Unit 4 - Hyperlipidemia Flashcards
what are lipoproteins? materials?
spherical particles with hydrophilic monolayer surface made of phospholipid, protein, and cholesterol
- shields hydrophobic lipid core of TG and cholesterol esters
- apoliporoteins provide structural stability to prticle, are required for assembly/secretion, and act as ligands and cofactors
what are the three compartments of plasma lipoprotein metabolism?
- exogenous lipid transport
- endogenous lipid transport
- reverse cholesterol transport
explain exogenous lipid transport?
- chol and TG ingested and emulsified in intestines bybile acids
- combined with PRO to form chylomicrons in gut wall
- secrted into circulation, delivering TG to adipose and muscles via LPL in plasma or vscular endothelial cells
- remaining chol-rich remnants deliver cholesterol to liver
explain endogenous lipid transport
- liver forms VLDL from TG, chol, and PRO, and secretes into circulation
- VLDL deliver TG to adipose and fat, and are converted into IDL and LDL
- chol-rich LDL delivers to peripheral tissues for cell membranes, steroids
- -delivers to nascent atheromas to be oxidized and phagocytosed by MP –> foam cells
- -deliver to liver (apo-100 binds to LDL-R to promote internalization)
what does intracellular cholesterol do to the cell?
3 regulatory effects
- decreases activity of HMG CoA reductase (rate-limiting in chol synthesis)
- activates ACAT (acetyl CoA: cholesterol acyltransferase) that esterifies free chol into chol ester for storage
- inhibits transription of gene encoding LDL-R (decreases further uptake of chol by cell)
explain reverse cholesterol transport
nascent HDL particles with PRO and small amt of phospholipid are secreted by gut and liver
-as HDL circulate in blood, they use plasma LCAT to get chol from peripheral tissues and atheromas, to be transported to liver
explain the pathogenesis of atherosclerosis
- endothelial injury
- low-grade inflammatoryresponse causing LDL accumulation and oxidation
- blood monocytes adhere, becoming macrophages
- MP phagocytose ox-LDL to become foam cells
- platelets adhere
- SMC migration deposits collagen
- necrosis, plaque lysis
what are primary hyperlipidemic states?
relatively rare disorders, each of which is caused by monogenic defect
-LDL receptor deficiency
what are secondarycauses of hyperlipidemia?
- hypothyroidism
- early nephrosis
- resolving lipemia
- immunoglobulin-lipoprotein complex disorders
- anorexia nervosa
- cholestasis
- hypopituitarism
- corticosteroid excess
what is polygenic-environmental hyerlipidemia?
most cases, due to several genes that predispose patient to milder forms of hyperlipoproteinemia particularly in the presence of excessive dietary intake of lipids, or other risk factors
- serum LDL cholesterol
- age
- HTN
- smoking
what is the goal of the AHA step 1 diet?
for many, may be the only treatment necessary
- attain normal bodyweight and minimize plasma lipids
- cholesterol < 300 mg/day
- total fat < 30% of total calories
- saturated fat < 10% total calories
what increases/decreases HDL cholesterol concentrations?
- estrogens > androgens
- exercise > puberty (in males)
- leanness > obesity
- alcohol (in moderation) > cigarette smoking
- familial hyperalphaproteinemia > familial HDL deficiency
- antihyperlipidemic drugs > DM II or hypertriglyceridemia
when is drug therapy considered?
if diet and weight loss haven’t lowered total and LDL cholesterol to desired ranges (160/130) within 6-12 months, or for patients with moderate risk of CHD
what is niacin? what are its effects on lipids? when do you use them?
vitamin only after conversion to NAD, but require larger amounts to show hypolipidemic effects
- affects virtually all lipid parameters
- increase HDL 15-35% (best)
- lower TG by 20-50% (as effective as fibrates and statins)
- reduces LDL by 5-25%
- useful for patients with both hypertriglyceridemia andlow HDL levels, but has numerous and serious side effects
what is the mechanism of niacin?
- reduced TG synthesis in liver, reducing hepatic VLDL production (and thus LDL levels)
- decreased lipolysis in adipose tissue, reducing transport of FFA to liver (thus decreasing hepatic TG synthesis)
- reduced hepatic clearance of HDL-apo A-1 (thus raising HDL levels)
what are adverse effects of niacin? resulting contraindications/
not serious, but lipid patient compliance
- flushing, pruritis of face and upper trunk (prostaglandin-mediated)
- skin rashes, acanthosis nigricans
- dyspepsia and reactivation of peptic ulcer disease
medically serious
- common hepatotoxicity, hyperglycemia, and hyperuricemia
- -contraindicated if DM or history of gout
- rarer toxic amblyopia, tachyarrhythmias, atrial fibrilation (in elderly), and myopathy (max doses)
what are fibrates? what are its effects on lipids? when are they used?
older family of related synthetic ethyl chlorophenoxyisobutyrates
- decrease VLDLs (20-50%), thus TGs
- variable effects on LDL levels
- increased (10%) HDL (modest)
- used for hypertriglyceridemia
what is clofibrate?
ester form of fibrates used in the past, but with declining usage due to adverse effects (gallstones), conflicting results during clinical trials, and better drugs vailable
what is the mechanism of fibrates?
ligands for nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-a)
- reduce TGs via PPAR-mediated:
- -stimulation of LPL synthesis, which would enhance clearance of TG-rich lipoproteins
- -inhibition of apo-C expression, enhancing clearance of VLDL
- increase HDL via PPAR-a stimulatio of apo AI and AII expression
what are adverse effects of fibrates?
usually well-tolerated, especially 2nd generation; ASE seen in 5-10% of patients, but doesn’t cause discontinuation
- GI side effects
- myositis flu-like syndrome
- potentiate action of oral anticoagulants (compete with albumin)
- increase lithogenicity of bile, but newer ones (like gemfibrozil) result in less gallstones
what are bile acid sequestrants? effects on lipids?
anion-exchange resins (+ charge to bind - bile acids)
- among oldest of hypolipidemic drugs, and also the safest (not absorbed from intestine)
- max doses reduce LDL up to 30%
- produce slight increase in both TG and HDL levels
what is cholestyramine?
polymer of styrene and divinylbenzene with quaternary amine active site group
-bile acid sequestrant that is a hygroscopic powder given with Cl- salts, insoluble in water
what is colestipol?
mixture of tertiary and quaternary amines
-bile acid sequestrant that is a hygroscopic powder given with Cl- salts, insoluble in water
what is the mechanism of bile acid sequestrants?
highly positively charged and bine negatively charged bile acids
- due to large size, they aren’t absorbed, and bound bile acids are excreted in stool
- over 95% of bile acids are normally reabsorbed, so interruption of this process depletes liver’s pool of bile acids, and hepatic bile acid synthesis increases
- thus hepatic cholesterol content declines, stimulating production of LDL receptors
- increased receptors increases LDL clearance and lowers LDL levels
- resins produce slight increase in both TG and HDL levels
