1.+Antihyperlipidemic+drugs+FrK.pptx

Antihyperlipidemic Drugs
Dr. Ferdous Khan
Associate Professor
Department of Pharmaceutical Sciences
North South University

This pharmacology lecture covers topics such as:
 Lipid hypothesis
 Pathophysiology of hyperlipidemia; lipids, cholesterol,
triglycerides, phospholipids, bile acids, fatty acids, lipoproteins,
apolipoproteins, chylomicrons, VLDL, LDL, HDL.
 Pathophysiology of atherosclerosis, and vascular inflammation.
 Mechanism of action of lipid-lowering drugs and their side
effects:
 HMG-CoA reductase inhibitors (statins)
 Nicotinic acid
 Fibrates
 Bile acid sequestrants
 Cholesterol absorption inhibitors
 Pcsk9 inhibitors
 Omega 3 fatty acids
Content

Lipid hypothesis
 The lipid hypothesis (cholesterol hypothesis) is a medical
theory which postulates a link between blood cholesterol
levels and the of cardiovascular diseases.
 According to this hypothesis "Measures used to lower the
plasma lipids in patients with hyperlipidemia will lead to
reductions in new events of coronary heart disease".
 More concisely, “Reduction of blood cholesterol significantly
reduces coronary heart disease".
 An accumulation of evidence has led to the acceptance of
the lipid hypothesis by most of the medical community.
 Hyperlipidemia (AKA high cholesterol) is the main risk factor
to the development of atherosclerosis, which can lead to
stroke and heart attack.

Absorption of lipids
Fatty acids and monoglycerides are
emulsified by bile salts to form micelles
Fatty acids enter the epithelial cells of
GIT and form triglycerides (TG)
TG combine with proteins inside the
Golgi body to form chilomicron
Chilomicrons enter the lacteal and are
transported away from the intestine
Hydrolytic enzymes called lipases digest
the fats into their component parts

Three major lipids of the blood

 A lipoprotein is a biochemical assembly whose primary
function is to transport lipid molecules in aqueous medium,
such as blood plasma or other extracellular fluids.
 Lipoprotein consist of a TG and cholesterol core, surrounded
by a phospholipid outer shell.
 The hydrophilic portions of phospholipids are oriented
outward toward the surrounding water and lipophilic portions
oriented inward toward the lipid center.
 Apolipoprotein, special kind of protein, is embedded in the
outer shell of phospholipid; thus both stabilize the complex
and give it a functional identity.
 Apolipoprotein also serve as cofactors for specific enzymes
involved in the metabolism of lipoproteins.
Lipid carrier: lipoprotein

 Main function of apolipoprotein is to stabilize the lipoprotein
structure and render solubility of the lipid component.
 Apolipoproteins interact with lipoprotein receptors and lipid
transport proteins, thereby participating in lipoprotein uptake
and clearance.
 There is an inverse relationship between the density and
size of lipoprotein particles.
 Fats have a lower density than water or smaller protein
molecules.
 The larger particles have a higher percentage of internal fat
molecules and vice versa.

Chylomicron
(80-1000 nm)
VLDL
(40-80 nm)
LDL
(20-30 nm)
HDL
(7-20 m)
IDL
(30-40 nm)

Lipoprotein Density Protein Lipid Lipid Composition
Chylomicron <0.96 2% 98% Triacylglycerol (88%)
CE (4%), PL (8%)
VLDL 0.950-1.006 10% 90% Triacylglycerol (55%),
CE (25%), PL (20%)
LDL 1.019-1.063 20% 80% Triacylglycerol (12%)
CE (59%), PL (28%)
HDL 1.063-1.210 40% 60% Triacylglycerol (12%)
CE (40%), PL (47%)
 Lipoproteins differ in size and density
 Density, measured originally by ultracentrifugation, is the
basis for their classification into 4 types.

Transportation of lipids
Lipoprotein Source Destination Role
Chylomicrons Intestine Many organs Deliver lipids of dietary
origin to body cell
VLDLs Liver Many organs Deliver endogenously
produced TG to body cells
LDLs Intravasicular
removal of TG
from VLDL
Blood vessels
Liver
Deliver endogenously
produced cholesterol to
various organs
HDLs Liver and
intestine
Liver and steroid-
hormone
producing glands
Remove and degrade
cholesterol
Each class of lipoprotein has a specific role in lipid transport,
and there are different pathways for exogenous and
endogenous lipids.

