamins with moderate doses
Combination therapy with statins is common
Cholesterol absorption inhibitors
Ezetimibe
Newest class
Inhibit cholesterol absorption from small intestine (exogenous and endogenous)
Deplete hepatic cholesterol (increase LDLR expression)
Used with other drugs, as limited benefit with mono therapy
Common with statin
No clinical trials yet prove evidence for decrease in CVD
Fibrates
First choice for patients with elevated serum triglycerides and/or reduced HDL
PPARalpha agonists
Reduce plasma triglycerides
Increasing chylomicron and VLDL clearance, reduced hepatic VLDL synthesis/secretion, promotes reverse cholesterol transport, anti-inflammatory
Generally well tolerated
(GIT irritation, liver toxicity, rash, cardiomyopathy)
PPARalpha
Ligand-activated TF that increases the expression of genes involved in lipid metabolism
Endothelial lipoprotein lipase
Hepatic fatty acid oxidation enzymes
Hepatic apo A1 and A2 (principle protein compartments of HDL)
Type IIa clinical approach
TLC, statins, resins, ezetimide
Alone or combination
Type IIb clinical approach
TLC, statins, resins, exetimide, niacin, vibrates
Alone, combination
Familial Type IIa
Gene defects in the LDL receptor gene
Elevated total cholesterol and LDL
Heterozygotes some response to statins or bile acid binding resins, combination are more effective
Homozygotes appear from childhood
Minimal effect of statins, resins and combinations
TLC and niacin are most effective
