HYPER LIPIDEMIA

Dr Hina Abrar
Objective
At the end of lecture students will be able to,
• Define hypercholestrolemia
• Discuss cholestrol synthesis and metabolism
• Explain etiology of hyperlipoproteinemia
• Enlist normal ranges
• Discuss types of hyperlipoproteinemia
• Explain drug classes with their mechanism
INTRODUCTION
• Plasma lipids are transported in complexes called
lipoproteins
• Metabolic disorders that involve elevations in any
lipoprotein species are termed hyperlipoproteinemias or
hyperlipidemias
• Hyperlipemia denotes increased levels of triglycerides
• Atherosclerosis causes death
• Lipoproteins that contain
apolipoprotein (apo) B-100 convey
lipids into the artery wall
• These are low-density (LDL),
intermediate-density (IDL), very-low-
density (VLDL), and lipoprotein(a)
(Lp[a])
Lipoprotein
• A lipoprotein is a biochemical assembly that
contains both proteins and lipids water-bound
to the proteins
• Many enzymes, transporters, structural
proteins, antigens, adhesins and toxins are
lipoproteins
• Examples include the high density (HDL) and
low density (LDL) lipoproteins which enable
fats to be carried in the blood stream.
 Functions of lipoproteins
• The function of lipoprotein particles is to transport lipids
(fats) (such as triacylglycerol) around the body in the
blood
• All cells use and rely on fats and cholesterol as building
blocks to create the multiple membranes.
• The lipoprotein particles have hydrophilic groups of
phospholipids, cholesterol and apoproteins directed
outward.
• Such characteristics makes them soluble in the salt
water-based blood pool
• Triglyceride-fats and cholesterol esters are carried
internally, shielded from the water by the phospholipid
monolayer and the apoproteins
Apolipoproteins
• Apolipoproteins are proteins that bind to
lipids (oil-soluble substances such as fat and
cholesterol) to form lipoproteins
• Functions:
• They are enzyme coenzymes
• Lipid transport proteins
• Ligands for interaction with lipoprotein
receptors in tissues
 Classification
• By Density
• Lipoproteins are larger and less dense, if they consist of
more fat than of protein. They are classified on the basis of
electrophoresis and ultracentrifugation.
• Chylomicrons carry triglycerides (fat) from the intestines to
the liver, skeletal muscle, and to adipose tissue
• Very low density lipoproteins (VLDL) carry (newly
synthesised) triacylglycerol from the liver to adipose tissue
• Low density lipoproteins (LDL) carry cholesterol from the
liver to cells of the body. LDLs are sometimes referred to as
the "bad cholesterol" lipoprotein
• High density lipoproteins (HDL) collect cholesterol from the
body's tissues, and bring it back to the liver. HDLs are
sometimes referred to as the "good cholesterol" lipoprotein
High-density lipoproteins (HDL)
• Exert several antiatherogenic effects
• They participate in retrieval of cholesterol from the artery
wall and inhibit the oxidation of atherogenic lipoproteins
• Low levels of HDL are an independent risk factor for
atherosclerotic disease and thus are a target for
intervention
• Cigarette smoking is a major risk factor for coronary
disease. It is associated with reduced levels of HDL.
• Diabetes, also a major risk factor, is another source of
oxidative stress
Chylomicrons
• Chylomicrons are large lipoprotein particles that
consist of triglycerides (85-92%), phospholipids (6-
12%), cholesterol (1-3%) and proteins (1-2%)
• They transport dietary lipids from the intestines to
other locations in the body
• Chylomicrons transport exogenous lipids to liver,
adipose, cardiac, and skeletal muscle tissue, where
their triglyceride components are unloaded by the
activity of lipoprotein lipase
• Chylomicrons are formed in the intestine and carry
triglycerides of dietary origin, (unesterified
cholesterol, and cholesteryl esters)
• Chylomicron (lipoprotein ) structure
ApoA, ApoB, ApoC, ApoE (apolipoproteins); T
(triacylglycerol); C (cholesterol); green (phospholipids)
• VLDL
• VLDL are secreted by liver and export triglycerides to
peripheral tissues
• VLDL triglycerides are hydrolyzed by LPL, yielding free
fatty acids for storage in adipose tissue and for
oxidation in tissues such as cardiac and skeletal
muscle
LDL

