Cholesterol 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
Cholesterol synthesis 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). 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.
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
Chylomicrons Large. Contain: apo B 48 (SI) apo B100(liver) apo E Source: dietary fat Life: 12-14hr Catabolized by lipoprotein lipase -> to Chylomicron remnants -> return to liver Free cholesterol liberated Trigs converted to FFA Replete w/ dietary trigs ->deliver trigs to skeletal muscle and adipose tissue 90% trigs
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
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
HDL Lots of Chol Few Trigs Apo A=good Synth. in liver Reverse Cholesterol Transport (RCT ) –transport cholesterol back to the liver for excretion –or to other tissues that need cholesterol to synthesize hormones
Lipoprotein separation Apo B Apo A..not counted cholesterol..
ADVANCED TESTING INFLAMMATORY MARKERS Lp-PLA 2 hsCRP Homocysteine by-product of methionine OTHER: Insulin Fibrinogen NT-proBNP Q-LDL VIT D Vascular inflammation Gen. inflammation Response to lipid rx Cardiac stress
GOALS Lower the LDL (<70-<160) Lower the non-HDL (30 pt > LDL) Raise the HDL (>40/50) Lower the Trigs (<150) National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) Risk stratification and treatment guidelines Framingham risk stratification LDL: NO risk factors< RF <130 High risk <100
OPTIONS: Statins Fenofibrates Niacin Omega 3 Fish Oil Bile Acid Sequestrants Ezetimide
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, erythros, grapefruit / grapefruit juice inhibit the P450 3A4, (lova-, simva-, less w/atorva) Most Chol produced at night, thus PM dosing
Statins: examples Crestor H2O sol 2C9/2C hr 88% Lipitorfat sol 3A4 7-14hr 96% Zocor gen.H2O sol 3A4 2hr 95% Pravachol$4fat sol % Lescolfat sol 2C9 1.2 >90% Mevacor$4fat sol 3A4 3hr >95% ??Livalo fat sol 2C9 Potency: $$Metab./SE T1/2Prot. Bind.
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.
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.
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
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
FENOFIBRATES USE to : TG ( LDL, VLDL, HDL) 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
PK OF FIBRATES Gemfibrozil Absorbed from GI tract Extensive hepatic conjugation T !/2 1.5hr (600 bid ac) Metabolites excreted in urine Fenofibrate: 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
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. Remember 2 phase metab… 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. Fibrates …
Toxicity 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) Thus rhabdomyolysis w/ statin 33x higher risk w/ cerivaststin/ Baycol 15x higher risk w/ other statins Trilipix only one approved for combo use.
Niacin vitamin B 3, nicotinic acid Other forms of vit B 3 : 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.
Niacin Blocks breakdown of fats in adipose tissue thuss FFAs->s secretion of VLDL and cholesterol by the liver. Bying VLDL levels, niacin alsos HDL sTC, TG (38%), VLDL, LDL (16%) HDL (22%) May lipoprotein(a)
Niacin Pharmacological doses : 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 30before or ibuprofen take w/meals, 8oz liquid resolves w/2wk, slow titrate slow- or "sustained"-release forms lessen flush
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.
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.
Niacin options: Niaspan (Tier 2) 1-2g qhs –start 500 x1mo, by 500 qmo; max 2g/d cyp450 Slo-Niacin Nicotinic acid vit B3 niacin Make sure its nicotinic acid!!
OMEGA 3 MOA:Nutritionally important n3 fatty acids: –α-linolenic acid (ALA) –eicosapentaenoic acid (EPA) –docosahexaenoic acid (DHA) All polyunsaturated EPA & DHA stimulate circulation breakdown of fibrin blood pressure trigs regular intakes Mi risk Body cannot synthesize n3 fatty acids Converts α-linolenic acid to ALA, EPA, DHA conversions slows if high levels of n6 fatty acids, (closely related, derived from linoleic acid)
Omega 3: n3 & 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. (n6 converted to pro-inflammatory prostaglandins) (N-3: ALA, DHA, EPA) To control the synthesis of n6 eicosanoids, consume more n3 n6:n3 fatty acids in oils: canola 2:1 soybean 7:1 Olive 13:1 sunfl(no n3) flax 1:3 cottonseed (almost no n3) peanut (no n3) grapeseed oil (almost no n3) corn oil 46:1
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.
Daily values Acceptable intake for n3 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. Foods: cold water oily fish 7x n3:n6 Salmon Herring Mackerel Anchovies sardines tuna (less n3)
OTC:Krill relatively new source of n3 fatty acids. Various claims are made in support of krill oil as a superior source of n3 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
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
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
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 TGs Ps
BILE ACID SEQUESTRANTS: MOA With in bile acids, cholesterol is converted to bile acid to normalize bile acid levels. Thus,ing plasma cholesterol concentrations. BAS exchange Cl- ions for bile acids. bind bile acids ->remove from enterohepatic circ. ->excrete in feces
Bile acid sequestrants hypercholesterolemia prevention of pruritus w/ chronic liver dz Post chole dumping syndrome 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 USES SE
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 2g 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 3 625mg/tab or powder 6 tab qd; w/meals; other drugs >4hr pre