Size and density of lipoproteins

VLDLc LDLc
High TG (55%)
Moderate cholesterol (25%)
Moderate phospholipid (20%)
Very low protein (10%)
Low TG (12%)
High cholesterol (59%)
Moderate phospholipid (28%)
Low protein (20%)
Made by the liver Various cells by the removal of TG
from VLDL
Transports TG from the liver to
the muscle and adipose tissue
Transports cholesterol throughout
the body via blood circulation
Density 0.95-1.02 g/ml Density 1.02-1.06 g/ml
High level may contribute to
atherosclerosis
Forms plaque on the wall of
arteries and causes
atherosclerosis
Size (40-80 nm) Size (20-30 nm)
Contains ApoB, ApoC, ApoE Contains ApoB-100
VLDL vs LDL cholesterol

Three major interconnected pathways are involved in
lipoprotein metabolism:
(1) Exogenous pathway: the transport of dietary fat
(2) Endogenous pathway: the transport of hepatic or
endogenous fat
(3) Reverse cholesterol transport (RCT) pathway
 These pathways are interdependent and disruptions in one
will affect the function and products of the others.
 For example, a mutation such as one in the ABC1 protein
can disrupt normal transport and processing of cholesterol.
 HDL-C appears to have cardioprotective properties because
of its involvement in RCT and inhibition of LDL-C) oxidation.
Pathways of lipoprotein metabolism

Smaller
Chylomicron
CE: Cholesteryl ester
Pathways of lipoprotein metabolism
IDL
IDL
Exogenous
pathway
(Clockwise)
Endogenous
pathway
(Anticlockwise)
RCT-pathway

Cholesterol and TG absorbed from the ileum
↓
Cholesterol and TG are transported as chylomicrons in lymph and
then into the blood capillaries
↓
Chilomicrons are distributed in muscle and adipose tissue
↓
TG is hydrolyzed into glycerol and FA by lipoprotein lipase (LPL)
↓
The tissues take up the free fatty acids and glycerol
↓
The chylomicron remnant (CMr), which contain ApoB-100 protein,
enters to the liver by LDLR
↓
CMr binds to receptors on hepatocytes and undergo endocytosis
Exogenous pathway

Cholesterol and TG are packaged into VLDL and then transported
from the liver to the muscle and adipose tissue
↓
In the muscle and adipose tissue TG is hydrolyzed to fatty acids and
glycerol by the action of LPL
↓
After loosing TG, the VLDL particles become smaller but retain
cholesterol and become LDL
↓
LDL provides cholesterol for the cell membranes and for synthesis of
steroids but also causes atherosclerosis
↓
Hepatic and non-hepatic cells take up LDL by LDLR
↓
In liver, LDL is converted into bile acids and secreted into the
intestines; in other cells it makes hormone and cell membrane
Endogenous pathway

 RCT is a mechanism by which the body removes excess
cholesterol with the help of HDLC from the peripheral tissues
and delivers them to the liver.
 From the liver the cholesterol is redistributed to other tissues
or removed from the body by the gallbladder.
 Immature HDL collects cholesterol from non-hepatic tissues.
 The cholesterol is converted to cholesteryl esters (CE) by the
enzyme LCAT (lecithin-cholesterol acyltransferase).
 The CE, with the help of cholesterylester transfer protein
(CETP), is transferred to chylomicron, VLDL, and LDL from
HDL in exchange of TG.
 Thus HDLC helps to reduce cholesterol in the blood.
Reverse cholesterol transport (RCT)

Good Cholesterol Bad Cholesterol
Good cholesterol brings lipid from
the blood into the liver
Bad cholesterol brings the lipid from
the liver to the blood
High-density lipoprotein Low-density lipoprotein
Takes LDL out of the blood and
prevent atherosclerosis
Forms plaque on the wall of arteries
and causes atherosclerosis
Level should be > 60 mg/dL Level should be < 140 mg/dL
Composed of high proportion of
protein, low TG and cholesterol
Moderate proportion of protein, low
TG and high cholesterol
Scavenge LDL from the blood and
helps to recycle it
Distribute cholesterol to the
peripheral tissue via blood
Contains Apo-A, Apo-E, Apo-C Contains Apo B-100
Density: 1.063-1.210 1.019-1.063
Diameter: 7-20 nm 20-30 nm
Good versus bad cholesterol

