Hypolipidemic

Drugs and plasma

expanders

Dr. Rishi Pal

Assistant Prof.
Deptt. of Pharmacology
 29-2

Cholesterol
• Critical substrate for the body:
– Fundamental building block of steroid
hormones

– Essential for building cell membranes, the

myelin sheath, and the brain

– Core component of bile salts, which helps

in digest dietary fats
 29-3

Lipoproteins
• There are several
different lipoproteins:

– Low-density lipoprotein (LDL)

– Very-low-density lipoprotein (VLDL)
– High-density lipoprotein (HDL)
 29-4

Triglycerides
• Main form of fat from diet

• Provide body with energy

• Chylomicrons:
– Very large lipoproteins that deliver
triglycerides to muscle and fat tissue
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© 2012 The McGraw-Hill Companies, Inc. All rights reserved.

 29-7

Hypolipidemic Drugs
• There are five
groups of drugs – HMG-CoA reductase
used in the inhibitors
management of – Cholesterol absorption
hyperlipidemia: inhibitors
– Bile acid sequestrants
– Fibric acid derivatives
– Nicotinic acid
 1-8

© 2012 The McGraw-Hill Companies, Inc. All rights reserved.

 29-9

Atherosclerosis
• Atherosclerosis is a
progressive condition
that leads to CAD and
PAD.

• Fat buildup inside the

• CAD—coronary artery
arteries—plaque
disease
• PAD—peripheral
artery disease
© 2012 The McGraw-Hill Companies, Inc. All rights reserved.
 1-10

© 2012 The McGraw-Hill Companies, Inc. All rights reserved.

 29-11

Atherosclerosis

• There are two types • Plaque buildup can

of plaque buildup: block arteries,
– Stable causing:
– Unstable – Angina
– TIA
– Stroke
– Intermittent
claudication

© 2012 The McGraw-Hill Companies, Inc. All rights reserved.

 29-12

Monitoring the Disease

• Risk factors for
atherosclerosis
– Age
– History of smoking
– Hypertension
– Premature menopause
– Obesity
– Diabetes mellitus
– Hyperthyroidism
 29-13

Monitoring the Disease

• The goals of treatment are:

– Lowering LDL cholesterol

– Reducing total serum cholesterol and

triglycerides

– Increasing HDL cholesterol

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© 2012 The McGraw-Hill Companies, Inc. All rights reserved.

HMG-CoA Reductase inhibitors
• Atorvasatatin
• Simvastatin
• Lovastatin
• Pravastatin
• Fluavastatin
• Rosuvastatin
 Bile acid binding resins
• Cholestyramine
• Colestipol
• Colesevelam
Intestinal cholesterol absorption
inhibitors
• Stanol esters
• Ezetimibe
 Activators of lipoprotein lipase
(Fibrates)
• Gemfibrozil
• Benafibrate
• Fenofibrate
• Ciprofibrate
 Inhibitor of VLDL secretion and
lipolysis
• Niacin (Nicotinic acid)

Miscellaneous: Gugulipid and fish oil

derivatives
 Statins

Fibrates LIPID-LOWERING
DRUGS Resins

Others

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 29-21

HMG-CoA Reductase Inhibitors

• Also referred to as statins
• MOA—inhibit enzyme that causes
cholesterol synthesis

• IND—adjunct to dietary treatment to

decrease total serum and LDL
cholesterol:
– Reduce LDL level up to 30%
– Raise HDL level up to 20%
 1-22

HMG-CoA Reductase Inhibitors

• An early, very important step in this process is
the conversion of acetyl-CoA molecules into
HMG-CoA, which is then converted to mevalonic
acid by HMG-CoA reductase. Mevalonic acid is
a rate-limiting pivotal step in steroid and
cholesterol biosynthesis

• The liver makes two-thirds of the daily

cholesterol requirement.
 1-23

HMG-CoA Reductase Inhibitor

• All of the statins reduce LDL up to 30 percent. When a
greater reduction of LDL is required, simvastatin (Zocor),
atorvastatin (Lipitor), and rosuvastatin (Crestor) reduce
more than 45 percent; in fact, rosuvastatin and
atorvastatin have been demonstrated to reduce up to 60
percent.

• All of the statins raise the HDL level up to 20 percent.

Again, simvastatin (Zocor), atorvastatin (Lipitor), and
rosuvastatin (Crestor) increase HDL more than 30
percent.
 1-24

© 2012 The McGraw-Hill Companies, Inc. All rights reserved.

