Embed Size (px)
Citation preview
Cardio-Vascular
Anti-lipidemicsStatins, Fibrates, Niacin,
Omega3, ezetimide…
8/2010
NUR 7755
HYPERLIPIDEMICS
• Total Chol• Trigs
PEOPLE don’t clog interstate…Chol. and Trigs don’t clog arteries…
Fats…not water soluble….
LIPOPROTEINS•HDL•LDL•IDL•VLDL•Chylo-microns
lipidsvehicles..not people clog highway
Each vehicle carries lots of Chol and Trigs (people)
LIPOPROTEINS•HDL•LDL•IDL•VLDL•Chylo-microns
LIPOPROTEINS
Chylo-microns
VLDL
IDL
LDL
HDLlipophilic Hydrophilic..water soluble
ligand
“Cholesterol”Substrates for cell membranes formation hormone synthesisneeded for ADEK vit absorption
Stored in gb as bileRequires transport proteinSources:
•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.
HMG pathway
“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
XANTHOMAS
SERUM
XANTHELASMA
Triglycerides
lipoproteins• Total
Chol• Trigs
• HDL• LDL• IDL• VLDL• Chylo-
microns
Chylomicrons
Large.Contain: apo B 48 (SI) apo B100(liver) apo E
Source: dietary fatLife: 12-14hrCatabolized by lipoprotein lipase -> to Chylomicron remnants -> return to liverFree cholesterol liberatedTrigs 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
LDLOnly 1
Lots of CholFew 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 dietIncreased intracellular Chol (from LDL catabolism) inhibits HMG-CoA
HDL
Lots of CholFew 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
Lipo
prot
ein
sep
arat
ion
Apo B Apo B Apo A
..not counted cholesterol..
LIPID Classes
Lipid cycleLDL enters endothelium…oxidized..macrophage attack..foam cell..plaque..
Atherosclerosis
Nl……mild……severe……..rupture
Phenotype OccurrenceLipoprotein Present in
ExcessChol Trig
IIA Common LDL >250 <150IIB Most common LDL,VLDL >250 150-400150-400III Rare VLDL remnants 375-500 600-800600-800IV Common VLDL 225-275 375-500375-500
VLDL
I Rare Chylomicrons 250-400 >2500>2500
V Rare Chylomicrons, 350-400 1700-25001700-2500
Fredrickson-Levy-Lees Classification of Fredrickson-Levy-Lees Classification of HyperlipoproteinemiaHyperlipoproteinemia
ADVANCED TESTINGLDL-S3GGE ｮ
HDL-S10GGE ｮ
ApoB (part #)
GENETIC:Lp(a)ApoELPA-Aspirin response
KIF6-Statin response
9p21-EarlyMI
CYP2C19: plavix response
DIET RESPONSE
’s coag. ->CVD risk x3.
ADVANCED TESTING
INFLAMMATORY MARKERSLp-PLA2
hsCRPHomocysteine by-product of methionine
OTHER:InsulinFibrinogenNT-proBNPQ-LDLVIT D
Vascular inflammation
Gen. inflammation
Response to lipid rxCardiac 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 guidelinesFramingham risk stratification LDL:
NO risk factors<1601-2 RF <130High risk <100
OPTIONS:
• Statins
• Fenofibrates
• Niacin
• Omega 3 Fish Oil
• Bile Acid Sequestrants
• Ezetimide
STATINS: best LDL reductionMOA: inhibits enzyme HMG-
CoA reductaseThus: cholesterol synthesisThus: synthesis of LDL
receptors Thus: LDL clearance
USE: LDLSE: LFTs, myalgias/ rhabdomyositisCI: antifungals, erythro’s, grapefruit / grapefruit juice inhibit the P450 3A4, (lova-, simva-, less w/atorva)•Most Chol produced at night, thus PM dosing
% LDL reduction:6% rule
Dosage 10mg 20mg 40mg 80mg• Crestor 46 52 55• Lipitor 39 43 50 60• Zocor 30 38 41 47• Pravachol 22 32 34 37• Lescol 22 25 36 35• Mevacor 21 27 31• Livalo
Statins: examples
• Crestor H2O sol 2C9/2C19 13-20hr 88%• Lipitor fat sol 3A4 7-14hr 96%• Zocor gen. H2O sol 3A4 2hr 95%• Pravachol $4 fat sol -- 1.8 50%• Lescol fat sol 2C9 1.2 >90%• Mevacor $4 fat sol 3A4 3hr >95%• ??Livalo fat sol 2C9
Potency: $$ Metab./SE T1/2 Prot.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 rice1998: FDA banned Cholestin2001: 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: MOAActivates “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…• Generic fenofibric acid 105• Gen. fenofibrate, micronized 200 w/ meals• Gen. fenofibrate/Triglide/Lofibra 160• Antara 130• Fenoglide 120 w/ meals• Fibricor 105• Lipofen ($25 cash) 150 w/meals• Tricor 145• Trilipix 135
•Lopid/generic gemfibrozil 600 bid, 30” ac, *caution w/ statin
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 FIBRATESGemfibrozil• 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 acidthen hepatic glucuronidation
T 1/2 fenofibric acid 20hr (134-200 qd) 60%excreted in urine25% 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…
ToxicityGemfibrozil 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 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.
NiacinBlocks 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)
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 15 -30”, 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
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 1500-3000 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
• niacinMake sure it’s nicotinic acid!!
OMEGA 3• MOA:Nutritionally important n−3 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 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)
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 13:1sunfl(no n−3)flax 1:3 cottonseed (almost no n−3) peanut (no n−3) grapeseed oil (almost no n−3) 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 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.
Foods: cold water oily fish7x n3:n6•Salmon•Herring•Mackerel•Anchovies•sardines
tuna (less n−3)
Omega 3: rx
Lovaza • Highly purified, more effective • Combination E-EPA / E-DHA• 4gm /d
TG 14-30% HDL 10%
DI: anticoagulantsSE: fish burp (freeze)Monitor: LFTs
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
EZETIMIDEMOA: • 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
TG’s
P’s
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 exchangeCl- ions for bileacids. • bind bile acids • ->remove fromenterohepatic 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
U
SE
S
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
