Basic Training Program

RPGLS
THE HUMAN BODY
 Overview of Anatomy &
Physiology

• Anatomy – The study of the structure of body

parts and their relationships to one another.

• Physiology – The study of the function of the

body’s structural machinery.
 Levels of Structural Organization

Smooth muscle cell

2 Cellular level
Cells are made up of molecules

1 Chemical level
Atoms combine to
form molecules

3 Tissue level
Tissues consist of
similar types of
cells

Connective
tissue
4 Organ level
Organs are made up of
different types of tissues
6 Organismal level
The human organism is
made up of many organ
systems
5 Organ system level
Organ systems consist of different
organs that work together closely
Figure 1.1
Levels of Structural Organization
• Chemical – atoms combined to form
molecules
• Cellular – cells are made of molecules
• Tissue – consists of similar types of cells
• Organ – made up of different types of tissues
• Organ system – consists of different organs
that work closely together
• Organismal – made up of the organ systems
Chemical organization
• All forms of matter living or nonliving are made
of limited no. of building blocks called
elements.
• Human body is made of 26 different element.
• C,H,O,&N --------96%
• Ca,P,K,S,Na,Cl,Mg,Fe----3.8%
• Additional 14 trace element—0.2%
What is your body made of?
99% of the mass of the human body:

• oxygen (65%)

• carbon (18.6%)

• hydrogen (9.7%)

• nitrogen (3.2%0

• calcium (1.8%)

• phosphorus (1.0%)
Chemical organization
• Carbohydrate:
– C,H,O—3%(Energy)
• Lipids:
– C,H,O---25%--Protection & energy storage.
• Proteins:
– C,H,O,N---18%--(Structural frame work).
 Molecular Level
– Carbohydrates
• Sugars and starches
– Lipids
• Fats and oils
– Proteins (formed from amino acids)
• Enzymes, hormones, antibodies
• Basis of life
– Nucleic acids (formed from nucleotides)
• DNA, RNA
• Determine what proteins are made
 Cell
◆ The cell is the basic
structural and functional
unit of the body.
◆ About 200 different type
of cells are basic unit of
human body.
• Cytology – study of the
cell
Basic Cell Functions
• Obtain nutrients and oxygen from surrounding
environment
• Perform chemical reactions that provide energy
for the cell
• Eliminate carbon dioxide and other wastes to
surrounding environment
• Synthesize needed cellular components
 Basic Cell Functions
• Reproduction
– Exception - nerve cells and muscle cells
lose their ability to reproduce during their
early development
• Sensing and responding to changes in
surrounding environment
• Control exchange of materials between cell
and its surrounding environment
 Cell
• Cytoplasm : It consists of
all the cellular content in
between plasma
membrane & nucleus.
• Cytosole : Fluid portion.
• Organelles : several type
of organ having specific
shape & function like
Cytoskeleton, Ribosome,
E.R, Golgi complex,
Lysosome,Mitochondria.
 Cell
• Cell Membrane: It is a
selective barrier that
regulates the flow of
materials into and out
the cell.
 Cell
• Cytoskeleton :
Provides a structural
framework for the
cell & gives a
particular shape to
cell. Helps in the
movement of
organelles in side
the cell.
 Cell
• Ribosome :
Ribosome's are site
for protein synthesis.
• Mitochondria : since
they generate most
of the ATP hence
called power house.
 Cell
• Endoplasmic
Reticulum : ER is an
extensive network of
folded membranes
that extends from
nuclear membrane
through out the

– steroid synthesis
– detoxification
– storage
 Cell
• Golgi complex :
– Receives protein from
ER and remakes them
into enzymes in
lysosomes
– Synthesizes
polysaccharides,
glycolipids,
glycoproteins,
lipoproteins, mucous
and secretes many of
them from the cell
 Cell
• Lysosomes :
Lysosome are
membrane enclosed
vesicles that form
from the golgi
complex & contains
60 type of digestive
& hydrolytic enzyme
 Cell
• Nucleus : Contains
most of the cell’s
gene which are
located on
chromosome.
Controls cellular
structure, directs
cellular activity
 Tissue
• Tissues:
– groups of cells which are similar in
structure and which perform common
or related functions.
• Histology:
– the study of tissues.
 Basic kinds of tissues
• Epithelial Tissue Locations: Epithelial tissue
consists of cells arranged in continuous
sheets, in single layer or multiple layers.
– Covers the body
– Lines the cavities, tubes, ducts and blood
vessels inside the body
– Covers the organs inside body cavities

–
Basic kinds of tissues
• Classification: Based on arrangements of cells epithelial
tissue is of three types :
1. Simple epithelial – Single layer-
Filtration,Absorption,Secretion
2. Stratified epithelial- Multiple layer-Protection.
3.Pseudostratified epithelium- one layer but appear as
multiple layer- Secretion & Movement.

Based on shape epithelial tissues can be classified as :

1. Squamous- Flat( Floor like)
2. Cuboidal- Cube like(Hexagoanl)
3. Columnar- Rectangular( Cilliated/ Noncilliated)
4. Transitional- Variable shape
 Connective Tissue
• Connective Tissue:
– Most abundant & widely distributed tissue.
• Connective Tissue Functions:
– Connects, binds and supports structures,
• Tendons, ligaments, etc.
– Protects organs and tissues,
– Major site of energy storage.
– Transports substances (blood).
– Main site for immune response.
 Classification
Embryonic connective tissue:
1. Mesenchyme- found in embryo &
all connective tissue arises from
it.
2. Mucous connective tissue- also
known as wharton’s jelly found
mainly in umblical cord.
 Classification
Mature connective tissue-
Loose connective tissue-
a. Areolar connective- Fibroblast,
Macrophage, Mast cell.
b. Adipose tissue- stores fat.
c. Reticular tissue- forms supporting
network.
 Classification
Dense connective tissue-
Dense regular (Parallel pattern)- Tendons & Most
ligament.

Dense irregular (sheet pattern)- Pericardium,

dermis, perichondrium (membrane surrounding
cartilage), periosteum (membrane surrounding
bone).

Elastic connective tissue- strong & can recoil to

its original shape. Lungs tissue, arteries.
 Classification
Cartilage – dense network of collagen fibres. it
has ability to assume its original shape after
deformation.
Hyaline cartilage- it is found at the end of large
bones,larynx,trachea.provides flexibility,
support,& smooth surface for movement.
Fibrocatilage - knee pads. Support & fusion.
Elastic cartilage – gives support & maintains
shape.
Bone & blood is also a type of connective tissue.
 Muscle Tissue
• Muscle Tissue:
– Muscle tissue consists of fibers that are
specialized for contraction. It provides motion &
maintenance of posture.
– Skeletal muscle tissue is attached to bones & its
action is voluntary.
– Cardiac muscle tissue forms most of the heart & its
action is involuntary.
• Muscle Tissue Functions:
– Movement
– Maintains posture
– Produces heat
– Pumps blood
– Peristalsis
 Nervous Tissue
• Nervous Tissue:
– Main component of the nervous
system,
ie., brain, spinal cord & nerves.
• Nervous Tissue Functions:
– Regulates & controls body functions
– Generates & transmits nerve impulses
– Supports, insulates and protects
impulse generating neurons.
 Organs

• Two or more types of primary tissue

• Organized to perform a particular
function
S0ME OF THE MAJOR ORGANS IN THE
HUMAN BODY
BRAIN

THE LUNGS

LIVER
THE STOMACH

THE BLADDER
 Nervous System
• Fast-acting control system
• Responds to internal and external changes
 Integumentary System
• Forms external body
covering
• Protects deeper tissues
from injury
• Synthesizes vitamin D
• Site of cutaneous
receptors
(pain, pressure, etc.) and
sweat
and oil glands
 Skeletal System
• Protects and supports
body organs
• Provides a framework for
muscles
• Blood cells formed within
bones
• Stores minerals
 Muscular System

• Locomotion
• Facial expression
• Maintains posture
• Produces heat
 Endocrine System

• Glands secrete
hormones that
regulate:
– Growth
– Reproduction
– Nutrient use
 Cardiovascular System
• Blood vessels
transport blood
– Carries oxygen and
carbon dioxide
– Also carries nutrients
and wastes
• Heart pumps blood
Lymphatic System/Immunity
• Disposes of debris in
the lymphatic system
• Houses white blood
cells (lymphocytes)
• Mounts attack against
foreign substances in
the body.
 Respiratory System
• Keeps blood supplied
with oxygen
• Removes carbon dioxide
• Gas exchange occurs
through walls of air sacs
in the lungs
 Digestive System
• Breaks down food into
absorbable units
• Indigestible foodstuffs
eliminated as feces
 Urinary System
• Eliminates
nitrogenous wastes
• Regulates water,
electrolyte, and acid-
base balance
 Male & Female Reproductive Systems
• Overall function is to
produce offspring
• Testes produce
sperm and male sex
hormones
• Ovaries produce
eggs and female
sex hormones
• Mammary glands
produce milk
Orientation and Directional
Terms
Orientation and Directional Terms
Orientation and Directional Terms
 LIFE PROCESSES

1. METABOLISM is the sum of all chemical reactions

in the body. Two major divisions:CATABOLISM,
providing the energy needed to sustain life through
the breaking down of food materials, and
ANABOLISM, which uses the energy from
catabolism to make numerous substances.

2. RESPONSIVENESS is the ability to detect and

respond to changes in the internal and /or external
environment.
 Homeostasis
Homeostasis is an (ideal or virtual) state of
equilibrium, in which all body systems are working
and interacting in an appropriate way to fulfill all the
needs of the person and/or the body.

When homeostasis is interrupted (e.g. by response

to a stressor), the body tries to restore it by
adjusting one or more physiological processes.
This stress-adaption mechanism includes
activation of the Hypothalamic-Pitauitary-Andrenal
Axis (HPA Axis) with the autonomous nervous
system and endocrine reactions of the body.
 Homeostasis
• How we keep things the same
– First, we need receptors to detect
when things such as temperature
change.
– Then we need a processing centre to
receive this information and coordinate
our response.
– Finally, we need effectors to produce
a response that ensures our body
Basics of Pharmacology
 Pharmacology

Pharmacology is a science that deals with the

mechanism of action of drugs, their uses and
the adverse effects of the drugs
What is a drug
A drug is a chemical substance that is used in
one of the following ways
❋ To prevent disease (vaccines)
❋ To diagnose disease (contrast media used in
X-rays)
❋ To control disease (such as anti-diabetic drugs)
❋ To cure diseases(such as an antibiotic)
Routes of administration of
drugs

❋ Oral
❋ Parenteral
❋ Local
Oral administration

Drugs given by mouth, to be swallowed

Some of the formulations used include
 Tablets
 Capsules
 Syrups and suspension
 Drops
Tablet formulations

 Plain release tablets

 Dispersible tablets
 Sugar coated tablets
 Enteric coated tablets
 Sustained release tablets
Oral administration advantages

 It is simple to use
 Can be done at home
 Does not require any medical assistance
 can be taken at a convenient time
 painless and safe
Oral drugs disadvantages

 Absorption can vary among patients

 Variability due to food and diseases of
the GI tract
 Cannot be used in unconscious
patients/uncooperative patients
 Large quantities of drugs cannot be used
 Taste and palatability limitations
 Special problems in vomiting diarrhea
 Dose can be missed or alternatively,
extra dosages may be taken
ROUTE OF DRUGS ADMINISTRATION
(Contd.)
The Parenteral routes are :
 Inhalation
 Injections

 Trans-cutaneous
 Trans-mucosal
 INJECTIONS
 Intra-dermal
 Subcutaneous
 Intramuscular
 Intravenous
 Intra-arterial
 Intra-thecal
 Intra-peritoneal
 Intra-medullary
 Intra-articular and intra-lesional
 Other Pharmaceutical Preparations

• Creams - o/w
• Ointments - w/o
• Gels, lotions
• Vaginal/rectal suppositories
• Nasal drops/aerosols
• Inhalers/sublingual
• Otic/opthalmic preparations
Injectable drugs – advantages

 Useful if drug is poorly absorbed orally

 If drug is destroyed by acid in the stomach
 Large dosed are needed
 Useful in unconscious patients/presence of
vomiting
 Rapid onset required in an emergency
 If the drug causes severe gastro-intestinal
irritation
Injectable drugs - disadvantages

 Needs medical assistance

 Painful
 Complications can occur
 Transfer of infections, if syringes and needles are
not sterilized
 Costlier
 Two ways to enter circulation

IM/IV
Liver

Oral Systemic circulation

Rest of the body

Main aspects of Pharmacology

Pharmacokinetics
❋ Pharmacokinetics is the detailed study of how
the body absorbs, distributes, metabolizes and
excretes a drug
Pharmacodynamics
❋ Pharmacodynamics is the detailed study of
effects of the drugs on the body
 Dissolution
• Dissolution is the amount of drug substance
that goes into solution per unit time under
standard conditions of solid/liquid interface,
temperature, and solvent composition.
 Dissolution
• Drug Absorption from a solid oral dosage depends
on the release of the drug substance from the drug
product (dissolution), the solubility, and the
permeability across the gastrointestinal tract. The
first aspect of the tablets is determined by the
manufacture of the product. The next two aspects
are determined by the properties of the active
pharmaceutical. All solid oral dosage forms can be
characterized according to these three properties.
 PHARMACOKINETICS

WHAT BODY DOES TO THE DRUG.

• DEALS WITH
– ABSORPTION
– DISTRIBUTION
– METABOLISM/BIOTRANSFORMATION
– EXCRETION
Absorption

The transfer of drug from its site of

administration to bloodstream is
called absorption

Site

Blood stream
Process of Absorption
• In order for a drug to have its effect after oral
administration it must go into solution and then
diffuse through the gut wall into the body. The first
step in that process is the disintegration of the
dosage form followed by dissolution of the active
ingredient.
 Process of Absorption
• One way to increase dissolution rate of poorly
soluble drugs is to increase the surface available
for dissolution. This is done by reducing particle
size or by dividing the dosage form into two smaller
tablets or capsules, with a larger combined surface
area. Other ways include increasing the
disintegration rate and deaggregation.
Where are oral drugs absorbed

While some drugs are absorbed in the stomach,

most drugs are absorbed in the small intestines.
Factors affecting absorption

 Chemical nature of drugs

 Molecular weight
 Solubility
 Gastric motility
 pH of absorbing site
 Area of absorbing surface
 Blood flow first pass metabolism
 Ingestion with or without food
Bioavailability
Fraction of drug in unchanged from that reaches
the systemic circulation after undergoing first pass
metabolism

Administration
Absorption
Portal circulation

Liver

First pass metabolism

Bioavailability
Systemic circulation
 Distribution

It is a reversible process by which a drug leaves

the systemic circulation and enters the
extracellular fluid or inside the cell
Compartments of distribution

 Intravascular (within the blood vessels)

 Intracellular (inside the cells)
 Extracellular (outside the cells)
 Transcellular (in fluids formed in body like CSF, bile)
 Protein binding

Some drugs can circulate in blood only if they

are combined with a protein molecule in the
blood. The percentage of drug that is bound to
a protein is called protein bound, while the rest
is termed as free drug.
Metabolism or Biotransformation
Most drugs are metabolized in the Liver

Metabolites
The end result of the metabolic process is termed
a metabolite. A metabolite is usually inactive, but
some metabolites retain some activity of the
parent compound.
Need of Metabolism

Metabolism prepares the drug for excretions from

the body through urine or bile. Drugs that are
soluble in water (hydrophilic) can easily pass into
the urine. But drugs that do not dissolve in water
(hydrophobic) need to be first converted into water
soluble metabolites before excretion can begin
Metabolism Types
Phase I reactions
Phase reactions are relatively simple reactions like
Oxidation, reductions and hydrolysis. They require
certain enzymes found in liver cells called CYP-450
enzymes
Phase II reactions
Phase II reactions are complex reaction also called
as conjugation reactions. They are required if
Phase I reactions cannot adequately convert drugs
into water-soluble forms.
Drug Interaction Drug
Interaction
• Drug interactions involving the cytochrome p450 system
are common
• Result from either enzyme inhibition or induction
• Enzyme inhibition involves competition with another
drug for enzyme binding sites
• Enzyme induction occurs when one drug stimulates
production of more enzymatic metabolism capacity
• Depends upon
- drug half-lives
- the rate of enzyme production, and
- individual genetic variations
 Common inducers and
inhibitors
• Inducers : e.g. Phenobarbital, Phenytoin,
Rifampin ( for Calcium Channel Blockers,
Ethinyl estradiol)

• Inhibitors : e.g. Azole antifungals

(esp.ketoconazole and itraconazole),
Cimetadine, Clarithromycin,
erythromycin and Protease inhibitors
( for the same drugs mentioned above)
Elimination or Excretion

Drugs are eliminated mainly through urine and

bile (stools). The other routes of excretion are
 Milk
 Sweat
 Lungs
Elimination kinetics-first
order

Most drugs follow first order kinetics of

elimination where a constant fraction of drug is
eliminated per unit fraction. The rate of
elimination is directly proportional to the plasma
concentration of drug. At higher concentrations
of drug, the amount of drug eliminated is more,
while at lower concentrations of drug: the
amount of drug eliminated is lower.
Elimination kinetics - zero
order

Few drugs follow zero order kinetics of elimination

where the rate of elimination is constant per unit
time. The amount of drug eliminated per unit time
is same, irrespective of the plasma concentration
of the drug
Cmax and Tmax
❋ If a chart of drug concentration versus time is
plotted, It would look like this
❋ Cmax is the highest concentration reached by
the drug while Tmax is the time required to
achieve the highest concentration.
Cmax

C
o
n
c

T max time
 Half life
It is the time needed for the plasma
concentration to fall to half the C max value

40 mcg

30mcg

20 mcg

10 mcg

0 1 2 3 4 5 6 7 8
 PHARMACODYNAMICS

WHAT DRUG DOES TO THE BODY

DRUG TARGETS
❋ Receptors
❋ Enzymes
❋ Nucleic acids
❋ Carrier molecules
❋ Ion channels
Receptors

Receptors are specialized target molecules,

present on cell surface or intracellularly, that
bind to drug and mediate pharmacological
actions.
Drug + receptor Drug-receptor complex

Effect
 Drug receptors

Many drugs attach to a receptors to produce its

effect. It is postulated that a drug molecule first
combines with its specific receptor protein on
the cell membrane to form a drug receptor
complex. The drug receptor complex than
activates cellular processes inside the cell that
ultimately causes the effects of the drug
 MIC90 OF A DRUG

MIC (MINIMUM INHIBITORY CONCENTRATION)

of a drug is the minimum concentration that is
required to inhibit at least 90% of the

microorganisms
Efficacy of a drug

The efficacy of drug is dependent on the

number of drug receptor complexes formed.
More the complexes formed more is the
efficacy
Potency of a drug

 Potency determines how much drug is required

to produce a given response, lower the dose
required more potent is the drug

 A more potent drug does not necessarily mean

that it is also more efficacious
 General principles of drug action

Dose-response quantitation

Potency of drug

100
Drug A Drug B
Biological effect

50 Drug A is more
potent than B,
but both have
same efficacy

Log drug concentration

Agonist drug
 Good affinity (binding capacity to receptor)
 Good intrinsic activity (the ability to cause changes in a cell)

Antagonistic drugs
 Good affinity
 Poor intrinsic activity
Antagonism can be reversible and irreversible and may be for
the same receptor (competitive) nor different receptor (non-
competitive)
Therapeutic window

Therapeutic window is a theoretical concept

calculated as the difference between the
concentration of a drug needed to cause side
effects and the concentration needed for drug
activity
 Tolerance

Certain drugs after prolonged use begin to show

reduced therapeutic benefits. The reason is that
the receptor on which the drug acts have reduced
in their number. Reduced receptors means that
there will be less drug receptor complexes formed
Drug dependency or Addiction

Some drugs particularly acting on the nervous

system cannot be suddenly stopped. On stopping
the drug patients develop physical symptoms like
raised blood pressure, tachycardia, sweating as
well irritation or violent behavior. This is because
patients develop dependency on the drug.
 FACTORS MODIFYING THE
EFFECTS OF A DRUG
 Body weight
 Age

 Sex

 Diet and environment

 Route of administration

 Emotional factors

 Genetic factors
 FACTORS MODIFYING THE
EFFECTS OF A DRUG (Contd.)
 Presence of disease
 Cumulation

 Other drugs and chemicals

 Additive effect

 Synergism

 Antagonism
 Additive Effect
1+1=2

When the total pharmacological action of

Two or more drugs administered together
Is equivalent to the summation of their
individual pharmacological actions
Eg: ephedrine + aminophylline in treatment
of bronchial asthma

Pharmacology & Pharmacotherapeutics, Satoskar;1997: pg

 Synergistic effect
1 + 1=X (>2)

When the total pharmacological action of

two or more drugs administered together
is more than the summation of their
individual pharmacological actions
Eg: Cotrimoxazole(sulphamethoxazole
+Trimethoprim) Septran

Pharmacology & Pharmacotherapeutics, Satoskar;1997: pg 45

Drug dosing

 OD - Once daily
 BD - twice daily
 TD - Thrice daily
 QD - Four times daily
 SOS - During emergency use
 HS - At bed time
 Stat - immediately
 ADVERSE DRUG REACTIONS
(ADR)
Any undesirable and unwanted effect that goes
along with the therapeutic effects of the drug
 Side effects

 Untoward effects

 Toxic effects

 Allergic / hypersensitivity effects

ADVERSE DRUG REACTIONS

• Side effects: occur at normal therapeutic

doses and are expected
• Untoward effects occur at therapeutic
doses and are unexpected
• Toxic effects occur at high doses and /or
manifest when the drug is used for a longer
duration
Clinical trials
Any investigation in humans
 To discover or verify the clinical,
pharmacological and/or other
pharmacodynamic effects of an
investigational product (s)
 To identify any adverse reactions,
to an
un investigational products
 To study absorption, distribution,
metabolism, and excretion of an
investigational product
 Clinical trials
PHASE OF A CLINICAL TRIAL
 Phase I (max tolerated dose & safety, comprises of
small no. of patients)
 Phase II ( therapeutic effect )

 Phase III (comparative study with the current standard

therapy, comprises of large no. of patients)
 Phase IV / Postmarketing surveillance (PMS)
continuing evaluation that takes place after FDA approval,
when the drug or treatment procedure is already on the
market and available for general use.
 Various Terminologies

• Bioavailability: This term means the rate and

extent to which the active ingredient or active
moiety is absorbed from a drug product and
becomes available at the site of action.

