Lipid Lowering

Agents
 Hyperlipidemia
2
 Elevated levels of triglycerides or
cholesterol and reduced HDL-C levels.
 Contributing factors may be:
Lifestyle or behavioral
Genetic
Metabolic conditions
 Major cause of atherosclerosis and
atherosclerosis-associated conditions,
such as coronary heart disease (CHD),
ischemic cerebrovascular disease, and
peripheral vascular disease.
 Lipoproteins

3
 Lipids are packaged in the bloodstream
into Lipoproteins
 Lipoproteins include: Chylomicrons and
remnants, VLDL,IDL, LDL,HDL and
Lp(a)
 The protein components, known as
apolipoproteins or apoproteins, provide
structural stability to the lipoproteins
 Common apolipoproteins include :A-I, A-
II, A-IV;B-48,B-100; C-I, C-II,C-III;E,
 Lipoproteins…
•Most water-insoluble lipids: cholesteryl esters and triglycerides;
•More water-soluble: apoproteins, phospholipids, and unesterified
cholesterol.
•Intestinal cholesterol absorption is mediated by Niemann-Pick
C1-like 1 protein (NPC1L1).
•Triglyceride synthesis is regulated by diacylglycerol transferase.
•After their synthesis in the endoplasmic reticulum, triglycerides
are transferred by microsomal triglyceride transfer protein (MTP)
to the site where newly synthesized apoB-48 is available to form
chylomicrons.
•Hepatic synthesis of cholesterol is catalyzed by- 3-hydroxy-3-
methylglutaryl coenzyme A (HMG-Co A) reductase enzyme.
 Low-Density Lipoproteins
Arise from the catabolism of IDL,t1/2 1.5 -2
days.
Two-thirds of plasma cholesterol is found
in the LDL.
Plasma clearance of LDL particles is
mediated primarily by LDL receptors.
The liver expresses a large complement of
LDL receptors and removes ~75% of all
LDL from the plasma.
Thyroxine and estrogen enhance LDL
receptor gene expression, which explains
their LDL-C-lowering effects.
 High-Density Lipoproteins
The metabolism of HDL is complex because of the
multiple mechanisms by which HDL particles are
modified in the plasma compartment and by which
HDL particles are synthesized.
ApoA-I is the major HDL apoprotein, and its plasma
concentration is a more powerful inverse predictor of
CHD risk than is the HDL-C level. ApoA-I synthesis is
required for normal production of HDL.
The membrane transporter ABCA1 facilitates the
transfer of free cholesterol from cells to HDL .
HL activity is regulated and modulates HDL-C levels.
 HDL…
HDL are protective lipoproteins that
decrease the risk of CHD; thus, high
levels of HDL are desirable.
 HDL also may protect against
atherogenesis by mechanisms not
directly related to reverse cholesterol
transport.
These functions include putative
antiinflammatory, antioxidative,
platelet antiaggregatory,
anticoagulant, and profibrinolytic
activities .
 Lipid Profile

Total Cholesterol < 200 mg/dl

LDL-Cholesterol < 100 mg/dl

HDL-Cholesterol ≥ 60 mg/dl

Triglycerides < 150 mg/dl

 Lipid lowering agents
10

1. HMG-Co A reductase inhibitors

2. Bile-acid sequestrants

3. Nicotinic acid

4. Cholesterol Absorption
inhibitors
5. Fibric acid derivatives
 HGM-Co A reductase inhibitors(statins)
Most effective and best-tolerated agents.
Competitive inhibitors
11 of 3-hydroxy-3-
methylglutaryl coenzyme A (HMG-CoA)
reductase.
Higher doses of the more potent statins
(e.g., atorvastatin and simvastatin) also can
reduce triglyceride levels caused by elevated
VLDL levels.
Include: lovastatin, atorvastatin, fluvastatin,
Simvastatin
 Pharmacokinetics
• After an oral dose, plasma concentrations of
statins peak in 1 to 4 hours.
12
The half-lives of the
parent compounds are 1 to 4 hours, except in the
case of atorvastatin, which has half-life of about
20 hours.
• Due to extensive first-pass hepatic uptake,
systemic bioavailability of the statins and their
hepatic metabolites varies between 5% and 30%
of administered doses.
• The liver biotransforms all statins, and more
than 70% of statin metabolites are excreted by
the liver with subsequent elimination in the
feces
 Adverse effects
 Dizziness, headache, insomnia, weakness.
 GI disturbance 13

