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104 Cards in this Set
- Front
- Back
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What lipoproteins are found on cholesterol?
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Apolipoprotein C, B100, E
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What are the four major classes of cholesterol?
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HDL, LDL, VLDL, Chylomicrons
size increases ----------------------------> density decreases ----------------------> cholesterol decreases -----------------> tag increases -----------------------------> |
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What do apoplipoproteins do?
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Provide structural stability and engage in biological functions (receptor recognition)
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What do chylomicrons do?
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transport exogenous trigylcerides from intestine to muscle and fat tissue
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Where are chylomicrons taken up?
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taken up in liver and secreted in bile
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What are the possible fates of chylomicrons?
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oxidation in the liver to bile acids or converted into VLDLs
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What do VLDLs do?
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transport endogenous triglycerides from liver to fat tissue
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What is the fate of VLDL?
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hydrolyzed by lipoprotein lipase to yield IDL then LDL
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What do LDLs do?
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transport cholesterol from liver to peripheral tissue
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How are LDLs removed from circulation?
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Taken up via LDL receptors that recognize apoB 100
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What does HDL do?
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transports cholesterol from tissues back to liver
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How is cholesterol removed from the body?
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billary excretion
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What is the half-life of LDL?
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2-4 days
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What is a major risk factor of atheroscleorsis?
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elevated LDL
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How does LDL lead to athersclerosis?
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LDL not taken up by LDL receptors is oxidized --> engulfed by macrophages --> become foam cells --> apoptosis and necrosis --> release of free radicals and proteolytic enzymes --> LOCAL INFLAMMATORY RESPONSE
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What are CVD risk factors?
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increased LDL
decreased HDL increased triglycerides smoking HTN type 2 DM age family hx |
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What is the normal value of LDL
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< 130mg/dl
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what is the normal value of HDL?
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35 mg/dl
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what is the normal value of triglycerides?
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150 mg/dl
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What are the 4 types of dyslipidemia?
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hypercholesterolemia
hypertriglyceridemia mixed hyperlipidemia disorders of HDL metabolism |
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What is hypercholesterolemia?
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increased total plasma cholesterol (TPC)
increased LDL normal triglyceride |
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What is the major cause of hypercholesterolemia?
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polygenic - no defined genetic cause
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What is the genetic cause of hypercholesterolemia?
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Familial (FH) - auto dominant involves defects/absences in LDL receptor
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What clinical features distinguish a heterozygot from a homozygote of FH Type IIa?
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heterozygote - tendon xanthomias, arcus cornea, TPC 275-500
homozygote - TPC >700, absence of LDL receptors, CDV @ < 20yrs |
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What is familial defective apoB100?
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auto dominant disease in which mutations decreases affinity of LDL particles for LDL-R
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What is hypertriglycerideemia?
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increased plasma triglyceride concentrations - 200-500 mg/dl
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What is familial hypertriglyceridemia?
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auto dominant, unknown genetics, common
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What is familial lipoprotein lipase deficiency?
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hypertriglyceridemia
absence of LPL auto dominant profound hypertriglyceridemia infants with pancreatitis, eruptive xanthomas, hepato-splenomegaly |
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What is apoCII deficiency?
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hypertriglyceridemia
rare autosomal disorder |
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What is mixed hyperlipidemia?
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increased total plasma cholesterol
increased LDL increased triglyceride decreased HDL |
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What is familial combined hyperlipidemia?
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mixed hyperlipidemia
common, moderately elevated of triglycerides and TPC but reduced HDL patients present with features of metabolic syndrome |
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What is dysbetalipoproteinemia?
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mixed hyperlipidemia
increased chylomicrons and VLDL remnants - hypertriglycerideemia and hypercholesterolemia males - symptoms at 30 females - symptoms at menopause |
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What are some causes of decreased HDL metabolism?
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rare genetic defects in:
apopA1, ABCA1, LCAT |
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What physiological state leads to hypertriglyceridemia?
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pregnancy
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What should be done first to correct cholesterol levels in patients?