• Bioequivalent Drug Products: This term

describes pharmaceutically equivalent products
that display comparable bioavailability when
studied under similar experimental conditions.
 Various Terminologies
• Pharmaceutical Equivalents - Drug products are
considered pharmaceutical equivalents if they contain
the same active ingredient in the same dosage form
and are identical in strength or concentration.
• Pharmaceutical Alternatives - Drug products that
contain the same therapeutic moiety, but are different
slats, esters, or complexes of that moiety or are
different dosage forms.
• Therapeutic Equivalents - Drug products which are
pharmaceutical equivalents and are expected to have
the same clinical effect and safety profile when
administered to patients under conditions specified in
the labeling.
 Bioequivalence

Means absence of a significant difference in

the rate and extent to which the active
ingredient in different pharmaceutical
alternatives becomes available at the site of
drug action when administered at the same
dose under similar conditions.
Pharmaceutical alternatives

Drug products that contain the identical

therapeutic moiety pr its precursor, but not
necessarily in the same amount or dosage
form or as the same salt or ester.
THANK YOU
 What is C.V system?
Cardiovascular system consist of :
Cardio + Vascular + system

Heart + Blood vessels

A system which consist of heart & blood

vessels and forms a system.
What C.V.system does?
– The heart pumps blood
– Blood vessels allow blood to circulate to all
parts of the body

Hence this system consist of

Blood + Blood vessels + Heart

 Blood
Blood carried within cardiovascular system usually
grouped with “connective tissue”.

Blood derived from cells in bone marrow of long &

flat bones.

A person has 4 to 6 liters of blood, 38% to 48% is

composed of the various blood cells, &
remaining 52% to 62% of the blood volume is
plasma, the liquid portion of blood.
Blood-Functions

Transport – oxygen, CO 2, cellular waste, nutrients,

hormones, enzymes.

Protection – immune response (white blood cells), blood

clotting.

Regulation – water balance, chemical levels, pH, body

temperature.
Composition of blood
 BLOOD COMPONENTS

•Cells (45%)

•Plasma (about 55%)

Plasma :
About 90% of plasma is simple water, remaining10%
= important proteins (3 main types)

•Albumins – promote water retention ( thus

maintaining normal blood volume & pressure)
•Fibrinogen – essential for blood clotting
•Globulins –Transport fat soluble material &lipid.
 BLOOD CELLS
• ERYTHROCYTES (RBC)
• LEUKOCYTES (WBC)
• PLATELETS
Blood vessels
 Types of blood vessels

• Artery
• Vein
• capillary
Blood vessels
 Blood Vessels: Anatomy
• Three layers (tunics)
• Tunica intima
• Endothelium
• Tunica media
• Smooth muscle
• Controlled by sympathetic nervous
system
• Tunica externa
• Mostly fibrous connective tissue
 Artery/Vein differences

Arteries (aa.) Veins (vv.)

Direction of Blood Away from Heart Blood to Heart
flow

Pressure Higher Lower

Walls THICKER: Tunica media THINNER: Tunica

thicker than tunica externa thicker than
externa tunica media
Lumen Smaller Larger

Valves No valves Valves (see next)

The Healthy Heart
 The Heart Wall

• Components of the heart wall include:

– Pericardium
– Myocardium
– Endocardium
 Heart

Right atrium Left atrium

Left
ventricle
Right ventricle

Heart chambers
Separation of chambers

• Interatrial septum
separates atria
• Intraventricular
septum separates
ventricles
• Both composed of
connective tissue as
well as muscle
 A-V Valves

• Tricuspid valve: Between

R atrium and R ventricle
• Bicuspid (mitral) valve:
Between L atrium and L
ventricle
Semilunar valves

• Pulmonary valve:
Between right ventricle
and pulmonary artery
• Aortic valve: Between left
ventricle and aorta
Path of blood through the heart
Coronary artery circulation
 Coronary Circulation
• Blood in the heart chambers does not nourish the
myocardium
• The heart has its own nourishing circulatory system
• Coronary arteries
• Cardiac veins
• Blood empties into the right atrium via the
coronary sinus

Slide
 Intrinsic Cardiac Conduction
System

75/min

40-60/min

30/min
 Intrinsic Conduction System
Function: initiate & distribute impulses so heart depolarizes
contracts in orderly manner from atria to ventricles .

SA node

AV node
Bundle of His

Bundle Branches

Purkinje fibers
 Extrinsic Control of Heartbeat
• A cardiac control center in the medulla
oblongata speeds up or slows down the heart
rate by way of the autonomic nervous system
branches.
– Sympathetic Stimulates heart rate

– Parasympathetic Slows heart rate

– Vasomotor - changes diameter of vessels.

 Heamodynamics
• Cardiac Cycle : All events associated with a
single heart beat including atrial systole &
diastole followed by ventricular systole &
diastole.

• HEART BEAT : The process of one complete

systole & one complete diastole is considered
as one beat. The time required for one beat is
0.8 sec. in one beat atrial systole takes 0.1 sec.,
ventricle systole takes 0.3sec & complete
cardiac diastole takes 0.4 sec.
 Heamodynamics
HEART RATE : The number of heart beat per
minute.
Heart rate – 60*0.8= 72-75 beat/ minute

Stroke Volume - amount of blood pumped out

of a ventricle each beat. Average resting
stroke volume = 70 ml.
(SV) = EDV - ESV
Blood Volume - quantity of blood in
cardiovascular system. Varies from 4-5 L. in
females to 5-6 L. in males
 Heamodynamics

• Systolic - Systole, or
contraction, of the heart is
initiated by the electrical
cells of the sinoatrial
node, peak arterial
pressure. Averages about
120 mm Hg in healthy
adults.
• Diastolic - Cardiac
Diastole is the period of
time when the heart
relaxes after contraction
in preparation for refilling
with circulating blood..
Averages between 70 -
80 mm Hg in healthy
adults.
 Heamodynamics
• VENOUS RETURN : The amount of blood reaching
back to the heart per minute.

• PRELOAD : The tension of ventricular myocardium at

the end of diastole.

• AFTERLOAD : The tension generated by ventricular

myocardium to pump the blood against vascular
resistance.
• Bradycardia - Heart beat less than 60/minute.
• Tachycardia - Heart beat more than 100/minute.
Left Ventricular Volumes - Definitions

End Diastolic Volume (EDV):Volume at the end of

diastole (end of ventricular filling).
EDV = 120ML

End Systolic Volume (ESV): Volume at the end of

systole (end of ventricular contraction)
ESV = 50ML

Ejection Fraction : The fraction of the blood ejected

during each contraction is called ejection fraction. (EF)
= EDV-ESV/ EDV = SV/EDV *100

Left ventricular norm for EF at Rest: approximately 62%

Left Ventricular norms for Max Exercise: approximately 80%
Pa
 Cardiac Output

Cardiac Output - the amount of blood pumped

by a ventricle per minute. Units may be in milliliters
or Liters per minute.
CO = SV * HR
Factors affecting C.O
• Venous Return
• Force of Contraction
• Frequency of heart beat
• Blood volume
• P.R
 Peripheral Resistance

• P.R --It represents the resistance to the

passage of blood through the arteries
especially in arterioles.

• Velocity of blood
• Viscosity of blood
• Elasticity of vessel walls
• Diameter of vessel
 The Electrocardiogram

• An electrocardiogram (ECG) is a recording

of the electrical changes that occur in the
myocardium during a cardiac cycle.

• .
 ECG Deflection Waves

(Pacemaker) Atrial repolarization

 ECG Deflection Waves
60 seconds ÷ 0.8 seconds = resting heart rate of 75
beats/minute

1st Degree
Heart
Block = P-
Q interval
longer
than 0.2
seconds.
 ECG Deflection Wave
Irregularities

Enlarged QRS =

Hypertrophy of
ventricles
 ECG Deflection Wave
Irregularities

Prolonged
QT Interval
=
Repolarization
abnormalities
increase
chances of
ventricular
arrhythmias.
 ECG Deflection Wave
Irregularities

Elevated
T wave :
Hyperkalemia
 ECG Deflection Wave Irregularities

Flat T
wave :
Hypokalemia
or ischemia
 Blood Pressure
“Blood pressure (BP) is the
pressure (force per unit area)
exerted by circulating blood on the
walls of blood vessels”

B.P = CO*PR
 Blood Pressure
 Measurement
 Arterial pressure is most commonly
measured via a sphygmomanometer.
 BP is always measured in the ratio of
systole vs diastole.
Units
 The predominantly used unit for blood
pressure measurement is mmHg (millimeter
of mercury).

 BP = Systole mm/Hg / Diastole mm/Hg

 BP = 120 mm/Hg / 80 mm/Hg
 Factors influencing blood
pressure

Blood Pressure = Blood Volume × Peripheral Resistance

• Blood volume loss due to injuries, hemorrhages, use of diuretics,

etc. = BP

• Blood volume increases due to increased

water retention from increased ADH
production, IVs or transfusions = BP
 Factors influencing blood pressure

Blood Pressure = CO × Peripheral Resistance

Cardiac Output = circulating blood volume

Cardiac Output = Heart Rate × Stroke Volume

Increased heart rate caused by the release of epinephrine

into blood by the adrenal glands = increased cardiac
output, which increases circulating blood volume, to
increase blood pressure.
 Factors influencing blood pressure

Blood Pressure = C.O × Peripheral Resistance

Peripheral Resistance affected by:
•blood viscosity (thickness)
•diameter of vessels (vasoconstriction/vasodilation)

Vasoconstriction = diameter = resistance = BP

Vasodilation = diameter = resistance = BP

•elasticity of arterial walls

Elastic Arterial Walls = BP

 How does body regulate the
Blood Pressure?

• In a normal healthy person BP may

increase or decrease according to need or
due to the above factors. But then it is
brought back to normal. This regulation of
blood pressure is done by two systems of
the body -
– Nervous System
– Renin Angiotensin Aldosterone System or
RAAS.
 Homeostatic Blood Pressure
Regulation Mechanisms
• Medullary Reflex Centers:

– Cardio acceleratory - increases heart rate

– Cardio inhibitory - decreases heart rate

– Vasomotor - changes diameter of vessels

 Renin Angiotensin Aldosterone System

Angiotensinogen

Renin
(Kidney)

Angiotensin I
ACE
(Lungs)

Aldosterone
Angiotensin II (adrenal gland)
Kidney-
Water & Na
Aldosterone Retention
Acts on MR Albuminuria
AT-2 AT-1
Vasoconstriction
Vasodilatation
Apoptosis ↑ Blood Pressure
Wound Healing
 HYPERTENSION

Based on the seventh Report of Joint National

Committee on Prevention, Detection, Evaluation
& Treatment of High Blood Pressure (JNC 7),
2003, Hypertension is defined as :-

“persistent rise of arterial blood pressure more

than 140mm/hg of systolic & 90mm/hg of
diastolic”. Any reading higher than these values
will be considered as hypertension
 CLASSIFICATION OF HTN

BP SBP mm/hg DBP mm/hg

Classification

Normal 120 80
Pre hypertension 120-139 80-89

Stage-1 140-159 90-99

Hypertension
Stage-2 More than 160 More than 100
Hypertension
 Types of hypertension

Hypertension is broadly classified as of two types :

1.Primary HTN/ Essential HTN- When the exact
cause is not known, it is called essential
hypertension.
However the risk factors even for primary HTN are :
 Excessive salt intake,
 Stressful life style,
 sedentary life style,
 Obesity,
 alcohol intake,
 Cigarette smoking.
 TYPES OF HYPERTENSION

Secondary HTN- secondary HTN is the

condition of increased blood pressure which
may be because of some disorder like vascular
disorder, renal disorder, endocrine disorder, or it
may be induced by drugs & pregnancy.
 CAUSE OF HYPERTENSION
Physiological mechanisms involved in
development of essential hypertension:
Cardiac output
Peripheral resistance
Renin-angiotensin-aldosterone system
Autonomic nervous system

Other factors:
Bradykinin
Endothelin
EDRF or nitric oxide
ANP (atrial natriuretic peptide)
Low birth weight
 Renin Angiotensin Aldosterone System
Brain-Stroke
Angiotensinogen
Heart-

Renin Fibrosis

(Kidney)
LVMI

Angiotensin I BV-
ACE Endothelial
(Lungs) dysfunction
Arterial
stiffness
Aldosterone
Angiotensin II (adrenal gland)
Kidney-
Water & Na
Aldosterone Retention
Acts on MR Albuminuria
AT-2 AT-1
Vasoconstriction
Vasodilatation
Apoptosis ↑ Blood Pressure
Wound Healing
 Other factors
Bradykinin : Bradykinin is a potent vasodilator that is
inactivated by angiotensin converting enzyme.
Endothelin : Endothelin is a powerful, vascular, endothelial
vasoconstrictor, which may produce a salt sensitive rise in blood
pressure. It also activates local renin-angiotensin systems.
Endothelial derived relaxant factor : EDRF now
known to be nitric oxide, is produced by arterial and venous
endothelium and causes vasodilatation.

Atrial natriuretic peptide: ANP is a hormone

secreted from the atria of the heart in response to increased
blood volume. Its effect is to increase sodium and water
excretion from the kidney as a sort of natural diuretic. A defect
in this system may cause fluid retention and hypertension .
Effects of High Blood Pressure
on Your Body

• Hardening of the arteries

• Stroke
• Heart attack
• Kidney damage
• Blindness
 What are the complications of
HYPERTENSION?

• Hypertension is called a silent killer as it is very difficult to

detect. It is generally detected during a routine check up. But
hypertension has serious complications which are chronic
and life threatening.
• The most common target organs damaged are -
• Heart and blood vessels, leading to -
– Ischemic heart Disease (atherosclerosis)
– Left Ventricular Hypertrophy
– Heart Failure
– Arrhythmia
– Peripheral vascular disease
• Kidney (Nephropathy) - May lead to kidney (renal) failure.
• Brain - May lead to stroke.
• Eye (Retinopathy) - May lead to blindness.
 COMPLICATION OF HTN
Micro vascular complication :
Renal disease

Autonomic neuropathy : urinary incontinence, orthostatic

hypotension.

Sexual dysfunction : hypertension & antihypertensive

therapies may contribute to sexual dysfunction in
diabetes.

Orthostatic hypotension : supine hypertension with

orthostatic hypotension can occur in person with
diabetes because of autonomic dysfunction.

Eye disease : hypertension can cause glaucoma, diabetic

retinopathy & potential blindness.
 COMPLICATION OF HTN

Macro vascular complication :

Cardiac disease : HTN can cause coronary artery
disease, CHF & Cardiomyopathy.

Cerebrovascular disease : HTN increase the risk

of stroke in diabetic patients.

Peripheral vascular disease : HTN increases the

risk of foot ulcer & amputation in patients with
diabetes.
 Controlling Your Blood
Pressure
• Lifestyle Changes
– Healthy eating plan
– Limit sodium
– Achieve a healthy
weight
– Exercise/physical
activity
• even without
weight loss
 Controlling Your Blood
Pressure

• Lifestyle Changes
– Don’t smoke
– Limit alcohol
– Manage stress
 Follow a Healthy Eating Plan

• Eat more fruits,

vegetables, low-fat dairy
foods
• Include whole grains,
poultry, fish and nuts
• Eat less fat, red meat,
sweets and sugared
beverages
 Limit Sodium and Salt

• Research shows that eating less

sodium and salt lowers blood pressure
• Lower your sodium intake by:
– Eating out less often
– Buying fresh, frozen or unsalted canned
foods
– Choosing foods with less than 400
mg/serving
– Buying low- or reduced-sodium, or no salt
added foods
– Using less salt
 Get Enough Potassium

• Potassium helps lower blood pressure

– Helps balance the amount of sodium in
your body
– If you don’t get enough potassium, you
can accumulate too much sodium
• Foods high in potassium include:
– Fruits, vegetables, dairy foods, and fish
 Lose Weight if Overweight

• Bigger people need

more blood to supply
nutrients to the body
• Losing even 10 pounds
can lower blood
pressure
 Be Physically Active

• Inactivity increases your

risk of being overweight
• Heart muscles have to
work harder with each
contraction, increasing
the force on the arteries
• Walking 30 minutes a day
helps lower blood
pressure
 Stop Smoking

• Smoking damages
blood vessel walls and
causes early hardening
of the arteries
• Nicotine narrows your
blood vessels and
forces your heart to
work harder
 Limit Alcohol

• Heavy drinking (3 or more

drinks/day) can damage your
heart muscle
• Cutting back to a moderate
level of drinking can lower your
blood pressure
– no more than 2 drinks a day
for men
– no more than 1 drink a day
for women
 Blood Pressure Medications
• Lower blood pressure in
many different ways
• More than one type may
be needed
– diuretics
– beta-blockers
– ACE-inhibitors
– calcium channel
blockers
 ISCHEMIC HEART DISEASE
• Ischemic (lack of blood supply) heart disease (IHD)
OR Coronary artery disease (CAD) or coronary
heart disease (CHD) occurs due to obstruction to
the blood flow to the heart muscles.

• Causes of obstruction -
– Atheroma - Deposition of fatty materials in the walls of the
arteries
– Thrombosis - Formation of a clot.
– Spasm - Sudden constriction of a portion or multiple
portion of artery
– Embolism - A moving clot or atheroma.
 Symptoms of IHD
• Heartburn,
• Nausea,
• Vomiting,
• Shortness of breath, and
• Heavy sweating.

• What are the most common

presentations of IHD?
– 1. Angina Pectoris.
– 2. Acute Myocardial Infarction (heart attack)
 What is angina?
Angina is chest pain or discomfort that occurs
when an area of your heart muscle doesn’t get
enough oxygen-rich blood.
Angina may feel like pressure or squeezing in
your chest.
The pain may occur in
shoulders,arms,neck,jaw or back.
 Types of Angina
Angina is of three types:
1. Stable angina:
1. This is the most common type.
2. It occurs when heart is working harder than usual.
3. The pain usually goes away in a few minute after taking rest.
4. It indicates a heart attack more likely in future.

Factors which triggers stable angina:

1. Physical exertion is the most common one.
2. Emotional stress
3. Heavy meals
4. Smoking
 Types of Angina
Unstable angina:
1. It occurs with or without exertion. Often occurs at rest.
2. Comes as a surprise.
3. Is more severe & lasts longer ( as long as 30 min.)
4. It occurs as the moving blood clot partially or totally blocks
an artery.
5. The pain usually doesn’t goes away by rest or medication.
6. It is a sign that a heart attack may happen soon.