 Hepatoxicity
 Rhabdomyolysis/myopathy
 hypersensitivity reactions
 The safety of statins during pregnancy
has not been established.
Contraindication: concurrent use of
gemfibrozil or Ezetimibe to avoid cause
myopathy.
 Nicotinic acid (Niacin)
Niacin is a water-soluble B-complex vitamin that
functions as a vitamin only14after its conversion to NAD.
In adipose tissue, it inhibits the lipolysis of
triglycerides by hormone-sensitive lipase, which
reduces transport of free fatty acids to the liver and
decreases hepatic triglyceride synthesis.
Niacin may exert its effects on lipolysis by inhibiting
adipocyte adenylyl cyclase cAMP production and
decreasing hormone-sensitive lipase activity
Reduction of triglyceride synthesis reduces hepatic
VLDL production, which accounts for the reduced LDL
levels.
Most effective drug available clinically for raising HDL.
 Pharmacokinetics
 Well absorbed orally,t1/2:1hr, widely distributed
15
following conversion to niacin amide.
 Large doses of niacin are excreted unchanged in the
urine.
 Triple therapy (niacin + statin + bile-acid sequestrant)
can decrease LDL cholesterol by 70% or more.
 Niacin, at doses used in humans, has been associated
with birth defects in experimental animals and should
not be taken by pregnant women.
 Adverse effects: Hepatotoxicity, flushing, pruritus,
hyperpigmentation.
 Use: hypertriglyceridemia and elevated LDL-C
 Fibric acid derivatives (Fibrates)
 Includes: Gemfibrozil and Fenofibrate
 Drug of choice
16 for severe
hypertriglyceridemia and high VLDL levels
 Three PPAR isotypes (, β, and ) have
been identified. Fibrates bind to PPARa,
which is expressed primarily in the liver
and brown adipose tissue and to a lesser
extent in kidney, heart, and skeletal
muscle.
 Fibrates reduce triglycerides through
PPAR-mediated stimulation of fatty acid
oxidation, increased LPL synthesis, and
reduced expression of apoC-III.
 Fibric acid derivatives (Fibrates)…
All of the fibrate drugs are absorbed rapidly and
efficiently (>90%) when given with a meal but less
efficiently when taken on an empty stomach.
The ester bond is hydrolyzed rapidly, and peak plasma
concentrations are attained within 1 to 4 hours.
More than 95% are bound to albumin.
Half-life;1.1 hours (gemfibrozil),20 hours (fenofibrate).
Widely distributed throughout the body.
Excreted predominantly as glucuronide conjugates;
60% to 90% of an oral dose is excreted in the urine,
with smaller amounts appearing in the feces.
Contraindicated in patients with renal failure.
 Adverse effect
 Fatigue/weakness, headache, nausea,
abdominal pain, diarrhea.
18

 Cholelithiasis, pancreatitis, hepatotoxicity,

rhabdomyolysis/myopathy,
hypersensitivity reactions
 Drug Interaction: Gemfibrozil displaces
warfarin from plasma albumin.
 Fibrates should not be used by children or
pregnant women.
 Use: Low HDL-C levels , severe
hypertriglyceridemia (triglycerides >1000
mg/dl) who are at risk for pancreatitis.
 Bile-acid sequestrants
Highly positively charged and bind negatively
charged bile acids. 19
Because of their large size, the resins are not
absorbed, and the bound bile acids are excreted
in the stool. Since over 95% of bile acids are
normally reabsorbed, interruption of this
process depletes the pool of bile acids, and
hepatic bile-acid synthesis increases. As a result,
hepatic cholesterol content declines, stimulating
the production of LDL receptors, an effect
similar to that of statins.
Includes: Colestipol, cholestyramine
 Bile-acid
• The resins sequestrants …
are generally safe, as they are not
systemically absorbed.
• Severe hypertriglyceridemia is a
contraindication to the use of cholestyramine
and colestipol since these resins increase
triglyceride levels.
• Cholestyramine and colestipol bind and interfere
with the absorption of many drugs, including
some thiazides, furosemide, propranolol, l-
thyroxine, digoxin, warfarin, and some of the
statins .
• Adverse effects: Constipation,Bloating,
indigestion, and nausea,Decrease uptake of fat-
soluble vitamin’s
• Contraindication: Hypersensitivity,Complete
 Cholesterol Absorption Inhibitors: Ezetimibe

 Newest class (early 2000s)

 Acts on cells of the brush
21
border of the SI
 Blocks absorption of dietary cholesterol as well as
cholesterol secreted in the bile probably through
targetting Niemann-Pick C1-like 1 protein
 Indicated as an adjunct to diet modification for
primary hypercholesteremia.
 The safety of ezetimibe during pregnancy has not
been established.
 Other than rare allergic reactions, specific
adverse effects have not been observed in
patients taking ezetimibe
Thank You!