 As a general rule, HDL is considered “good” cholesterol,
while LDL is considered “bad.”
 Because HDL carries cholesterol to the liver, where it is
removed from the blood before it builds up in the arteries.
 LDL, on the other hand, takes cholesterol directly to your
arteries.
 This can result in atherosclerosis, a plaque buildup that can
even cause heart attack and stroke.
 Triglycerides make up the third component of lipid and act
as unused calories that are stored as fat in the blood.
 Eating more calories than you burn can cause TG to build
up in the bloodstream, increasing the risk for heart attacks.
Good versus bad cholesterol

 LDL receptors are critically important in determining the
concentration of circulating LDL, and hence the
development and progression of atheromatous disease.
 The low-density lipoprotein receptor (LDL-R) is a protein of
839 amino acids.
 LDL-R mediates the endocytosis of cholesterol-rich LDL.
 It is a cell-surface receptor that recognizes the apoprotein
B100, which is embedded in the outer phospholipid layer of
VLDL and its remnants: LDL and IDL particles.
 The receptor also recognizes the ApoE protein found in
chylomicron remnants and IDL.
 It is most significantly expressed in bronchial epithelial cells
and adrenal gland and adrenal cortex.
LDL-Receptor

 The gradual buildup of cholesterol and fibrous tissue in
plaques in the wall of the coronary arteries or other arteries,
typically over a few years, is termed as atherosclerosis.
 Inflammatory cells, (esp. macrophages), move into affected
arterial walls which causes chronic inflammation of the wall.
 Over time, they (macrophage) become filled with cholesterol
products, particularly LDL, and become foam cells.
 In response to growth factors secreted by macrophages,
smooth muscle and other cells try to stabilize the plaque.
 A stable plaque may have a thick fibrous cap with
calcification.
 If there is inflammation, the cap may be thin or ulcerate.
Atherosclerosis

Atherosclerosis
 The plaque is made up of excess fat, collagen, and elastin.
 Exposed to the pressure associated with blood flow plaques,
having thin lining, may rupture and trigger the formation of a
blood clot (thrombus).

Stages of plaque development
Fatty streak formation: Earliest visible lesions appear as
areas of yellow discoloration on artery’s inner surface; blood
flow is not yet impeded at this stage.
Endothelial dysfunction: Endothelial dysfunction increases
the permeability of endothelial cells and allows the entry of
LDLc in the vessel subintima; these lipids then serve as pro-
inflammatory mediators that initiate leukocyte recruitment.
Chemical modification of lipoproteins:
Oxidation: of LDLc by local ROS derived from endothelial
cells. Oxidized LDLc has pro-inflammatory and antigenic
properties and contributes to leukocyte recruitment and
foam cell formation.
Glycation: in diabetic patients

Leukocyte recruitment: Ox-LDL induces pro-inflammatory
cytokine production (e.g. IL-1, TNF-α) by the endothelial
cells. Those cytokines in turn promote increased
expression of adhesion molecules (e.g. VCAM-1, ICAM-1,
and selectin) to bind leukocytes. Then leukocytes leaves
the blood vessel by diapedesis. Chemoattractant molecules
(MCP-1, IL-8) direct leukocyte migration into the vessel
intima.
Foam cell formation: Upon entering the intima, monocytes
differentiate into phagocytic macrophages and upregulate
their expression of scavenger receptors (SR). SR mediate
the uptake of ox-LDL into macrophages. Macrophages
develop into foam cells which produce more cytokines that
continue the process of atherosclerotic plaque formation.
Stages of plaque development

Injury to the endothelium causes LDL-cholesterol transported into
the vessel wall (in the subintima)
↓
Endothelial cells generate free radicals that oxidise LDLc (ox-
LDLc) initiates inflammatory response
↓
Injured or dysfunctional endothelium express cell adhesion
molecules (CAM)
↓
CAM helps monocyte attachment and migration of monocytes from
the lumen into the intima
↓
Within the intima monocytes differentiates into macrophage
↓
Macrophages uptake ox-LDLc via ‘scavenger’ receptors
Development of atherosclerosis

Such macrophages are called foam cells because of their
‘foamy’ histological appearance
↓
Subendothelial accumulation of foam cells form fatty streaks
↓
Cytokines and growth factors are released by macrophages
and endothelial cells
↓
This causes proliferation of smooth muscle and deposition of
connective tissue components (collagen, elastin)
↓
Gradually the fibrofatty plaque and complicated plaque
formation occurs