.
 Types of Angina
Variant or Prinzmetal’s angina:

1. It is rare. It usually occurs at rest (midnight or,

early morning).
2. The pain can be severe.
3.It occurs because of coronary spasm.
4. This may occur in the patient with or without CAD
 Who is at risk for Angina?
Angina is a symptom of an underlying heart condition usually
CAD. So if a person is at risk for CAD he is also at risk for
angina.
risk factor angina include :
1. Unhealthy cholesterol level.
2. High BP
3. Cigarette smoking
4. Insulin resistance
5. Overweight
6. Lack of physical activity
7. Age
8. Family history

Treatment

The common medicines include, aspirin, beta blockers,

nitroglycerine, calcium channel blockers, isosorbide mononitrate
and nicorandil.
Answer the following?
• What is angina?
• What are the different types of angina?
• What is prinzmetal angina?
• What is unstable angina?
• Who is at risk for Angina?
Factors that may initiate the process of
atherosclerosis are-
1.High LDL level
2.Prolonged high BP
3.Carbon monoxide in cigarette smoking
4.High glucose level in DM
 When Platelets, lipids & other
At injury site cholesterol
Component of blood comes in
& triglyceride collects
Contact with cholesterol they stimulates
The smooth cell in arterial wall to
Proliferate & forms a plaque.

Additional damage is that a plaque

As an atherosclerotic plaque May provide roughened surface that
Develops & enlarges it Attracts platelet & initiate clot formation
Obstruct the blood flow$$ & further obstructing the blood flow

Moreover a thrombus may An emboli floats in the blood freely

dislodge to become an emboli & obstruct blod flow in other vessels
 Development of
Coronary Atherosclerosis:
 Coronary Artery Disease
• Atherosclerosis
– Define: thickness and hardening of the arteries
caused by deposits of fat and fibrin which harden.
– Leads to decreased lumen and decreased blood flow
and ischemia and death of the tissue
• Arteriosclerosis
– Define: loss of elasticity and abnormal thickening or
hardening of the walls of the arteries which can be
due to accumulation of lipids, cholesterol, calcium or
thrombus.
– May also lead to occlusion of the lumen of the vessel,
usually at the bifurcation of the vessels
– May develop collateral circulation if develops slowly
Signs and Symptoms
• Usually none until > 60%
• Pain usual symptom but may experience
dyspnea
• May have irregular heart rate
• N/V may also accompany the other symptoms
• Called angina
– Unstable – persistent, even at rest
– Prinzmetal's – variant, and may occur
without atherosclerosis
 Myocardial Infarction (MI)
A heart attack (myocardial infarction) occurs when an
area of heart muscle dies or is permanently damaged
because of inadequate supply of oxygen to that area.

Symptoms

Chest pain behind the sternum (breastbone) is a major symptom of

heart attack. Often, the pain radiates from your chest to your arms
or shoulder; neck, teeth, or jaw; abdomen or back.
 Myocardial Infarction (MI)

• The pain typically lasts longer than 20

minutes and is generally not fully
relieved by rest or nitroglycerine, both
of which can clear pain from angina.
• The pain can be intense and severe or
quite subtle and confusing. It can feel
like:
• Squeezing or heavy pressure
• A tight band on the chest
• “An elephant sitting on chest”
• Bad indigestion
Angiogram - Embolism Infarction
• Cardiac catheterization: the procedure
involves inserting a long,flexible,radiopaque
catheter into a peripheral vein for right side
& into a peripheral artery for left side to
check/ measure the pressure in heart &
blood vessel & identify the location of septal
& valvular defects.
• Angiography – this procedure may be
used to visualize coronary artery, aorta,
pulmonary blood vessel to access the
structural abnormality.

• Angiography can be used to inject clot

dissolving drugs such as streptokinase or
tissue plasminogen activator(t-PA) into a
coronary artery to dissolve an obstructing
thrombus.
CABG
 Medical Treatment
• Decrease risk factors
– Diet
– Control cholesterol/triglycerides
– Exercise
– Smoking
– Hypertension
• Drugs
– Calcium channel blockers
– Nitroglycerin
– Low dose ASA
• Surgery
There are various treatment option designed
to increase the blood supply. These
options are:
1. Nitroglycerine
2. Beta blockers
3. Lipid lowering agent
4. Clot dissolving agent
5. CABG
6. PTCA
 stroke
When blood supply to any part of the brain is
interrupted, resulting in tissue death and loss of
brain function.

common symptoms
 Changes in vision,
 Speech, and comprehension;
 Weakness;
 Vertigo;
 Loss of sensation in a part of the body; or
changes in the level of consciousness,
Transient Ischemic Attack (TIA )

• A brain disorder caused by temporary

disturbance of blood supply to an area
of the brain,resulting in a sudden, brief
(less than 24 hours, usually less than 1
hour) decrease in brain functions.
Answer the following?
• What is plaque?
• What is thrombus?
• What is ischemia?
• What is embolus?
• What is embolism?
• What is MI?
• What is atherosclerosis?
• What decreases the risk of CAD?
• What are the treatment option for CAD?
What is heart failure?
• Heart failure is a condition in which the heart
can’t pump blood the way it should. In some
cases, the heart can’t fill with enough blood.
In other cases, the heart can’t send blood to
the rest of the body with enough force.
• Heart failure develops over time as the
pumping of the heart grows weaker. It can
affect the right side of the heart only or both
the left and right sides of the heart
 Classification of heart failure
• Right Heart Failure
- The inability of the right side of the heart to
adequately pump venous blood into the
pulmonary circulation.
- Right-side heart failure may cause fluid to
build up in the feet, ankles, legs, liver,
abdomen, and, rarely, the veins in the neck.
• Clinical symptoms due to fluid congestion:

– shortness of breath
– edema (pooling of fluid in lungs and body)
 Classification of heart failure
• Left Heart Failure - The inability of the left side
of the heart to pump into the systemic
circulation. Clinical symptoms due to poor
blood flow to the body:
– difficulty exercising
– fatigue
– dizziness (due to low blood pressure)
The leading causes of heart failure are
diseases that damage the heart. These
include:
– Coronary artery disease (CAD),
– High blood pressure, and
– Diabetes
Cause of Heart failure
• Heart failure is caused by many conditions
that damage the heart muscle, including:
– Coronary artery disease
– Arrhythmias
– Cardiomyopathy — damage to the heart muscle from
causes other than artery or blood flow problems.
– High blood pressure (hypertension)
– Valve disease Heart defects present at birth
– Diabetes Mellitus
– Chronic kidney disease
 How does heart failure develop?

• Narrowed arteries that supply blood to the heart muscle—

coronary artery disease.
• Past heart attack, or myocardial infarction, with scar tissue
that interferes with the heart muscle’s normal functioning.
• Left Ventricular Hypertrophy.
• High blood pressure.
• Valvular heart disease due to previous rheumatic fever or
other causes.
• Primary disease of the heart muscle itself, called
cardiomyopathy.
• Congenital heart defects (birth defects)
• Infection of the heart valves and/or heart muscle itself—
endocarditis and/or myocarditis
 What is NYHA classification?
• The New York Heart Association (NYHA)
Functional Classification provides a simple
way of classifying the extent of heart failure. It
places patients in one of four categories based
on how much they are limited during physical
activity; the limitations/symptoms are in regards
to normal breathing and varying degrees in
shortness of breath and or angina pain:
N YH A
 Treatment options
• Life style modifications - Bed rest, Exercise,
Diet
• Drug therapy
– ACE –Inhibitors/ ARBs in selected
patients
– Diuretics
– Beta blockers
– Digoxin
• Surgical procedures - Replacements of
valves, etc.
 What is kidney?
kidneys are two bean-
shaped organs near the
middle of your back. Their
main function is to
eliminate excess fluid and
waste material from your
blood
 What are the function of
kidney?
• Filtration of the blood
• Reabsorption of vital nutrients, ions and water.
• Secretion of excess materials
• Activation of Vitamin D.
• Release of Erythropoietin.
• Release of Renin.
• Release of Prostaglandins.
• Secretion of H (+1) and reabsorption of HCO3 (-
1).
 Nephron

The physiological
unit of the
kidney used for
filtration of
blood and
reabsorption and
secretion of materials
 Functions of Nephron
Structures
• Afferent Arteriole
– Transports arterial blood to the
glomerulus for filtration
• Efferent Arteriole
– Transports filtered blood from the
glomerulus , through the peritubular
capillaries and the vasa recta, and to the
kidney venous system
 Functions of Nephron
Structures
• Glomerulus
– The site for blood filtration
– operates as a nonspecific filter; in that, it will remove both
useful and non-useful material
– the product of the glomerulus is called filtrate.
• Bowman’s Capsule
– A sac that encloses Bowman’s Capsule and transfers
filtrate from the glomerulus to the Proximal Convoluted
Tubule (PCT)
 Functions of Nephron
Structures
• Proximal Convoluted Tubule (PCT)
– A thick, constantly actively segment of the nephron that
reabsorbs most of the useful substances of the filtrate:
sodium (65%), water (65%), bicarbonate (90%),
chloride (50%), glucose (nearly 100%!), etc.
– The primary site for secretion (elimination) of drugs,
waste and hydrogen ions.

• Decending Limb of the Loop of Henle

– A part of the counter current multiplier
– freely permeable to water and relatively impermeable to
solutes (salt particles)
– receives filtrate from the PCT, allows water to be
absorbed and sends “salty”filtrate on the the next
segment. “Saves water and passes the salt”
 Functions of Nephron
Structures
• Ascending Limb of the Loop of Henle
– a part of the counter current multiplier
– impermeable to water and actively transports (reabsorbs)
salt (NaCl) to the interstitial fluid of the pyramids in the
medulla. “Saves salt and passes the water.”
– the passing filtrate becomes dilute and the interstitium
becomes hyperosmotic

• Distal Convoluted Tubule (DCT)

– receives dilute fluid from the ascending limb of the Loop of
Henle
– Variably active portion of the nephron
– When aldosterone hormone is present, sodium is
reabsorbed and potassium is secreted. Water and chloride
follow the sodium.
 Functions of Nephron
Structures
• Collecting Duct
– receives fluid from the DCT
– variably active portion of the Nephron
– when ant diuretic hormone (ADH) is present, this duct will
become porous to water. Water from the collecting duct
fluid then moves by osmosis into the “salty”
(hyperosmotic) interstitium of the medulla.
– The last segment to save water for the body

• Glomerulus
– the Glomerulus is the site of filtration
– the filtration mechanism is sieve-like and consists of
fenestrated glomerular capillaries, podocytes and a
basement membrane that allows free passage of water
and solutes smaller than plasma proteins
 Helps in

Increase the amount of

urine produced by the kidneys.
Increase sodium excretion
Indications for Diuretic Use
• Edema associated with congestive heart failure
• Acute pulmonary edema
• Liver disease (including cirrhosis)
• Renal disease
• Hypertension
• Conditions that cause hyperkalemia
 The facts
• Despite the availability of numerous classes of
effective antihypertensive drugs, BP fails to be
adequately controlled in up to 50% of hypertensive
patients.

• Poorly controlled BP is a key determinant in the

development of cardiac failure.
 The facts
• Patients with apparent essential hypertension has
been identified with an elevated ratio of
aldosterone.

• Patients with heart failure or following MI

demonstrate that aldosterone blockade offers
added benefit in individuals with advanced
cardiovascular disease
ACEI & ARBs are widely used to
manage hypertension, MI, CCF as
they suppress Aldosterone levels
but….
Aldosterone synthesis escape

….With chronic use,

aldosterone levels return to
pretreatment levels

Occurs in 40% patients with

CCF

Formulary Oct 2002;Medscape:Br J Cardiol 2004

 Also….
Angiotensin II K & ACTH
Adrenal gland

Aldosterone

With ACEI/ARB, aldosterone

synthesis is not completely inhibited
 Aldosterone Escape
• Angiotensinogen, Renin, Ang I, II are locally
produced in several other tissues

• They cause long lasting effects on cell growth,

formation of tissues matrix, apoptosis etc

• On tissue level alternate pathways for production

of Ang II is more important than that produced by
vascular endothelium
 Aldosterone Escape
Angiotensinogen Ang I
Renin from Kidney
(From Liver)
ACE from
Cathepsin A vascular
Cathepsin G
Chymase
Tonin Endothelium

Cathepsin D
Ang II

Inactive
peptides
 Effects of Aldosterone
The classic concept
Secreted by zona glomerulosa of adrenal gland
– Stimulated by angiotensin-2, K,ACTH
Regulates K & Na transport
Causes Na & water retention
causes K excretion
Increases volume overload & causes HTN
 Effects of Aldosterone
The new concept
 Aldosterone also
MR receptors
synthesized by:
identified in:
Endothelial cell
 kidney
Vascular smooth
muscle  heart
Locally in blood  blood vessels
vessels, brain &  brain
myocardium

Circulation:2003
 Role of Aldosterone
Aldosterone

MR

Heart Vascular Kidney Brain

Endoth Hypertension H’GE

LVH
dysfn
 Renal system & Aldosterone
• Aldosterone promotes myocardial and aortic
fibrosis and nephrosclerosis

• Ang II and aldosterone stimulate expression of

PAI-1 that promote PAI-1 and ECM accumulation.

• Plasminogen activator inhibitor-1 (PAI-1) is the

major physiological inhibitor of plasminogen
activators

• Increased PAI-1 causes atherosclerotic plaque, in

the glomeruli in thrombotic microangiopathy, and
in lupus nephritis
 Finally CV effects of
ALDOSTERONE
• Endothelial dysfunction
• Vascular inflammation
• Myocardial ischemia
• Necrosis
• Increase collagen synthesis
• Increase in PAI – 1 activity
• Decrease in baroreceptor sensitivity
• Increase in ROS
• Increased cardiocyte apoptosis
If “Aldosterone” is so deadly
The Mighty Spironolactone

The “Aldactone”
 Aldactone
• It is a synthetic 17-lactone drug that is a
aldosterone antagonist in a class of
pharmaceutical called Mineralocorticoid receptor
antagonist, used primarily to treat heart failure,
ascites in patients with liver disease, as well as
high blood pressure
 Mechanism of action

• Spironolactone inhibits the effect of

aldosterone by competing for intracellular MR
receptor.

• MR receptors are located at various places

hence spironolactone offers multiple benefits.
 Role of Aldosterone
Aldosterone

MR

Heart Vascular Kidney Brain

Endoth Hypertension H’GE

LVH
dysfn
 Role of Aldactone
Aldactone

MR

Heart Vascular Kidney Brain

Prevents Lowers volume Reduces the

Prevents arterial overload & lowers risk of stroke
worsening of stiffness BP
HF.
Regresses
LVH
 The Randomized Aldactone
Evaluation Study
Objective - The Effect of Spironolactone on Morbidity
and Mortality in Patients with Severe Heart Failure.

Design - The Randomized Aldactone Evaluation Study

(RALES) was designed to test the hypothesis that daily
treatment with 25 mg of spironolactone would
significantly reduce the risk of death from all causes
among patients who had severe heart failure as a result
of systolic left ventricular dysfunction and who were
receiving standard therapy, including an ACE inhibitor, if
tolerated.
 The Randomized Aldactone
Evaluation Study
• Design-
– No. of patient- 1663
– Patient type - Diagnosed for HF in
last six weeks times.
– Patient NYHA class- 3 &4
– Ejection fraction - 35%
– Treatment - - ACEI, Diuretic,Digitalis
– Duration - 36 months
 The Randomized Aldactone
Evaluation Study
• Results
– The trial was discontinued early because an interim
analysis determined that spironolactone was
efficacious.

– There were 30 percent reduction in the risk of death

among patients in the spironolactone group.

– In addition, patients who received spironolactone had

a significant improvement in the symptoms of heart
failure, as assessed on the basis of the New York
Heart Association functional class .
 The Randomized Aldactone
Evaluation Study
• Conclusions
– Blockade of aldosterone receptors by
spironolactone, in addition to standard
therapy, substantially reduces the risk of
both morbidity and death among patients
with severe heart failure. (N Engl J Med
1999:341:709-17.)
• ALDACTONE : Indication & Dosage

– Essential Hypertension: 50-100mg/day OD or Div. Doses

– CHF & other oedematous states:100 -200mg/day
– Nephrotic syndrome: 100-200mg/day

• ALDACTONE -Adverse Effects

– Gynaecomastia - dose dependent-- reversible
– G.I. - nausea, vomiting, diarrhoea
– Irregular menses
– Drowsiness, Lethargy, headache
 Spiromide
Composition:
Frusemide 20 mg
Spironolactone50 mg
MOA:
Frusemide Inhibit Na/K/Cl ATPase in ascending loop of
henle & hence helps in sodium excretion. It is a potent
diuretic & acts even in case of decreased GFR.
& Spironolactone inhibit aldosterone’s effect at the
receptor in DCT & collecting duct, reducing Na and
water retention
Spiromide (Pharmacokinetics)
• Spironolactone: • Frusemide:
– – Bioavailability- 60-64%
Bioavailability- 90%
– – Half life 2hrs
Half life 2o hrs
– – Onset of act within
Onset of act 24-48 hr
1hr
– Peak of action 48-72 hr
– Peak of action 1-2 hr
– Duration of action 48-72 hr
– Duration of action 6-8hrs
 Spiromide ( Rationale)

• Long term diuretic therapy constitutes an

important treatment option in hypertension and
edema. Thiazides and loop diuretics are most
commonly employed. Thiazides are known to
be associated with hypokalemia,
hyperuricemia, impaired glucose tolerance and
altered lipid profile. Frusemide, a loop diuretic
having similar effects, also causes
hypokalemia. Hypokalemia is the main
undesirable side effect of Thiazides and
Frusemide.
 Spiromide ( Rationale)

• Potassium salt supplementation is not well

tolerated by GI tract. Hence, K+-sparing diuretics
like spironolactone are preferable. They also give
added natriuresis, thus allowing lower dose of the
other diuretic. The lower dose minimizes
hypokalemia and risk of hyperuricaemia and
impaired glucose tolerance too.
• Frusemide and spironolactone combination has
been shown to be effective in hypertension and
CHF.
 Spiromide

Indication:
CHF
Hepatic cirrhosis with ascites
Nephrotic Syndrome

Dosage:

1-4 tablets in single or divided dose.

 Spiromide in CHF
• In congestive cardiac failure due to falling cardiac
output there is congestion of lungs, liver etc
leading to breathlessness (pulmonary oedema)
and decreased exercise tolerance (capacity). Due
to activation of RAAS and sympathetic overactivity
there is abnormal salt and water retention
worsening the condition.

• Spiromide by causing extreme diuresis it promptly

relieves pulmonary oedema and decrease venous
pressure.
 Spiromide in Hepatic cirrhosis

• Due to anatomical distortion portal blood cannot

bypass liver causing increased portal venous
pressure and filtration of fluid in peritoneal cavity
causing ascites.
• Due to decreased liver function adequate amount of
proteins are not synthesized, decreasing the
osmotic pressure of blood, favoring development of
ascites.
• Collection of fluid in abdomen cause decreased
blood volume and decreased blood pressure
leading to abnormal salt and water retention
(↑RAAS). Aldosterone levels are abnormally
increased.
• Frusemide and Spironolactone decrease fluid
overload and antagonise aldosterone respectively.
 Spiromide (Adverse Effects)
• Gynaecomastia,
• Decrease in libido
• Menstrual irregularities in females
• Diarrhoea,
• Abdominal cramps,
• Headache, drowsiness,
• Impotence,
• Skin rash,
 Demator
• Demator (Torsemide) is a pyridine-sulfonyl urea
type loop diuretic mainly used in the management
of edema associated with congestive heart failure.
It is also used at low doses for the management of
hypertension.

• Pharmacokinetic data :
– Bioavailability : 80-90%
– Protein binding: 99%
– Metabolism :80%(hepatic)
– Half life :3.5hr
:7-8hr in cirrhosis
• Therapeutic considerations :
– Catogery :C
– Routes : Oral/ I.V
 Is it time for a newer and
better loop diuretic?
• The degree of kaliuresis that the drug
(Frusemide) induces can lead to
potentially fatal consequences, especially
in metabolically deranged states such as
congestive heart failure and renal failure.

• Frusemide is a quick and short acting

drug (owing to its short half-life 1 hour)
and hence is more useful for intravenous
administration in emergencies.
 Is it time for a newer and better
loop diuretic?
• Frusemide is exclusively excreted by the
kidneys. Hence any compromise in renal
function impairs clearance of the drug. This
leads to accumulation of metabolites in patients
with severe renal impairment, which could lead
to toxicity.

