The high risks of lipids and its relevance towards the development of different cardiovascular diseases has been known to all where this present slide focuses on that only along with the different treatment procedures,.

1. HYPERLIPIDEMIA
PRESENTED BY : ANAND SAGAR TIWARI
M.PHARM ( FIRST SEMESTER)
DEPARTMENT OF PHARMACOLOGY
GUIDED BY: Mr. ASHOK KUMAR DASTAPUR

2. OVERVIEW
•Basic concepts
•Hyperlipidemia
•Effect on heart
•Anti-hyperlipidemics

16. INTRODUCTION
 Hyperlipidemia is defined as abnormally raised/elevated
levels of any or all lipids in the blood.
It results from abnormalities in lipid metabolism or plasma
lipid transporters or a disorder in the synthesis and
degradation of plasma lipoproteins.
Hyperlipidemia is a broad term also called
hyperlipoproteinemia is a common disorder in developed
countries.
It is the most common form of dyslipidemia.
Lipoproteins are transported in a protein capsule where the
size of the capsule or lipoprotein determines its density.
Lipoproteins of low density are the main cause for
hyperlipidemia.

17. CLASSIFICATION
•Hyperlipidemia may be basically classified as:
I. Familial (Primary hyperlipidemia): Caused by
specific genetic abnormalities
II. Secondary hyperlipidemia : Results from
another underlying disorder that leads to
alterations in the plasma lipid and protein
metabolism.
III.Idiopathic hyperlipidemia: Cause is unknown.

18. FAMILIAL HYPERLIPIDEMIA
Familial hyperlipidemia are classified according to the
Fredrickson classification, which is based on the pattern of
lipoproteins on electrophoresis or ultracentrifugation .
It does not account for HDL directly and it does not distinguish
among the different genes that may be partially responsible for
some of these conditions. It can be classified as:
I. Hyperlipoproteinemia type 1(Familial lipoprotein lipase
deficiency)
II. Hyperlipoproteinemia type 2 (FH & PH)
III. Hyperlipoproteinemia type 3 (Familial dysbetalipoproteinemia)
IV. Hyperlipoproteinemia type 4 (Hypertriglyceridemia)
V. Hyperlipoproteinemia type 5(Familial combined
hyperlipidemia)

19. Hyperlipidemias are also classified as in
which type of lipids are elevated:
HYPERCHOLESTEROLEMIA
HYPERTRIGLYCERIDEMIA or
BOTH IN CASE OF COMBINED
HYPERLIPIDEMIA

20. Lipids are carried in plasma in lipoproteins after
getting associated with several apoproteins.
Plasma lipid concentrations are dependent on the
concentration of lipoproteins.
The core of lipid consists of triglycerides(TGs) or
cholesteryl esters(CHEs).
The outer polar layer consists of and apoproteins
phospholipids, free cholesterol(CH).
Based on the particle size and density lipoproteins
are classified into 6 types.

21. Classification of lipoproteins
• Lipoproteins can be classified into 6 types based on their particle
size and density. Also they all have some role to play . These can
be described as follows along with their sources:
1. Chylomicrons : Role in dietary TG transport obtained from diet
2. Chylomicrons remnants : Role in dietary CH transport obtained
from diet and Chy.
3. VLDL : Role in endogenous TG transport synthesized in liver.
4. IDL : Role in transporting CH & TG to liver and source of LDL
obtained from VLDL.
5. LDL : Role in transport of CH to tissues and liver and obtained
from IDL.
6. HDL : Role in the removal of CH from tissues and it is present in
tissue cell membrane

24. Chylomicrons
Greek chylos meaning juice (of plants and animals) and
micron meaning (small particle) are lipoprotein molecules
that consist of triglycerides(85-92%), phospholipids(6-12%),
cholesterol(1-3%), and proteins(1-2%).
Due to their density relative to lipoproteins, they are also
commonly known as Ultra Low Density Lipoproteins(ULDL) in
modern usage.
These transport lipids absorbed from the intestine to
adipose, cardiac and skeletal muscle tissue where their
triglyceride components are hydrolyzed by the activity of
lipoprotein lipase , allowing the free fatty acid to be
absorbed by the tissues.