Healthy
Fatty
streak
Fibrofatty
plaque
Complicated
plaque

Genetic predisposition is the main risk
factor of CHD

Goal of lipoprotein level for prevention of
coronary heart disease

Persons are categorized into one of three levels of risk, to
identify group-specific treatment modalities:
1. High-risk, established IHD or IHD risk equivalents
(diabetes, noncoronary forms of atherosclerotic disease).
The treatment goals is to have LDL-cholesterol (LDL-C)
levels < 100 mg/dl.
2. Moderately high-risk, multiple (more than two) risk
factors. The treatment goals is to have LDL-cholesterol
(LDL-C) levels < 130 mg/dl.
3. Lower-risk, zero to one risk factor. The treatment goals is
to have LDL-cholesterol (LDL-C) levels < 160 mg/dl.
Goal of lipoprotein level for prevention of
coronary heart disease

 Dyslipidemia is an abnormal amount of lipids (e.g. TG,
cholesterol and/or fat phospholipids) in the blood.
 Dyslipidemia is a risk factor for the development of
atherosclerotic cardiovascular disease (ASCVD).
 ASCVD includes coronary artery disease, cerbrovascular
disease, and peripheral artery disease.
 In developed countries, most common dyslipidemia is
hyperlipidemia: an elevation of lipids in the blood.
 Though dyslipidemia is a risk factor for ASCVD, abnormal
levels doesn't mean that lipid lowering agents need to be
started.
 Other factors, such as comorbid conditions and lifestyle in
addition to dyslipidemia should be considered.
Dyslipidemia

Hyperlipidemia
 Hyperlipidemia is abnormally elevated levels of any or all
lipids (fats, cholesterol, or triglycerides) or lipoproteins in
the blood.
 Hyperlipidemia may be classified into 2 types:
 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.
 Also, hyperlipidemia may be idiopathic, that is without
known cause.

Dyslipidemia Hyperlipidemia
Dyslipidemia is an abnormal
amount of lipids (e.g.
triglycerides, cholesterol and/or
fat phospholipids) in the blood.
Hyperlipidemia is abnormally
elevated levels of any or all lipids
(fats, cholesterol, or triglycerides)
or lipoproteins in the blood.
Dyslipidemia is the superset of
hyperlipidemia
Hyperlipidemia represents a
subset of dyslipidemia and a
superset of hypercholesterolemia.
It is classified based on the
amount of lipid and lipoprotein
It is classified based on the
amount of chylomicron, LDL, and
VLDL
Dyslipidemia and hyperlipidemia

Familial hyperlipidemia (primary)

 Acquired hyperlipidemias may mimic primary forms of
hyperlipidemia and can have similar consequences.
 It may result in increased risk of premature atherosclerosis
or, when associated with marked hypertriglyceridemia, may
lead to pancreatitis and other complications of the
chylomicronemia syndrome.
 Acquired hyperlipidemia is characterized by high fat and
cholesterol in the blood due to other conditions or
medications.
 Diabetes, low thyroid hormone levels, kidney disease and
some other metabolic disorders cause hyperlipidemia.
 Some drugs can also cause hyperlipidemia, including
alcohol, diuretics, estrogens and beta-blockers.
Acquired (secondary)

• Diabetes Mellitus
• Use of drugs such as diuretics, beta blockers, estrogens
Other conditions leading to acquired hyperlipidemia include:
Hypothyroidism
Renal Failure
Nephrotic Syndrome
Alcohol
Some rare endocrine and metabolic disorders
peripheral insulin resistance
carnitine deficiency
Common causes of acquired
hyperlipidemia

1. Xanthoma
2. Xanthelasma of eyelid
3. Chest Pain
4. Abdominal Pain
5. Enlarged Spleen
6. Liver Enlarged
7. High cholesterol or
triglyceride levels
8. Heart attacks
9. Higher rate of obesity and
glucose intolerance
10. Pimple like lesions
across body
11. Atheromatous plaques in
the arteries
12. Arcus senilis
Hyperlipidemia usually has no noticeable symptoms and tends
to be discovered during routine examination or evaluation for
atherosclerotic cardiovascular disease.
Signs and symptoms of hyperlipidemia

HMG CoA Reductase
inhibitors
Rosuvastatin
Atorvastatin
Simvastatin
Pravastatin
Ovastatin
Fluvastatin
Fibrates
Gemfibrozil
Fenofibrate
Niacin
Nicotinic acid
Bile acid sequestrants
Colesevelam
Colestipol
Cholestyramine
Cholesterol absorption
inhibitors
Ezetimibe
Lipid lowering drugs
ω-3 fatty acids
Docosahexaenoic and
Eicosapentaenoic acids
PCSK9 inhibitors
Alirocumab
Evolucumab
A variety of natural statins are produced by Penicillium and
Aspergillus fungi as secondary metabolites.