• Bioavailability of frusemide is erratic(11-90% )

and this adds to unpredictability of response &
also shows intra-patient variability.
 Is it time for a newer and better
loop diuretic?
• Frusemide induced a significant increase in
calcium excretion and a corresponding
decrease in serum calcium concentrations. This
can lead to osteoporosis over a period of time.
 Why “Demator”?
• Demator produces intense diuresis and
natriuresis comparable to that of frusemide.
10-20 mg of Demator = 40 mg of frusemide.

• Demator, and not frusemide, has been shown to

inhibit aldosterone binding to its receptor in the
rat kidney.
 Why “Demator”?
• Demator has been reported to have a
weaker kaliuretic effect than other loop
diuretics this feature results in better
electrolyte balance and a lesser risk of
hypokalemia.

• Demator did not significantly change

calcium excretion or serum calcium
levels. Hence, Demator has calcium
sparing effect.
 Why “Demator”?
• Demator does not cause changes in lipid profile,
glucose metabolism and serum uric acid and
creatinine. Hence can be used for chronic
ailments like hypertension .

• As compared to frusemide, the absorption

profile of torsemide is more predictable as the
bioavailability of torsemide is 76-96% as
compared to 11-90% with frusemide. Torsemide
also has a faster onset of action, and exerts a
more sustained action as compared to
frusemide.
 Why “Demator”?
• The drug is metabolized to a large extent in the
liver (80%). Renal clearance of the parent drug
accounts for approximately 20% of the total
clearance. Hence safe in patients with renal
failure.
 Benefits beyond frusemide
• in congestive heart failure :
– TORIC (Torsemide in Congestive Heart Failure)
– n=1377 with NYHA class II-III CHF
– Diuretic therapy with torsemide 10 mg or frusemide 40
mg or other diuretics in addition to their existing standard
CHF therapy for 12 months.

– Outcme:
• Mortality was significantly lower in the torsemide (2.2%)
than in the frusemide/other diuretics group (4.5%).
• Torsemide treatment was associated with a significantly
lower total mortality and cardiac mortality. Also, a
significantly greater proportion of patients in the torsemide
group showed improvement in the NYHA class compared to
patients treated with frusemide or other diuretics.

TORIC study throw up the exciting possibility that

torsemide, by its specific pharmacological profile & anti-
aldosterone effect , might provide additional benefits in
CHF, which are beyond its pure diuretic effect.
 Benefits beyond frusemide
• in renal failure:
– Trials in chronic renal failure confirm that torsemide (100-200
mg) is a high ceiling diuretic and has effects on urine volume
and electrolyte excretion similar to those of frusemide. Long-
term use of torsemide has been found to be safe and
effective.

– Torsemide is free from the rebound decrease in electrolyte

excretion. Torsemide has also been found to be effective in
patients undergoing haemodialysis.

– In patients with nephrotic syndrome, torsemide in oral

dosages of up to 200 mg/day and in combination with
spironolactone shown greater diuretic and natriuretic effect
with torsemide as compared to frusemide

References
1. J Cardiovasc Pharmacol 1993; 22 (suppl 3): S59-S70
Benefits beyond frusemide
• in ascites :
– Torsemide and frusemide have been compared in
cirrhotic patients receiving spironolactone and sodium-
restricted diets. Torsemide induced a remarkably higher
natriuretic and diuretic effect than frusemide. Body
weight loss was also significantly higher with torsemide
(2.5 + 1.6 vs 0.2 + 1.3 kg).

– In another study, the torsemide group had greater free

water clearance and greater sparing of potassium,
magnesium and phosphate than frusemide recipients.
This suggests that torsemide is a better alternative to
frusemide in hepatic cirrhosis.
 Benefits beyond frusemide

• Torsemide in hypertension :
– Thiazides are recommended as first-line drugs for
hypertension. Loop diuretics such as frusemide have
proven to be less effective in controlling blood
pressure than thiazides. In contrast, torsemide has
been found to be as effective as thiazides
(hydrochlorothiazide and a combination of
hydrochlorothiazide and a potassium sparing diuretic)
in small doses for the therapy of hypertension without
changes in serum electrolytes or metabolic indicators.

– The dosages of torsemide used in the treatment of

hypertension, typically 2.5 or 5 mg/day, are described
as non-diuretic.
 Advantages of Demator over
frusemide
• Torsemide is more potent than frusemide on
a weight per weight basis. 10-20 mg of
torsemide produces effects equivalent to that
of 40 mg of frusemide.

• Torsemide has a fast onset of action and

produces intense diuresis, which is
comparable to that of frusemide. However,
unlike frusemide, which is short acting,
torsemide has a more sustained diuretic
action.
 Advantages of Demator over
frusemide
• Torsemide has a more predictable absorption
profile and better bioavailability than frusemide.
Frusemide has an erratic and highly variable
bioavailability, which leads to unpredictability of
response. This may affect the overall outcomes
with frusemide.

• Torsemide is potassium sparing in nature: this is

attributable to its aldosterone-inhibiting property.
Torsemide also prevents calcium loss.
 Advantages of Demator over
frusemide
• Studies have shown that in congestive heart failure,
torsemide-treated patients were less likely to be
readmitted for heart failure and for all cardiovascular
causes. Torsemide is also associated with decreased
mortality rates. It also results in reduced overall costs.

• Torsemide is excreted mainly via the hepatic route;

hence high doses up to 100-200 mg in advanced chronic
renal failure may be used. Frusemide, on the other hand,
accumulates in renal failure and causes toxicity.
 Advantages of Demator over
frusemide
• Torsemide has been used in combination with
spironolactone in cirrhosis of liver with ascites. This
decreases potassium loss and further imbalance of
electrolytes. Frusemide on the other hand causes
potassium loss and adds to imbalance of
electrolytes.

• Torsemide is the first loop diuretic indicated for the

treatment of hypertension. Doses required are sub-
diuretic doses (2.5 to 5 mg) and do not have any
biochemical or electrolyte adverse effects.
Torsemide may be used alone or in combination
with other drugs for hypertension
 CONCLUSION
“In conclusion, it may be said that torsemide is a
diuretic that combines the pharmacological profile
of loop diuretics in high doses and thiazides in low
doses. It is a potent diuretic and is associated with
lesser risk of hypokalemia and alterations of
biochemical parameters”.
 DOSAGE AND
ADMINISTRATION
• Congestive Heart Failure
– The usual initial dose is 10 mg or 20 mg of once-
daily oral or intravenous DEMATOR. If the diuretic
response is inadequate, the dose should be titrated
upward by approximately doubling until the desired
diuretic response is obtained. Single doses higher
than 200 mg have not been adequately studied.

• Chronic Renal Failure

– The usual initial dose of DEMATOR is 20 mg of
once-daily oral or intravenous DEMATOR. If the
diuretic response is inadequate, the dose should be
titrated upward by approximately doubling until the
desired diuretic response is obtained. Single doses
higher than 200 mg have not been adequately
studied.
 DOSAGE AND
ADMINISTRATION
• Hepatic Cirrhosis
– The usual initial dose is 5 mg or 10 mg of once-daily
oral or intravenous DEMATOR, administered together
with an aldosterone antagonist or a potassium-sparing
diuretic. Single doses higher than 40 mg have not been
adequately studied.
– Chronic use of any diuretic in hepatic disease has not
been studied in adequate and well-controlled trials.

• Hypertension
– The usual initial dose is 5 mg once daily. If the 5 mg
dose does not provide adequate reduction in blood
pressure within 4 to 6 weeks, the dose may be
increased to 10 mg once daily. If the response to 10 mg
is insufficient, an additional antihypertensive agent
should be added to the treatment regimen.
 Side effects
• Dizziness
• Headache
• Nausea
• Weakness,
• Vomiting,
• Hyperglycemia
• Excessive urination,
• Hyperurecemia
• Hypovolemia
• Impotence
• Esophageal hemorrhage, and dyspepsia
 DRUG INTERACTIONS

• Patients receiving high doses of salicylates may

experience salicylate toxicity when DEMATOR
is concomitantly administered.
• The natriuretic effect of DEMATOR (like that of
many other diuretics) is partially inhibited by the
concomitant administration of indomethacin.
• Co administration of probenecid reduces
secretion of DEMATOR into the proximal tubule
and thereby decreases the diuretic activity of
DEMATOR.
 Topdip
• Composition
• Indications
• Dosage
• MOA
• Pharmacokinetics
• Advantages
 Topdip
Composition
• Amlodipine besylate equivalent to
2.5mg/5mg/10mg amlodipine
 What are the indications &
dosage for Topdip?

Indications
• Hypertension
• Chronic stable / vasospastic Angina
Dosage
• Hypertension
• 5-10mg OD
• 2.5mg OD (elderly, hepatic failure)
• Chronic stable / vasospastic Angina
• 10 mg OD
How does Topdip Act?
 What are the key pharmacokinetic
features of Amlodipine?

• Bioavail (%): 64-90

• Onset (min): 30-60
• Protein Binding: 93
• Half-life (h): ~ 40 h
• Tmax (h): 6-12
 What are the advantages of
Topdip?
• Round the clock control due to long t 1/2
• Aids patient compliance with OD dosing
• Favourable safety profile
• Effective as monotherapy and in combination
with diuretics, ACEIs and beta blockers
• Useful in hypertensive patients of all ages with
concomitant diseases viz. asthma,
hyperlipidemia, diabetes, CHD and renal
disease
 What is Topdip AT?
What are its indications & dosage?

Composition
• Atenolol 50 mg + Amlodipine 5 mg

Indications
• Hypertension, prophylaxis of chronic stable
angina.

Dosage
• 1 tablet once daily
 What is Topdip AT?

• Atenolol
– Beta blocker, Selective, Water- soluble
• Amlodipine
– Long acting CCB with Sustained and smooth
pharmacodynamics
• Pharmacokinetic compatibility
• Low ADR profile of each
• Patient compliance
 Pharmacokinetic features of
Amlodipine & Atenolol in Topdip AT

Amlodipine Atenolol

• Bioavail (%): 64-90 • Absorption: 50%

• Bioavailability: 50 - 60%
• Onset (min): 30-60
• Half-life: 6-9 hours
• Protein Binding: 93 • Protein binding:16%
• Half-life (h): 40 h • Excreted: 50% unchanged in
• Tmax (h): 6-12 feces
• Does not cross blood brain
barrier - Low lipid solubility
 In what dosage is Atenolol
prescribed?
Hypertension
Initial 50 mg OD either alone or in conjunction with a
diuretic
Increase dosage to 100 mg/day

Angina
Initial 50 mg OD, Increase to 100 mg OD
In MI and SVA : intravenous formulations used
 What are the advantages of
Atenolol?
∀ ↓ BP & oxygen demand by blocking +ve inotropic
& chronotropic action of catecholamines
• Cardioselective ( B1); No unwanted (B2)
bronchoconstrictor effects, can be used in
asthmatics
• Water soluble beta-blocker. Hence low incidence of
CNS side effects
• No ISA unlike metoprolol
• No effect on glucose metabolism : Useful in
diabetic hypertensives
• Effective in elderly
 Topdip AT
Advantages

• OD dosing improves patient compliance

• Better clinical response with lesser side effects due to
reduction in the doses of the individual drugs
• Enhancement of antihypertensive & antianginal action
• Alteration (reduction) of adverse effects viz. Amlodipine may
inhibit alpha adrenergic mediated vasoconstriction caused
by atenolol
• At high doses, beta-1 selectively is lost.Since in combination,
lower doses are used, selectivity is retained.
ACEDIP
 ACEDIP

COMPOSITION

Lisinopril 5 mg + Amlodipine 5 mg

INDICATIONS & DOSAGE

• Hypertension
• Resistant Hypertension
• Diabetic Hypertension
• 1 tablet once daily
 ACEDIP

RATIONALE

Calcium Channel Blocker ACEI

(Amlodipine) + (Lisinopril)

• Afterload Preload & Afterload

• Inhibits Ca++ entry Inhibits ACE

SYNERGISTIC ANTIHYPERTENSIVE EFFECT

 ACEDIP

IN RESISTANT HYPERTENSION

• Superior BP control, than monotherapy

• n = 330, 79 outpatient clinics
• Reduction of DBP & SBP
- Effective ( in 77.65% patients )

Mathew JAG et al, Indian Pract,

1998: 51(6): 441-447.
 ACEDIP

IN DIABETIC AND OR OBESE

HYPERTENSIVES

• Superior BP control, than monotherapy

• Improves insulin sensitivity
• Antiproteinuric effects
• Lesser cough
• Better compliance
Mathew JAG et al, Indian Pract,
1998: 51(6): 441-447.
 ACEDIP

SUMMARY
•Synergistic action - Superior BP control than
monotherapy
•1 tablet daily in hypertension
( Resistant,Diabetic,Obese)
– Diabetic hypertensives : Improves insulin sensitivity,
Antiproteinuric effects
– Obese / Hyperlipidemic hypertensives : Lipid neutral
•Aids patient compliance - OD dosing Lesser cough,
edema
Mathew JAG et al, Indian Pract,
1998: 51(6): 441-447.
 ACEDIP

ADVANTAGES
 Synergism of antihypertensive effect
 Lower doses of each drug required leading
to better clinical response with lesser side
effect
 Due to their long elimination of half-life,
they can be administered once daily,
hence improved patients’ compliance and
better clinical response.
 Amlodipine activates sympathetic nervous
system. Lisinopril counterbalances this
effect by decreasing sympathetic outflow.
 Vasoprotective and cardioprotective
effects
 Fewer tablets to be administered, this
leads to increased patients’ convenience
 Avoiding Cardiovascular Events through
COMbination Therapy in Patients
LIving with Systolic Hypertension
• Objective: To determine if amlodipine besylate /
benazepril will confer reduction in cardiovascular
morbidity and mortality in high-risk hypertensive subjects
when compared with the combination of benazepril and
HCTZ.

• Design :
– Multinational, double-blind clinical trial
– Patient - 11,508 subjects (550 centers)
– Duration: 5-year
 Conclusions

• The results of ACCOMPLISH provide compelling

evidence for initial combination therapy with ace/ccb and
challenges current diuretic based guidelines.
• It was stopped early because treatment with
antihypertensive combination therapy--the ACE inhibitor
benazepril plus the calcium-channel blocker
amlodipine--was more effective than treatment with the
ACE inhibitor plus diuretic.
 Losatec
Composition:
Losartan Losartan 25mg,
Losartan 50mg,
 Renin Angiotensin Aldosterone System
Brain-Stroke
Angiotensinogen
Heart-

Renin Fibrosis

(Kidney)
LVMI

Angiotensin I BV-
ACE Endothelial
(Lungs) dysfunction
Arterial
stiffness
Aldosterone
Angiotensin II (adrenal gland)
Kidney-
Water & Na
Aldosterone Retention
Acts on MR Albuminuria
AT-2 AT-1
Vasoconstriction
Vasodilatation
Apoptosis ↑ Blood Pressure
Wound Healing
Effect of Angiotensin - ii at AT1 &
AT2 receptor
Mechanism of action
LOSARTAN
AII receptor (AT1) blocker

Vasodilation

Afterload

Reduction in BP
 Pharmacokinetics
• Absorption: Losatec is well absorbed on oral
administration.
• Bioavailability - 33%.
• Protein Binding: 99%.
• Half-life: 6-9 hours respectively.
• Excretion: Following oral administration of
Losatec, approximately 35% of the radioactivity
is recovered in the urine and about 60% in the
faeces.
 Losatec
• Indications
– Losatec is indicated for the treatment of hypertension; it may
be used alone or in combination with other antihypertensive
agents. Losatec is indicated in diabetic nephropathy.

• Dosage
– Usual starting dose is 50 mg once daily.
– Losatec can be administered with or without food once or
twice daily with total daily doses ranging from 25 to 100 mg.
– If the antihypertensive effect measured at trough using once
daily dosing is inadequate, a twice daily regimen at same total
daily dose or an increase in dose may give a more
satisfactory response.
 Losatec
The USPs of Losatec
– First angiotensin II receptor blocker
– Selective A II receptor (Type AT1) antagonist
– Patients with/ susceptible to cough on ACEIs
– Unresponsive/ Intolerant to current therapy
– No rebound hypertension on abrupt withdrawal unlike Beta
blockers
– No change in heart rate unlike Calcium Channel blockers
– No effect on glomerular filtration rate, renal plasma and
filtration fraction
– Reduction of mortality and left ventricular mass
– Reduction in the risk of stroke
– Reno – protection in diabetics
 Losartan Intervention for Endpoint
Reduction in Hypertension Study
(LIFE Study)
Objective- Double-blind, randomized trial to
compare the effects of losartan and atenolol on
cardiovascular morbidity and mortality in high-risk
patients with hypertension and left ventricular
hypertrophy (LVH).
• Population
9,193 patients (55 to 80 years old) from 945 sites in 7
countries
previously treated or untreated essential
hypertension (systolic BP 160–200 mmHg or
diastolic BP 95–115 mmHg)
1,195 patients (13%) had diabetes at baseline
 LIFE Study
Summary
• Losartan-based compared with atenolol-based
antihypertensive therapy was associated with:
– A reduction in the combined primary endpoint
of cardiovascular death, stroke or MI (-13%)
– Fewer strokes (-25%)
– similar blood pressure reduction
– Losartan reduced the rate of new-onset diabetes (-25%)
• In the diabetic subgroup, losartan reduced the rate
of:
– Combined endpoint of cardiovascular death,
stroke and MI (-25%)
– All-cause mortality (-39%)
 LIFE Study
• Conclusions
– Losartan reduced the combined risk of
cardiovascular morbidity and mortality compared
to atenolol with benefits not explained by blood
pressure reduction
– Losartan reduced the rate of new-onset diabetes
– `Losartan was significantly better tolerated than
atenolol
– Among diabetics, losartan reduced
cardiovascular morbidity and mortality
Reduction of Endpoints in Non-insulin dependent
diabetes mellitus with the Angiotensin II
Antagonist Losartan(RENAAL)
The question addressed by this study is: does taking
losartan reduce the progression of kidney disease in
patients with type 2 diabetes and established kidney
disease?

