1. CV Pharmacology-
Drugs Used in Treating Hyperlipidemia
Prepared and presented by:
Marc Imhotep Cray, M.D.
BMS / CK-CS Teacher
http://www.imhotepvirtualmedsch.com/
Recommended Reading:
Management of
Hyperlipidemic States
Formative Assessment
Practice question
Clinical:
E-Medicine Articles
Hypertriglyceridemia

2. 2
Definition
 Hyperlipidemia, hyperlipoproteinemia or
dyslipidemia is the presence of raised or
abnormal levels of lipids and/or lipoproteins in
the blood
 Lipids are insoluble in aqueous solution
 Lipids (fatty molecules) are transported in a
protein capsule, and the density of the lipids and
type of protein determines the fate of the
particle and its influence on metabolism

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Definition(2)
 Lipid and lipoprotein abnormalities
are extremely common in the general
population, and are regarded as a highly
modifiable risk factor for
cardiovascular disease due to the
influence of cholesterol,
 one of the most clinically relevant lipid
substances, on atherosclerosis
 In addition, some forms may predispose
to acute pancreatitis
Learn more:
http://themedicalbiochemistrypage.org/cholesterol.html
Hyperlipidemia
A 4-ml sample of hyperlipidemic
blood with lipids separated into
the top fraction
(http://en.wikipedia.org/wiki/Hy
perlipidemia#Classification)

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From:http://www.emedicine.com/MED/topic2921.htm#Multimediamedia3

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Links to Cholesterol Metabolism and
Lipoprotein
themedicalbiochemistrypage.org
 Intestinal Uptake of Lipids
 Composition of Lipoprotein Complexes
 Lipid Profile Values
 Classification of Apoproteins
 Chylomicrons
 Very Low Density Lipoproteins, LDLs
 Intermediate Density Lipoproteins,
IDLs
 Low Density Lipoproteins, LDLs
 High Density Lipoproteins, HDLs
 LDL Receptors
 Clinical Significance of Lipoprotein
Metabolism
Cholesterol Biosynthesis
http://themedicalbiochemistryp
age.org/cholesterol.html

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Fredrickson classification of hyperlipidemias (http://en.wikipedia.org/wiki/Hyperlipidemia#Classification)
Hyperlipo-
proteinemia
Synonyms Defect
Increased
lipoprotein
Main
symptoms
Treatment
Serum
appearance
Estimated
prevalence
Type I
Buerger-Gruetz
syndrome or
familial
hyperchylomicr
onemia
Decreased
lipoprotein
lipase (LPL)
Chylomicrons
Acute
pancreatitis,
lipemia
retinalis,
eruptive skin
xanthomas,
hepatosplenom
egaly
Diet control
Creamy top
layer
One in
1,000,000[
Familial
apoprotein CII
deficiency
Altered ApoC2
LPL inhibitor in
blood
Type II
Familial
hypercholester
olemia
LDL receptor
deficiency
LDL
Xanthelasma,
arcus senilis,
tendon
xanthomas
Bile acid
sequestrants,
statins, niacin
Clear
One in 500 for
heterozygotes
Familial
combined
hyperlipidemia
Decreased LDL
receptor and
increased ApoB
LDL and VLDL
Statins, niacin,
fibrate
Clear 1 in 100
Type III
Familial
dysbetalipoprot
einemia
Defect in Apo E
synthesis
IDL
Tuboeruptive
xanthomas and
palmar
xanthomas
Fibrate, statins Turbid One in 10,000
Type IV
Familial
hypertriglycerid
emia
Increased VLDL
production and
decreased
elimination
VLDL
Can cause
pancreatitis at
high
triglyceride
levels
Fibrate, niacin,
statins
Turbid One in 100
Type V
Increased VLDL
production and
decreased LPL
VLDL and
chylomicrons
Niacin, fibrate
Creamy top
layer and turbid
bottom

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Pathobiology of Atherosclerosis
 When excess cholesterol deposits on cells and
on the inside walls of blood vessels it forms an
atherosclerotic plaque
 The first step of atherosclerosis is injury to the
endothelium which results in atherosclerotic lesion
formation
 When the plaque ruptures, blood clots form which
lead to decreased blood flow, resulting in
cardiovascular events

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Complications of Hyperlipidemia
 Macrovascular complications:
 Unstable Angina (chest pain)
 Myocardial Infarction (heart attack)
 Ischemic Cerebrovascular Disease (stroke)
 Coronary Artery Disease (heart disease)
 Microvascular complications:
 Retinopathy (vision loss)
 Nephropathy (kidney disease)
 Neuropathy (loss of sensation in the feet and legs)

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Risk Factors for Hyperlipidemia
 High fat intake
 Obesity
 Type 2 diabetes mellitus
 Advanced age
 Hypothyroidism
 Obstructive liver disease
 Genetics
 Drug induced: glucocorticoids, thiazide diuretics,
beta blockers, protease inhibitors, sirolimus,
cyclosporine, progestins, alcohol