Strategy for Controlling Hyperlipidemia

 Statins are also known as 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG-CoA) reductase inhibitors.
 They belongs to the first-line and the most effective
treatment for patients with elevated LDL cholesterol.
 Inhibits the first committed enzymatic step of cholesterol
synthesis.
 Therapeutic benefits include:
 Plaque stabilization
 Improvement of coronary endothelial function
 Inhibition of platelet thrombus formation, and
 Anti-inflammatory activity
Statins: HMG CoA reductase inhibitors

The value of lowering the level of cholesterol with statin drugs
has now been demonstrated in-
1) patients with CHD with or without hyperlipidemia
2) men with hyperlipidemia but no known CHD, and
3) men and women with average total and LDL
cholesterol levels and no known CHD.
HMG CoA reductase inhibitors
 Lovastatin and simvastatin are lactones that are hydrolyzed
to the active drug.
 Pravastatin and fluvastatin are active as such.

Mechanism of action of HMGCR inhibitors
Inhibition of HMG CoA reductase:
 Because of their strong affinity for the enzyme, this drug
compete effectively to inhibit HMG-CoA reductase.
 This enzyme catalyzes the rate-limiting step of mevalonic
acid pathway in cholesterol biosynthesis.
 Statins fit into the enzyme's active site and compete with
the native substrate (HMG-CoA).
 This competition reduces the rate by which HMG-CoA
reductase is able to produce mevalonate, the next molecule
in the cascade that eventually produces cholesterol.
 By inhibiting de novo cholesterol synthesis, they deplete the
intracellular supply of cholesterol.

Increase in LDL receptors:
 As a compensatory mechanism low level of intracellular
cholesterol causes the cell to increase the number of
specific cell-surface LDL receptors which absorb LDL
cholesterol from the plasma.
 Thus, the plasma cholesterol is lowered due to the
internalization of LDL-cholesterol.
Increase HDL level:
They can also increase plasma HDL levels resulting in an
additional lowering of risk for CHD.
Decreases the secretion of VLDL.
Decrease of triglyceride also occur.
Mechanism of action of HMGCR inhibitors

Mechanism of action of statins

 Effective in lowering plasma cholesterol levels in all types of
hyperlipidemias.
 The main biochemical effect of statins is to reduce plasma
LDL-cholesterol.
 There is also some reduction in plasma triglyceride and
increase in HDL. Other benefits includes:
 Improved endothelial function
 Reduced vascular inflammation
 Reduced platelet aggregability
 Increased neovascularisation of ischemic tissue
 Increased circulating endothelial progenitor cells
 Stabilization of atherosclerotic plaque
Benefits of statin therapy

 As statins are metabolized by the liver, these drugs may
increase the level of liver enzymes and thus increase the
risk of hepatotoxicity.
 Patients who are homozygous for familial
hypercholesterolemia, lack LDL receptors and therefore,
benefit much less from treatment with these drugs.
 For this reason, statins may be less effective in reducing
LDL-cholesterol in people with familial
hypercholesterolemia.
 In spite of the protection afforded by cholesterol lowering,
about 1/4 of the patients treated with these drugs still
present with coronary events.
Limitation of statin therapy

Muscle:
 Myopathy and rhabdomyolysis (breakdown of skeletal
muscle fibers with leakage of muscle contents into the
circulation) have been reported only rarely.
 This is due to the statin-mediated inhibition of mevalonate
and coenzyme Q10 (CoQ10) production.
 Mevalonic acid acts as a precursor for many compounds
which are necessary for maintaining the integrity of muscles.
 CoQ10 is an important molecule for muscle function and
sugar regulation.
 Statin-associated autoimmune myopathy (SAAM), also
known as anti-HMGCR myopathy, is a rare form of muscle
damage caused by the immune system in people who take
statin medications.
Adverse effects of statins

Adverse effects of statins
Liver: Biochemical abnormalities in liver function have
occurred with the HMG CoA reductase inhibitors. Evaluation
of liver function and measurement of serum transaminase
levels should be done periodically. These return to normal on
suspension of the drug therapy.
Drug interaction: Combining any statin with a fibrate or
niacin (other categories of lipid-lowering drugs) increases the
risks for rhabdomyolysis.
Monitoring liver enzymes and creatine kinase is especially
recommended in those-
on high-dose statins
on statin+fibrate combinations
in the case of muscle cramps
who have kidney dysfunction