• Results-
– Losartan treatment was associated with:
– 28% risk reduction of ESRD over a mean of 3.4 years (P
= 0.002)
– 25% risk reduction of a doubling of the serum creatinine
concentration (P = 0.006)
– 35% decrease in the level of proteinuria (P < 0.001)
Reduction of Endpoints in Non-insulin dependent
diabetes mellitus with the Angiotensin II
Antagonist Losartan(RENAAL)
– 32% risk reduction in the rate of first
hospitalization for heart failure (P < 0.005)
– The benefits exceeded those attributable to
changes in blood pressure. Morbidity from
cardiovascular causes was similar in the two
groups, as was all-cause mortality.
• Conclusion---Losartan conferred
significant renal benefits in patients with
type 2 diabetes and was generally well
tolerated.
 LOSATEC- H
Composition:
Losartan 50 mg + Hydrochlorothiazide 12.5 mg
tablet
 Complementary actions
• First of a new class of AII receptor blockers
+ diuretic (thiazide)
 Dosage
• 1 tablet OD
• Can be increased to 2 tablets OD
(Max.)
 Mechanism of action
LOSARTAN HYDROCHLOROTHIAZIDE
AII receptor (AT1) Diuretic
blocker (inhibits sodium

reabsorption)

Vasodilation Preload

Afterload Blood volume

Reduction in BP
 Pharmacokinetics

• Compatible
– No interaction between Losartan &
Hydrochlorothiazide
– No difference between young and elderly
• Losartan Hydrochlorothiazide
T ½ 2h (6-9h) 5.6 – 14.8h
• Dosing frequency
OD OD
 PHARMACODYNAMICS –
COMPATIBLE

• Additive BP reduction- BP reduction

greater than either component
alone
• Smooth and Sustained BP
reduction for 24 hours by Losartan
plus hydrochlorothiazide
 PLACE IN THERAPY

• Patients requiring addition of diuretic to

Losartan monotherapy or any other
monotherapy
• Patients not responding to other FDCs (ACEIs
+ HCTZ/CaCB + HCTZ) due to inadequate BP
control
• Patients not tolerating other FDCs (due to
adverse effects eg. ACEI induced cough /
CaCB induced edema)
• In all age groups – Elderly & young
Nervous System

The nervous system is highly organized network of

billion of neurons that carries out vital tasks of
human body, such as sensing smells, producing
speech, remembering, providing signal that
controls body movement & regulating the
operation of internal organs.
• These diverse activities can be grouped into
three basic functions:
– Sensory function (Afferent neurons)
– Integrative function
– Motor function (Efferent neurons)
Organization of Nervous System
Nervous System:
1. Central nervous system
1. Brain
2. Spinal cord
2. Peripheral nervous system
1. Somatic nervous system
2. Autonomic nervous system
3. Enteric nervous system
Central nervous
system

• Brain
• Spinal cord
 Introduction to the Brain
• 100 billion neurons
• A typical neuron has about
1,000 to 10,000 synapses (that
is, it communicates with 1,000 –
10,000 other neurons,muscle
cells, glands, etc.).
• 100 trillion synapses

– Structures
• Divided into 3 general
areas
– Functions
• Controls the bare
necessities of life
• Location for primal
drives and emotions
• Intellectual thought,
imagination, perception,
interpretation, etc.
Protections and Coverings
• Cranial bones- Hard bony structure which
protects the brain called cranium.
• Meninges – Meninges are three layers of
connective tissue which encircles the entire
spinal cord & brain.
– Cranial meninges – encircles the brain.
– Spinal meninges – encircles the spinal
cord.
Meninges has three layers:
1. Dura mater- External
2. Arachnoid mater- Middle
3. Pia mater- Inner
Protections and Coverings
• Cerebrospinal Fluid- CSF is a
clear, colorless liquid found in
between pia mater & arachnoid
mater which protects the brain
against injury. It also carries
oxygen, glucose & other chemical
required by neurons & neuroglia.
• CSF has three main function:-
– Mechanical protection- serves as
shock absorber & protects the
delicate tissue of CNS.
– Chemical protection- provides an
optimal environment for accurate
neuronal signaling.
– Circulation- CSF is a medium for
exchange of nutrients & waste
products between the blood &
nervous tissue.
 Protections and Coverings
• Blood-Brain
Barrier
– A function of glial cells
• Secrete chemicals
that maintain the BBB
• Absorb materials from
blood
• Extract materials from
brain
– Cells of capillaries form
tight junctions
– Differential rates of
passage of certain
materials

UT-GSM 2008
 Adult Brain
– Forebrain
• Cerebrum
• Thalamus & hypothalamus
– Midbrain
– Hindbrain
• Cerebellum & pons
• Medulla oblongata
 Cerebrum
(seat of intelligence)
Hemispheric Specialization
• Right side processes:
• Creativity
• Patterns
• Spatial Awareness
• Context
• It Recognizes:
• Faces
• Places
• Objects
Hemispheric Specialization
Left side processes:
• Speech
• Analysis
• Time
• Sequence
It Recognizes:
• Letters
• Numbers
• Words
 Senses and integrates Hearing,
Its primary function
sensation's) Organization
is the processing, Spatial awareness and of language
Memory Formation
Emotions integration, Perception Information
Decision making interpretation, (Awareness of body/ Retrieval
Reasoning etc. of VISION body parts (Memory and
Personality in space and in Memory
and visual stimuli.
relation to each other) Formation)
 FUNCTIONAL AREAS OF
CEREBRUM (Basal Ganglia)

• The main function of basal ganglia is:

– Initiation & termination of movements.
– Subconscious contraction of skeletal muscle
(e.g. automatic arm swings while walking &
laughing in response to a joke)
– Attention , memory & planning
– Acts with limbic system & regulates emotional
behaviors.
 FUNCTIONAL AREAS OF
CEREBRUM( Thalamus &
Hypothalamus)
THALAMUS :
It is a paired oval mass of gray matter. It acts
as relay station for sensory impulses from periphery
to brain. The main function is:
• Inform us of our
emotional state
• Relay information
concerned with
motor requirements
& actions
• Integrate visual and
auditory reflexes
 Hypothalamus
– Location – under
thalamus
– Structure
• Clusters of nerve cell
bodies
– Autonomic centers
– Initiates primal drives
• Hunger, thirst, sex, rage,
etc.
• Controls autonomic
nervous system
– “fight or flight”
sympathetic response.
– Controls pituitary
gland (“master gland”
of endocrine system)
 Limbic System

• Controls Mood and attitude

• Stores highly charged
emotional memories
• Controls appetite and sleep
cycles

– Includes parts of several

anatomical structures
• Cerebrum
• Hypothalamus
• Thalamus
 Anatomy of Limbic System

• Amygdala
– Involved in anger, &
fear
• Hippocampus
– Is important in the
formation of memories
– Korsakoff’s syndrome
 Anatomy of
Limbic System

• Thalamus
– Relay sensory information to
the cerebral cortex
• Hypothalamus
– Important to metabolic
behaviors, eating, drinking,
sexual behaviors, and
regulating emotions
 Mid-Brain
• Location
– The midbrain extends from the pons to the
lower portion of thalamus.
– Mid-brain contains several nuclei & right &
left substantia Nigra which are large darkly
pigmented substance.
– Neurons that releases dopamin extends
from the sbbstantia nigra to the basal
ganglia & helps control subconscious
muscle activities.
 Hindbrain

• Pons
– Relay station
 Medulla Oblongata
• The lowest part of the brain stem
• Merges into the spinal cord
• Includes important fiber tracts
• Contains important control centers
• Heart rate control
• Blood pressure regulation
• Breathing
• Swallowing
• Vomiting

Copyright © 2003 Pearson Education, Inc. publishing as Benjamin Cummings

 Cerebellum
• Regulates the activity of muscles
• Not concerned with conscious sensations
• Modulator centre between cerebral cortex and
peripheral motor movements
• What cerebral cortex initiates
cerebellum regulates
• Co-ordinates activities associated with
maintenance of balance and equilibrium
• Damage to it causes clumsy, un-coordinate
muscular movements.
 THE NERVOUS SYSTEM

Spinal cord
• Link between brain and body organs
• Situated in vertebral canal
• Covered by Meninges and CSF
• Central gray matter - H.shaped
• Peripheral white matter
Spinal cord

• Sensory nerves Motor nerves

 THE NERVOUS SYSTEM

Autonomic Nervous System :

• Deals with automatic or involuntary functions

e.g. rate and force of heart beat
secretion of glands of GIT

• Sympathetic Nervous system

ANS
Parasympathetic nervous System
 THE NERVOUS SYSTEM

Sympathetic Nervous System :

• Neurotransmitter released at synapse

Noradrenaline/Adrenaline

• Therefore alsocalled as Adrenergic NS

• Receptors are therefore called as Adrenergic

receptors

• Sympathetic NS prepares the body to deal with

FIGHT, FRIGHT AND FLIGHT
 THE NERVOUS SYSTEM
Parasympathetic Nervous
System :

• Neurotransmitter released at synapse is Acetycholine.

• Therefore parasympathetic NS is called cholinergic
NS.
• Receptors are therefore called as cholinergic
receptors.
• Parasympathetic NS slows down body activities
(PEACEMAKER) except digestion and absorption of
food.
• Normally, 2 outflows work concurrently to regularise
internal body status in tune with outside world.
 Histology of Nervous
tissue
Nervous tissue consists of two type of cells.
1. Neurons- Carries vital function like sensing,
thinking, resembling, controlling muscle
activity & regulating secretion.
2. Neuroglia – Supports, nourish & protect the
neurons & maintain homeostasis in the
interstitial fluid which bathes neurons.
Neurons have the property
to produce & carry
electrical impulse.

Parts of Neuron:
Cell Body
Dendrites
Axon

UT-GSM 2008
 Neurons
dendrites

cell
axon with body
myelin sheath

Schwann
cell

synapses
Moore’s COA5 2006
 Dendrites (receptors)
Cell Body (processing Take in excitatory & inhibitory
center) stimuli
Inside is called the SOMA
 Dendrites
Dendrites are the "receiving"
surface of the neuron.

The axon is the part of

the neuron which conducts
an electrical signal called an
action potential.

The soma
soma (cell body) of a
neuron contains the nucleus
(DNA) of the cell & cytoplasm
cytoplasm
that
that includes
includes organelles
organelles such
such as
as
lysosome,
lysosome, mitochondria,
mitochondria, &
& golgi
golgi
complex..
complex. It also manufactures
neurotransmitters.
neurotransmitters
• Myelin- The axon of most neurons are surrounded by lipid &
protein covering called Myelin sheath that is produced by
neuroglia. Axon without such cover is known as
unmyelinated & those covered known as myelinated axons.

Two types of neuroglia produce MYELIN sheath.

– Schwann cells- PNS
– Oligodendrocytes – CNS

• White matter- aggregation of myelinated & unmyelinated

axons.

• Gray matter- Aggregation of cell bodies, dendrites &

unmyelinated axons.
 Sensory (Afferent) vs. Motor (Efferent)
sensory (afferent) nerve

e.g., skin

(pseudo-) unipolar neurons conducting impulses

from sensory organs to the CNS

motor (efferent) nerve

e.g., muscle
multipolar neurons conducting impulses
from the CNS to effector organs (muscles & glands)
Gray’s Anatomy 38 1999
Chemicals that cross the synapse between
two neurons & can cause either excitation
or inhibition of postsynaptic neurons.
 Neurotransmitter
NT can be divided into two classes based on
size. They are:
1. Small Molecule NT-
1. Acetylcholine- Ach is excitatory at some synapse
such as neuromuscular junction & it is also inhibitory
at other synapse as it slows the heart rate.
2. Amino acids- Glutamate & Aspartate have powerful
excitatory effect. Half of the excitatory neurons in
CNS communicate via Glutamate. Inactivation of
Glutamate occurs via reuptake.
3. GABA- Gamma amino butyric acid & Glycine are
important inhibitory NT. GABA is mainly found in CNS
& in Spinal cord half of the synapse use GABA & half
uses Glycine
 Neurotransmitter
• Biogenic Amines- Certain amino acids are modified & decarboxylated
to produce Biogenic amine. They are also known as catecholamine.
– Nor epinephrine- plays role in arousal, dreaming & regulating the
mood.
– Dopamine- plays role in emotional responses, addictive behavior
& pleasure experience. Dopamine also help in maintaining the
muscle tone.

• Biogenic amines are synthesized from the amino acid tryosine.

• Two enzyme that break-down catecholamine 1.catecol—o-
methyltransferase & Monoamine oxidase.

• 5-HT- Plays role in sensory perception, temp.regulation, mood

control, appetite & induction of sleep
Neurotransmitters and behavior
Norepinephrine (NE)
 Normal role
 affects mood ( in depression, in mania)
 levels associated with aggression,
impulsivity
 mediates reward, arousal, fear
 high concentration in locus ceruleus
 locus ceruleus stimulation causes fear in
monkeys
 released by energetic/anxiety provoking stress
 released NE levels correlated with intensity.
 associated with activation of the
SNS( tachycardia, tachypnea, hypertension
 Dopamine
• What is dopamine?
– A neurotransmitter produced in several area of
brain.
– A neurohormone released by hypothalamus to
inhihibit prolactin.
– Dopamine in BG helps in movement( level
causes PD).
– Dopamine in frontal lobe help in cognitive
function & disorders in this region will cause
decline in neurocognitive functions (memory,
attention, problem solving).
– Dopamine in limbic system regulates mood &
behaviour.
– Dopamine helps in acquiring new behaviour.
 Dopamine
• Decreased level: • Increased level:
– PD – Addiction
– Muscle rigidity – Suspicious & prone to
– Unstable posture misinterpret.
(stooped) – More intense
– Loss of balance suspiciousness.
– Mask like facial – Sense organ will get
expression. affected.
– Impairment in – Hallucination.
intllectual activity – Delusions.
– Impair ability to focus
(ADHD)
Dopamine & mental disorder
level in meolimbic system causes
hallucination & delusion.
Level in mesocortical region can cause apathy
& social withdrawl.
Level in nigrostriatal tract will cause EPS.
Level in tubero in fundibular tract will cause
gynaecomsti.
 Dopamine Receptor Data
Receptor
Subtype D1 D2 D3 D4 D5
Localisatio Caudate, Caudate, Nucleus Frontal cortex, Hippocampus,
accumbens,
n
putamen, putamen, olfactory midbrain, hypothalamus
tubercle,

nucleus nucleus islands of amygdala,

accumbens, accumbens, Calleja
olfactory olfactory cardiovascular
tubercle tubercle system
Likely Locomotion, Locomotion, Locomotion, Mostly Learning and
Physiologica unknown -
memory
l Roles
reward, reward, possible role possible role in
reinforcement, reinforcement, in cognition cognition and
and emotion emotion,

learning and learning and hypertension

memory, memory,
 Serotonin
• What is serotonin?
– Regulates bodily process such as sleep, libido, body
temperature.
– Brains oil.
– When serotonin is low , we experience problems with
concentration & memory.
 Serotonin
• Moderately low level • Severely low:
– Sleep disturbance – Thinking speed will
– Appetite disturbance increase
– Reduced libido – Focus more on torturing
– memories
Social withdrawal
– – Emotionally numb
Frequent crying spells
– – Outbursts will begin
Low self-esteem
– – Evil thought
Loss of personality
 Acetylcholine (ACh) as NT

• ACh is both an excitatory and inhibitory NT,

depending on organ involved.

• Nicotinic ACh receptors:

– Found in autonomic ganglia and skeletal muscle
fibers.

• Muscarinic ACh receptors:

– Found in the plasma membrane of smooth and
cardiac muscle cells, and in cells of particular
glands.
Dopaminergic pathway
Dopaminergic pathways are neural pathways
in the brain which transmit the neurotransmitter
dopamine from one region of the brain to
another.

There are eight dopaminergic pathways, but

the four major ones are:

Mesolimbic pathway
Mesocortical pathway
Nigrostriatal pathway
Tubero infundibular pathway
Mesolimbic pathway
This pathway originates in the ventral
tegmental area and innervates several
structures of the limbic system, including the
nucleus accumbency.

The mesolimbic pathway is important for

memory and for motivating behaviours.

By blocking this pathway, antipsychotic drugs

reduce the intense emotions caused by
conditions such as schizophrenia.
 Mesocortical pathway
The mesocortical pathway also originates in
the ventral tegmental area, but projects to the
frontal cortex and surrounding structures.

Malfunction in this pathway might be the cause

of some of the symptoms of schizophrenia,
such as hallucinations and disordered thinking.

Medications that block this pathway reduce

psychotic delirium, but also reduce the overall
activity of the frontal lobes.
 Nigrostriatal pathway

Nigrostriatal pathway projects axons from the

substantia nigra to the striatum (caudate
nucleus and putamen), which is involved in
motor control.

Degeneration of the neurons in this pathway is

associated with the trembling and muscular
rigidity symptomatic of Parkinson’s disease.
Tuberoinfundibular pathway

The tuberoinfundibular pathway, which

connects the hypothalamus to the pituitary
gland, where it influences the secretion of
hormones such as prolactin.
 Psychosis

• Psychosis (from the Greek "psyche",

for mind or soul, and "-osis", for
abnormal condition).
• Literally means abnormal condition of
the mind, and is a generic psychiatric
term for a mental state often described
as involving a "loss of contact with
reality".
• People suffering from psychosis are
said to be psychotic
 Signs and symptoms

People with psychosis may have one or

more of the following:
• Hallucinations
– A hallucination is defined as sensory
perception in the absence of external stimuli.
– Hallucinations may occur in any of the five
senses and take on almost any form, which
may include simple sensations (such as
lights, colors, tastes, and smells) to more
meaningful experiences.
Types of hallucinations
Auditory hallucinations
• also known as Paracusia, particularly of one or more
talking voices.
• Other types of auditory hallucination include exploding
head syndrome and musical ear syndrome.

Olfactory hallucinations
• Phantosmia is the phenomenon of smelling odors
that aren't really present. The most common odors
are unpleasant smells such as rotting flesh, vomit,
urine, feces, smoke, etc.

Tactile hallucinations
• This type of hallucination is often associated with
substance use, such as someone who feels bugs
crawling on them (known as formication) after a
prolonged period of cocaine or amphetamine use.
 Delusions

• A delusion, in everyday language,

is a fixed belief that is either false,
fanciful, or derived from deception.
 Types of delusion
• Delusion of control: This is a false belief that another
person, group of people, or external force controls one's
thoughts, feelings, impulses, or behavior.
• Nihilistic delusion: A delusion whose theme centers on
the nonexistence of self or parts of self, others, or the
world. A person with this type of delusion may have the
false belief that the world is ending.
• Delusional jealousy (or delusion of infidelity): A
person with this delusion falsely believes their spouse or
lover is having an affair.
• Delusion of guilt or sin (or delusion of self-
accusation): This is a false feeling of remorse or guilt of
delusional intensity.

• Delusion of reference: The person falsely believes that

insignificant remarks, events, or objects in one's
environment have personal meaning or significance. For
instance, a person may believe they are receiving
special messages from newspaper headlines.
 Types of delusion
• Erotomania is a delusion in which one believes that another
person is in love with him or her.

• Grandiose delusion: An individual is convinced they have

special powers, talents, or abilities. Sometimes, the individual may
actually believe they are a famous person or character (for
example, a rock star).

• Persecutory delusions: These are the most common type of

delusions and involve the theme of being followed, harassed,
cheated, poisoned or drugged, conspired against, spied on,
attacked, or obstructed in the pursuit of goals.

• Somatic delusion: A delusion whose content pertains to bodily

functioning, bodily sensations, or physical appearance. Usually
the false belief is that the body is somehow diseased, abnormal,
or changed—for example, infested with parasites.
 Thought disorder

• Thought disorder describes an

underlying disturbance to conscious
thought and is classified largely by its
effects on speech and writing.
• Affected persons show loosening of
associations, that is, a disconnection and
disorganization of the semantic content
of speech and writing. In the severe form
speech becomes incomprehensible and
it is known as "word-salad".
 Depression
• What is depression?

– Depression refers to a state of low mood.

– DSM (Diagnostic & statistical manual of

mental disorder) defines “ a depressed
person experiencing feelings of sadness,
helplessness & hopelessness”.
 Types of depression
• Atypical depression- inability to experience
pleasure. Excessive sleep & increased
appetite.
• Melancholic depression- severe depression.
• Seasonal affective disorder
• Major depressive disorder
• Bipolar disorder
 Schizophrenia
Schizophrenia is often described in terms of
positive & negative symptoms.

Positive symptom- an excess or distortion of

normal function. They include delusion,
hallucination & thought disorder.

Negative symptom- Diminution or the loss of

normal function. They include flat emotion,
alogia, anaerobia, avolition, asociality
 Schizophrenia
• How is schizophrenia diagnosed?
– According to the revised fourth edition of
the Diagnostic & Statistical Manual of
Mental Disorder, to be diagnosed with
schizophrenia, three diagnostic criteria
must be met:
• Characteristic symptoms: Two or more of the
following, each present for much of the time
during a one-month period (or less, if
symptoms remitted with treatment).
– Delusions
– Hallucinations
– Disorganized speech,
– Grossly disorganized behavior (e.g. dressing
inappropriately, crying frequently) or catatonic
behavior
– Negative symptoms—affective flattening (lack or
decline in emotional response), alogia (lack or
decline in speech), or avolition (lack or decline in
motivation)
Schizophrenia
• Social/occupational dysfunction: For a
significant portion of the time since the onset of
the disturbance, one or more major areas of
functioning such as work, interpersonal relations,
or self-care, are markedly below the level
achieved prior to the onset.

• Duration: Continuous signs of the disturbance

persist for at least six months. This six-month
period must include at least one month of
symptoms (or less, if symptoms remitted with
treatment).
D1
D1 D2
D2

Dopamine
Receptors

D3 D5
D4
 Dopamine Hypothesis
of
Mesocortical
Schizophrenia
pathway
Nigrostriatal
pathway
Hypoactivity: (part of EP system)
negative
symptoms

Mesolimbic
pathway
Tuberoinfundibular pathway
Hyperactivity:
(inhibits prolactin release)
positive
Adapted from Inoue and Nakata. Jpn J Pharmacol. 2001;86:376.
symptoms
 Pathways Symptom Neuro- Remarks
s Transmitters
1) MESOLIMBIC +ve DA > 5HT Hallucination,
Delusions seen
2) MESOCORTICAL -ve 5HT > DA Apathy,
social withdrawal
seen
3) NIGROSTRIATAL SIDE- ACH > DA E.P.S.
EFFECT
4) TUBERO- SIDE- PROLACTIN Gynaecomastia
INFUNDIBULAR EFFECT >DA
 Dopamine theory:
dopaminergic systems in CNS
Dopamine tract Innervation Function D-antagonist
effects

Mesolimbic Limbic areas Arousal, memory, Psychosis relief

(amygdala…) stimulus processing,
behaviour –
spontaneity, motivation,
assertivity, self-
confidence

Mesocortical Cortex – frontal and Communication, Psychosis relief

prefrontal cognition, social Akathisia?
functions and stress
response

Nigro-striatal Caudate Nucl., Extrapyramidal system Movement disorders

Putamen and movement
coordination

Tubero-infundibular Pituitary gland Prolactin secretion Hyperprolactineamia,

regulation galactorhea,
gynecomastia
 Antipsychotic medication
• Antipsychotics are a group of psychoactive drugs
commonly but not exclusively used to treat
psychosis.