25. ORIGIN
Chylomicrons are formed in the ER in the absorptive cells
(enterocytes) of the small intestine.
In the villi microvilli a lot of surface area for absorption.
Newly formed chylomicrons are secreted through the
basolateral membrane into the lacteals joining to lymph to
form chyle.
Lymphatic vessels carry the chyle to the venous return of
the systemic circulation.
From there the chylomicrons supply the tissue with fat
absorbed from the diet.

26. Chylomicrons remnants
Once triglyceride stores are distributed, the
chylomicron returns APOC2 to the HDL(but
keeps APOE),and , thus, becomes a chylomicron
remnant, now only 30-50 nm.
APOB48 and APOE are important to identify the
chylomicron remnant in the liver for endocytosis
and breakdown.

28. Intermediate density lipoproteins
Intermediate density lipoproteins (IDLs) belong to the
lipoprotein particle family and formed from the
degradation of VLDL as well as HDL.
Each native IDL particle consists of proteins that
encircles various lipids , enabling ,as a water soluble
particle, these lipids to travel in the aqueous blood
environment as part of the fat transport systems
within the body.
Size is in the range of 25-35 nm.
IDL transport a variety of triglyceride fats and
cholesterol and ,like LDL, can also promote the growth
of Atheroma.

29. VLDL , a large triglyceride-rich lipoprotein secreted by
the liver transports triglyceride to adipose tissues and
muscle . The VLDL are removed in the capillaries by
the enzyme lipoprotein lipase and the VLDL returns to
the systemic circulation as IDL.
The IDL particles have lost most of their triglyceride
but they retain cholesteryl esters.
Some of the IDL remain in the circulation where they
are converted into LDL.
IDL contain multiple copies of the receptor ligand
ApoE in addition to a single copy of ApoB-100.

32. Very Low Density Lipoprotein(VLDL)
VLDL with density relative to extracellular water is a
type of lipoprotein made by the liver from
triglycerides, cholesterol and apolipoproteins.
These have a diameter of 30-80 nm.
It functions as a the body’s internal transport
mechanism for lipids and transports endogenous
triglycerides, phospholipids, cholesterol and
cholesteryl esters.
It serves for long range transport of hydrophobic
intracellular messengers like the morphogen Indian
Hedgehog(protein).

34. Low Density Lipoprotein (LDL)
LDL is one of the five major groups of lipoprotein which
transport all fat molecules around the body in the
extracellular water.
However LDL can contribute to atherosclerosis if it is
oxidized within the walls of the arteries.
Though regarded as bad lipids they are not exactly bad and
conduct nutrients to vessels that large LDL cannot reach.
A single LDL particle is about 220-275angstroms in diameter,
typically transporting 3000-6000 fat molecules/particle.
LDL particles are thought to evade the endothelium and
become oxidized since the oxidized forms may be easily
retained by the proteoglycans.

36. High Density Lipoprotein (HDL)
High density lipoproteins are of the five major groups of
lipoproteins.
They are typically composed of 80-100 proteins per particle
(organized by one, two or three ApoA ; more as the particles
enlarge picking up and carrying more fat molecules) and
transporting up to hundreds of fat molecules per particle.
It is the smallest of lipoproteins and contains the highest
proportion of proteins to lipids.
Mainly transports cholesterol to liver or steroidogenic
organs as adrenals, ovary and testes and finally removed by
HDL receptors such as scavenger receptor BI(SR-BI).

44. TREATMENTS

50. Statins(HMG-CoA reductase inhibitors)
These are a class of lipid lowering agents that reduce
mortality and illness in those who are at a higher risk
of cardiovascular disease.
They inhibit the enzyme HMG-CoA reductase which
plays a central role in the production of cholesterol
and high cholesterol levels are associated with CVD.
These are effective in lowering LDL cholesterol and
are widely used for primary prevention in people at
high risk of heart related diseases.
e.x. Atorvastatin, Lovastatin, Simvastatin etc.

