Hypolipidemic drugs

or
Drug Treatment of
Hyperlipidemia

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 Learning objectives
 List goals of therapy of hyperlipidemia
 Classify the antihyperlipidemic drugs.
 Explain the mechanism of action of drugs used
in treatment of hypercholesterolemia &
hypertriglyceridemia.
 State the specific medication’s class effects on
lipoproteins
 Deduce the different antihyperlipidemic drugs in
treatment of combined hyperlipidemia.
 Tabulate the difference between the different
antihyperlipidemic drugs as regards; mechanism
of action, side effects & therapeutic uses.
 Goals of Therapy
 Prevent myocardial infarction and
sudden cardiac death.

 Prevent additional damage.

 Reverse the atherosclerosis.

 Prevention and treatment of

pancreatitis.
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 Types of Therapy
 Lifestyle change:
 Diet

 exercise

 Drugs

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 Major Hypolipidemic
HMG-CoA reductase
Drugs
inhibitors Fibric acid derivatives
Lovastatin Gemfibrozil (Lipur®)
Pravastatin (Vasten®) Fenofibrate (Fegenor®)
Simvastatin (Zocor®) Clofibrate
Fluvastatin (Lescol ®)
Atorvastatin (Tahor®) Bile acid ion-exchange
Rosuvastatin (Crestor®) resins
Cholestyramine (Questran
®)
Niacin (Nicotinic acid)
Crystalline niacin Cholesterol absorption
inhibitor
Sustained release Ezetimibe (Ezetol®) 5
1. HMG CoA Reductase Inhibitors
The “Statins”

Lovastatin
Simvastatin
Pravastatin
Fluvastatin
Atorvastatin
Rosuvastatin
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 Mechanism of action of statins
Acetyl-CoA
Statins
HMG-CoA  Mevalonate Isopentenyl-PP
HMG-CoA
Reductase

Farnesylated
Protein (i.e. Ras)
Farnesyl-PP

Squalene

 Cholesterol

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 Biochemical effects of statins

 Increased LDL membrane receptors increase

binding of Apo E-containing IDL to LDL-R:
Removal of LDL precursors.

 Reduce degradation of LDL-R.

 Decrease plasma lipids -- LDL-C and TG by

inhibiting hepatic VLDL synthesis   the
number of VLDL, IDL and LDL particles in
plasma

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 Plasmalemma
Cholesterol

SREBP
Protease
activation (inactive)
LDL-R
expression

SREBP (active) Nucleus

Sterol Regulatory LDL-R gene
Element Binding
Proteins
SRE

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 Pharmacokinetics of statins
 Undergo an extensive first pass
metabolism.

 Lovastatin and simvastatin: prodrugs.

 Half-life ≈ 2 hr.

 Dosing: once/day.

 Eliminated as metabolites in faeces

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 Pharmacologic effects and
Therapeutic uses
 Lipid/lipoprotein effects
 LDL chol 
 HDL chol 
 Triglycerides
 Major use
 To Lower LDL Chol

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 Figure 3 Pleiotropic effects of statins on the vasculature

Clinical Science www.clinsci.org Clin. Sci. (2003) 105, 251-266 13

 Adverse actions of statins
 Myositis
 Rhabdomyolysis
 increased liver transaminases
 Most frequent with fibric acid coadmin-
istration: a pharmacokinetic drug
interaction.

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 Contra-indications
 Absolute contraindication
 Active or chronic liver disease

 Relative contra-indication
 Concommitant use of cyclosporins,

macrolide antibiotics, various

antifungals & cyp inhibitors

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2. The Bile Acid Binding
Resins

Cholestyramine

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Antilipemic Drugs: Bile Acid Binding Resins

Enterohepatic
Circulation of Bile
Liver
Gall
Bladder

*
Small
Intestine
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 Mechanism of action of Bile Acid
Binding Resins
• Bile acids are created in the liver using
cholesterol and are secreted into the small
intestine to aid in digestion.
• They are reabsorbed in the distal end and are
taken back to the liver in the portal
circulation.
• Bile acid binding resins prevent the
reabsorption of bile acids, causing them to be
eliminated via the large bowel.
• This forces the liver to remove cholesterol
from the circulation (via an upregulation of
LDL-C receptors) in order to make more bile,
causing a decreases systemic cholesterol
levels.
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 Pharmacologic profil of Bile Acid
Binding Resins
 Lipid/lipoprotein effects
 LDL chol 
 HDL chol 
 Triglycerides - No effect or increase
 Major use
 Lower LDL cholesterol
 Contraindication
 Familial dysbetalipoproteinemia
 Adverse effects
 Upper & lower GI common;
 decreased absorption of other drugs

