2 HYPERLIPIDEMICS Total Chol Trigs Fats…not water soluble…. LIPOPROTEINS HDLLDLIDLVLDLChylo-micronsPEOPLE don’t clog interstate…Chol. and Trigs don’t clog arteries…
3 lipids LIPOPROTEINS HDL LDL IDL VLDL Chylo-microns vehicles..not people clog highwayLipid panels count cholesterol…Each vehicle carries lots of Chol and Trigs (people)
4 LIPOPROTEINS Chylo-microns VLDL IDL LDL HDL ligand lipophilic Lipids: molecules which includes fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, phospholipids, and others.Functions: energy storage, structural components of cell membranes, signaling molecules.Chol. Ester: ester of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol. Cholesteryl Esters have a lower solubility in water than CholesterolChole-sterol : alcohol formPhospholipid: lipid w phospherous group.. Neg chargelipophilicHydrophilic..water soluble
5 “Cholesterol” Stored in gb as bile Requires transport protein Sources: Substrates forcell membranes formationhormone synthesisneeded for ADEK vit absorptionStored in gb as bileRequires transport proteinSources:liver synthesis (20-25%)intestinesadrenal glandsreproductive organsanimal foods
6 Cholesterol synthesis starts w/ 1 molecule of acetyl CoA and 1 molecule of acetoacetyl-CoA => dehydrated to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA).=> reduced to mevalonate by the enzyme HMG-CoA reductase.This is the regulated, rate-limiting and irreversible step in cholesterol synthesis and is the site of action for the statin drugs (HMG-CoA reductase competitive inhibitors).
8 “Triglycerides” Most dietary fats are “tri” glycerides. Glycerol molecule PLUS 3 fatty acid molecules.triglyceride form not absorbable in duodenum“pancreatic lipase” enzyme releases the fatty acidsMono-glycerides & di-glycerides are absorbableUsed as energy sourceRequire a transport protein
11 ChylomicronsReplete w/ dietary trigs ->deliver trigs to skeletal muscle and adipose tissueLarge.Contain:apo B 48 (SI)apo B100(liver)apo E90% trigsSource: dietary fatLife: 12-14hrCatabolized by lipoprotein lipase ->to Chylomicron remnants ->return to liverFree cholesterol liberatedTrigs converted to FFA
12 VLDL/IDL VLDL Synthesized in liver-> contain excess Triglyceride (& Cholesterol) not used by the liver for synthesis of bile acids.contain apolipoprotein B100 and apo E in shell.=>Secreted by liver-> vessels cleave and absorb trigs -> leave IDL molecules (w/ even more chol) >Half are taken up by the liver for metabolism into other biomolecules then to LDLother half continue to lose triacylglycerols in the bloodstream until they form LDL molecules, w/ highest % of cholesterolRegulated by diet, hormonesInhibited by chylomicron remnants in liver
13 LDL Only 1 Lots of Chol Few Trigs ApoB=bad! LDL carries chol to end organs.Receptors recognize Apo B.Remaining LDL-Chol is taken back to liver & degradedUnless: over production, reduced receptors, fat in dietIncreased intracellular Chol (from LDL catabolism) inhibits HMG-CoA
14 HDL Reverse Cholesterol Transport (RCT ) Synth. in liverLots of CholFew TrigsApo A=goodReverse Cholesterol Transport (RCT )transport cholesterol back to the liver for excretionor to other tissues that need cholesterol to synthesize hormonesphoto
15 Lipoprotein separation Apo BApo BApo ALipoprotein separationChol amount is by weight or volume… not counted particles… may be VWs… may be buses..Not the Chol that counts… but the Lipoproteins..not counted cholesterol..
27 Statins: examples Potency: $$ Metab./SE T1/2 Prot. Bind. Crestor H2O sol 2C9/2C hr %Lipitor fat sol 3A hr %Zocor gen. H2O sol 3A hr %Pravachol $4 fat sol %Lescol fat sol 2C >90%Mevacor $4 fat sol 3A hr >95%??Livalo fat sol 2C9
28 Red Yeast Rice & Statins bright reddish-purple fermented rice, which acquires its color from being cultivated w/ the mold Monascus1970's researchers in US & Japan were isolating lovastatin from Aspergillus and monacolins from Monascus, (same yeast used to make red yeast rice, but cultured under carefully controlled conditions.)lovastatin (Mevacor) & monacolin K chemically identical.
