LIPOPROTEINS

Complexes that transport plasma lipids

free fatty acids are carried in albumin;
products of TG hydrolysis
Agents Used in Dyslipidemia Hyperlipoproteinemia : lipoprotein

Angelico L. Alejo,MD. Hyperlipemia : triglycerides

Department of Pharmacology 2 major sequelae:
a) Acute Pancreatitis
b) Atherosclerosis

Apolipoproteins FACTORS IN ATHEROGENESIS

vehicle in w/c cholesterol is transported
into artery wall 1. Hypertension
LDL IDL. VLDL..Lp (a) L

2. low level of HDL

ATHEROSCLEROSIS PLAQUES:
foam cells
collagen, fibrin, calcium 3. cigarette smoking
occlude coronary vessels
rupture of unstable plaques 4. diabetes

Factors in atherogenesis PATHOPHYSIOLOGY OF

HYPERLIPOPROTEINEMIA
5. Obesity Normal Metabolism Structure
lipoproteins contain cholesteryl esters &
6. corticosteroids excess Triglycerides
unesterified cholesterol & phospholipids &
apoproteins surrounds the core
7. chronic infection
B48(intestine) in chylomicrons & their
remnants
B100 (liver) VLDL, IDL, LDL, Lp(a)

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 Synthesis & Catabolism
SYNTHESIS & CATABOLISM
A.Chylomicrons
largest of all lipoproteins ; ( 100-1000nm) formed
in intestines
B. VLDL
carry TGs, unesterified cholesterol & secreted by the liver (30- 80 nm)
cholesteryl esters, enters the extra cellular principal carriers of TG synthesized in the
lymph & goes to the thoracic duct to circulation liver
TGs are removed (hydrolysis by the lipoprotein catabolism of VLDL remnants IDL&LDL
lipase) resulting to size of chylomicrons w/c
are then taken up by liver cells C. LDL
cholesterol is then excreted back to plasma as catabolyzed in liver & liberates cholesterol
lipoproteins 20-30 nm

SYNTHESIS & CATABOLISM SYNTHESIS & CATABOLISM

D. HDL E. Lp(a) LIPOPROTEIN
Absorb cholesterol derived from cell from LDL & the Lp(a) protein linked by a
breakdown in tissues and transfer it to disulfide bridge
VLDL and LDL highly homologous with plasminogen but
7-20 nm not activated
levels fr 0 to over 200 mg/dL in serum-
gene determined ; inhibits thrombolysis

HYPERLIPOPROTEINEMIC STATE HYPERLIPOPROTEINEMIC STATE

3. Familial Combined Hyper lipoproteinemia
(Multiple type)
1. Primary Hypertriglyceridemia 4. Familial Dysbetalipoproteinemia
2. Familial Hypertriglyceridemia 5. Primary Hypercholesterolemia
= Familial Hypercholesterolemia
Severe (Mixed type) = Familial Detective Apolipoprotein B
= Familial Combined Hyperlipoproteinemia
Moderate ( Endogenous) = Lp (a) Hyperlipoproteinemia
= Unclassified Hypercholesterolemia
= HDL Deficiency

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 Secondary Hyperlipoproteinemia Secondary Hyperlipoproteinemia
Hypertriglyceridemia
Diabetes Mellitus Hypercholesterolemia
Alcohol ingestion Hypothyroidism
Nephrosis / Uremia Nephrosis
Estrogens Anorexia nervosa
cholestasis
Corticosteroid Excess
corticosteroid excess
Hypothyroidism
hypopituitarism
corticosteroid excess

DIETARY MANAGEMENT OF
HYPERPROTEINEMIA
dietary cholesterol & saturated fats LDL
carbohydrates intake will VLDL
sucrose & other simple sugars may
VLDL in patient w/ hypertriglyceridemia
oat bran may LDL
alcohol intake will VLDL secretion by the
liver and cause triglycerides
Management
weight reduction lowers LDL & VLDL
intake of complex carbohydrate & fibers
unsaturated fat intake is allowed
avoid alcohol
include oat bran in diet
o-mega 3 fatty acids in fish oil can
triglycerides (should be regulated)

DRUG MANAGEMENT
A. VLDL SECRETION INHIBITORS:
Niacin (Nicotinic Acid)
B. FIBRIC ACID DERIVATIVES
(LIPOPROTEIN LIPASE STIMULANTS):
Clofibrate. Fenofibrate, bezafibrate,
Gemfibrozil
C. BILE ACID BINDING RESINS :
Cholestyramine, Colestipol, Colesevelam
DRUG MANAGEMENT
D.COMPETITIVE INHIBITORS OF
HYDROXY METHYL GLUTARYL (HMG
CoA Reductase) : simvastatin,
lovastatin, pravastatin, fluvastatin,
rosuvastatin, atorvastatin
E..PROBUCOL
F. INHIBITORS OF INTESTINAL STEROL
ABSORPTION| Ezetimibe