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3. Fibric Acid Derivatives (Fibrates) :
Gemfibrozil
Fenofibrate
Clofibrate

[For the treatment of

hypertriglyceridemia (TGs),
Drug of choice to lower serum
TGs] 20
 Pharmacologic profil of
Fibric Acid Derivatives
 Lipid/lipoprotein effects
 LDL chol  5-20%
 HDL chol  10-35%
 Triglycerides  20-50%
 Major uses
 HyperTGs, atherogenic dyslipidemia
 Contraindications
 Severe hepatic or renal insufficiency
 Adverse effects
 Dyspepsia, cholesterol gall stones,
myopathy

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 Gemfibrozil (Lipur™)
 Mechanism of action
 Fibrates activate specific transcription factors belonging to the nuclear hormone

receptor superfamily, termed peroxisome proliferator-activated receptors (PPARs).

 The PPAR- mediates fibrate action on HDL cholesterol levels via transcriptional

induction of synthesis of the major HDL apolipoproteins, apoA-I, apoA, acyl

coenzyme A oxidase, and possibly that of lipoprotein lipase

 Pharmacologic effects
 Decreases VLDL by
• fatty acid oxidation
• increase in lipoprotein lipase (LPL) expression and synthesis
• reduced expression of apoC-III in the liver
 Increases HDL
• increase in apoA-I and apoA-II expression   HDL levels

 Additional effects
• Inhibits coagulation and enhances fibrinolysis

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 4. Nicotinic Acid
(Niacin)
Water soluble vitamin: unrelated to
lipid reducing action.

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Pharmacologic profil of Nicotinic
Acid (Niacin)
 Lipid/lipoprotein effects
 LDL chol 
 HDL chol 
 Triglycerides 

 Major use
 Most lipid and lipoprotein abnormalities

 Adverse effects
 Flushing, hyperglycemia or gout, upper GI

distress, hepatotoxicity,

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 Mechanism of Action of
Nicotinic Acid (Niacin)
  hepatic VLDL synthesis by inhibiting adipose tissue
lipolysis
  VLDL clearance by  LPL activity

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 Pharmacokinetics of
Nicotinic Acid
 Oral absorption is excellent.
 Half-life: 1 hr = frequent
dosing.

 Renal elimination: metabolites

and parent compound.

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 5. Inhibitors of cholesterol
absorption: Ezetimibe
 blocks
cholesterol
absorption in
jejunal
enterocytes
 Ezetimibe plus
statin: Greater
decrease in
LDL than
increasing
statin dose.
 No important
adverse effects
OR significant
drug
interactions 27
 Combination therapy
 Rationale
 Use lower doses to avoid toxicity

 Greater effect than maximal dose of

one drug alone

Statin - bile acid sequestrant

 Combined hyperlipidemia
Statin - fibrate

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 Combination therapy
 Rationale
 Use lower doses to avoid toxicity

 Greater effect than maximal dose of

one drug alone

Statin - bile acid sequestrant

 Combined hyperlipidemia
Statin - fibrate
Statin - nicotinic acid
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 Summary of Adverse actions
Drug class Side effects
Statins Muscle pain & weakness, myositis,
increased liver enzymes,

Bile acid sequestrants GI distress, constipation, flatus

Niacin Flushing, increase uric acid and gout,

dyspepsia, dry skin, hepatotoxicity

Cholesterol absorption Mild GI distress

inhibitor
Fibric acids (gemfibrozil) Dyspepsia, myopathy 30
Who Should be Treated with Lipid Lowering Drugs?

LDL Levels > 190 mg/dl and 0-1 risk factors

LDL Levels < 160 mg/dl and 2+ risk factors
CAD + LDL > 100 mg/dl

RISK FACTORS
Smoking Obesity Diabetes
Low HDL Family History of early CAD
Hypertension Age

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