Cholesterol
Outline
• What is cholesterol?
– Synthesis
– Functions
– Lipoproteins
• Drugs to reduce cholesterol
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Statins
Bile-Acid Sequestrants
Niacin (Nicotinic Acid)
Fibric Acid Derivatives
Ezetimibe and the Inhibition of Dietary Cholesterol
What is cholesterol?
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Waxy, fat-like substance
Steroid alcohol (sterol)
Found in all cells of the body
75% of cholesterol is synthesized
– 25% comes from diet
Cholesterol synthesis
• Synthesized primarily in the liver
• Occurs in the cytoplasm and ER
• The HMG-CoA Reductase reaction is ratelimiting
– Highly regulated
– Target of pharmaceutical intervention
• Very complex process involving over 30
enzymes
Functions of Cholesterol
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Cell membranes
Sex hormones
Hormones released by the adrenal glands
Production of bile acids
Vitamin D
Dangers of High Cholesterol Levels
• Atherosclerosis
– Increased coronary heart disease risk
– Heart attack
– Angina
– Stroke
Lipoproteins
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Chylomicrons
Very low density lipoproteins (VLDL)
Intermediate-density lipoproteins (IDL)
Low density lipoproteins (LDL)
High density lipoproteins (HDL)
Class
% Protein
% Cholesterol
% Phospholipid
% Triglyceride
Chylomicrons
<2
8
7
84
VLDL
10
22
18
50
IDL
18
29
22
31
LDL
25
50
21
8
HDL
33
30
29
4
Apolipoproteins
• Six major classes
– A, B, C, D, E and H
Apolipoprotein
Site of Synthesis
Function(s)
ApoA-I
Liver, intestine
Structural in HDL; reverse
cholesterol transport
ApoA-V
Liver
Modulates triglyceride
incorporation into hepatic
VLDL
ApoB-100
Liver
Structural protein of VLDL,
IDL, LDL
ApoB-48
Intestine
Structural protein of
chylomicrons
ApoE
Liver, brain, skin, gonads,
spleen
Structural in HDL; reverse
cholesterol transport
Chylomicron
Triglyceride, LDL and HDL Metabolism
Atherosclerosis
Risk Factors
• Diet
• Medical conditions
– Diabetes
– Hypertension
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Genetics
Sex
Age
Smoking
Inactivity & obesity
Drugs Therapy of Hyperlipidemia
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5.
Statins
Bile-Acid Sequestrants
Niacin (Nicotinic Acid)
Fibric Acid Derivatives
Ezetimibe and the Inhibition of Dietary
Cholesterol
Statins
• Competitive inhibitors of HMG-CoA reductase
– Decreased cholesterol synthesis
– Increased expression of the LDL receptor gene
• Reduce LDL levels
• Documented in reducing fatal and nonfatal
CHD events, strokes, and total mortality
– Adverse effects were similar in placebo and drug
groups
Statins
Zocor
Lipitor
Crestor
Effects on Triglycerides & Lipoprotein
Levels
• Decrease triglycerides in
hypertriglyceridemic
– 35-45%
• Increase HDL-C
– Normal patients: 5-10%
– Low patients: 15-20%
• Decrease LDL-C
– 20-55%
• Non-lipid lowering effects
– Endothelial function (Enhances
production of nitric oxide)
– Anti-inflammatory
– Reduce venous
thromboembolic events
• 43%
• Adverse Effects
– Hepatotoxicity
• Elevated hepatic transaminase
values
• One case of liver failure per
million person-years of use
– Myopathy
• One death per million
prescriptions caused by
rhabdomyolysis
Bile-Acid Sequestrants
• Highly positively charged
– Bind negatively charged bile acids
• Large size keeps them from being absorbed
– Secreted in stool
• Hepatic bile-acid synthesis increases
– Hepatic cholesterol declines stimulating the
production of LDL receptors and lowers LDL levels
– Partially offset by the enhanced cholesterol synthesis
caused by upregulation of HMG-CoA reductase
• Combining these with a statin substantially increases their
effect
Bile-Acid Sequestrants
Effects on Lipoprotein Levels &
Adverse Effects
• Dose dependent decrease
in LDL-C
– Normal dose: 12-18%
reduction
– Maximal dose (2x normal):
Up to 25% reduction
• GI side effects
• HDL-C: Increase 4-5%
