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Cardio-Vascular. Anti-lipidemics Statins, Fibrates, Niacin, Omega3, ezetimide… 8/2010 NUR 7755. HYPERLIPIDEMICS. Fats…not water soluble…. Total Chol Trigs. LIPOPROTEINS HDL LDL IDL VLDL Chylo-microns. PEOPLE don’t clog interstate… Chol. and Trigs don’t clog arteries….

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cardio vascular

Cardio-Vascular

Anti-lipidemics

Statins, Fibrates, Niacin,

Omega3, ezetimide…

8/2010

NUR 7755

hyperlipidemics
HYPERLIPIDEMICS

Fats…not water soluble….

  • Total Chol
  • Trigs
  • LIPOPROTEINS
  • HDL
  • LDL
  • IDL
  • VLDL
  • Chylo-microns

PEOPLE don’t clog interstate…

Chol. and Trigs don’t clog arteries…

lipids

LIPOPROTEINS

  • HDL
  • LDL
  • IDL
  • VLDL
  • Chylo-microns
lipids

vehicles..not people clog highway

Each vehicle carries lots of Chol and Trigs (people)

lipoproteins
LIPOPROTEINS

ligand

Chylo-microns

VLDL

IDL

LDL

HDL

lipophilic

Hydrophilic..water soluble

cholesterol
“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
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).
triglycerides
“Triglycerides”
  • Most dietary fats are “tri” glycerides.
  • Glycerolmolecule 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
triglycerides9
Triglycerides

XANTHOMAS

SERUM

XANTHELASMA

lipoproteins10
lipoproteins
  • Total Chol
  • Trigs
  • HDL
  • LDL
  • IDL
  • VLDL
  • Chylo-microns
chylomicrons
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

vldl idl
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
slide13

Only 1

LDL

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

slide14
HDL

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
lipoprotein separation
Lipoprotein separation

Apo B

Apo B

Apo A

..not counted cholesterol..

lipid cycle

LDL enters endothelium…oxidized

..macrophage attack..foam cell..plaque..

Lipid cycle
slide19

Atherosclerosis

Nl……mild……severe……..rupture

fredrickson levy lees classification of hyperlipoproteinemia

I

Rare

Chylomicrons

250-400

>2500

IIA

Common

LDL

>250

<150

IIB

Most common

LDL,VLDL

>250

150-400

III

Rare

VLDL remnants

375-500

600-800

IV

Common

VLDL

225-275

375-500

V

Rare

Chylomicrons,

350-400

1700-2500

VLDL

Fredrickson-Levy-Lees Classification of Hyperlipoproteinemia

Lipoprotein

Phenotype

Occurrence

Present in

Chol

Trig

Excess

advanced testing
ADVANCED TESTING

GENETIC:

Lp(a)

ApoE

LPA-Aspirin response

KIF6-Statin response

9p21-EarlyMI

CYP2C19: plavix response

’s coag. ->CVD risk x3.

DIET RESPONSE

advanced testing22
ADVANCED TESTING

INFLAMMATORY MARKERS

Lp-PLA2

hsCRP

Homocysteine by-product of methionine

Vascular inflammation

Gen. inflammation

OTHER:

Insulin

Fibrinogen

NT-proBNP

Q-LDL

VIT D

Cardiac stress

Response to lipid rx

goals
GOALS

“National Cholesterol Education Program (NCEP)

Adult Treatment Panel III (ATP III)”

Risk stratification and treatment guidelines

Framingham risk stratification

  • Lower the LDL (<70-<160)
  • Lower the non-HDL (30 pt > LDL)
  • Raise the HDL (>40/50)
  • Lower the Trigs (<150)

LDL:

NO risk factors<160

1-2 RF <130

High risk <100

options
OPTIONS:
  • Statins
  • Fenofibrates
  • Niacin
  • Omega 3 Fish Oil
  • Bile Acid Sequestrants
  • Ezetimide
statins best ldl reduction
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 P4503A4, (lova-, simva-, less w/atorva)
  • Most Chol produced at night, thus PM dosing
ldl reduction 6 rule
% 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
Statins: examples

Potency:

$$

Metab./SE

T1/2

Prot.

Bind.

  • 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
red yeast rice statins
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
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
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
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
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
fenofibrates33
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
PK OF FIBRATES

Fenofibrate:

Absorbed in intestine

hydrolyzed by esterases in intestine to form active metabolite fenofibric acid

then hepatic glucuronidation

T 1/2 fenofibric acid 20hr (134-200 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
remember 2 phase metab
Remember 2 phase metab…

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.
toxicity
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 ’sAUC & 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
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.
niacin38
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)
niacin39
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
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
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 1500-3000mg/day can also potentially have severe AE.
  • Monitoring of liver enzymes is necessary.
niacin options
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 it’s nicotinic acid!!

omega 3
OMEGA 3
  • EPA & DHA
  • stimulate circulation
  •  breakdown of fibrin
  •  blood pressure
  •  trigs
  • regular intake ‘s Mi risk
  • MOA:Nutritionally important n−3 fatty acids:
    • α-linolenic acid (ALA)
    • eicosapentaenoic acid (EPA)
    • docosahexaenoic acid (DHA)
  • All polyunsaturated
  • 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
Omega 3: n−3 & n-6 fatty acids

n−6:n−3 fatty acids in oils:

canola 2:1

soybean 7:1

Olive 13:1

sunfl(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

  • 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-inflammatoryprostaglandins)
  • (N-3: ALA, DHA, EPA)
  • To control the synthesis of n−6 eicosanoids, consume more n−3
omega 3 otc
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

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 1.6grams/day for men and 1.1grams/day for women
  • Higher intakes : protection against CAD
  • 3g 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.
omega 3 rx
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

otc krill
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
ezetimide
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 GIepithelial cells and hepatocytes
  •  cholesterol absorption leads to an upregulation of LDL-receptors thus  LDL-c uptake into cells, thus decreasing plasma levels
zetia
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 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
BILE ACID SEQUESTRANTS: MOA

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.
bile acid sequestrants53
Bile acid sequestrants

USES

  • 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

SE

bile acid sequestrant
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

slide55

Get those buses off the road!!

the end!

Questions? Email: debkfp@hotmail.com