• Antipsychotics are also referred to as neuroleptic

drugs. The word neuroleptic is derived from Greek:
(neuro referring to the nerves) and (leptic meaning
take hold of ).Thus, the word means taking hold of
one's nerves.

• Antipsychotics are broadly divided into two groups,

the typical or first-generation antipsychotics and
the atypical or second-generation antipsychotics.
 Antipsychotics - Classification

Typical
Atypical
or
Conventional
Chlorpromazine Thioridazine Clozapine, Olanzapine
Trifluoperazine, Haloperidol Risperidone
Atypical antipsychotics

Olanzapine Clozapine Quetiapine

Serotonin- Dopamine
Antagonists (SDA’s)

Risperidone Sertindole Ziprasidone

 Typical antipsychotic
• The typical antipsychotic are classified according to
their chemical structure. It is sometime referred as
major tranquilizers.
• They acts by D2 receptor antagonism
• First generation antipsychotics
• Butyrophenones
– Haloperidol
– Droperidol (Droleptan)
• Phenothiazines
– Chlorpromazine
– Fluphenazine
– Perphenazine
– Prochlorperazine
• Thioxanthenes
– Chlorprothixene
– Flupenthixol
– Thiothixene
 Atypical / second generation
antipsychotic
• Classified based on pharmacological property.

• Acts on both 5-HT & D-receptor.

• Used to treat schizophrenia, acute mania, bipolar

mania, psychotic agitation.

– Clozapine, Olanzapine, Quetapine, Resperidone,

Ziprasidone , Sertindole, Amisulpride
 Serenase
• Serenase contains haloperidole.

• Haloperidol is a typical antipsychotic. It is in the

butyrophenone class of antipsychotic
medications and has pharmacological effects
similar to the phenothiazines.

• Haloperidol was discovered by Paul Janssen. It

was developed in 1957 by the Belgian
company Janssen Pharmaceutica and
submitted to first clinical trials in Belgium in the
same year. It was approved by the U.S. Food
and Drug Administration on April 12, 1967.
 Pharmacology
Bioavailability Approx. 60 to 70% (tablets
and liquid)

Metabolism Hepatic

Half life 12 to 36 hours

Excretion Biliary and renal

 Uses
• Acute psychosis
• Acute manic phases
• Hyperactivity, aggression.
• Acute delirium
• Adjunctive treatment of alcohol and opioid withdrawal
• Treatment of severe nausea/emesis (postoperative,
side-effects of radiation and cancer chemotherapy)
• Adjunctive treatment of severe chronic pain, always
together with analgesics
• Therapeutic trial in personality disorders such as
borderline personality disorder
• Also used in the treatment of intractable hiccups
 Contraindications

Absolute
• Preexisting coma, acute stroke
• Severe intoxication with alcohol or other
central depressant drugs
• Known allergy against haloperidol or other
butyrophenones or other drug ingredients
• Known heart disease; when combined will
tend towards cardiac arrest
 Contraindications
Special caution needed
• Preexisting Parkinson's disease
• Patients at special risk for the development of QT
prolongation
• Compromised liver-function (as haloperidol is metabolized
and eliminated mainly by the liver, dose reductions and/or
spaced intervals may be needed)
• Patients with hyperthyreosis; the action of haloperidol is
intensified and side-effects are more likely. Initiate an
effective therapy of hyperthyreosis.
• IV injections: inject slowly to avoid hypotension or
orthostatic collapse. Avoid IV injections in cardiovascular
unstable patients (preexisting hypotension, shock,
concomitant antihypertensive therapy, heart insufficiency).
Prefer in these cases moderate oral or IM doses.
 Adverse effects
• Extrapyramidal side-effects
• Tardive dyskinesia
• Akathisia
• Dry mouth,
• Lethargy,
• Restlessness of akathisia,
• Muscle-stiffness,
• Muscle-cramping, restlessness, tremors,
• weight-gain;
 Section IV
Product
Information
 FAQ
• Q1: What is Serenace? (Which group does it belong
to? What is the composition?)
• Q2: What are the indications?
• Q3: How do we define the indications?
• Q4: What is EPS?
• Q5: How to handle EPS question?
• Q6: How to handle Atypical antipsychotics question?
• Q7: Why do doctors use liquid and injection?
• Q8: How does haloperidol differ from
chlorpromazine?
• Q9: What is the recommended dose of Serenace ?
 Q1: What is Serenace?

• Which group does it belong to?

– Main group Antipsychotic/ Neuroleptic/
Antischizophrenic
– Sub-group Typical / 1st generation antipsychotic

[Others: Atypical]
– Chemical group Butyrophenone

[Others:Phenothiazines,
Thioxanthines]
 Q1: What is Serenace? (Contd.)

• What is the composition?

– Serenace tablets
• Haloperidol 1.5 mg, 5 mg, 10 mg and 20
mg
– Serenace liquid 15 ml bottle
• Haloperidol 2 mg/ml
– Serenace injection 1 ml ampoule
• Haloperidol 5 mg/ml
Q2: What are the indications?

• Main indication Schizophrenia

• Others Acute psychoses
Delirium
Manic states
Anxiety states
Q3: How do we define the
indications?
– 2 kinds of psychiatric illnesses

– Psychosis Detached from reality

Eg. Schizophrenia,
Depression
– Neurosis In touch with reality
Eg. Anxiety
Q3: How do we define the
indications? (Contd.)
• Schizophrenia
– Positive symptoms
Agitation
Delusion (Impaired thought content ~ fixed false belief)
Hallucination (Impaired perception ~ false perception)
Disorganized speech
Disorganized behaviour (grooming)
– Negative symptoms
Withdrawal and apathy (flat emotion)
 Q3:How do we define the
indications? (Contd.)
• Schizophrenia (Contd.)
– Prevalence 1-3%,
disease of adolescent/young adult
– Sex equally distributed
– Age earlier in men
– Course 20% recover after 1st episode
50% relapse in 6-8 months
75% relapse in 18 months
Q3: How do we define the indications? (Contd.)

• Acute Psychosis
– Symptoms of schizophrenia for less
than 6 months
– DSM IV diagnosis based on symptom
duration
• < 1 month Brief psychotic disorder
• 1-6 months Schizophreniform disorder
• > 6 months Schizophrenia
 Q3: How do we define the
indications? (Contd.)

• Delirium Symptoms of schizophrenia

due to organic causes
(trauma, infection, cancer etc)

• Impairment of consciousness
• Marked distortion of perception of world
- Hallucinations - Illusions
- Delusions - Mood changes
 Q3: How do we define the indications?
(Contd.)

• Mania Symptoms: abnormally /

persistentlyelevated or
irritable mood
• Anxiety Fear disproportionate to
external stimulus, 10-15%
of all out-patients
 Q4: What is EPS?

• EPS ~ Extra-Pyramidal syndrome

• Why EPS with typical antipsychotics?
– Rx should block dopamine receptors (D2R) in
MESOLIMBIC pathway (responsible for emotions) →
cures psychotic symptoms
– Since D2R are present in NIGROSTRIATAL
pathway (responsible for movements), Rx blocks
D2R here too
→ causes movement disorders (EPS)
Q4: What is EPS? (Contd.)

• Kinds of EPS
Acute dystonia
• Sudden tonic contraction of muscles of
tongue, neck, back, mouth & eyes.
• Young males, early in treatment, 10%
Parkinsonism
• Rigidity (stiff muscles), Bradykinesia (shuffling
gait), tremors
• Women, > 40 years, early in treatment, 15%
Q4: What is EPS? (Contd.)

• Kinds of EPS (Contd.)

Tardive dyskinesia
• Late-onset (Tardive) movement disorder
(dyskinesia)
• Abnormal movement of muscles of head, limbs
and trunk
• Older patients, rare in early stages
 Q5: How to handle EPS
question?
• Reasons for preferring Serenace over others
– Side effect of EPS with Serenace better than
weight gain liabilities with atypical
antipsychotics
– EPS manageable - Once tolerance develops
no drugs for EPS required
– EPS minimal - Incidence of 10-15%, seen in
specific patient profiles (age, sex etc)
 Q6: How to handle Atypical
antipsychotics question?
• Quote from British Medical Journal
– Authored by : National Schizophrenia
Guideline Development Group, UK
– Conducted a systematic review of 52 trials
involving 12649 patients comparing typical
vs atypical antipsychotics.
Q6: How to handle Atypical antipsychotics
question? (Contd.)

• Weight gain liabilities with atypical

antipsychotics like olanzapine
• Glucose intolerance, Diabetes,
Dyslipidemia with atypical agents
 Q7: Why do doctors use liquid and
injection?
• Rapid neuroleptization
– For control of acute psychotic symptoms
– Cmax, inj= 30 min Cmax, oral = 1.5h
– Hourly IM doses till control is achieved
– Usual practice - Administer 2 doses and add a
sedative
 Q7: Why do doctors use liquid and
injection? (Contd.)
• Compliance
– Patients suffer from delusion of
persecution (someone is trying to
poison me) . You can mix the liquid in
fruit juice and administer
Q8: How does haloperidol differ from
chlorpromazine?

Phenothiazine side effects :

(Not usually occuring with
haloperidol)

• Postural hypotension.
• Weight gain and fluid retention.
• Soporific effects
• Hypothermia
 Q9: What is the recommended dose of
Serenace ?
• Acute cases
5-10 mg/day short-term
• Early (1st 6 mo)
5-20 mg/day
• Maintenance
Reduce dose by 50% over 3-6 months
Recommended optimal dose 6-12 mg (Am Psych
Assoc1997)
 Haloperidol v/s Olanzapine
Pathways HALOPERIDOL OLANZAPINE
1) MESOLIMBIC ++ +
2) MESOCORTICAL _ +
3) NIGROSTRIATAL ++ +

4) TUBERO- + _
INFUNDIBULAR
Conclusion :

 Haloperidol is a strong DA antagonist. Olanzapine is a

weaker binder of DA and hence weak DA antagonist.

 Olanzapine has less S/E like EPS and Gynaecomastia

as compared to Haloperidol, but is less efficacious as far
as controlling +ve symptoms of Schizophrenia are
concerned.
Tardive Dyskinesia
 Dopamine and Antipsychotics

• 65% D2 receptor occupancy is required for efficacy

• 80% D2 receptor occupancy is correlated with EPS
• Shorter time of D2 receptor occupancy is correlated
with lower EPS
 Research program to evaluate the
effectiveness of antipsychotic medications for
schizophrenia and Alzheimer’s disease in “real-
world” settings
 Side Effects of Atypical Antipsychotics: Shift in Risk Perception

Prior Safety Concerns Current Safety Concerns

Diabetes

Neurologic Side Effects

EPS + TD

Weight Gain CVD

Hyper
Glycemia
Weight
Gain

Insulin
Insulin CVD Dyslipidemia
Resistance
Resistance
Hyper-
QTc Hyper- lipidemia
glycemia EPS QTc
Schizophrenia Acute
Psychosis

Effectiv
e in Delirium
Manic
episodes in Mania,&
Bipolar Anxiety
 What is the recommended dose of
Serenace ?
• Acute cases
5-10 mg/day short-term
• Early (1st 6 mo)
5-20 mg/day
• Maintenance
Reduce dose by 50% over 3-6
months
Recommended optimal dose 6-12 mg (Am Psych
Assoc1997)
 Adverse Effects of Antipsychotic Medication
Adverse Haloperid Pericyazine Risperido Olanzapin Clozapine
ne
effects ol (Low pot) e
(High pot)
Sedation + +++ + ++ ++++

Postural + ++ ++ + +++
Hypotension

Anticholiner + +++ - ++ +++

gic effects

Extrapyrami +++ ++ ++ * -/+ -/+

dal effects

Weight Gain ++ + + ++ +++

Tardive +++ ++ + + ** + **
Dyskinesia
**
* Typically at doses over 6mg but may be lower in some patients
** Results extrapolated from shorter term trials

Adaopted from “Using the new antipsychotic agents” by Louric K Aust. Doc. No. 25, June 1999
Drug Daily oral Sedation Postural Anticholinergi Extrapyramid Weight gain
dose range hypotensio c al
(mg) n
Newer agents

clozapine 100-600 +++ +++ +++ +[NB1] +++

olanzapine 5-20 ++ + + +[NB1] ++

quetiapine 300-700 + ++ + +[NB1] ++

risperidone 0.5-6 + ++ 0 +[NB1] +

(initially)
Traditional agents

chlorpromazin 50-1000 +++ +++ ++ ++ ++

e
droperidol 5-10 (IM) ++ + + +++ +

fluphenazine 5-20 ++ + + +++ +

haloperidol 0.5-20 + + + +++ +

pericyazine 25-75 +++ ++ +++ ++ +

pimozide 2-12 ++ + + ++ +

thioridazine 50-600 +++ +++ +++ ++ ++

thiothixene 10-40 + + + +++ +

trifluoperazine 10-50 ++ + + +++ +

zuclopenthixol 50-150 (IM) +++ + ++ +++ +

acetate [NB2]

zuclopenthixol 10-75 +++ + ++ +++ +

dihydrochlorid
e
0 = negligible or absent; + = mild; ++ = moderate; +++ = marked; IM = intramuscular

[NB1] rarely a problem at usual therapeutic doses

[NB2] single dose, not to be repeated for 2 to 3 days

 Lipid
• Second name used for “fat”.
• Constitutes 18-25% of body mass.
• Usually insoluble in water but soluble in chloroform
& ether.
• Not more than 35% of energy intake should come
from fat. Saturated fat should not make up more
than 15% of the total fat intake.
 LIPID DIGESTION
• Stomach - lingual lipase and gastric lipase attack
triacylglycerols and hydrolyse a limited number of FA.

• Small Intestine - acid chyme (stomach contents) stimulates

mucosa cells to release hormone (choleocystokinin) which
stimulates gall bladder and pancreas to release bile and
digestive enzymes respectively (bile acids help emulsify fat
droplets thus increasing their surface area).

• Other mucosa cells release secretin which causes pancreas to

release bicarbonate rich fluid to neutralise chyme.
 FUNCTIONS OF LIPIDS:

• Major components of cell membranes.

• Required to solubilise fat soluble vitamins

• Biosynthetic precursors (e.g. steroid hormones from

cholesterol)

• Protection (e.g. kidneys are shielded with fat in fed

state)
• Insulation
Lipid family members
• Triglyceride:
– Most plentiful in body & diet.
– May be solid (fat) or liquid (oil) at room
temp.
– Highly concentrated form of energy.
– Provides 2 times more energy as compared
to carbohydrate & protein.
– Stored in adipose tissue.
Lipid family members
• Triglyceride:
– Cocoa butter, palm oil,& coconut oil
contains TG which has saturated fats.
– Olive oil & peanut oil contains TG which has
monounsaturated fats.
– Canola oil, corn oil, safflower oil, sunflower
oil,& soybean oil has polyunsaturated fats.
Lipid family members
• Phospholipids: lipid attached with phosphate group.
Major component of cell membrane.

• Cholesterol: minor component of cell membrane &

precursor of bile salts, vitamin D,& steroid harmone.

• Steroid: body cell synthesize steroid from

cholesterol.

• Bile salt: needed for digestion of fats.

• Vitamin D: helps in calcium absorption.

Enzymic digestion of lipids in small
intestine
2-monoacylglycerol
• Enzymic digestion generates more polar products that form
mixed micelles of free fatty acids, 2-monoacylglycerol,
cholesterol & bile salts that are adsorbed (except bile salts
which pass through to ileum – see later).

• Once adsorbed fatty acids and 2-monoacylglycerol are

recombined to form triacylglycerol.

• Triacylglycerol + cholesterol + phospholipid + proteins form

a lipoprotein complex called a chylomicron which transports
the lipids in the circulation.
 Apoproteins
• Apoproteins are only weakly associated with a
particular lipoprotein and are easily transferred
to another lipoprotein of a different class.
Apoproteins have various functions including:
– Structural role
– Binding sites for receptors
– Activators or co-enzymes for enzymes involved with
lipid metabolism
Apolipoprotein

ApoA -I
 Lipoproteins
• As lipids are hydrophobic hence only the
smallest lipid can dissolve in blood plasma.

• The other lipids to become soluble in blood

plasma form a complex with protein called
“Lipoprotein”.
 Lipid transport in the circulation

Proteins (apoproteins)

Cholesterol
Non polar lipids in
core
(TAG and
H O
HO
cholesterol esters)

Lipids are insoluble in plasma. In order to be transported they are

combined with specific proteins to form lipoproteins:
 The five classes of lipoprotein
(all contain characteristic amounts TAG, cholesterol,
cholesterol esters, phospholipids and apoproteins)

Diameter Major apoliproteins

Class (nm) Source and function
Chylomicrons 500 Intestine. Transport of A, B48, C(I,II,III) E
Increasing density

(CM) dietary TAG

Very low density 43 Liver. Transport of B100, C(I,II,III) , E
lipoproteins endogenously
(VLDL) synthesised TAG
Low density 22 Formed in circulation by B100
lipoproteins partial breakdown of
(LDL) IDL. Delivers cholesterol
to peripheral tissues

High density 8 Liver. Removes “used” A, C(I,II,III), D, E

lipoproteins cholesterol from tissues
(HDL) and takes it to liver.
Donates apolipoproteins
to CM and VLDL
 Chylomicrons
• Assembled in intestinal mucosal cells.
• They enter the lymphatic system and enter the blood via the thoracic
duct.
• They contain mostly TAG.
• Nascent chylomicrons contain apoprotein B48 but pick up others
apoproteins from high density lipoproteins (HDL) once they enter the
circulation.

Apoprotein
phospholipid

Cholesterol ester

Cholesterol

TAG (86%)
Function is to transport dietary TAG to the adipose tissues where
it can be stored as fat or to muscles where the constituent fatty
acids can be used for energy.
This animation shows how chylomicrons are metabolised
once they enter the circulation from the lymphatic system

B48
B48 Tissues

CM
CM CII
E Lipoprotein
B48 lipase

Taken up by CII
E CMR
liver (via LDL receptors)

E CII
B48
HDL
E CMR CII Capillary wall
(endothelial surface)
Chylomicron summary
• Synthesised in intestine.

• Contain mostly dietary TAG (with a little

cholesterol, cholesterol ester & phospholipid.

• Transport TAG to tissues and deliver remaining

cholesterol & cholesterol ester to the liver.
 Very Low Density Lipoprotein
(VLDL)
• Synthesised in the liver. Contain mostly TAG but with a significant
amount of cholesterol and cholesterol ester.
– 90% lipid, 10% protein
• Nascent VLDL contains apoprotein B100 but pick up others from
HDL in the circulation.
– Apo B-100
•Receptor binding
Apo C-II
•LPL activator
Apo E
•Remnant receptor binding

Function:
•Function is to transport endogenously synthesised TAG in
fasting state to the extra hepatic tissues where it can be stored
as fat or to muscles where the constituent fatty acids can be
used for energy. The cholesterol is delivered to extra hepatic
tissues once VLDL has been metabolised to LDL.
 This animation shows how VLDL are metabolised
once they enter the circulation from the liver

B100 Tissues

VLDL B100

LDL Lipoprotein
Some LDL taken up lipase
E CII
by liver (LDL receptors)

Having lost TAG to

tissues LDL contains a
large proportion of
cholesterol/cholesterol
esters
Capillary wall
Some LDL taken up by (endothelial surface)
other tissues (LDL receptors).
LDL delivers cholesterol and
TAG to the extra hepatic tissues.
E CII
HDL
 VLDL summary
• Synthesised in liver.
• Contain mostly dietary TAG (with a little
cholesterol, cholesterol ester & phospholipid.
• Converted to LDL which contain an increased
proportion of cholesterol & cholesterol ester (due
to loss of TAG).
• Transport TAG and cholesterol from liver to
tissues.
• Cholesterol in LDL referred to as “bad
cholesterol” since LDLs are implicated in
atherosclerosis
Intermediate Density Lipoprotein
(IDL)

Synthesized from VLDL during VLDL degradation

Triglyceride transport and precursor to LDL
– Apo B-100
• Receptor binding
– Apo C-II
• LPL activator
– Apo E
• Receptor binding
Low Density Lipoprotein (LDL)

– Synthesized from IDL

– Cholesterol transport
– 78% lipid, 58% cholesterol &
CE
– Apo B-100
• Receptor binding
High density lipoprotiens
• Act as a reservoir for apoproteins which can be donated or received from other lipoproteins.
• Also play a vital role in scavenging “used” cholesterol (reverse cholesterol transport):

apoproteins
HDL receptor mediated HDL
HDL endocytosis by liver
HDL
Liver
some cholesterol
ester transferred to
“used” cholesterol circulating VLDL
transferred to HDL and
converted to cholesterol
VLDL
ester

Cholesterol can be
LDLreceptor converted to bile salts
Peripheral mediated for excretion or
tissues LDL endocytosis LDL repackaged in VLDL
for redistribution
 High density lipoprotiens
summary
• HDL carries “used” cholesterol (as CE) back to the
liver. Also donate some CE to circulating VLDL for
redistribution to tissues.