29 Red Yeast rice 1998: FDA banned Cholestin 2001: decision reversed on appeal; FDA sent Warning Letters to companies selling red yeast rice; disappeared x yrs2003: began to reappear2007: FDA :consumers should not buy or eat red yeast rice products, may contain an unauthorized harmful drug2010: 30+ brands available. Many avoid FDA restriction by not having any appreciable moncolin content.Labels / websites say no more than "fermented according to traditional Asian methods" or "similar to that used in culinary applications.” (no mention of cholesterol)If they do not contain/claim to contain lovastatin, and do not make a claim to cholesterol-> not subject to FDA action.monacolin content of red yeast rice dietary supplements can vary widely.
30 Fenofibrates: MOAActivates “Peroxisome Proliferator Activated Receptor type alpha” (PPARα). lipolysis & elimination of trig-rich particlesby activating lipoprotein lipase and apo CIII productionPPARα also synthesis of apoproteins AI & AII VLDL & LDL HDLphoto
31 Fibrate MOAActivate peroxisome proliferator activated receptor a (PPAR a) hepatic lipogenesis and VLDL secretion fatty acid oxidation in liver and muscle lipoprotein lipase activity transcription of Apo AI and AII transfer of phospholipid and chol to HDLRemodel LDL particles
33 FENOFIBRATES USE to :TG (LDL, VLDL, HDL) SE: GI, rashes, pruritus, urticaria, photosensitivity, myopathyCI: liver insufficiency, gallstones, RIgall stones: lithogenicity of bile b/c chol to phosphoipids & bile saltsFeno: creatinine w/o in cr clFeno may prevent albuminuria, may induce regression of albuminuriaHi protein binding ‘s INR w/ coumadin ( coumadin dose 25-35%)May homocysteine b/c p-par-aMet: 3A4
34 PK OF FIBRATES Fenofibrate: Gemfibrozil Absorbed in intestine hydrolyzed by esterases in intestine to form active metabolite fenofibric acidthen hepatic glucuronidationT 1/2 fenofibric acid 20hr ( qd)60%excreted in urine25% in fecesGemfibrozilAbsorbed from GI tractExtensive hepatic conjugationT !/2 1.5hr(600 bid ac)Metabolites excreted in urine
35 Remember 2 phase metab… Fibrates… Phase 2: involves conjugation - Phase 1:oxidation.May involve reduction or hydrolysis of drugOxidation is catalysed by CYP450 enzymes and results in the loss of electrons from the drugresulting drug metabolite is still often chemically active.Fibrates…Phase 2: involves conjugation -attachment of an ionized group to the drug.Ionized groups include glutathione, methyl or acetylConjugated w/ hydrophylic substance such as glucuronic acid…glucuronidationmakes substances more water-soluble,thus, easier elimination through urine or faeces (via bile from the liver).allows easier transport around the body.Sometimes less toxic after glucuronidation.
36 Gemfibrozil inhibits glucuronidation and cyp450 metab of statins “Changes in CYP enzyme activity may affect the metabolism and clearance of various drugs.if one drug inhibits the CYP-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels.”Thus ’s AUC & Cmax of all statins (except fluvastatin)ToxicityThus rhabdomyolysis w/ statin33x higher risk w/ cerivaststin/ Baycol15x higher risk w/ other statinsTrilipix only one approved for combo use.
37 Niacin vitamin B3, nicotinic acid Other forms of vit B3 : nicotinamide ("niacinamide")Niacin is converted to nicotinamideAlthough identical in vitamin activity, nicotinamide does not have the same pharmacological effects as niacinNicotinamide does not reduce cholesterol or cause flushing.Nicotinamide may be toxic to the liver at doses exceeding 3 g/day for adults.
38 Niacin Blocks breakdown of fats in adipose tissue thus ’s FFA’s-> ’s secretion of VLDL and cholesterol by the liver.By ’ing VLDL levels, niacin also ’s HDL’sTC, TG (38%), VLDL, LDL(16%)HDL (22%)May lipoprotein(a)
39 Niacin Pharmacological doses :1.5 - 6 g/d SE:flushing, itching,rash, acanthosis nigricans, hyperuricemia (hi dose, exac. gout)GI: dyspepsia, liver toxicity (>2gm/d, slow release)Hyperglycemia (hi dose), cardiac arrhythmiasFlush duration ”, itching sensationmediated by prostaglandinblocked by 325mg ASA 30”before or ibuprofentake w/meals, 8oz liquidresolves w/2wk, slow titrateslow- or "sustained"-release forms lessen flush
40 inositol dietary supplement, esterified with niacin sold as "flush-free" or "no-flush" niacinoften marketed and labeled as niacinmisleading consumers into thinking they are getting the active form of the medication.this form does not cause the flushinglipid-modifying evidence is contradictory, at best.
41 Niacin/ NiaspanAHA & NCEP state: only prescription niacin should be used to treat dyslipidemiasand only under the management of a physician.Because: niacin at effective intakes of mg/day can also potentially have severe AE.Monitoring of liver enzymes is necessary.
