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Statins, Fibrates, Niacin,

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Presentation on theme: "Statins, Fibrates, Niacin,"— Presentation transcript:

1 Statins, Fibrates, Niacin,
Cardio-Vascular Anti-lipidemics Statins, Fibrates, Niacin, Omega3, ezetimide… 8/2010 NUR 7755

2 HYPERLIPIDEMICS Total Chol Trigs Fats…not water soluble…. LIPOPROTEINS
HDL LDL IDL VLDL Chylo-microns PEOPLE don’t clog interstate… Chol. and Trigs don’t clog arteries…

3 lipids LIPOPROTEINS HDL LDL IDL VLDL Chylo-microns
vehicles..not people clog highway Lipid 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 Cholesterol Chole-sterol : alcohol form Phospholipid: lipid w phospherous group.. Neg charge lipophilic Hydrophilic..water soluble

5 “Cholesterol” Stored in gb as bile Requires transport protein Sources:
Substrates for cell membranes formation hormone synthesis needed for ADEK vit absorption Stored in gb as bile Requires transport protein Sources: liver synthesis (20-25%) intestines adrenal glands reproductive organs animal 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).

7 HMG pathway

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 acids Mono-glycerides & di-glycerides are absorbable Used as energy source Require a transport protein


10 lipoproteins Total Chol Trigs HDL LDL IDL VLDL Chylo-microns

11 Chylomicrons Replete w/ dietary trigs ->deliver trigs to skeletal muscle and adipose tissue Large. Contain: apo B 48 (SI) apo B100(liver) apo E 90% trigs Source: dietary fat Life: 12-14hr Catabolized by lipoprotein lipase -> to Chylomicron remnants -> return to liver Free cholesterol liberated Trigs 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 LDL other half continue to lose triacylglycerols in the bloodstream until they form LDL molecules, w/ highest % of cholesterol Regulated by diet, hormones Inhibited 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 & degraded Unless: over production, reduced receptors, fat in diet Increased intracellular Chol (from LDL catabolism) inhibits HMG-CoA

14 HDL Reverse Cholesterol Transport (RCT )
Synth. in liver Lots of Chol Few Trigs Apo A=good Reverse Cholesterol Transport (RCT ) transport cholesterol back to the liver for excretion or to other tissues that need cholesterol to synthesize hormones photo

15 Lipoprotein separation
Apo B Apo B Apo A Lipoprotein separation Chol 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..


17 LIPID Classes

18 Lipid cycle LDL enters endothelium…oxidized
..macrophage attack..foam cell..plaque.. Lipid cycle If no LDL… chol can’t cross cell wall anyway. LDL.. Oxidized.. Acted on by macrophage… becomes foam cell.. Becomes plaque

19 Atherosclerosis Nl……mild……severe……..rupture

20 Fredrickson-Levy-Lees Classification of Hyperlipoproteinemia
Phenotype Occurrence Present in Chol Trig Excess VLDL I Rare Chylomicrons >2500 V Chylomicrons, IIA Common LDL >250 <150 IIB Most common LDL,VLDL >250 III Rare VLDL remnants content IV Common VLDL

ApoE LPA-Aspirin response KIF6-Statin response 9p21-EarlyMI CYP2C19: plavix response ’s coag. ->CVD risk x3. phptp DIET RESPONSE

Homocysteine by-product of methionine Vascular inflammation Gen. inflammation OTHER: Insulin Fibrinogen NT-proBNP Q-LDL VIT D phptp Cardiac stress Response to lipid rx

23 GOALS Lower the LDL (<70-<160)
“National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III)” Risk stratification and treatment guidelines Framingham risk stratification LDL: NO risk factors<160 1-2 RF <130 High risk <100 Lower the LDL (<70-<160) Lower the non-HDL (30 pt > LDL) Raise the HDL (>40/50) Lower the Trigs (<150)

24 OPTIONS: Statins Fenofibrates Niacin Omega 3 Fish Oil
Bile Acid Sequestrants Ezetimide

25 STATINS: best LDL reduction
MOA: inhibits enzyme HMG-CoA reductase Thus:  cholesterol synthesis Thus: synthesis of LDL receptors Thus: LDL clearance USE: LDL SE: LFTs, myalgias/ rhabdomyositis CI: antifungals, erythro’s, grapefruit / grapefruit juice inhibit the P450 3A4, (lova-, simva-, less w/atorva) Most Chol produced at night, thus PM dosing

26 % LDL reduction:6% rule Dosage 10mg 20mg 40mg 80mg Crestor 46 52 55
Lipitor Zocor Pravachol Lescol Mevacor Livalo

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 Monascus 1970'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 yrs 2003: began to reappear 2007: FDA :consumers should not buy or eat red yeast rice products, may contain an unauthorized harmful drug 2010: 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: MOA Activates “Peroxisome Proliferator Activated Receptor type alpha” (PPARα).  lipolysis & elimination of trig-rich particles by activating lipoprotein lipase and  apo CIII production PPARα also  synthesis of apoproteins AI & AII  VLDL & LDL  HDL photo

31 Fibrate MOA Activate 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 HDL Remodel LDL particles

32 Fenofibrates… Generic fenofibric acid 105
Gen. fenofibrate, micronized 200 w/ meals Gen. fenofibrate/Triglide/Lofibra 160 Antara Fenoglide w/ meals Fibricor Lipofen ($25 cash) w/meals Tricor Trilipix Lopid/generic gemfibrozil bid, 30” ac, *caution w/ statin