51. Mechanism of action (MoA)
70-75% of plasma LDL is removed by hepatocytes by
receptor mediated endocytosis and cholesterol esters from
LDL molecules are hydrolyzed in the liver to free cholesterol.
de novo synthesis of cholesterol takes place in liver by a
pathway involving formation of mevalonic acid by the
enzyme HMG-CoA reductase.
Statins inhibit this rate limiting step.
Thus decreasing hepatic cholesterol synthesis and
increasing synthesis of high affinity LDL receptors.
Increased clearance of cholesterol-rich plasma LDL with
subsequent reduction in plasma LDL cholesterol where the
effect is dose dependent with full effect seen in 6 weeks.

53. PHARMACOKINETICS
Orally administered and absorption of statins varies
between 40-90%.
Fluvastatin is absorbed almost completely.
Lovastatin and simvastatin are prodrugs and
hydrolyzed in the GI tract to the active metabolites.
Atorvastatin , rosuvastatin are fluorinated
compounds that are active as such .
All undergo first-pass metabolism and most of the
dose is excreted in the bile; only about 5-20 % is
excreted in the urine.

54. SIDE EFFECTS
i. Muscle pain
ii. Increased risk of Diabetes Mellitus.
iii.Abnormal blood levels of liver enzymes.
iv.Severe side effect includes Muscle damage

55. Adverse drug reaction
Mostly mild and dose dependent they may cause reversible
rise in the hepatic aminotransferase level.
Rarely it may be marked and accompanied by muscular pain
(myositis) and even myopathy.
Rhabdomyolysis is rare.
Rarely statins may cause impotence, gynecomastia, memory
loss, insomnia, mood changes and depression.
Also they are contraindicated in pregnancy and in woman
planning to be pregnant, during breast-feeding, in children
and in patients with severe liver disease.

56. Drug interactions
• Combination of a statin with a fibric acid derivative and
nicotinic acid potentiates the rise in plasma CPK level.
• Lovastatin , simvastatin undergo metabolism by CYP3A4 and
their toxicity can be increased by the concurrent use of
hepatic microsomal enzyme inhibitor such as ketoconazole,
isoniazid, erythromycin etc.
• Fluvastatin and rosuvastatin are metabolized by hepatic
CYP2C9. Inhibitors of this enzyme like ketoconazole and
cimetidine can increase the plasma levels of these statins.
• Max. dose is 10 mg in patients taking Amiodarone, dilitiazem
and 20 mg in people with amlodipine and ranolazine.

57. Therapeutic uses
1. Statins are useful in both primary and secondary
prophylaxis of hypercholesterolemia.
2. Indicated during MI or any cardiovascular event
3. Patient less than 70 years old with known IHD.
4. Diabetes mellitus.
5. Subjects with strong family history of premature
cardiovascular disease.
6. Individuals with clinical evidence of ASCVD.
7. Subjects with primary elevation of LDL> 190mg%

58. DRUG STARTING/MAX DOSE
Lovastatin 10/80
Pravastatin 10/20
Simvastatin 5/20
Fluvastatin 20/60
Atorvastatin 10/40
Rosuvastatin 2.5/20

59. Cholesterol Absorption inhibitors
• EZETIMIBE : Mechanism of action
• This prodrug , 2-azetidinone is converted in intestine to an
active metabolite ezetimibe glucournide (t1/2-22 hr.).
• It binds to intestinal mucosal transporter NPC1L1 protein and
decreases delivery of dietary and biliary cholesterol to the
liver.
• Thus inhibiting absorption of cholesterol by the small
intestine.
• Reduction of hepatic cholesterols stores causes increase in
LDL receptors on the hepatocytes and an increased LDL
cholesterol decreases with minimal increase in HDL-C.
• It also interrupts the entero-hepatic cycling of cholesterol.

61. Adverse Reactions
1. Fatigue
2. Dizziness
3. Abdominal discomfort
4. Diarrhoea
5. Arthralgia
6. Hypersensitivity reactions

62. Therapeutic uses
•It can be used as monotherapy in the dose
of 5-10 mg/day.
•It acts synergistically when combined with
statins and particularly useful in patients
who don’t tolerate large doses of statins.