 Pravastatin and fluvastatin are almost completely absorbed
after oral administration.
 Oral doses of lovastatin and simvastatin are from 30 to 50
percent absorbed.
 Lovastatin and simvastatin must be hydrolyzed to their acid
forms.
 Due to first-pass extraction, the primary action of these
drugs is on the liver.
 Excretion takes place principally through the bile and feces,
but some urinary elimination also occurs.
 Their half-lives range from 1.5 to 2 hours.
Pharmacokinetics of statins

 Fibrates are fibric acid derivatives which are used for a
range of metabolic disorders, mainly hypercholesterolemia,
and are therefore hypolipidemic agents.
 Several agents are available including bezafibrate,
ciprofibrate, gemfibrozil, fenofibrate, and clofibrate.
 Fibrates (prototype): clofibrate.
Clofibrate
Fibrates

Bezafibrate
Ciprofibrate
Clofibrate
Fenofibrate
Gemfibrozil
Fibrates

 Fibrates act through the activation of peroxisome
proliferator-activated receptors alpha (PPARα).
 Upon activation PPARα heterodimerizes with RXR.
 This dimer then binds to the PPRE.
 This induces or suppress the transcription of a number of
proteins and enzymes involved in lipid metabolism.
 Among the proteins Apolipoprotein A1, Apolioprotein A2,
and Apolipoprotein C3 are the most important.
 Fibrates Increase the expression of Apo-A1 and Apo-A2
which causes increased synthesis of HDL cholesterol.
 On the other hand, fibrates suppress the Apo-C3 which
reduces TG synthesis but stimulates -oxidation.
Mechanism of action of fibrates

The retinoid X
receptor (RXR)

 Among the enzymes which are induced by the interaction of
fibrates with PPARa is lipoprotein lipase (LPL).
 LPL catalyzes the release of free fatty acid from the diacyl
glycerol (DAG).
 This action LPL is important for bringing of the fat molecules
to the adipose tissue from the blood.
 The net effects of fibrates include:
Increased degradation of VLDLc
Decreased VLDLc synthesis
Reduced level of LDLc
Reduced plasma TG levels
Increased plasma HDLc by increased synthesis

1. Myalgia (muscle pain): One of the most common side
effects of fibrates is muscle pain.
2. Liver dysfunction: Fibrates can cause elevated liver
enzymes and liver dysfunction, although this is rare.
3. Gastrointestinal symptoms: Fibrates can cause nausea,
abdominal discomfort, and diarrhea.
4. Gallstones: Fibrates decrease the synthesis of bile acids
and thus increases the risk of developing gallstones.
5. Interactions with other drugs: Fibrates can interact with
statins, leading to potential adverse effects.
6. Increased risk of rhabdomyolysis: Fibrates can increase
the risk of rhabdomyolysis, a serious condition that results
in muscle breakdown and can cause kidney failure.
Adverse effects of fibrates

 Severe liver disease
 Gallstones
 Pancreatitis
 Hypersensitivity to the drug
 Pregnancy and breastfeeding
 Severe renal impairment
 Simultaneous use with statins in some cases
Contraindications of fibrates

Niacin (nicotinic acid)
 Niacin, also known as nicotinic acid, is an organic
compound and a form of vitamin B3.
 It can be synthesized by plants and animals from the
amino acid tryptophan.
 Niacin, as a dietary supplement, is used to treat pellagra, a
disease caused by niacin deficiency.
 Niacin is a prescription medication.
 The lipid lowering dose (2-3 g) of
niacin is far excess of the
recommended dietary intake (20
mg) for vitamin functions.

 The activation of the nicotinic acid receptor (GPR109A) on
adipocytes induces a Gi-mediated inhibition of adenylyl
cyclase (AC) activity.
 Reduced activity of adenylyl cyclase results in a decreased
level of cAMP in the adipocytes.
 A critical level of cAMP is necessary for the activation of
protein kinase A (PKA).
 PKA activates hormone-sensitive lipase (HSL) and
adipocyte triglyceride lipase (ATGL) both of which are
necessary for lipolysis.
 Thus reduced activation of HSL and ATGL reduces the
breakdown of TG into FFA and glycerol.
 Thus niacin reduces the availability FFAs to the liver which
in turn reduce the synthesis of the blood-circulating lipids.
Mechanism of action of Niacin