• HDL taken up by liver and degraded. The

cholesterol is excreted as bile salts or repackaged in
VLDL for distribution to tissues.

• Cholesterol synthesis in the liver is regulated by the

cholesterol arriving through HDL (and dietary
cholesterol returned by chylomicron remnants).

• Cholesterol (CE) in HDL is referred to as “good

cholesterol”.
Pathway responsible for transport & maintenance of
lipid level-Exogenous pathway

TG in food

mixed with bile in GI tract

Absorbed by cell

combines with phospholipids, cholesterol & apolipoproten

forms chylomicrons

reaches to adipose & muscle tissue

lipoprotein lipase causes hydrolysis of TG

FFA are delivered to tissue

Endogenous pathway
Liver utilizes stored TG’s + cholesterol+
Phospholipids + apo B to form
VLDL

Receives Apo C-II (LPL activator) & Apo E

(Remnant receptor binding) from HDL

Reach to adipose tissue

& muscle tissue

Hydrolysis of TG by LPL to
Free fatty acid
LIPID TRANSPORT - Overview
 Reverse Cholesterol Transport and HDL

High Density Lipoprotein (HDL)

– Move lipids back to liver
– Lipid-free Apo A1 is secreted by
liver into circulation,
– ApoA1
• Scavenges free cholesterol
leaving tissue via the ABC-1
transporter
• Co-factor for enzyme lecithin-
cholesterol acyltransferase
(LCAT) that esterifies free
cholesterol
– Mature HDL is taken up by liver via
hepatic scavenger receptor class B
HDL: gives Apo C,E for
• Secreted to bile
VLDLclearance VLDL
• Steroid synthesis
(nascent) (serum)
• VLDL synthesis Apo B Apo B, C, E
 Hyperlipidemia
“ Hyperlipidemia is a state of increased in the concentration of
TG’s & cholesterol in blood.”

Cause :
1. Increased LDL
2. Decreased HDL
3. Increased remnants lipoprotein like IDL & CM
remnants.

Type:
a. Primary- Due to genetic defects
b. Secondary- Metabolic disturbance
 Fredrickson’s classification of
hyperlipidemia
• Type-1- elevation in CM & TG
• Type-2A- Elevation in LDL
• Type-2B- Elevation in both LDL & TG
• Type-3 - defect in VLDL remnant
clearance.
• Type-4 - TG level (250-500mg/dl)
• Type-5 - elevated level of CM & VLDL
 Arpitor
Arpitor is Atorvastatin. Atorvastatin is a potent
synthetic HMG CoA-reductase inhibitor. It
lowers plasma cholesterol levels by inhibiting
endogenous cholesterol synthesis.
Atorvastatin also has additional beneficial
effects on arterial structure and function i.e.,
anti-atherosclerotic and antithrombotic effects.
 MOA
HMG CoA Reductase
HMG CoA Reductase
Inhibitor

Arpitor

Mevalonic Acid

Cholesterol

The formation of mevalonate is the rate-limiting step in

endogenous cholesterol synthesis. This is catalyzed by the
enzyme HMG CoA reductase. Atorvastatin selectively &
competitively inhibits HMG CoA reductase. By decreasing the
production of mevalonate, Atorvastatin reduces hepatic
cholesterol biosynthesis
 Pharmacokinetic

• Absorption : Rapidly absorbed on

oral administration;
• Peak plasma levels: within 1-2 hours.
• Protein binding: 98%
• Its’ long-acting inhibitory effect is due to the
presence of active metabolites (Ortho and
Para hydroxylated derivatives). 70 % of
inhibitory action is due to the metabolites.
This is responsible for the high potency of
the drug
• Half-life : 14 hours
 Indication
• Atorvastatin is indicated to reduce
• Total-Cholesterol
• LDL cholesterol
• Apolipoprotein B
• Triglycerides
• in patients with Hypercholesterolemia and
combined hyperlipidemia.
 Dosage
– Initial dose 10mg/day
– Dose range 10 to
80mg/day.
– Atorvastatin can be administered as
single dose at any time of the day.
– Atorvastatin can be administered with
or without food
 Pleiotropic effects of
statins

• ↓ Platelet activation
• ↓ Coagulation
• ↑ Endothelial function
• ↓ Reactive oxygen species
• ↑ NO bioactivity
• ↓ AT1 receptor
• ↓ Effects on collagen
• ↓ MMPs
• ↓ Endothelin
 Side effects

• Atorvastatin is generally well tolerated,

with mild and transient reactions.Most
commonly reported side effects are
– Constipation
– Dyspepsia
– Flatulence
– Myalgia
– Allergy &
– Abdominal pain
 How is Atorvastatin superior to
Lovastatin ?

• More prolong inhibition of HMG

-CoA reductase.
• Leading to greater reduction in
LDL-C, TG, Apo-B and TC
•
Atorvastatin exhibited more potent
cholesterol lowering activity, as it
was more difficult to displace the
drug from the microsomal HMG A r p i t oL ro v a s t
CoA reductase.
• Greater reduction in LDL-C, TG, L D L -C -3 7 % -2
Apo-B and TC2
• T rig ly c e rid e -1 6 % -8
T o t a l C h o l e s t-e2 r7o%l -2
• Atorvastatin 10 mg produced
LDL-C reductions greater than Apo B -3 0 % -2
Lovastatin 20 and 40 mg

% P a t i e n t a c h 7i e8 %v e d 6
 How is Atorvastatin superior to
Lovastatin ?
• Effect seen from starting dose
• The maximum gain in life expectancy was
achieved with Atorvastatin
• 36 % reduction in cardiovascular complication
in CAD patient compared to patients
undergoing angioplasty.
• Ensures patients compliance
• Cost effective therapy
 How is Atorvastatin superior to
Simvastatin?

• More prolong inhibition of HMG

-CoA reductase. Leading to
greater reduction in LDL-C, TG,
Apo-B and TC.
• Atorvastatin exhibited more
potent cholesterol lowering
activity, as it was more
difficult to displace the drug A r p i t oS ri m va
from the microsomal HMG CoA
reductase. L D L -C -3 9 % -3
• Atorvastatin 10 mg produced T r ig ly c e r id e -2 7 % -1
LDL-C reductions comparable
or greater than T o t a l C h o l e s t- e3 0r o% l -2
• Simvastatin 10, 20 and 40 mg
• Effect seen from starting dose
% P a t i e n t a c h7 i 6e %v e d 5
T a r g e t L D L -C le v e ls
Effects of Statins on Lipids

S ta tin

R o su v a sta t
Effect of lipid-modifying therapies on
lipids

Therapy

Bile acid
sequestrants
Summary of Drug Choice

L ip id
abnorm
 What we will learn?

• Metabolism & Energy sources.

• How body utilizes these sources.
• Focus on INSULIN and its various roles
• Type-2 Diabetes mellitus & pathogenesis
 What we will learn?

• Diagnosis of Type-2 Diabetes mellitus

• Complications of Type-2 diabetes
• Mechanism of complications
• Management
• Pharmacological therapies available
 Energy for human life

Proteins
Carbohydrate

Fats
 Most common energy
sources
• Carbohydrates

• Fats
Most common energy sources

• Proteins
 Gasoline for human being

• Two major fuels –

– Glucose (Carbohydrate)
– Fatty acids (Fats)
 What is a Carbohydrate?
Carbohydrates are compounds which
have the following basic composition:
I
(CH2O)n or H - C - OH
I
Classified as –
 Monosaccharides
 Disaccharides
 Oligosaccharides
 Polysaccharides
Simple Sugars:Mono and
Disaccharides
• Monosaccharides – single sugar
unit
– Glucose
• Found in fruits, vegetables,
honey
• used for energy
– Fructose
• “fruit sugar”
• Found in fruits, honey, corn
syrup
– Galactose
• Found as part of lactose in milk
Disaccharides – two
linked sugar units
– Sucrose: glucose + fructose
• “table sugar”
• Made from sugar cane and sugar
beets
– Lactose: glucose + galactose
• “milk sugar”
• Found in milk and dairy products
– Maltose: glucose + glucose
• Found in germinating cereal
grains
• Product of starch breakdown
 Complex Carbohydrates

• Oligosaccharides
– dried beans, peas, lentils
• Rafinose (gal-glu-fru)
• Stachyose (gal-gal-gal-fru)
• Metabolized by intestinal bacteria
• Gaseous effects
 Complex Carbohydrates

• Polysaccharides
– contain 100’s or 1000’s of
monosaccharide units
– starch-digestible
– fiber-indigestible
– Glycogen
 Glycogen
• Importance
– Stored form of glucose.
– Major sites – Muscles and Liver; 75% is stored in
muscles.
– Liver: major site for glycogen synthesis
• ~10% of wet weight of liver
– Muscles
• Glycogen < 1% weight
• Used as energy when body requires energy.
• Important for “instant” energy
 Glycogen Storage

• Skeletal muscle
– Function: serve as fuel reserve for
synthesis of ATP during muscle contraction
• Liver
– Function: maintain blood glucose
concentration in times of fasting

Total amount of stored carbohydrate is

sufficient to fulfill the energy requirements of
a person for ~1/2 day!
Carbohydrate Digestion

Also known as
a-glucosidase
enzymes
 Metabolism of Carbohydrates

• Glucose is primary energy source for

the human body
• Brain is the most important glucose
consumer (50%)
• Metabolism results in:
1. Energy (ATP) production (conversion to CO2 +
H2O)
2. Storage as glycogen in liver or triglyceride in
adipose tissue
3. Conversion to keto acids, amino acids, or
protein
Regulation of Blood Glucose
Concentration

Glycolysis Glycogenesis

Pathways of Glucose Metabolism

Gluconeogenesis Glycogenolysis
 Glycolysis (glucose  pyruvate)
• Derived from the Greek stem glyk-,
"sweet," and the word lysis,
"dissolution."
• Glycolysis: sequence of reactions that
metabolizes one molecule of glucose to
2 molecules of pyruvate (triose sugar)
• Also produce 2 molecules of ATP
• Anaerobic
– Pyruvate to lactate
• Aerobic
– Pyruvate to acetyl-CoA
 Gluconeogenesis

• Synthesis of glucose from noncarbohydrate

sources (pyruvate, amino acids, lactic acid)
• Converts lactate or amino acids to glucose
in starvation or stress
• Opposite of glycolysis
Glycogenesis (glucose  glycogen)
i.e. genesis = creation
• In times of glucose excess (after eating), any
glucose that is not used immediately is taken
up by the liver and muscle where it can be
converted into glycogen
• Glycogen is synthesized depending on the
demand for glucose and ATP (energy)
• If both are present in relatively high amounts,
then the excess of insulin promotes the
glucose conversion into glycogen for storage
in liver and muscle cells
Glycogenolysis (glycogen  glucose)
i.e. lysis = break down

• When blood glucose concentration

drops, there is a breakdown of
glycogen to make glucose
• Mobilizes stored glycogen in liver &
skeletal muscle
Regulation of Blood Glucose

• Glucose metabolism is under the

control of various hormones.

Most common are -

– Insulin
– Glucagon
– Epinephrine
– Somatostatin
Regulation of Blood Glucose
• Pancreas: Islet of
Langerhans (α , β , δ )

– Controls blood
glucose levels by
secreting hormones
into the blood
1. α -cells (20-30% of
islet cells)
- Glucagon
1. β -cells (60-70% of
islet cells)
- Insulin
1. δ -cells (2-8% of islet
cells)
- Somatostatin
 Insulin
• First hormone
identified
(1920’s) by
Banting and
Best
• Released when
glucose is
abundant
(elevated plasma
glucose) and
stimulates:
 How insulin is synthesized?

Preproinsulin
NH2

S S

S S

HOOC
S S
 How insulin is synthesized?

Proinsulin
NH2

S S

S S

HOOC
S S
 How insulin is synthesized?

Insulin
HOOC NH2 β -
chain
S S

S S

HOOC NH2 α -
S S chain

C - peptide ESR11-08
 Role of C-Peptide
• Insulin is difficult to measure
• Half-life is only 5 mins
• Rapidly inactivated by various
enzymes.
• C-Peptide has 30 mins half life
• Synthesized in equimolar conc to
that of insulin
• Determines amount of insulin
secreted from b-cell
 How insulin is secreted?
• Insulin is secreted in 2 phases –
1. First phase
– Sharp peak
– Within 3-5 mins of glucose intake
– Completed within 10 mins
– Release of mature granules.

• Promotes peripheral utilization of the

prandial nutrient
load.
• Suppresses hepatic glucose output.
• Limits post prandial glucose elevation
 How insulin is secreted?

2. Second phase
– Release of secretory
granules that are mobilized
within the beta cell for
release.
– Granules contain newly
synthesized insulin.
– Second Phase helps to
attain normoglycemia.
 Insulin – the “hormone of
plenty”
• Increases glucose uptake by muscle and adipose
cells
• Helps in increasing cells to breakdown glucose,
releasing its energy in the form of ATP
• The liver and muscle to store glucose as glycogen
(short-term energy reserve)
• Adipose tissue to store glucose as fat (long-term
energy reserve)
• Glycogen synthesis and protein synthesis

Insulin is the ONLY hormone that lowers

circulating glucose level!
Insulin: Summary
 Where insulin affects?
Insulin

Muscles Liver

Glucose Glycogenolysis
Uptake
Gluconeogenesis
Adipose cells
Glycolysis
Glycogenesis Lipogenesis

Brings plasma glucose level back to normal

 Glucagon Action on Cells:
Dominates in Fasting State Metabolism
• Secreted from a-cells of pancrease

• Major target organ: liver

• Stimulates production of glucose by glycogenolysis

and gluconeogenesis

• Glucagon prevents hypoglycemia by ↑ cell production

of glucose

• Principal hormone for producing a rapid increase in

plasma glucose concentration

• Secretion is suppressed in hyperglycemia

Glucagon Action on Cells

Endocrine response to hypoglycemia

 Epinephrine – “fight or flight”

• Catecholamine secreted by the adrenal

medulla
• Serves as a backup for glucagon

• Stimulates glucagon secretion and inhibits

insulin secretion by pancreas
• Stimulates glycogen breakdown
(glycogenolysis) and decreases glucose use
• Physical/emotional stress epinephrine
production, releasing glucose for energy
 Somatostatin

• Secreted by g-cells of pancreas

• Primary act is to inhibit secretion of

insulin and glucagon

• Secreted by range of tissues

(pancreas, intestines, CNS)
 Main Human Glucose
Transporters
Transporter Tissue Insulin
dependent?
GLUT1 RBCs, brain, kidney No

GLUT2 β -cells of pancreas, No

small intestine, kidney
GLUT3 Neurons, placenta No

GLUT4 Skeletal & cardiac YES

muscle, adipose tissue

GLUT5 Small intestine, kidney, No

brain, adipose tissue
GLUT7 Some liver cells No
 Insulin Secretion
Ca++

K+ Depolarization
Voltage
ATP
dependent Ca+
sensitive K+ +
channels
channels
Binds and open
closes

Ca++
Glucose ATP

Secretary
granules
GLUT-2

Insulin
High
Glucose
 Insulin

Insulin
Receptor

Seri
es o
f e nz
reac
tion

GLUT 4
 Mode of action of Insulin

Glucose
Insulin enters

Insulin GLUT-4
Receptor
Translocation
of GLUT-4
Series of
reaction
Glucose

Glycogen Glycolysis
Mode of action of insulin
Sources of blood glucose in the various nutritional states

fed postabsorptive gluconeogenic prolonged

40 Exogenous
(glucose
Glucose 30 from diet)
glucose from
Used gluconeogenesis
g/hr glucose from (lactate + amino acids) glucose from
20 liver glycogen gluconeogenesis
(mostly lactate)

10

0
4 8 12 16 2 7 42
HOURS DAYS
 Hyperglycemia & Hypoglycemia

 Hyperglycemia – too
little insulin

 Hypoglycemia – too little

intake or too much insulin
What’s “normal”?
Action of Insulin on LIPID metabolism
Triglycerides

Insulin
Non esterified Fatty acid (NEFA or FFA)

Acetyl CoA Ketone bodies

Hence insulin -
•Decreases lipolysis
•Increases lipogenesis
•Decreases ketoacidosis
Insulin on Protein metabolism
Amino acid

Insulin

Protein

Insulin –
•Increases protein synthesis
•Decreases proteolysis
Summary of insulin action
Increases –
– Glucose uptake
– Glycolysis
– Glycogenesis
– Lipogenesis
– Protein synthesis

Decreases –
•Gluconeogenesis
•Glycogenolysis
•Lipolysis
•Ketogenesis
•Proteolysis
Diabetes Mellitus
Disease, Pathogenesis &
Management
 Definition
A group of metabolic disorders comprising
of abnormal carbohydrate, fat and protein
metabolism and characterized by chronic
or persistence hyperglycemia
 Due to lack of insulin hormone
OR
 Improper insulin secretion
Risk Factors for Diabetes
• Family history of diabetes
• Obesity (> 20% over desired body weight or BMI > 27 kg/m2
• Age > 45 years
• Sedentary life style
• Some ethnic groups ( Indians, African-Americans and native
Americans, asian americans)
• Gestational diabetes or delivering a baby weighing more than 9
pounds (4kg or more)
• High blood pressure ( > 140/90mmHg)
• High blood levels of triglycerides (> 250mg/dl)
• low HDL cholesterol level (<35mg/dl)
Symptoms of diabetes
• Frequent urination - Polyuria
• Excessive thirst - Polydypsia
• Excessive hunger - Polyphagia
• Fatigue
• Weight loss
• Blurred vision.

Symptoms more prominent in

Type-1 DM
Types of Diabetes Mellitus

• Most common types are –

– Type-1 Diabetes mellitus

– Type-2 Diabetes mellitus

– Gestational diabetes.
 Type-1 Diabetes mellitus

• Due to total destruction of b-cells of the pancreas.

• Autoimmune destruction of islets
• Most prominent during childhood
• Therapy involves Insulin injection
Type-2 Diabetes mellitus

• Most common type of diabetes (>90%)

• Related to genetic defect and life style and
food habits.
• Consists of 2 common defects –
1. Insulin resistance
2. B-cell impairment or Impaired insulin
secretion.
Genes & / or Life style and
diet

Abnormal
Insulin β -cell
resistance function

Type 2 diabetes
 Insulin resistance

• Decreased ability of normal insulin to act

effectively on peripheral tissues (muscle
& adipose tissues) and liver.

• b-cell has to secrete more insulin to

maintain normal glucose level.
Cause of Insulin resistance
FFA has been found to be one
of the major culprit

• Central or visceral obesity is the major cause

• Adipocytes secretes high conc of FFA.
• FFA enters muscle cells and interferes with
insulin signaling system
• Thereby less GLUT 4 translocation
• Less glucose uptake
Cause of Insulin resistance

• Adipocytes also secretes various

biochemicals like resistin, leptin, THF-α
& adiponectin

• Low adiponectin level or high conc of

resistin, leptin, THF-α has been
associated with insulin resistance
 Hyperinsulinemia
• Persons with IR, requires higher insulin level to
bring glucose back to normal.

• B-cells secretes additional insulin to compensate.