• Combined with statins or
niacin: 40-60% reduction
• Adverse Effects
– Generally safe
– Hyperchloremic acidosis
– Are not used in patients
with hypertriglyceridemia
• May increase triglycerides
Niacin (Nicotinic Acid)
• Inhibits the lipolysis by hormone-sensitive lipase
– Reduces transport of free fatty acids to the liver
– Decreases hepatic triglyceride synthesis
• May inhibit diacylglycerol acyltransferase-2
– Rate-limiting in triglyceride synthesis
– Reducing triglyceride synthesis reduces hepatic VLDL
production
• Raises HDL levels by decreasing the fractional
clearance of apoA-I in HDL
Effects on Lipoprotein Levels &
Adverse Effects
• Increases HDL: 30-40%
• Lowers triglycerides by
35-45%
• Reduces LDL: 20-30%
• Half-life: 60 minutes
– Requires 2-3 doses/day
• Therapeutic Use
– Hypertriglyceridemia
and low HDL levels
• Adverse Effects
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Flushing
Dyspepsia
Hepatotoxicity
Hyperglycemia
Fibric Acid Derivatives: PPAR Activators
• Mechanism of action still remains unclear
– Thought to interact with peroxisome proliferatoractivated receptors (PPARs)
• Bind to PPARα
– Increase LPL synthesis
– Reduce expression of apoC-III
– Stimulate apoA-I and apoA-II
Fibric Acid Derivatives: PPAR Activators
Effects on Lipoprotein Levels &
Adverse Effects
• Decreases triglycerides
• Increases HDL-C
• LDL-C can decrease,
increase or be
unchanged
• Should not be used in
patients with renal
failure or hepatic
dysfunction
• Therapeutic Use
– Type III
hyperlipoproteinemia
– Hypertriglyceridemia
– Chylomicronemia
syndrome
• Adverse Effects
– Rash
– Hair loss
– Fatigue
Ezetimibe and the Inhibition of Dietary
Cholesterol Uptake
• Inhibits cholesterol absorption by enterocytes
in the small intestine
– 54% in humans
• Inhibits the transport protein NPC1L1
Combination Therapy & Adverse
Effects
• Reduces LDL by 15-20%
alone
• Reduces LDL by 60% in
combination with
simvastatin
• Should not be given
with bile-acid
sequestrants
• Adverse Effects
– Rare allergic reactions
Videos
• http://www.youtube.com/watch?v=9Tbo0GfDcg
• Cholesterol
• Atherosclerosis
Mechanism of Action Statins
• Inhibit an early and rate limiting step in
cholesterol biosynthesis
• Inhibiting hepatic cholesterol synthesis results in
increased expression of the LDL receptor gene
– Decreased free cholesterol causes membrane-bound
SREBPs to be cleaved and translocated to the nucleus
to bind the sterol responsive element of the LDL
receptor gene. This enhancnes transcription and
increases the synthesis of LDL receptors
• It also reduces the degradation of LDL receptors
Adverse Effects
• Hepatotoxicity
– Elevated hepatic transaminase values
– One case of liver failure per million person-years
of use
• Myopathy
– One death per million prescriptions caused by
rhabdomyolysis
Bile-Acid Sequestrants
• One of the oldest hypolipidemic drugs
• Safest
– Not absorbed from the intestine
• Used as a second agent if statins are not
sufficient
• Maximal dose can reduce LDL-C by up to 25%
– Cause bloating and constipation so compliance is
low
Mechanism of Action
• Inhibits the lipolysis by hormone-sensitive lipase
– Reduces transport of free fatty acids to the liver
– Decreases hepatic triglyceride synthesis
• May inhibit diacylglycerol acyltransferase-2
– Rate-limiting in triglyceride synthesis
– Reducing triglyceride synthesis reduces hepatic VLDL
production
• Raises HDL-C levels by decreasing the fractional
clearance of apoA-I in HDL
Mechanism of Action
• Still remain unclear
• Thought to interact with peroxisome
proliferator-activated receptors (PPARs)
– Bind to PPARα and stimulate fatty acid oxidation,
increase LPL synthesis and reduce expression of
apoC-III to reduce triglycerides
– Bind to PPARα to stimulate apoA-I and apoA-II
expression to increase HDL-C levels
Mechanism of Action
• Inhibits the transport protein NPC1L1
• Inhibits absorption by 54% in humans