HSL: Hormone sensitive lipase; ATGL: adipocyte triglyceride lipase
Mechanism of action of niacin

Mechanism of action of niacin
The decrease in free fatty acid (FFA) levels induced by
nicotinic acid results in a substrate shortage for hepatic:
 Triglyceride (TG) synthesis and release
 Production of VLDL-C and release

 Niacin also directly inhibits the action of diacylglycerol
acyltransferase 2 (DGAT2) a key enzyme for TG synthesis.
 Niacin increases apolipoprotein A1 levels by inhibiting the
breakdown of this protein, which is a component of HDL-C.
 It also inhibits the hepatic uptake of HDL-cholesterol by
suppressing the production of cholesterol ester transfer
protein (CETP) gene.
 It stimulates the ABCA1 transporter in monocytes and
macrophages and upregulates PPARγ, resulting in reverse
cholesterol transport.
 By other mechanisms niacin reduces clearance of HDL-C
and hence increases serum level of HDL-C.
 Increases HDL-C/LDL-C ratio.
Additional lipid lowering mechanisms of niacin

Additionally nicotinic acid can reduce the progression of
atherosclerosis by direct (lipid-independent) effects on
endothelial and immune cells.
1. Nicotinic acid can reduce the expression of endothelial
adhesion molecules involved in the binding and
recruitment of immune cells.
2. Through the activation of hydroxycarboxylic acid (HCA2)
receptor on monocytes or on macrophages, nicotinic acid
inhibits the recruitment of cells to atherosclerotic lesions.
3. Through the activation of HCA2, nicotinic acid increases
the efflux of free cholesterol (FC) from macrophages. The
cholesterols molecules are taken up by HDL particles.
Lipid-independent antiatherogenic effects of
nicotinic acid

Blood
Lipid-independent antiatherogenic effects of
nicotinic acid

 The bile acid sequestrants are a group of resins used to
bind certain components of bile in the GIT.
 In general, those are classified as hypolipidemic agents,
although they may be used for purposes other than
lowering cholesterol.
 For example, they are also used in the treatment of chronic
diarrhea due to bile acid malabsorption, hyperthiroidism,
and liver cirrhosis.
 Use of these agents as hypolipidemic drugs has decreased
markedly since the introduction of the statins, which are
more effective than bile acid sequestrants.
Bile acid sequestrant resins

 These insoluble, nonabsorbable anion-exchange resins
bind bile acids within the intestines.
 Bile acids are synthesized from cholesterol.
 They disrupt the enterohepatic circulation of bile acids by
combining with bile constituents and thus prevent their
reabsorption from the gut.
 Lowering the bile acid concentration causes hepatocytes to
increase conversion of cholesterol to bile acids.
 Consequently the intracellular cholesterol concentration
decreases in the liver.
 This in turn increases hepatic uptake of cholesterol-
containing LDLc particles from the blood.
Mechanism of action of bile acid sequestrants

Mechanism of action of bile acid sequestrants

Indications:
 These agents have been shown to be safe and effective in
lowering LDL-C especially in patients with moderately
elevated levels, in primary prevention, in young adult men,
and postmenopausal women.
 They are effective in combination with other agents.
Currently available agents:
1. Cholestyramine: 2-8 g by mouth in two daily doses
2. Colestipol: 2-16 g by mouth in one or two daily doses
3. Colesevelam: 625 mg/tablet by mouth in one daily dose
for one week.

Precautions
 These resins are taken just before meals and present
palatability problems in patients.
 Gastrointestinal (GI) intolerance, especially constipation
flatulence, and dyspepsia are frequent.
 Absorption of many other drugs can be affected. Hence
other drugs should be taken 1 h before or 4 hrs after resins.
Adverse effects
In general, they do not have systemic side effects. However,
they may cause problems in the GIT, such as constipation,
diarrhea, bloating, and flatulence. Some patients complain of
the bad taste. They can also reduce the absorption of fat
soluble vitamins.