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 NIACIN (Nicotinic Acid)
A. Kinetics
it is a water soluble vitamin
B. MECHANISM OF ACTION(MOA)
inhibition of VLDL secretion
in turn decreasing LDL production
no effect on bile acid production
reduction of circulating fibrinogen reduces
thrombus formation & atherogenesis
inhibition of cholesterogenesis w/c hepatic
uptake of LDL
catabolism of HDL is decreased
NIACIN Toxicity
harmless cutaneous vasodilation w/ warm
sensation(prostaglandin mediated)
premedicate with aspirin
pruritis, rashes, dry skin, acanthosis
nigrans
nausea, abdominal discomfort Rx ~
take antacid
~ contraindicated if patient has peptic
ulcer
FIBRIC ACID DERIVATIVES(FIBRATES)
Gemfibrozil, Fenofibrate, Bezafibrate
A.Pharmacokinetics
comes from clofibric acid
bound to albumin & distributed to
extracellular space & tissues
60% excreted in urine as glucoronide
25% feces
half life = 12 hrs.
NIACIN
C. THERAPEUTIC USES
alone or in combination w/ bile acid
resin, or reductase inhibitor
DOSE
bid or tid w/ meals, start w/ 100 mg &
increasing to 2-6 gm/day
NIACIN TOXICITY
transaminase & alk phos but not assd
w/ serious liver toxicity
~ however, rarely, severe acute hepatic
necrosis may occur
in blood sugar may aggravate diabetes
uric acid may aggravate gout
arrythmia
toxic amblyopia
FIBRATES
B. MOA
ligands for nuclear transcription
receptor PPAR alpha
clearance of triglyceride rich
lipoproteins by in lipoprotein lipase
secretion of VLDL from liver
fecal excretion of cholesterol is
moderate HDL
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 FIBRATES
C. Therapeutic Uses & Dosage
HYPERTRIGLYCERIDEMIA
Familial dysbeta lipoproteinemia
no effect on patient w/ Congenital
Deficiency of lipoprotein lipase
(Primary Chylomicronemia)
Dose = 1 gm bid
GEMFIBROZIL
congener of clofibrate
VLDL & activity of lipoprotein lipase
a free carboxylic acid
absorbed in intestine & bound to plasma
proteins
goes thru enterohepatic circulation
may cross placenta
half-life 1 hrs.
70% excreted thru kidneys
GEMFIBROZIL
Toxicity
skin rash / GIT & muscular
symptoms (myopathy)
transaminase & alk phos./
potentials coumarin & indanedione
hepatic / renal dysfunction
FIBRATES ADVERSE EFFECTS
nausea, abdominal discomfort/ myalgia
MYOPATHY, K + / cholelithiasis
enhances hypoglycemic effect of sulfonylureas
potentiates anticoagulant effect of coumarin &
indanedione by platelet activity
Rare : rhabdomyolysis/ dermatitis~ hepatic
toxicity / bone marrow depression ~
arrythmia ~ renal dysfxn ~ libido in men /
breast tenderness in men ~ brittle hair /
alopecia
GEMFIBROZIL
MECHANISM OF ACTION
activity of lipoprotein lipase
VLDL , modest LDL = HDL
Therapeutic Use
= triglycerides more effectively than
clofibrate
Dose = 600 mg oral bid
OTHER CONGENERS
FENOFIBRATE
more potent than clofibrate in decreasing
LDL
excreted in the Kidney
100 mg tid
BEZAFIBRATE
more potent than clofibrate
200 mg tid
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 BILE ACID BINDING RESIN
Colestipol , Cholestyramine
useful for hyperlipoproteinemia w/ LDL only
if TG & LDL are high, these drugs may even
VLDL
Pharmacodynamics
insoluble in water; not absorbed in GIT
the resin binds bile acid in the GIT lumen &
prevent their reabsorption
A. Kinetics
large polymeric insoluble cationic resins
COLESTIPOL & CHOLESTYRAMINE
C. THERAPEUTIC USES
for patient w/ Heterozygous
familial Hypercholesterolemia
For Primary Hypercholesterolemia
if used in patient w/ combined
Hyperlipidemia, VLDL may so add
niacin
relieves itching patient w/
cholestasis & bile salt accumulation
BILE ACID RESINS TOXICITY
Constipation, bloating sensation/ heartburn
diarrhea/ steatorrhea/ malabsorption of Vit. K
~ leads to hypoprothrombinemia
malabsorption of folic acid
chance of gallstone formation ~ rare
dry flaking skin
impaired absorption of some drugs
~ digitalis ~ vancomycin ~ thiazide ~ thyroxin
~ warfarin ~ iron ~ tetracycline ~ folic acid
~ phenylbutazone ~ aspirin
BILE ACID BINDING RESIN
B.Mechanism of Action
bile acids & cholesterol metabolites are
normally absorbed in jejunum & ileum
when the resin is given, it binds w/ the
bile acid & thus excreted w/o being
absorbed
uptake of LDL & IDL fr plasma results
from up regulation of LDL receptors in the
liver
COLESTIPOL & CHOLESTYRAMINE
useful in Tx of digitalis toxicity to
prevent further absorption
DOSAGE 5 gm Colestipol 4 gm
Cholestyramine
granular prep in sachet
mixed w/ juice or water at 2-3 doses/
day w/ each meal
COMPETITIVE INHIBITOR OF HMG CoA
REDUCTASE ( STATINS)
Lovastatin/ Simvastatin/ Pravastatin/
Atorvastatin/ Rosuvastatin/ Fluvastatin
A. Pharmacokinetics
Lovastatin, Simvastatin ~ inactive lactone
~ hydrolyzed in GIT to active betahydroxyl
Pravastatin ~ active
Lovastatin ~ 30% is absorbed in GIT
~ of this amount, 90% goes to liver & excreted
into bile, while 10% is excreted in urine
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 B. MECHANISM OF ACTION
The STATINS
C.Therapeutic Use/ dose
PARTIAL INHIBITION OF THE ENZYME & useful alone
IMPAIR SYNTHESIS OF ISOPRENOIDS or in combination w/ bile acid binding
& THE PRENYLATION OF PROTEINS resin or niacin
LDL receptors affinity> fractional Contraindications
catabolic rate of LDL & the liver extraction ~ pregnancy ~ lactating women
of VLDL ~ children(restricted)
LDL Given dinner
Dose: 10 80 mg/day