SE: GI, rashes, pruritus, urticaria, photosensitivity, myopathy CI: liver insufficiency, gallstones, RI gall stones:  lithogenicity of bile b/c  chol to phosphoipids & bile salts Feno:  creatinine w/o  in cr cl Feno may prevent albuminuria, may induce regression of albuminuria Hi protein binding ‘s INR w/ coumadin ( coumadin dose 25-35%) May  homocysteine b/c p-par-a Met: 3A4

34 PK OF FIBRATES Fenofibrate: Gemfibrozil Absorbed in intestine
hydrolyzed by esterases in intestine to form active metabolite fenofibric acid then hepatic glucuronidation T 1/2 fenofibric acid 20hr ( qd) 60%excreted in urine 25% in feces Gemfibrozil Absorbed from GI tract Extensive hepatic conjugation T !/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 drug Oxidation is catalysed by CYP450 enzymes and results in the loss of electrons from the drug resulting 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 acetyl Conjugated w/ hydrophylic substance such as glucuronic acid …glucuronidation makes 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) Toxicity Thus  rhabdomyolysis w/ statin 33x higher risk w/ cerivaststin/ Baycol 15x higher risk w/ other statins Trilipix only one approved for combo use.

37 Niacin vitamin B3, nicotinic acid
Other forms of vit B3 : nicotinamide ("niacinamide") Niacin is converted to nicotinamide Although identical in vitamin activity, nicotinamide does not have the same pharmacological effects as niacin Nicotinamide 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 arrhythmias Flush duration ”, itching sensation mediated by prostaglandin blocked by 325mg ASA 30”before or ibuprofen take w/meals, 8oz liquid resolves w/2wk, slow titrate slow- or "sustained"-release forms lessen flush

40 inositol dietary supplement, esterified with niacin
sold as "flush-free" or "no-flush" niacin often marketed and labeled as niacin misleading consumers into thinking they are getting the active form of the medication. this form does not cause the flushing lipid-modifying evidence is contradictory, at best.

41 Niacin/ Niaspan AHA & NCEP state: only prescription niacin should be used to treat dyslipidemias and 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.

42 Niacin options: Niaspan (Tier 2) 1-2g qhs Slo-Niacin Nicotinic acid
start 500 x1mo,  by 500 qmo; max 2g/d cyp450 Slo-Niacin Nicotinic acid vit B3 niacin Make sure it’s nicotinic acid!!

43 OMEGA 3 MOA:Nutritionally important n−3 fatty acids:
α-linolenic acid (ALA) eicosapentaenoic acid (EPA) docosahexaenoic acid (DHA) All polyunsaturated OMEGA 3 EPA & DHA stimulate circulation  breakdown of fibrin  blood pressure  trigs regular intake ‘s Mi risk Body cannot synthesize n−3 fatty acids Converts α-linolenic acid to ALA, EPA, DHA conversions 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, leukotriene N6 & 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−3 n−6:n−3 fatty acids in oils: canola 2:1 soybean 7:1 Olive :1 sunfl(no n−3) flax :3 cottonseed (almost no n−3) peanut (no n−3) grapeseed oil (almost no n−3) corn oil :1

45 Omega 3: OTC OTC 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
Mackerel Anchovies sardines tuna (less n−3) Daily values Acceptable intake for n−3 is 1.6 grams/day for men and 1.1 grams/day for women Higher intakes : protection against CAD 3 g of total EPA/DHA qd safe, no increased risk of bleeding Perceived risk heavy metal poisoning Heavy metals selectively bind with protein in the fish flesh rather than accumulate in the oil.

47 Omega 3: rx Lovaza Highly purified, more effective
Combination E-EPA / E-DHA 4gm /d TG 14-30% HDL 10% DI: anticoagulants SE: fish burp (freeze) Monitor: LFTs

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 acids B/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 absorption Specifically, 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 Zetia LDL 18% 2 major, high-quality clinical trials (2008,2009) showed that it did not improve clinically significant outcomes panel of experts concluded in 2008 that it should "only be used as a last resort". Formulations: Zetia10mg, Vytorin (Simva+Zetia) SE: HA, diarrhea Rare: myalgia,  LFTs, rash, angioedema, myopathy

51 Bile Acid sequestrants
Bile Function: -made in liver -stored in gb -released in to duodenum Where it emulsifies fats: -hydrophilic & hydrophobic side, thus aggregate around fat (trigs & phospholipids) to form micelles Then absorbed by intestinal villi TG’s P’s photo

BAS exchange Cl- ions for bile acids. bind bile acids ->remove from enterohepatic circ. ->excrete in feces With in bile acids, cholesterol is converted to bile acid to normalize bile acid levels. Thus, ’ing plasma cholesterol concentrations.

53 Bile acid sequestrants
hypercholesterolemia prevention of pruritus w/ chronic liver dz Post chole dumping syndrome USES No 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-> deficiency SE

54 Bile Acid Sequestrant Cholestyramine Tier 1 4g/scoop qd-bid, by 4g/d qmo Max 24g.d; pre-meals 1-6x/d Colestid Tier 3 1gm tab/ 5g/pkt or scoop g qd-bid; max 16/g/d; give other meds >1hr pre or 4hr post Colestipol Tier 1 Prevalite Tier 1 sugar free 4gm/scoop Questran Tier 3 4g/scoop Questran Light Tier 3 4g/scoop sugar free Welchol Tier mg/tab or powder 6 tab qd; w/meals; other drugs >4hr pre

55 the end! Get those buses off the road!!

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