43 OMEGA 3 MOA:Nutritionally important n−3 fatty acids: α-linolenic acid (ALA)eicosapentaenoic acid (EPA)docosahexaenoic acid (DHA)All polyunsaturatedOMEGA 3EPA & DHAstimulate circulation breakdown of fibrin blood pressure trigsregular intake ‘s Mi riskBody cannot synthesize n−3 fatty acidsConverts α-linolenic acid to ALA, EPA, DHAconversions slows if high levels of n−6 fatty acids,(closely related, derived from linoleic acid)
44 Omega 3: n−3 & n-6 fatty acids 1979: “eicosanoids” discovered: thromboxanes (platelet function), prostacyclins, leukotrieneN6 & N3 compete to be converted to eicosanoids; so ratio of 3:6 affects type eicosanoids produced.(n−6 converted to pro-inflammatory prostaglandins)(N-3: ALA, DHA, EPA)To control the synthesis of n−6 eicosanoids, consume more n−3n−6:n−3 fatty acids in oils:canola 2:1soybean 7:1Olive :1sunfl(no n−3)flax :3cottonseed (almost no n−3)peanut (no n−3)grapeseed oil (almost no n−3)corn oil :1
45 Omega 3: OTCOTC products claim to contain health promoting 'omega 3', but contain only α-linolenic acid (ALA), not EPA or DHA.They contain plant oils that must be converted to DHA -> less efficient.DHA & EPA are made by microalgae in seawater, consumed by fish, accumulate in internal organs.
46 Daily values Foods: cold water oily fish 7x n3:n6 Salmon Herring MackerelAnchoviessardinestuna (less n−3)Daily valuesAcceptable intake for n−3 is 1.6 grams/day for men and 1.1 grams/day for womenHigher intakes : protection against CAD3 g of total EPA/DHA qd safe, no increased risk of bleedingPerceived risk heavy metal poisoningHeavy metals selectively bind with protein in the fish flesh rather than accumulate in the oil.
48 OTC:Krill relatively new source of n−3 fatty acids. Various claims are made in support of krill oil as a superior source of n−3 fatty acidsB/c less contamination, contain a special antioxidant called astaxanthin.However, numerous studies have found krill is often contaminated by pollution and astaxanthin hasn't been demonstrated to have a very potent antioxidant capacity
49 EZETIMIDE MOA: localizes at brush border of SI cholesterol absorptionSpecifically, binds to a critical mediator of cholesterol absorption, the Niemann-Pick C1-Like 1 (NPC1L1) protein on the GI epithelial cells and hepatocytes cholesterol absorption leads to an upregulation of LDL-receptors thus LDL-c uptake into cells, thus decreasing plasma levels
50 ZetiaLDL 18%2 major, high-quality clinical trials (2008,2009) showed that it did not improve clinically significant outcomespanel of experts concluded in 2008 that it should "only be used as a last resort".Formulations: Zetia10mg, Vytorin (Simva+Zetia)SE:HA, diarrheaRare: myalgia, LFTs, rash, angioedema, myopathy
51 Bile Acid sequestrants Bile Function:-made in liver-stored in gb-released in to duodenumWhere it emulsifies fats:-hydrophilic & hydrophobic side, thus aggregate around fat (trigs & phospholipids)to form micellesThen absorbed by intestinal villiTG’sP’sphoto
52 BILE ACID SEQUESTRANTS: MOA BAS exchangeCl- ions for bileacids.bind bile acids->remove fromenterohepatic circ.->excrete in fecesWith in bile acids, cholesterol is converted to bile acid to normalize bile acid levels.Thus, ’ing plasma cholesterol concentrations.
53 Bile acid sequestrants hypercholesterolemiaprevention of pruritus w/ chronic liver dzPost chole dumping syndromeUSESNo systemic side effects.GI: constipation, diarrhea, flatulence.CI: bind other drugs, preventing absorption.spaced several hours apart from other drugs.bind fat-soluble vitamins, ADEK-> deficiencySE
54 Bile Acid SequestrantCholestyramine Tier 1 4g/scoop qd-bid, by 4g/d qmo Max 24g.d; pre-meals 1-6x/dColestid Tier 3 1gm tab/ 5g/pkt or scoop g qd-bid; max 16/g/d;give other meds >1hr pre or 4hr postColestipol Tier 1Prevalite Tier 1 sugar free 4gm/scoopQuestran Tier 3 4g/scoopQuestran Light Tier 3 4g/scoop sugar freeWelchol Tier mg/tab or powder6 tab qd; w/meals; other drugs >4hr pre
55 the end! Get those buses off the road!! Questions?