D. STATINS TOXICITY
1. serum aminotransferases
malaise, anorexia, LDL.Severe
hepatotoxicty
~ if > 3x normal, discontinue drug ~
risk if given w/ niacin
2. creatine kinase activity
general muscular pain w/ heavy physical
activity
rhabdomylysis w/ myoglobinuria w/c
lead to renal shutdown
STATINS toxicity
myopathy may occur w/ Lovastatin used alone
but incidence is if used with clofibrate,
niacin, cyclosporine, erythromycin
~ discontinue drug if creatinine kinase is 2x
normal
lens opacity
lupus like hypersensitivity
discontinue if patient has other serious illness,
trauma, or will undergo major surgery

PROBUCOL
PROBUCOL
does not resemble other drugs
HDL substantially
mechanism of action unclear LDL only marginally
inhibit sterol biosynthesis reduces atherogenesis by inhibiting
improve transport of cholesterol formation of foam cells in intima
from periphery to liver 500 mg bid
lipophilic toxicity = arrythmia
goes to adipose tissue & stays disadvantage = lowers HDL too
there for a long time

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 INHIBITORS OF INTESTINAL EZETIMIBE
STEROL ABSOPRTION B. MOA
EZETIMIBE: first member > selective inhibitor of intestinal
A.Kinetics cholesterol absorption and
is readily absorbed and conjugated in the intestine phytosterols
inhibit phytosterol and cholesterol intestinal
absorption
> effective in the absence of dietary
enterohepatic circulation cholesterol
half life is 22 hours inhibits cholesterol reabsorption in the
excreted in the feces (50%) bile
administered with fibrates and reduced with
cholestyramine

Ezetimibe Ezetemibe toxicity

C. Therapy & Dosage Low incidence of impaired hepatic function

primary hypercholestrolemia Rare :myositis

liver function test initially and at 2-4
months
used in 5-20 mg per day
inhibits
phytosterol&chole.absorption

TREATMENT WITH DRUG

COMBINATION
USEFUL WHEN:
1. LDL levels are significantly increased
during treatment of hypercholesterolemia
with a resin
2. LDL & VLDL levels are both initially
3. LDL & VLDL levels are not normalized w/
a single agent
4. Elevated levels of Lp(a) or HDL deficiency
coexist w/ other hyperlipidemias.

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 DRUG COMBINATION DRUG COMBINATION
1. FIBRIC ACID DERIVATIVES & BILE ACID
BINDING RESINS
3.NIACIN & RESINS
> in familial combined hyperlipidemia intolerant Controls VLDL levels during resin therpay
of niacin; risk of cholelithiasis of familial combined hyperlipoprotinemia or
other disorders involving both VLDL &
2. HMG CoA REDUCTASE INHIBITORS & BILE
LDL levels
ACID BINDING RESINS
> familial hypercholesterolemia but may not
Rx: heterozygous familial
control levels of VLDL in some patients with
hypercholesterolemia
familial combined hyperlipoprotinemia 4. NIACIN & STATINS
> stains one hr before or 4 hrs afater the resins In familial hypercholesterolemia
Most effective & practical combination

DRUG COMBINATION Thank You !

5. STATINS & EZETIMIBE
> synergistic in primary
hypercholesterolemia & in homozygous
familial hypercholesterolemia

6, TERNARY COMBINATION OF RESINS,

NIACIN & STATINS
> In severe disorders involving elevated LDL