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How to Diagnose Patients with
Hyperlipidemia
 The fasting lipid profile (TC, LDL-C,
HDL-C, TG) is analyzed
 The following individuals are
recommended for screening:
 All adults 20 years and older should be
screened at least once every 5 years
 Individuals with family history of
premature cardiovascular disease should
be screened more frequently

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How to Diagnose Patients with
Hyperlipidemia (2)
 History and physical
examination:
 Presence of cardiovascular
risk factors or cardiovascular
disease
 Family history of premature
cardiovascular disease,
hyperlipidemia, or diabetes
mellitus
 Diabetes mellitus or glucose
intolerance
 Central obesity
 High blood pressure
 Presence or absence of risk
factors
 Presence or absence of
kidney or liver disease,
peripheral vascular disease,
abdominal aortic aneurysm,
cerebral vascular disease
 An individual with a
combination of lipid profile
with history and physical
exam, will be treated
according to the ATP III
guideline
See: Adult Treatment Panel III (ATP III) Guidelines
National Cholesterol Education Program Slide Shows

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Lipoprotein Level Classification
 LDL-C < 100 mg/dL-----------------------------Optimal
 100-129 mg/dL --------------------------Near or above optimal
 130-159 mg/dL---------------------------Borderline high
 160-189 mg/dL --------------------------High
 > or = 190 mg/dL -----------------------Very high
 Total -C
 <200 mg/dL------------------------------ Desirable
 200-239 mg/dL---------------------------Borderline high
 > or= 240 mg/dL-------------------------High
 TG-C:
 <150 mg/dL------------------------------Optimal
 150-199 mg/dL --------------------------Borderline high
 200-499 mg/dL --------------------------High
 > or = 500 mg/dL -----------------------Very high
 HDL cholesterol:
 <40 mg/dL -------------------------------Low
 >60 or = 60 mg/dL --------------------- High

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Treatment Goals
1. Reduce total cholesterol and LDL
(bad) cholesterol
2. Prevent the formation of
atherosclerotic plaques and stop the
progression of established plaques
3. Prevent heart disease
4. Prevent morbidity and mortality

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Non-Pharmacological Treatment
Lipid lowering therapy should be
started with lifestyle modification
for at least 12 weeks
1. Increase physical activity
2. Weight reduction
3. Diet modification:
 Total fat 25-35% of total calories
 Saturated fat <7% of total calories
 Polyunsaturated fat up to 10%
total calories
 Monounsaturated fat up to 20%
total calories
 Carbohydrates 50-60% total
calories
 Fiber 20-30 g/ day total calories
 Protein 15% total calories
 Cholesterol <200 mg/day
 Total calories Achieve and
maintain desirable body weight
See: Treatment of Diabetic Dyslipidemia /
Medscape WebMD Med Student Section

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Pharmacological Treatment
 If non-pharmacological
treatment is not successful, a lipid-
lowering drug should be started,
especially in high risk populations
 1st step:
 Initiate LDL-lowering drug
therapy
 Start with statins, bile acid
sequestrants, or nicotinic acid
 Evaluate after 6 weeks
 2nd step:
 If goal was not reached,
intensive lipid-lowering treatment
should be started
 Increase dose of statins
 Bile acid sequestrants or nicotinic
acid should be added
 Evaluate after 6 weeks
 3rd step:
 If goal is not reached,
intensive lipid lowering
should be continued or
individual should be
referred to a lipid specialist
 If goal was reached, other
lipid risk factors should be
treated
 4th step:
 Monitor response and
compliance

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Pharmacological Treatment
Statins (HMG CoA Reductase Inhibitors)
 Atorvastatin (Lipitor® )
 Simvastatin (Zocor®)
 Lovastatin (Mevacor®): extended release
 Pravastatin (Pravachol®)
 Fluvastatin (Lescol®):
 Lescol XL: 80 mg tablets
 Rosuvastatin (Crestor®): tablets

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Statins (HMG CoA Reductase
Inhibitors)(2)
Effectiveness of statins:
 Reduce LDL cholesterol by 18-55%
Decrease TG by 7-30%
 Raise HDL cholesterol by 5-15%
 Statins are the most effective in
lowering LDL cholesterol
 Statins are the most effective in patient
who has low HDL and high LDL

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Statins (HMG CoA Reductase
Inhibitors)(3)
Mechanism of action:
 Statins inhibit HMG-CoA reductase
(enzyme involved in cholesterol
synthesis) thus decreasing mevalonic
acid production and stimulating LDL
breakdown
Click and learn more

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Statins (HMG CoA Reductase
Inhibitors)(4)
Side effects:
 Muscle aches
 Increased liver enzymes Muscle break
down leading to renal failure
 Fatigue, mild stomach disturbances,
headache, or rash

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Statins (HMG CoA Reductase
Inhibitors)(5)
Avoid use in:
 Active or chronic liver disease and pregnancy
Use with caution with:
 Concomitant use of cyclosporine, macrolide
antibiotics, antifungal agents.
 For example: Itraconazole, ketoconazole,
erythromycin, clarithromycin, cyclosporine,
nefazodone, HIV antiretrovirals
 When statins are used with fibric acids and niacin,
appropriate caution should be taken because of
increasing incidence of muscle breakdown