• LDL is catabolized chiefly in hepatocytes and other cells

by receptor-mediated endocytosis
• Cholesteryl esters from LDL are hydrolyzed, yielding free
cholesterol for the synthesis of cell membranes
• Cells also obtain cholesterol by synthesis via a pathway
involving the formation of mevalonic acid by HMG-CoA
reductase
• Normally, about 70% of LDL is removed from plasma by
hepatocytes
• Unlike other cells, hepatocytes can eliminate cholesterol
by secretion in bile and by conversion to bile acids
Causes
Classification Hyperlipidemias

• Hyperlipidemias may basically be classified as either

• Familial (also called primary) caused by specific genetic
abnormalities
• Acquired (also called secondary) when resulting from another
underlying disorder that leads to alterations in plasma lipid and
lipoprotein metabolism
• Hyperlipidemia may be idiopathic, that is, without known
cause.
• Hyperlipidemias may also be classified directly into which
types of lipids are elevated, that is
• Hypercholesterolemia
• Hypertriglyceridemia
• or both in combined hyperlipidemia
Familial (primary)

• Familial hyperlipidemias are classified according to the

Fredrickson classification which is based on the
pattern of lipoproteins on electrophoresis or
ultracentrifugation
• It was later adopted by the World Health Organization
(WHO)
 The most common causes of acquired
hyperlipidemia are:
• Diabetes mellitus (insulin is known to activate LPL in
adipocytes and its placement in the capillary
endothelium)
• Use of drugs such as diuretics, beta blockers, and
estrogens

Other conditions leading to acquired hyperlipidemia include:

• Hypothyroidism
• Renal failure
• Nephrotic syndrome
• Alcohol
• Some rare endocrine disorders and metabolic disorders
TREATMENT GOAL
• The occurrence of CHD is positively associated with high
total cholesterol and even more strongly with elevated
LDL cholesterol in the blood.
• In contrast to LDL cholesterol, high levels of HDL
cholesterol have been associated with a decreased risk
for heart disease.
• Reduction of the LDL level is the primary goal of
cholesterol-lowering therapy
• Treatment of the underlying condition, when possible, or
discontinuation of the offending drugs usually leads to an
improvement in the hyperlipidemia.
• Specific lipid-lowering therapy may be required in certain
circumstances
• Another acquired cause of hyperlipidemia, although not
always included in this category, is postprandial
hyperlipidemia, a normal increase following ingestion of
food
Management:

• For treatment of type II, dietary modification is the initial

approach but many patients require treatment with statins
(HMG-CoA reductase inhibitors) to reduce cardiovascular
risk
• If the triglyceride level is markedly raised, fibrates may be
preferable due to their beneficial effects
• Combination treatment of statins and fibrates, while
highly effective, causes a markedly increased risk of
myopathy and rhabdomyolysis and is therefore only done
under close supervision
• Other agents commonly added to statins are ezetimibe,
niacin and bile acid sequestrants.
• Dietary supplementation with fish oil is also used to
reduce elevated triglycerides, with the greatest effect
occurring in patients with the greatest severity
• There is some evidence for benefit of plant sterol-
containing products and ω3-fatty acids
DIETARY MANAGEMENT OF
HYPERLIPOPROTEINEMIA
• Sucrose and other simple sugars raise VLDL in
hypertriglyceridemic patients
• Alcohol can cause significant hypertriglyceridemia by
increasing hepatic secretion of VLDL
• Synthesis and secretion of VLDL are increased by
excess calories
• The conclusion that diet suffices for management can
only be made after weight has stabilized for at least 1
month
BASIC & CLINICAL PHARMACOLOGY OF
DRUGS USED IN HYPERLIPIDEMIA

• Drugs should be avoided in pregnant and lactating

women and those likely to become pregnant.
• All drugs that alter plasma lipoprotein concentrations
may require adjustment of doses of warfarin and
indandione anticoagulants.
• Children with heterozygous familial
hypercholesterolemia may be treated with a resin or
reductase inhibitor, usually after 7 or 8 years of age,
when myelination of the central nervous system is
essentially complete
• The decision to treat a child should be based on the
level of LDL, other risk factors, the family history, and
the child's age
• Drugs are rarely indicated before age 16
Classification of Drugs
• COMPETITIVE INHIBITORS OF HMG-COA
REDUCTASE (REDUCTASE INHIBITORS;
"STATINS")
• NIACIN (NICOTINIC ACID)
• FIBRIC ACID DERIVATIVES (FIBRATES)
• BILE ACID–BINDING RESINS
• INHIBITORS OF INTESTINAL STEROL
ABSORPTION
• TREATMENT WITH DRUG COMBINATIONS
COMPETITIVE INHIBITORS OF HMG-COA REDUCTASE (REDUCTASE
INHIBITORS; "STATINS")