 29-25

HMG-CoA Reductase Inhibitors

• Adverse effects:
– Headache, dizziness, alteration of taste,
insomnia, abdominal cramping and
photosensitivity
• May cause myalgias, leg ache, and
muscle weakness
• Contraindicated during pregancy
 29-26

Cholesterol Absorption
Inhibitors
• Ezetimibe:
– MOA—blocks absorption of cholesterol
in the intestines
• Decreases VLDL
• Decreases circulating LDL cholesterol
– IND—treatment of hyperlipidemia in
conjunction with diet alteration
 29-27

Cholesterol Absorption
Inhibitors

• Ezetimibe:
– Modestly reduces total cholesterol, LDL,
and triglyceride blood levels
– Ideal to combine with other hypolipidemic
drugs
– Adverse effects—abdominal pain, fatigue,
coughing, diarrhea, back pain, and
arthralgia
 29-28

Bile Acid Sequestrants

• MOA—bind bile salts and cholesterol in
the GI tract, preventing absorption of both
• IND—hyperlipidemia:
– Increased elimination of bile salts, cholesterol, and
other fats in the faeces.
– Adverse effects include GI disturbances, severe
constipation, and fecal impaction.
– Most serious adverse effect is intestinal
obstruction.
 29-29

Nicotinic Acid
• MOA—affects cholesterol synthesis through
a G proteins coupled receptor:
– Inhibits triglyceride lipase
– Stimulates lipoprotein lipase
– Decreases free fatty acid release and removes
triglycerides
• IND—hyperlipidemia
• Adverse effects—flushing, nausea, vomiting,
and diarrhea
 29-30

Fibric Acid Derivatives (Fibrates)

• Gemfibrozil:
– MOA—inhibits breakdown of fat into
triglycerides, and limits liver production
of triglycerides
– IND—to decrease triglycerides
– Adverse effects—nausea, vomiting,
diarrhea, and flatulence
 Gugulipid
• Consists of Z and E gugulsterone
• Inhibit cholestrol biosynthesis and also
enhance rate of cholesterol excretion
• Dose 25 mg 3 times a day
• Reduced total CH, LDL-C with an
elevation of HDL-C
• It is well tolerated, no side effect, except
loose stool
 Fish oil derivative
• Omega-3-fatty acids
• Eicosa-pentanoic and docosa-hexanoic
acid
• Prophylaxis use in high risk patient of CAD
• Usually formulated with vit.E
 Combination drug therapy
• Bile acid binding resins+Fibrates
• Bile acid binding resins+Niacin
• Bile acid binding resins+Statins
• Bile acid binding resins+Niacin+ Statins
• Niacin+Statin (Atorva 10+ Nia 500)
• Statins+Ezetimibe
• Statins+Fibrate
 29-34

Hypolipidemic Drugs
 29-35

Preferred Therapy
• All hypolipidemic drugs are indicated as
adjunctive therapy to reduce elevated
cholesterol levels.
• HMG-CoA reductase inhibitors are the
most prescribed.
• Cholestyramine can also be used in the
treatment of partial biliary obstruction.
 29-36

Contraindications
• Systemic hypolipidemic drugs should not
be used in patients with liver dysfunction.

• Bile acid sequestrants should not be used

in patients with biliary obstruction.

• Statins should not be used in pregnant

women.
 29-37

Drug Interactions
 New drugs
• Cholesteryl ester transfer protein (CETP)

• Torcetrapib
• Anacetrapib
Blood substitutes and
plasma expenders
 Hypovolaemia
• Shock is a state of acute circulatory failure

• So, it is essential to restore intravascular

blood volume as quickly as possible

• Intravenous fluid therapy

 Types of fluid used for
replacement
• Whole blood and plasma
• Plasma substitute:
• a) Colloidal: Dextran, hydroxyethyl starch
polyvenyl pyrrolidone, oxypolygelatin.
b) crystalline: NaCl, dextrose solution
 Desirable properties of plasma
expenders
1. Should exert oncotic pressure comparable to plasma.
2. Should retain in circulation and not leak out in tissues
or too rapidly disposed.
3. Should be pharmacodynamically inert.
4. Should not be pyrogenic or antigenic
5. Should not interfere with grouping and cross matching
of blood.
6. Should be stable and easily sterilizable and cheap.
 Substance employed are
• Human albumin
• Dextran
• Polygeline
• Hetastarch
 Albumin
• 100ml of 20% human albumin solution is osmotic
equivalent of about 400ml of fresh frozen plasma or 800
ml of whole blood.

• Not interfere with blood group and coagulation process.

• Crystalloid solutions must be infused concurrently for

optimum benefit.

• It is expensive.
 Dextran
• Dextran-40: 10% in dextrose or in NaCl

• Dextran-70, expends plasma volume for 24 hr.

• 500-1000 ml in 30 min. and 100 ml by continuous infusion for 2-3

days.

• Be careful in patients of Renal impairment, CHF or

Polycythaemia.

• Dextran-70 & dextran 110: 6% in dextrose or in NaCl, used for

hypovolaemic or haemorrhagic shock
 Polyvenylpyrrolidone
• It is synthetic water soluble preparation
with MW 35,000-40,000.

• It is sterile solution in buffered

physiological saline

• It has tendency to bind with insulin and

penicillin
 Gelatin
• MW 30,000
• 500-1000 ml of 3.5-4% used in low blood
volume
• Expends plasma volume for 12 hr
• More expensive than dextran
 Contraindications
• Severe anemia
• Cardiac failure
• Pulmonary edema
• Liver disease
• Renal insufficiency
 Electrolyte and water
replacement
• Normal saline (0.9%)
• Dextrose 5%