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therapeutic lifestyle changes
can reduce TPC by 5-25% |
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What are the anithyperlipidemic drugs?
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HMG CoA reductase inhibitors (statins)
Niacin (vitamin B3, nicotinic acid) Fibrates Bile-acid binding agents Cholesterol absortption inhibitors Combination drug therapy |
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When are HMG-CoA reductase inhibitors (statins) used?
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First line and most effective treatment for elevated LDL
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What are the statins?
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lovastatin
pravastatin simvastatin fluvastatin atorvastatin rosuvastatin |
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What is the MOA of statins?
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inhibit activity of HMG CoA reductase
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What are statins
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analogues of HMG
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What is the relative potency of the statins?
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RAS LPF
rosuvastatin > atorvastatin > simvastatin > lovastatin > pravastatin > fluvastatin |
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Which statins inhibit cytochrome P450 3A4?
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LSA
lovastatin, simvastatin,, atorvastatin |
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How is fluvastain metabolized?
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by alternate CYP450 pathways
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Which statins are not metabolized by CYP450s?
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pravastatin and rosuvastatin
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How do statins decrease TPC levels?
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Inhibit production of cholesterol and increase LDL receptor expression
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When is a case of hypercholesterolemia non responsive to statins?
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in homozygotes of famial hypercholesterolemia - that lack LDL receptors
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What are the adverse effects of statins?
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myopathy and or myositis with rhabdomyosis
can get increases in serum transaminases + liver enzymes |
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when is statin use cautioned?
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in patients with liver disease?
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What can statins be combined with?
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1. bile acid binding agent or cholesterol absorption inhibitor - additive effects
2. with Niacin - increased risk of myopathy 3. with fibrates - increase risk of rhabdomyolysis |
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Drug interactions to be aware of when taking statins?
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Drugs metabolized by CTP450
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What are the CI of statins?
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Pregnancy
breastfeeding active liver disease |
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When are inhibitors of bile acid reabsorption used?
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Second line treatment for lipid reduction
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What are the bile acid reabsorption inhibitors?
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cholestyramine
colesevelam colestipol |
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What is the MOA of inhibitors of bile acid production?
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cationic polymer resins that bind to negatively charged bile acids in small intestine - prevents reabsoprtion
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What is the effect of decreased bile acid reabsorption?
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decreased bile acid reabsorption --> increased conversion of cholesterol to bile acids
LDL receptor expression increased --> increased removal of LDLs from circulation |
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What are the pharmokinetics of inhibitors of bile acid reabsorption?
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taken orally, water insoluble
uncomfortable to ingest - suspend in OJ excreted totally in feces |
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Why do inhibitors of bile acid lower TPC levels?
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because 90% of bile acid is reabsorbed
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When should inhibitors of bile acid reabsorption be used?
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They are the DOC for type IIa (familial hypercholesterolemia) and type IIIb (familial combined hyperlipidemia)
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Why use cholestyramine?
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releives pruritis caused by accumulation of bile acids in patients with billiary obstruction
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What are the adverse effects of inhibitors of bile acid reabsorption?
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constipation, nausea, bloating, flatulance
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Which inhibitor of bile acid reabsorption has few side effects?
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colesevelam
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What are the drug combinations that can be used with inhibitors of bile acid synthesis?
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combine with statins or niacin to reduce LDL
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what are the drug interactions of inhibitors of bile acid synthesis?
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decreased absorption of fat soluble vitamins
decreased absorption of Digoxin, Warfarin |
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When are inhibitors of bile acid reabsorption CI?
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hypertriglyceridemia - they can upregulate VLDL and triglyceride synthesis
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Why use Niacin?
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is the most effect agent for increasing HDL
also reduces VLDL, LDL, and triglyceride plasma levels |
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What is Niacin?
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nicotinic acid or vitamin B3
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What is the MOA of Niacin?
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at gram doses inhibits lipolysis in adipose tissue
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What is the effect of Niacin?