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Statins (HMG CoA Reductase
Inhibitors)(6)
Drug- food interaction:
 Grapefruit juice increases concentration of statins
 Pravastatin, rosuvastatin & fluvastatin concentrations
are not affected by grapefruit juice
Monitoring:
 Muscle soreness, tenderness, or pain
 Liver function tests : baseline, 4-6 weeks after starting
therapy, and then annually
 Muscle enzyme levels when individual has muscle pain

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Bile Acid Sequestrants
Mechanism of action:
 Bile acid sequestrants bind to bile acids
in the intestine, thus inhibits uptake of
intestinal bile salts into the blood and
increases the fecal loss of bile salt-
bound LDL

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Bile Acid Sequestrants(2)
1) Cholestyramine (Questran®):
Usual dose: 4 g by mouth 1-2 times a day with meal
to a maximum of 24 g per day
2) Colesevelam (Welchol®)
Usual dose: 3 tablets by mouth twice daily with
meals or 6 tablets once daily with a meal
3) Colestipol (Colestid®)
 Usual dose:
 Granules: 5-30 g by mouth daily given once or 2-4 times a
day with meal
 Tablets: 2-16 g by mouth daily

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Bile Acid Sequestrants(3)
Effectiveness:
 Reduces LDL cholesterol by 15-30%
 Increases HDL cholesterol by 3-5%
 Increases TG
Drug interaction:
 Decreased absorption of fat soluble Vitamins:
A, D, E, K, C and folic acid
 Decreased absorption of other drugs:
tetracycline, thiazide diuretics, aspirin,
phenobarbital, pravastatin, digoxin

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Bile Acid Sequestrants(4)
Side effects:
 Stomach upset, constipation accompanied by heart burn,
nausea, and bloating
Avoid use in:
 A disease called dysbetalipoproteinemia
 Triglycerides >400 mg/dL
Use caution if:
 Triglycerides >200 mg/dL
 Colesevalam is much better tolerated than
cholestyramine or colestipol
 Statins and other drugs should be taken 1-2 hours before
and 4-5 hours after bile acid sequestrants

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Nicotinic Acid
Mechanism of action:
 Nicotinic acid decreases the clearance of
ApoA1 to increase HDL; it inhibits the
synthesis of VLDL
Effectiveness:
 Decreases LDL cholesterol by 5-25 %
 Increases HDL cholesterol by 15-35%
 Decreases TG by 20-50%
 Nicotinic acid is the most potent drug that
increases HDL cholesterol

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Nicotinic Acid(2)
Side effects:
 Flushing (taking aspirin or ibuprofen can reduce
symptoms)
 Increases blood glucose due to impaired insulin
sensitivity
 Gout
 Liver toxicity associates with sustained release form
(Niaspan)
 Upper stomach distress and muscle weaknes
Avoid use in:
 Chronic liver disease
 Severe gout
Use with caution in:
 Type 2 diabetes (high dose)
 Gout
 Peptic ulcer disease

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Fibric Acids
Mechanism of action:
 Fibric acid up-regulates fatty acid transport
protein and fatty acid oxidation; thus it
reduces the formation of VLDL, increases
formation of HDL, and enhances the
breakdown of TG
Agents:
Gemfibrozil (Lopid®)
Fenofibrate (Tricor®)

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Fibric Acids(2)
Effectiveness:
 Reduces LDL cholesterol by 20-50% with normal
TG
 Increases LDL cholesterol with high TG
 Reduces TG by 20-50%
 Increases HDL cholesterol by 10-20%
 Fibric acids are very effective in lowering TG and
preventing pancreatitis
 Fibric acids reduce VLDL, but fibric acids might
increase LDL and total cholesterol

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Fibric Acids(3)
Side effects:
 Dyspepsia, gallstones, muscle ache, rash
 Unexplained non-coronary heart disease deaths
seen in a World Health Organization (WHO) study
 Weakness, tiredness, elevations in muscle enzyme
Avoid use in:
 Severe renal disease
 Severe hepatic disease
Drug interaction:
 Fibric acids bind to albumin and increase the
effect of anticoagulants

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Ezetimibe (Zetia)
Mechanism of action:
 Inhibits absorption of cholesterol in the small
intestine; thus it decreases the delivery of cholesterol
to the liver and increases the clearance of cholesterol
from the blood
Side effects: chest pain, dizziness, diarrhea, abdominal
pain
Drug interaction:
 Bile acid sequestrants decrease ezetimibe
concentrations
 Ezetimibe should be spaced 2 hours before or 4
hours after bile acid sequestrants administration
 Fibric acids increase ezetimibe concentrations

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Recommended Reading:
Management of
Hyperlipidemic States
Formative Assessment
Practice question
Clinical:
E-Medicine Articles
Hypertriglyceridemia
For Further Study