63. Nicotinic Acid
•Niacin also known as nicotinic acid is an organic
compound and a form of vitamin B3.
•This vitamin in large doses effectively and rapidly
reduce plasma TG by lowering VLDL levels.
•LDL levels diminish more slowly and HDL levels
rise during therapy.

64. Mechanism of action
• In the adipose tissue, nicotinic acid inhibits adenylyl
cyclase, and prevents lipolysis by hormone sensitive
lipase.
• This reduces the transport of fatty acids to the liver.
• In the liver it reduces both synthesis and esterification
of fatty acids.
• The end result is reduction in the hepatic production
of VLDL and in plasma TG, VLDL cholesterol and LDL
cholesterol.

65. Adverse Reactions
•Intense cutaneous flushing
•Pruritus by increasing the local prostaglandin
levels.
•Nausea
•Diarrhoea, Vomiting
•Clinical jaundice
•Hyperglycemia
•Hyperuricemia
•Abnormalities of liver function

66. Therapeutic uses
•Nicotinic acid is useful in all forms of
hyperlipoproteinemia except type 1 and is a drug
of choice in type 5 hyperlipoproteinemia.
•Usual dose is 2-8 g/day.

67. Fibrates
 The fibrates are a class of amphipathic
carboxylic acids.
They are used for a range of metabolic
disorders, mainly hypercholesterolemia, and are
therefore hypolipidemic agents.
These are the derivatives of fibric (isobutyric
acid) and include gemfibrozil, benzafibrate and
fenofibrate.

69. Mechanism of action
These drugs stimulate the nuclear transcription
receptor, Peroxisome Proliferator Activated Receptor-
alpha that controls the expression of gene, which
mediate TG metabolism.
They increase lipoprotein lipase activity (lpL) and the
hydrolysis of TG and promote HDL production.
They reduce the incorporation of fatty acids into
VLDL in the liver, thus inhibiting its synthesis and
secretion.
The plasma TG declines by 50% and cholesterol by
10-15%.

71. Pharmacokinetics
Almost completely absorbed from the gut,
are highly protein bound(more than 90%).
 Largely excreted unchanged in the urine.

72. Adverse reactions
Allergic reactions
Nausea and Diarrhoea.
Serious effect on skeletal(myositis) and cardiac
muscles reported.
Long therapy causes gallstone formation
Therapeutic uses: These drugs are effective in
reducing mainly plasma TG. Fenofibrate is preferred to
gemfibrozil.

73. Bile Acid Sequesterants

74. Mechanism of action
• Basic ion exchange resins supplied in the chloride
form.
• Bind bile acids in the intestine interrupting their
enterohepatic circulation.
• Fecal excretion of bile salts and CH is increased.
• This indirectly leads to enhanced hepatic metabolism
of CH to bile acids.
• More LDL receptors are expressed on liver cells
clearance of plasma IDL, LDL and indirectly that of
VLDL is increased.

76. Adverse reactions
I. Nausea and vomiting
II. Heartburn and constipation
III. Interferes with fat absorption and fat soluble
vitamins.
IV. Also interferes with the absorption of thyroid
hormones, tetracyclines , warfarin and
phenobarbitone.

77. Combination therapy
• Several drug combinations are available for the treatment
of combined hyperlipidemia (elevated LDL-C and elevated
triglycerides, generally with concurrent low HDL-C).
• Statins plus niacin have been successfully used in this
setting.
• Statin plus fibrate and stain plus fish oil combinations also
is helpful.
• The potential benefits of combination therapy must be
weighed against the potential disadvantages, including
complexity of the medication regimen, higher cost,
problems with adherence and increased incidence of
adverse effects.

79. LATEST TRENDS in
HYPERLIPIDEMIA
THERAPY

83. Reference
Essentials of medical pharmacology : KD
Tripathi
Pharmacology and Pharmacotherapeutics :
Rege , Satoshkar, Bhandarkar
Internet