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leads to a decrease in lipolysis --> less substrates available for VLDL --> less substrate for LDL synthesis
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What are the pharmokinetics of Niacin?
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taken orally
converted to nicotinamide --> incorporated into NAD |
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How is Niacin excreted?
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niacin and its metabolites are excreted in urine
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When is Niacin used?
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when statins are CI
tx of familial hyperlipidemias in combo with other agents to treat severe hypercholesterolemia most potent increaser of HDL |
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what are the adverse effects of Niacin?
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1. cutaneous flush, pruritis - prevented with NSAIDs - occurs during first few weeks
2. hyperuricemia 3. hepatotoxicity 4. impaired insulin sensitivity 5. w/ statin increase risk of myopathy |
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what drug interactions should one be aware of with Niacin use?
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use with statins can increase risk of myopathies
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When is Niacin use cautioned?
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in diabetics
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What do fibrates do?
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reduce VLDL and TGs and increase HDL
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what are the fibrates?
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fenofibrate and gemfibrozil
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What is the MOA of the fibrates?
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bind to and activated perioxisome proliferator-activated receptor a (PPARa)
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where is perioxisome proliferator-activated receptor a found?
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hepatocytes, skeletal muscle, macrophages, heart
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what is the effect of fibrates on cholesterol?
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changes in lipid metabolism lead to decreased TGs and increased HDL
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How are fibrates excreted?
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in urine as glucuronide conjugates
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What is the PK of fibrates?
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completely absorbed after oral dose
widely distributed |
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What is the MOA of fibrates?
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When are Fibrates used?
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for the treatment of hypertriglyceridemias
patients who do not respond to diet or other drugs |
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when are fibrates the DOC?
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for dysbetalipoproteinemia
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What are the adverse effects of Fibrates?
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mild GI effects
cholelithiasis myositis - patients w/ renal insufficiency |
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When should fibrate used be cautioned?
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in patients with renal insufficieny - could get myositis
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What drug interactions exist with fibrate use?
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competes w/ coumadin for plasma binding sites and potentiates anticoagulant activity
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when are fibrates CI?
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Pregnancy - safety not established
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What do cholesterol absorption inhibitors do?
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reduce LDL
(small decrease in triglycerides and small increase in HDL) |
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What are the cholesterol absorption inhibitors
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ezetimibe, plant sterols
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What is the MOA of cholesterol absorption inhibitors
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inhibit intestinal absorption of dietary + billiary cholesterol
reduce LDL cholesterol by inhibiting hepatic production of VLDL |
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What is the effect of reduced hepatic cholesterol?
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reduced hepatic cholesterol --> up-regulation of LDL receptor
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What are the PK of cholesterol absorption inhibitors?
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primarily metabolized in small intestine and liver
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How are cholesterol absorption inhibitors excreted?
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biliary and renal excretion
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When to use cholesterol absorption inhibitors?
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complimentary to statins so used in combination when response to statin is inadequate
hypercholesterolemia when statins CI |
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what are the adverse effects cholesterol absorption inhibitors?
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diarrhea, abdominal pain, headache
rash and angio-edema (rare) |
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when are inhibitors of cholesterol absorption CI?
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breastfeeding
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What do omega-3 fatty acids do?
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decrease triglycerides
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what are the omega-3 fatty acids?
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EPA and DHA
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What is the MOA of omega-3 fatty acids?
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reduce triglyceride biosynthesis and increase fatty acid oxidation
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when are omega-3 fatty acids used as treatment?
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when triglycerides > 500mg/dl
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when is a single drug not enough?
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patients w/ combined hypertriglyceriedemia and hypercholesterolemia
patients w/ high LDL and low HDL |
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What are some combinations for reducing dyslipidemia?
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-ezetimibe + statin - further reduce LDL 15-20%
-statins + resin -fibrate + statin - use less statin |
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What is the rule of 6?
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if statin dose is doubled, there is only a 6% decrease in LDL
but if combined it can be decreased by 12-15% |
