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44 Cards in this Set
- Front
- Back
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lipoprotein production pathway
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CH and TG in the liver combined to VLDL. This travels through the blood and the lipoprotein lipase turns it into FFA and IDL. IDL can either go back to the liver or turn into LDL. This LDL then can go to the liver or go to extrahepatic tissue.
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Where are the three sources of CH for the liver?
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food from small intestine
LDL and other lipoproteins in blood de novo synthesis |
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how is cholesterol de novo synthesized in the liver?
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LDL from the blood combines with the LDL receptors in the liver. Simultaneously, HMG CoA is converted to Mevalonate by HMG CoA Reductase, which is then turned into cholesterol when combines with LDL.
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What is the rate limiting enzyme in the synthesis of cholesterol?
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HMG CoA Reductase. Inhibitors of HMG CoA Reductase, aka Statins, are used to stop this synthesis of cholesterol.
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What happens in the liver with a statin?
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the HMG CoA reductase is inhibited, decreasing the mevalonate and cholesterol, but there is an upregulation of LDL receptors, which means there will be a GIANT removal of LDL form circulation. The liver still needs LDL in order to make CH in order to make bile.
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What effect will statins have on TGs?
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there will be a modest decrease in VLDL synthesis (less CH for VLDL synthesis), increase clearance of IDLs by the LDL receptors, so there will be a MODEST reduction of TG
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end result of LDL, TG and HDL from using statins?
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LDL- LARGE reduction
TG- modest HDL- modest |
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Doubling the dose of of a statin...
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...reduces the LDL by only about 6% more.
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Half lives of statins...
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Atorvastatin and Rosuvastatin have long half lives (19-30hrs), but all others have less than 4 hr half lives.
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End result of using statins.
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slow the progression of atherosclerosis, reduce CHD, MI, revascularization procedures, stroke, PVD, and death.
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Whats the major thing that statins do to decrease the risk of heart attack?
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Decrease LDLs.
Another cardioprotective effect that isnt lipid lowering is the decrease in inflammation. |
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Clinical use of statins
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hypercholesteroemia, mixer hyperlipidemia, hyperTGemia.
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Why are short half life statins used at night?
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you don't eat at night, so you're eliminating a source of CH. You will get more liver CH de novo synthesis.
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Statin adverse effects
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-GI problems- all CH can
-Elevation of hepatic transaminases and possible liver toxicity (rare) |
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Muscle pain isn't such a bad side effect from statins, right?
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no, it is. It can progress to myopathy and elevated creatine kinase. and then this can get worse and you can piss brown urine and have rhabdomyolysis. this is excessive skeletal muscle damage and there is now myoglobin in the urine.
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name drug interactions that can increase the incidence of myopathy when combined with statins
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fibrates, niacin, and CYP3A4 inhibitors (from cyclosporine, azole antifungals, erythromycin, grapefruit)
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Contraindications of statins
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active hepatic disease
pregnancy and lactation (the fetus needs a lot of CH) |
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Name some bile acid binding resins
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-Cholestyramine
-Colestipol -Colesevelam |
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Where does bile acids come from, and where does it go?
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bile acids are one product from cholesterol made in the liver. After bile is used in the GI tract, its taken back up (reabsorbed) in the liver to be reused.
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What is anion exchange resin?
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it's a piece of plastic with a chloride on it. this binds to the bile acid to form an anionic bile acid that is not absorbed, preventing recirculation and is excreted. The chloride on the resin exchanges with the bile acid in this process. Since you reduce the bile recirculation, you need to make more bile, so you will use more cholesterol by increasing the LDL receptors on the liver cells by taking them out of the bloodstream.
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End result of using bile acid resins
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LDL- decrease by 15-30%
TG- transient increase (esp with hyper TGemia) HDL- wimpy 3-5% increase |
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What is the rationale for taking the resin before meals?
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bile is released when eating so you need bile for the resin to stick to.
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Clinical use for Bile Acid Binding Resins
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-hyperCH
-NOT for hyperTG -take before meals -gradually increase dose |
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Name a cholesterol Absorption Inhibitor
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Ezetimibe
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MoA of ezetimibe
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prevents CH absorption from the intestinal villi.this will decrease the delivery of intestinal CH to the liver.
this decreases hepatic CH stores and increases clearance of CH from the blood. |
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What doesnt ezetimibe do?
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does not alter intestinal TG or fat-soluble vitamin absorption.
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End result of using CH absorption inhibitors
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LDL- 15-20% (MODERATE)
TG- 6% decrease HDL- 4-9% increase |
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clinical uses for CH abs inhibs
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-hyperCH
-monotherapy -combo with statin (to lower the dose of the statin) -in combo with fibric acid derivative. |
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whats good about the adverse effects of ezetimibe
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doesnt got much. no liver toxicity. no rhabdomyolysis. just GI upset.
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Niacin MoA
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binds to the GPR109A receptor on the adipocytes activating Gi. this decrease in cAMP production and PKA activity. PKA phosphorylates hormone sensitive lipase (HSL) the key enzyme responsible for TG hydrolysis with subsequent fatty acid mobilization from adipose tissue. Therefore niacin decreases HSL and TG hydrolysis in adipocytes. overall there's less free fatty acids delivered to the liver for TG synthesis.
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what is DGAT2?
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the final step in cellular TG synthesis. TG + CH + ApoB makes up VLDL. without the other components to make the VLDL, the ApoB is degraded. Niacin inhibits DGAT2 in hepatocytes, thus decreasing TG synthesis in the liver, and more ApoB degradation.
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end result of niacin's inhibition of DGAT2
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less ApoB means less lipoproteins that need ApoB, like VLDL and LDL. The VLDLs that are made are smaller which ultimately will make large, buoyrant LDLs
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end result of Niacin
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LDL- modest decrease
TG- large decrease HDL- LARGE INCREASE Lp(a)- decrease (only one) |
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Clinical use of niacin
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-hyperTGemia
-mixed hyperlipidemia -hyperCHemia -used at high doses -titrate to avoid flush |
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What happens if you combine a statin with niacin?
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-large reduction of TG
-Larger reduction of LDL -raises HDL |
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what happens if you combine cholestyramine with niacin?
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large decrease of TG
large increase of HDL large decrease of LDL (40-60%) TG reduction better with statin/niacin and HDL greater increase with niacin/statin |
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Adverse rxns of niacin
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Flushing- PG mediated dilation of skin capillaries, which is harmless. Increase activity of ERK (extracellular regulator kinase) which leads to increase PGD2, then vasodilation
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What can you do to prevent the niacin flush besides titration?
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use aspirin to stop PGs
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Contraindications with niacin
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-chronic liver disease
-active peptic ulcer -gout -high doses in Type 2 Diabetes. |
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Fibric Acid Derivatives
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-Gemfibrozil
-fenofibrate -fenofibric acid |
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Fibric Acid Deriv. MoA?
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activates peroxisome proliferator activated receptor-alpha (PPAR-alpha)
-> increase extrahepatic lipoprotein lipase activity -> increase VLDL catabolism/clearance. -> less small, dense LDL particles and more large buoyant LDL particles |
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end result of FADs
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TG- decrease 20-50%
HDL- increase 10-35% LDL- variable change ( usually small) *ones that decrease TG a lot increase HDLs a lot. |
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clinical use of FADs
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hyperTGemia
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adverse Rxns of FADs
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-Gall stone formation (increases the saturation of the CH in the bile, mainly with clofibrate)
-myopathy and rhabdomyolysis (in combo with statin, more with gemfibrozil than fenofibrate) |