• These compounds are structural analogs of HMG-CoA

(3-hydroxy-3-methylglutaryl-coenzyme A
• Lovastatin,
• Atorvastatin
• Fluvastatin
• Pravastatin
• Simvastatin
• Rosuvastatin
Mechanism of Action

• HMG-CoA reductase mediates the first committed step in

sterol biosynthesis
• The active forms of the reductase inhibitors are structural
analogs of the HMG-CoA intermediate that is formed by
HMG-CoA reductase in the synthesis of mevalonate
• These agents block this action
• Because of their strong affinity for the enzyme, they
compete effectively to inhibit HMG CoA reductase, the
rate-limiting step in cholesterol synthesis.
• By inhibiting de novo cholesterol synthesis, they deplete
the intracellular supply of cholesterol
Therapeutic Uses & Dosage
• Because cholesterol synthesis occurs predominantly at

night, reductase inhibitors should be given in the

evening if a single daily dose is used
• Absorption generally is enhanced by food

• Daily doses vary from 10 mg to 80 mg

• Reductase inhibitors are useful alone or with resins,

niacin, or ezetimibe in reducing levels of LDL

• Women who are pregnant, lactating, or likely to become

pregnant should not be given these agents

 Toxicity
• Liver: Biochemical abnormalities in liver function have
occurred with the HMG CoA reductase inhibitors
• Therefore, it is prudent to evaluate liver function and
measure serum transaminase levels periodically
• These return to normal on suspension of the drug
• Hepatic insufficiency can cause drug accumulation
• Muscle: Myopathy and rhabdomyolysis (disintegration or
dissolution of muscle) have been reported only rarely
• In most of these cases, patients usually suffered from renal
insufficiency or were taking drugs such as cyclosporine,
itraconazole, erythromycin, gemfibrozil, or niacin
• Plasma creatine kinase levels should be determined
regularly
NIACIN (NICOTINIC ACID)
• Niacin (vitamin B3) is converted in the body to the amide,

which is incorporated into niacinamide adenine

dinucleotide (NAD)
• Niacin decreases VLDL and LDL levels, and Lp(a) in most

patients
• It often increases HDL levels significantly
• Mechanism of Action
• Niacin strongly inhibits lipolysis in
adipose tissue, the primary producer
of circulating free fatty acids.
• The liver normally uses these
circulating fatty acids as a major
precursor for triacylglycerol
synthesis.
• Therefore, a reduction in the VLDL
concentration also results in a
decreased plasma LDL
concentration.
• Thus, both plasma triacylglycerol (in
VLDL) and cholesterol (in VLDL and
LDL) are lowered.
• Lowering the level of plasma
fibrinogen, niacin can reverse some
of the endothelial cell dysfunction
contributing to thrombosis.
Therapeutic Uses & Dosage
• Niacin lowers plasma levels of both cholesterol and
triacylglycerol.
• Therefore, it is particularly useful in the treatment of
familial hyperlipidemias.
• Niacin is also used to treat other severe
hypercholesterolemias, often in combination with other
antihyperlipidemic agents.
• It is the most potent antihyperlipidemic agent for raising
plasma HDL levels, which is the most common indication
for its clinical use.
Toxicity
• The most common side effects of niacin therapy are an
intense cutaneous flush (accompanied by an
uncomfortable feeling of warmth) and pruritus
• Administration of aspirin prior to taking niacin decreases
the flush, which is prostaglandin mediated
• The sustained-release formulation of niacin, which is
taken once daily at bedtime, reduces bothersome initial
adverse effects
• Niacin inhibits tubular secretion of uric acid and, thus,
predisposes to hyperuricemia and gout
• Impaired glucose tolerance and hepatotoxicity have
also been reported
FIBRIC ACID DERIVATIVES (FIBRATES)

• Fenofibrate and gemfibrozil are derivatives of

fibric acid that lower serum triacylglycerols and
increase HDL levels.
• Both have the same mechanism of action.
• However, fenofibrate is more effective than
gemfibrozil in lowering plasma LDL cholesterol
and triglyceride levels.
Mechanism of Action

• These agents function primarily as ligands for the

nuclear transcription receptor, peroxisome proliferator-

activated receptor-alpha (PPAR- )
• They increase lipolysis of lipoprotein triglyceride via LPL