 Cholesterol absorption inhibitors are a class of compounds
that prevent the uptake of cholesterol from the small
intestine into the circulatory system.
 Most of these molecules are monobactams but show no
antibiotic activity.
 Most commonly used agent is ezetimibe which is used as
an adjunct to diet and statins in hypercholesterolaemia.
 It inhibits absorption of cholesterol from the duodenum by
blocking the transport protein NPC1L1.
 NPC1L1 (Niemann-Pick C1-Like 1) are present in the brush
border of enterocytes and hepatocytes.
Cholesterol absorption inhibitors

Mechanism of action of Ezetimibe

 NPC1L1 protein cycles between the plasma membrane (PM)
and endocytic recycling compartment (ERC).
 The ERC stores cholesterol and NPC1L1.
 When the extracellular cholesterol concentration is high,
cholesterol is incorporated into the cell membrane (PM) and is
sensed by cell surface localized NPC1L1.
 NPC1L1 and cholesterol are then internalized together through
clathrin/AP2-mediated endocytosis and transported along
microfilaments to the ERC in vesicles.
 When the intracellular cholesterol level is low, ERC-localized
NPC1L1 moves back to the PM along microfilaments in order to
absorb cholesterol.
 Ezetimibe hinders the interaction of the NPC1L1/cholesterol
complex with the AP2-clathrin complex.
Mechanism of action of Ezetimide

Results: 1) Reduction of cholesterol incorporation into
chylomicrons and delivery to hepatocytes; 2) increased
synthesis of cholesterol and LDL receptors in hepatocytes;
3) decreased serum LDL and cholesterol levels.
Advantages: Clinically safe; effective; used as
monotherapy in statin-intolerant patients; also used in
combination with statins in statin-tolerant patients for further
reduction of serum LDL and cholesterol.
Because of its high potency compared with resins (a daily
dose of 10 mg), it represents a useful advance as a
substitute for resins as supplementary treatment to statins in
patients with severe dyslipidaemia.
Disadvantages: No effect on TG absorption; a new class
of anti-atherosclerotic drug – long term effect not known.
Ezetimide

Newer drugs for the treatment of dyslipidemia
1. PCSK9 Inhibitors
 PCSK9: proprotein convertase subtilsin-kexin type 9.
 PCSK9 is a serine protease that plays a central role in
cholesterol metabolism in the liver by enhancing the
degradation of LDLRs.
 LDLR can be recycled or degraded in the lysosomal
process after internalization.
 Circulating PCSK9 binds to the LDLRs directing the
LDLRs to the lysosome.
 Once internalized into the lysosome LDLR is degraded in
to smaller peptides and thus the number of LDLR is
reduced in the cell membrane.

Mechanism of action of PCSK9 inhibitors
 By blocking PCSK9, PCSK9 inhibitors can reduce LDLRs
degradation and increase the number of LDLRs, which in
turn enhances LDLRs recycling and reduces the LDL-C
level.
 Binding of PCSK9 to the low density lipoprotein (LDL)
receptor leads to the degradation of LDL receptor at
lysosome.
 PCKS9 inhibitor, a monoclonal antibody against PCKS9,
inhibits the binding of PCSK9 and LDL receptor.
 This binding results in the recycling of LDL receptor and
increased expression of LDL receptor at cell membrane.

Mechanism of action of PCSK9 inhibitors

PCSK9 directed agents under development

Type Mechanism Effect
HMGCR
inhibitor
Reduces cholesterol synthesis leading to upregulation
of LDLR; increases LDLC uptake by the hepatocytes
↓LDLC
Fibrates ↓TG
Niacin ↓LDLC
↑HDLC
Bile acid
resins
↓LDLC
Ezetimibe ↓LDLC
PCSK9
inhibitors
↓LDLC
Summary

Biochemistry: https://www.youtube.com/watch?v=PkKH8lTxvzA
Lipoprotein: https://www.youtube.com/watch?v=llWn7imdHVk
Metabolism-Exo: https://www.youtube.com/watch?v=OJuBBkcgezc
Metabolism-Endo: https://www.youtube.com/watch?v=5GsphYmXDR8
Reverser cholesterol: https://www.youtube.com/watch?v=B-Mgs8cwr2E
Metabolsim-2: https://www.youtube.com/watch?v=9dghtf7Z7fw
Pathology: https://www.youtube.com/watch?v=R6QTiBfzULE
Pharmacology: https://www.youtube.com/watch?v=Of1Aewx-zRM
Metabolism: https://www.youtube.com/watch?v=wQY0xpwqPfQ
https://www.frontiersin.org/articles/10.3389/fphys.2018.00526/full
Helpful links

1.+Antihyperlipidemic+drugs+FrK.pptx

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to 1.+Antihyperlipidemic+drugs+FrK.pptx

Similar to 1.+Antihyperlipidemic+drugs+FrK.pptx (20)

Recently uploaded

Recently uploaded (20)

1.+Antihyperlipidemic+drugs+FrK.pptx