• Intracellular lipolysis in adipose tissue is decreased

• Levels of VLDL decrease, in part as a result of

decreased secretion by the liver

• Some increase in HDL protein has been reported
Therapeutic Uses & Dosage
• These drugs are useful in hypertriglyceridemias in
which VLDL predominate and in
dysbetalipoproteinemia/ type III hyperlipoproteinemia.
• They also may be of benefit in treating the
hypertriglyceridemia that results from treatment with
viral protease inhibitors
• The usual dose of gemfibrozil is 600 mg orally once or
twice daily
• The dosage of fenofibrate (as Tricor) is one to three 48
mg tablets (or a single 145 mg tablet) daily
• Absorption of gemfibrozil is improved when the drug is
taken with food
• Metabolize by liver and excrete by urine
 Adverse effects:

• Gastrointestinal effects: The most common adverse effects are mild

gastrointestinal disturbances
• Lithiasis: Because these drugs increase biliary cholesterol

excretion, there is a predisposition to the formation of gallstones.

• Muscle: Myositis (inflammation of a voluntary muscle) can occur

with both drugs; thus, muscle weakness or tenderness should be

evaluated
• Patients with renal insufficiency may be at risk

• Myopathy and rhabdomyolysis have been reported in a few patients

taking gemfibrozil and lovastatin together

BILE ACID–BINDING RESINS

• Colestipol,
cholestyramine, and
colesevelam are useful
only for isolated increases
in LDL.
• In patients who also have
hypertriglyceridemia, VLDL
levels may be further
increased during treatment
with resins
 Mechanism of Action
• Colestipol, cholestyramine, and colesevelam are
anionexchange resins that bind negatively charged bile
acids and bile salts in the small intestine.
• The resin/bile acid complex is excreted in feces, thus
preventing the bile acids from returning to the liver by the
enterohepatic circulation.
• Lowering the bile acid concentration causes hepatocytes to
increase conversion of cholesterol to bile acids, resulting in
a replenished supply of these compounds, which are
essential components of the bile.
• Consequently, the intracellular cholesterol concentration
decreases, which activates an increased hepatic uptake of
cholesterol-containing LDL particles, leading to a fall in
Therapeutic Uses & Dosage
• Treat Type IIa and Type IIb hyperlipidemias.

• Cholestyramine can also relieve pruritus caused by

accumulation of bile acids in patients with biliary

obstruction
Pharmacokinetics:
• Cholestyramine, colestipol, and colesevelam are taken
orally
• Because they are insoluble in water and are very large
(molecular weights are greater than 106), they are neither
absorbed nor metabolically altered by the intestine
• Instead, they are totally excreted in the feces
Adverse effects:
• Gastrointestinal effects: The most common side effects are
gastrointestinal disturbances, such as constipation, nausea, and
flatulence
• Colesevelam has fewer gastrointestinal side effects than other bile
acid sequestrants.
• Impaired absorptions: At high doses, cholestyramine and colestipol
(but not colesevelam) impair the absorption of the fat-soluble
vitamins (A, D, E, and K)
• Drug interactions: Cholestyramine and colestipol interfere with the
intestinal absorption of many drugs for example, tetracycline,
phenobarbital, digoxin, warfarin, pravastatin, fluvastatin, aspirin,
and thiazide diuretics
• Therefore, drugs should be taken at least 1 to 2 hours before, or 4
to 6 hours after, the bile acid binding resins
INHIBITORS OF INTESTINAL STEROL ABSORPTION

• Ezetimibe is the first member of a group of drugs that

inhibit intestinal absorption of phytosterols and cholesterol
• Its primary clinical effect is reduction of LDL levels
Mechanism of Action

• Ezetimibe is a selective inhibitor of intestinal absorption of

cholesterol and phytosterols
• A transport protein, NPC1L1, appears to be the target of
the drug
• It is effective even in the absence of dietary cholesterol
because it inhibits reabsorption of cholesterol excreted in
the bile
 Pharmacokinetics and Toxicity
• Ezetimibe is primarily metabolized in the small intestine
and liver via glucuronide conjugation (a Phase II reaction),
with subsequent biliary and renal excretion
• Patients with moderate to severe hepatic insufficiency
should not be treated with ezetimibe
• A formulation of ezetimibe and simvastatin has been
shown to lower LDL levels more effectively than the statin
alone
TREATMENT WITH DRUG COMBINATIONS
• Fibric Acid Derivatives & Bile Acid–Binding Resins
• HMG-CoA Reductase Inhibitors & Bile Acid–Binding
Resins
• Niacin & Bile Acid–Binding Resins
• Niacin & Reductase Inhibitors
• Reductase Inhibitors & Ezetimibe
• Reductase Inhibitors & Fibrates
• Ternary Combination of Resins, Ezetimibe, Niacin, &
Reductase Inhibitors
Reference:
Katzung Pharmacology