• Puts additional stress on b-cells

• Person may be normal or diabetic

• Risk factor for various cardiovascular disease

 Hyperinsulinemia
800
Insulin resistance
700
Insulin secretion (pmol/min)

Healthy
600

500

400

300

200

100

6 a.m. 10 a.m. 2 p.m. 6 p.m. 10 p.m. 2 a.m. 6 a.m.

Time
 B-cell impairment
• Condition where the beta cells are unable to produce
sufficient insulin as per rise in blood glucose level due
to both reduced β-cell mass and functional
abnormalities of the β-cell.
• Reduced β-cells works hard to compensate for the
synthesis of adequate insulin.
• Leads to β-cell fatigue.
• Development of progressive rise in glucose level
• Leading to development of frank diabetes type-2
 Natural History of Type 2 Diabetes
Obesity IGT* Diabetes Uncontrolled
Hyperglycemia
Postmeal
Plasma glucose
glucose
Fasting glucose
120 (mg/dL)

Relative β -cell Insulin resistance

function Progressive reduction in beta cell mass
100 (%)
Insulin level

-20 -10 0 10 20 30
Years of diabetes

Adapted from International Diabetes Center, Minneapolis, Minnesota.

 Result of IR & b-cell
impairment

1. Decrease glucose uptake in storage cells

2. Increased glucose production from liver

Hyperglycemia
 Types of Diabetes Type-2

• Obese
– Very high degree of insulin resistance
compared to b-cell impairment
• Non-obese
– Very high degree of b-cell impairment
compared to insulin resistance
Diagnosis of Type-2 Diabetes

FPG (Fasting plasma glucose test)

Category FBS (mg/dl)

Normal < 100
Impaired (IFG) 100 - 125
Diabetes ≥ 126
IFG = Impaired fasting glucose tolerance
 Diagnosis of Type-2
Diabetes
OGTT (Oral glucose tolerance test)

Category PPG (mg/dl)

Normal < 140
(IGT) OR Prediabetic 140 - 199
Diabetes ≥ 200
IGT = Impaired glucose tolerance
 Glycosylated Hemoglobin test
(HbA1c)

• Glucose forms irreversible

complex with proteins

• Normal value 4 - 6%

• Used to monitor during

treatment

• Gives a good indication of

blood glucose during the
previous 3 - 4 months.

• Target level of less than 7.0

% indicates good control
Complications of Type-2 Diabetes
mellitus
 Complications
• Acute complications
• Diabetes Ketoacidosis (DKA)
• Non-ketotic hyperosmolar state (NKHS)

• Chronic complications
• Vascular
• Non-vascular
 Diabetic Ketoacidosis (DKA)

Life threatening complication in Type-1 DM o

patients with lack of insulin
Inadequate insulin

Excess lipolysis leading to increased FFA

Increases ketone bodies leading to ketoacidosis

Coma or death
 Diabetic Ketoacidosis (DKA)

Symptoms are –
• Nausea and vomiting.
• Thirst / polyuria.
• Abdominal pain.
• Altered mental function.
• Shortness of breath.

Treatment – Insulin
injection
 Non-Ketotic Hyperosmolar
State (NKHS)
• reported in all age groups, but it most frequently affects
older patients with type 2 diabetes
• initiating event in hyperosmolar hyperglycemic state is
glucosuric diuresis
• Decreased intravascular volume or underlying renal
disease decreases the glomerular filtration rate, causing
the glucose level to increase.
• The loss of more water than sodium leads to
hyperosmolarity
 Non-Ketotic Hyperosmolar
State (NKHS)

Symptoms are –
• Polyuria.
• Orthostatic hypotension.
• Neurological symptoms like - altered
mental status,
lethargy, seizure and possibly coma.

Treatment
1. Vigorous intravenous rehydration,
2. Electrolyte replacement
3. Administration of intravenous insulin,
 Chronic Complications

• Vascular
– Microvascular
– Retinopathy
– Neuropathy
– Nephropathy
– Marcovascular
– Cardiovascular disease
– Cerebrovascular disease
– Peripheral vascular disease
Layers of blood vessels
Hyperglycemia damages only a particular
subset of cell types:
capillary endothelial cells in the retina,
mesangial cells in the renal glomerulus,
and neurons and Schwann cells in peripheral
nerves.

What is distinct about these cells that makes

them so vulnerable to hyperglycemia?
So why does damage occur only in the few cell
types involved in diabetic complications? The
answer is that
• Most cells are able to reduce the
transport of glucose inside the cell
when they are exposed to
hyperglycemia, so that their internal
glucose concentration stays
constant.

• In contrast, the cells damaged by

hyperglycemia are those that cannot
do this efficiently.
• Thus, diabetes selectively damages cells,
like endothelial cells and mesangial cells,
whose glucose transport rate does not
decline rapidly as a result of
hyperglycemia, leading to high glucose
inside the cell.

• This is important, because it tells us that

the explanation for what causes
complications must involve mechanisms
going on inside these cells, rather than
outside.
Important 4 pathways which cause
complications are:

• Increased Flux Through the Polyol Pathway

• AGE pathway

• PKC pathway

• Hexosamine pathway
PAI-1
 Microvascular Complications

Retinopathy
• Leading cause of blindness
• Starts with a small areas of
balloon-like swelling in the
retina's tiny blood vessels.
Hemorrhages in non-proliferative diabetic
• As the disease progresses, retinopathy
blood vessels that nourish
the retina are blocked.

New blood vessel growth around optic nerve in

proliferative diabetic retinopathy
 Microvascular Complications
Retinopathy
• At this advanced stage,
the signals sent by the
retina for nourishment
trigger the growth of
new blood vessels.
• These new blood
vessels are abnormal
and fragile.
• If they leak blood,
severe vision loss and
even blindness can
result. Hemorrhage from new blood vessel growth in proliferative
diabetic retinopathy
 Microvascular Complications

Neuropathy
• Damage to the nerves that helps to feel sensations such as
pain
• Two types

1. Peripheral Neuropathy
• Nerve damage in the feet can result in a loss of
foot sensation, increasing risk of foot problems.
Symptoms include –
• Tingling
• Numbness (severe or long-term numbness
can become permanent)
• Burning
 Microvascular Complications

Neuropathy
2. Autonomic Neuropathy

• Autonomic neuropathy most often affects the digestive

system, especially the stomach, blood vessels, urinary
system, and sex organs. Symptoms can be –

– Bloating, Diarrhea, Constipation, Heartburn, Nausea,

Vomiting, Feeling full after small meals
– Blacking out when you stand up quickly , Increased heart rate,
Dizziness, Low blood pressure
– Sexual dysfunction (males & females)
– Unable to completely empty bladder, Bloating, Incontinence
(leaking urine), Increased urination at night
 Microvascular Complications

Diabetic Nephropathy
• Most common cause of
kidney failure.
• Five stages in the progression to
kidney failure in people with
diabetes

• Stage 1 (very early diabetes) Increased demand upon

the kidneys is indicated by an above-normal glomerular
filtration

• Stage 2 (developing diabetes) The GFR remains

elevated or has returned to normal; development of
microalbuminuria
 Microvascular Complications
Diabetic Nephropathy

• Stage 3 (overt, or dipstick-

positive diabetes or
macroalbuminuria);
Hypertension may develop

• Stage 4 (late-stage
diabetes). "advanced clinical
nephropathy." GFR < 75
milliliters per minute. Almost all
patients have hypertension at
stage 4.
• Stage 5 (end-stage renal disease, ESRD) -
GFR <10 mL/min) and renal
replacement therapy (i.e., hemodialysis, peritoneal
dialysis, kidney transplantation)
is needed
Macrovascular Complications

Cardiovascular
complications
• More than 60% of DM patients dies
due to CAD
• Most common CVD includes –
• Hypertension
• CAD
• Heart Failure
 Macrovascular Complications
Cardiovascular
complications
Hypertension
Category SBP DBP
Normal < 120
and < 80
Pre hypertension 120- 139 and / or
80-89
Hypertension
Stage 1 140 - 159 and / or
90-99
Stage 2 Sustained increase
>160 in “Systolic
and“/ Blood
or
>100 Pressure > 140 mmHg and / or
“Diastolic” Blood Pressure > 90
Macrovascular Complications
Cardiovascular
complications
Hypertension

● Closely associated with Hyperinsulinemia

● High insulin may cause Na+ & H2O
retention
●Diabetes patients has higher risk of
developing hypertension than normal
persons.
Macrovascular Complications
Cardiovascular
complications
Manageme
nt
● Therapeutic lifestyle management
● Pharmacological therapy
● Most preferred choices are ACEI and ARBs
● Others – Diuretics, Calcium channel
blockers, b-blockers etc
Macrovascular Complications
Cardiovascular
complications
CAD (Coronary Artery
Disease
When there is an Imbalance between

Demand of Blood Supply of Blood

(Oxygen) (Oxygen)
Macrovascular Complications

Cardiovascular
complications
• Causes of Obstruction
Atheroma (Atherosclerosis)
Thrombosis
Embolism
Spasm
Macrovascular Complications
Cardiovascular
complications
Symptoms
Angina Pectoris
– Stable

– Unstable

– Variant or Prinzmetal’s

Acute Myocardial Infarction

Macrovascular Complications
Cardiovascular
complications

Heart attack
• Death of muscle tissue
due to lack of oxygen
Macrovascular Complications
Cardiovascular
complications
Manageme
nt
Life Style Modifications

Drug Therapy

Surgery -Bypass and Angiolasty

 Macrovascular Complications
Cardiovascular
complications
• Therapy
• O2 supply O2 demand

• Drugs
• Nitrates
• Beta blockers
• Calcium channel blockers
• Potassium channel openers
• Metabolic modifier
Macrovascular Complications
Cardiovascular
complications

Surgical Procedures
• Bypass surgery
• Balloon angioplasty
 Macrovascular Complications
Cardiovascular
complications
Heart Failure
Inability of the heart to pump sufficient blood to
meet the body’s metabolic requirement

Major cause - CAD

• Class I : Heart disease with no limitations in physical activity

• Class II : Heart disease with slight limitations in physical activity.
Comfortable at rest
• Class III : Heart disease with marked limitations in physical activity.
May present at rest
• Class IV : Heart disease with discomfort at any activity
Macrovascular Complications

Cerebrovascular
complications
Stroke
Blood supply is interrupted,
resulting in tissue death and loss of
brain function

Transient Ischemic
Attack (TIA)
A brain disorder caused by
temporary
disturbance of blood supply to an
area of the brain, resulting in a
sudden, brief decrease in brain
Macrovascular Complications
Peripheral vascular disease

• Blocking of an artery
in the peripheral
region of the body
• Major cause -
atherosclerosis
 Non Vascular Complications
•Galucoma, Cataract
•Diabetic foot ulcer
•Gastroparesis
•Sexual dysfunction
•Skin changes
Biochemical mechanism of
the development of diabetic
complications
 Hypothesis 1

Activation of protein kinase Cβ

Increase glucose level

Increase formation of diacylglycerol

Activates enzyme Protein Kinase Cβ

Increases cell proliferation and permeabilty

Damage to cells
 Hypothesis 2

Glycation
Increased glucose level

Forms complexes with cellular proteins called

AGE (Advanced glycated end products)

Causes cellular dysfunction

 Hypothesis 3

Oxidative stress
High glucose

Increases formation of reactive intermediates of

oxygen reduction - O2-, H2O2 and OH-

May cause oxidative damage to proteins, lipids

and nucleotides leading to cell damage.
 Hypothesis 4

Polyol Pathway

Hyperglycemia

Conversion of Glucose to Sorbitol by “aldolase

reductase”

Causes osmotic changes in cells

Cellular damage
Management of Diabetes Type-2
 Goals

Immediate Goals: to stabilize the blood

sugar
Long-term goals:
To prolong life,
Relieve symptoms, and
Prevent long-term complications
Treatment Modalities

• Life style modifications

– Diet and Exercise

• Pharmacological therapy.
Importance of achieving tight
glycemic control
• Various landmark studies have confirmed that
by decreasing glucose level there is a
significant reduction in risk of microvascular
and macrovascular complications.

– UKPDS (United Kingdom Prospective Diabetes

Study)
– DCCT (Diabetes Control and Complication Trial)

– The Kumamoto Study

– DPP
 UKPDS

• Objective: improved glucose control of

Type 2 diabetes will prevent clinical
complications

• Design: Prospective observational study in

23 hospital based clinics in England, Scotland,
and Northern Ireland. 3642 patients were
included in analyses of relative risk. Total
duration was approximately 10 years.
 UKPDS
Results: Each 1% reduction in mean HbA1c was
associated with reductions in risk of -
– 21% for any end point related to diabetes,

– 21% for deaths related to diabetes,

– 14% for myocardial infarction, and

– 37% for microvascular complications

Conclusions: Any reduction in HbA1c is likely to reduce

the risk of complications, with the lowest risk being in
those with HbA1c values in the normal range ( < 6.0%).
 DCCT
• Clinical study conducted from 1983 to 1993 by
the National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK)

• Involved 1,441 volunteers with type 1 diabetes

and 29 medical centers in the United States
and Canada. Volunteers had diabetes for at
least 1 year but no longer than 15 years.

• They also were required to have no, or only

early signs of, diabetic eye disease.
 DCCT
• The study compared the effects of two
treatment regimens—standard therapy and
intensive control—on the complications of
diabetes.

Result : Lowering blood glucose reduces risk

– Eye disease (Retinopathy) - 76% reduced risk

– Kidney disease (Nephropathy) - 50% reduced risk

– Nerve disease (Neuropathy) - 60% reduced risk

– Cardiovascular disease - 35%

 Kumamoto Study

• OBJECTIVE — To examine whether intensive glycemic

control could decrease the frequency or severity of
diabetic microvascular complications.

• DESIGN - 110 patients with type 2 diabetes (55 with no

retinopathy and 55 with simple retinopathy were
randomly assigned to multiple insulin injection therapy
(MIT) groups and administered three or more daily
insulin injections or assigned to conventional insulin
injection therapy (CIT) groups and administered one or
two daily intermediate-acting insulin injections. Incidence
of nephropathy (normoalbuminuria, microalbuminuria,
and albuminuria) were also monitored.
 Kumamoto Study

• RESULTS — the cumulative percentages of worsening

in retinopathy and nephropathy were significantly lower in
the MIT group than in the CIT group.

• CONCLUSIONS — Intensive glycemic control can

delay the onset and progression of the early stages of
diabetic microvascular complications in Japanese
patients with type 2 diabetes.
United States Diabetes Prevention
Program: Results

Intensive Lifestyle
Placebo Intervention Metformin
(n = 1082) (n = 1079) (n = 1073)

Wt loss: 0.1 kg Wt loss: 5.6 kg Wt loss: 2.1 kg

Diabetes: 29% Diabetes: 14% Diabetes: 22%

United States Diabetes Prevention
Program: Results
Intensive Lifestyle
Placebo Intervention Metformin
(n = 1082) (n = 1079) (n = 1073)

Wt loss: 0.1 kg Wt loss: 5.6 kg Wt loss: 2.1 kg

Diabetes: 29% Diabetes: 14% Diabetes: 22%

Risk reduction: Risk reduction:
58% 31%
Anti - Diabetic Drugs
Type-2 Diabetes Mellitus
• Oral Hypoglycemic agents.
– Sulfonylureas – e.g., Glibenclamide, Gliclazide,
Glipizide and Glimepiride.
– Non-sulfonylureas (Magletinides) – e.g.,
Repaglinide and Nateglinide.
• Anti-hyperglycemic agents.
– Insulin sensitizers –
Biguanides – e.g., Metformin.
Thiazolidinediones – e.g., Rosiglitazone and
Pioglitazone.
– α -Glucosidase inhibitors – e.g., Acarbose,
Miglitol.
Anti - Diabetic Drugs
• Insulin analogoues – e.g., Bovine, porcine
and human.
• Newer agents –
– Aldolase reductase inhibitors – e.g., Aminoguanidine.

– Insulin mimetic agents – e.g., Vanadium salts.

– Glucagon antagonists – e.g., β 3-adrenergic agonists.

– Potentiators of insulin secretion – e.g., Glucagon like

peptide amide.
Combination therapy

Commonly used combinations are:

– Sulfonylurea and metformin
– A glitazone and a Sulfonylurea or insulin
– Non- SU and metformin
– Sulfonylurea and insulin
– Any other drug mentioned above and insulin
 Triple Therapy

The use of a glitazone in combination with

metformin and a sulfonylurea in patients
who have not responded to monotherapy
or with combination of two oral agents have
also been approved by FDA.
 Treatment Failure

• Primary failure
• No response with a drug given for
the first time
• Secondary failure
• Gradual lose of action of a drug
when used for a prolonged period.
E.g., Sulfonylureas.
BENCLAMET
(Metformin)
 BENCLAMET (Metformin)

• Belongs to the class of drugs

called Biguanides

• Oral antihyperglycemic agent

 Mechanism of action

Decreases gluconeogenesis

Less Glucose output from liver

Decreases glucose in blood

Glucar to some extent can also -

● Improves insulin sensitivity in peripheral
tissues.

● Decrease intestinal absorption of glucose.

 Pharmacokinetics

– Food decreases and delays absorption

– Bioavailabilty is 50 - 80% under fasting

conditions.
– Excreted unchanged in urine.

– Plasma half-life is 6.2 hours.

 Pharmacodynamics

Effect On Blood Glucose

• Significantly decreases hepatic glucose
production.
• Decreases fasting and postprandial plasma
glucose, but mainly FPG.
 Pharmacodynamics
Cardioprotective effects

Variables Effects
Bodyweight Decrease
BPNo effect
Triglycerides Decrease to neutral
Total Cholesterol Decrease to neutral
LDL Decrease to variable
HDL Increase to variable
Lipoprotein(a) Decrease
Hypercoagulability Decrease
C-Reactive Protein Decrease to variable
Endothelial function Improve
Cardiovascular Events Decrease
 Indication
• Drug of first choice in obese with type-2
diabetes mellitus.
• USFDA approved in children > 10 years of
age with type-2 DM.
• Metabolic Syndrome.

• IGT and to prevent diabetes in patients with

IGT.
 Dosage
• Dose of BENCLAMET has to be individualized

• The recommended starting dose of

BENCLAMET is 500 mg b.i.d or 850 mg once a
day with meals.

• The maximum dose is 2550 mg per day.

• BENCLAMET can be combined with insulin,

sulfonylureas or glitazones if there is no
response with monotherapy.
Adverse Effects
• Diarrhea, nausea, vomiting, abdominal
bloating, flatulence, anorexia, which
decreases with continuous use.

• Unpleasant metallic taste, which resolves

spontaneously
Drug Interactions

There is no significant drug

interactions with BENCLAMET
Contraindications
• Hypersensitivity.

• Acute or chronic acidosis.

• Renal disease.

• Congestive heart failure.

 Precautions & Warnings

• Incidence of lactic acidosis is very low with

This is particularly in patients with renal
disease.

• Alcohol may potentiate effects of metformin

on lactate metabolism.

• Hypoglycemia may occur when used as a

combination therapy.
GLIMETOP
Glimepiride
GLIMETOP
GLIMETOP is an oral hypoglycemic and
belongs to class of drugs known as
Sulfonylurea.

GLIMETOP is a second generation

sulfonylurea.
 Mode of Action
• Binds with sulfonylurea receptors (SUR) and
causes closure of ATP sensitive K+ channels.

• This leads to depolarization of cell membrane.

• Voltage dependent Ca++ channels open up.

• Influx of extracellular Ca++ triggers release of

insulin.

GLIMETOP can stimulate the release

of insulin from functional beta cells
 Mode of action
• Some extrapancreatic effect also, that
is GLIMETOP also increases peripheral
insulin sensitivity to some extent.

• Major effect is due to stimulation of

beta cells
Pharmacokinetics
• Some active metabolites are present.
• Excreted in feces.
• Elimination half-life is 5 hours, can increase to 9
hours after multiple doses.

• No significant differences in pharmacokinetics

of elderly.
 Pharmacodynamics
• Significantly improves both first and second
phase of insulin secretion.

• Stimulates insulin production primarily after

meals when glucose concentrations are
highest, but controls glucose throughout the
day.

• Causes significant decrease in serum HbA1c

level.
 Pharmacodynamics
• Maintains myocardial preconditioning.

• Causes significantly less hypoglycemia

compared to glibenclamide.

• Safe in renal failure patients; no dosage

adjustment is required.
 Indications
• Treatment of type-2 diabetes mellitus as an
adjunct to diet and exercise

• First drug of choice in lean type-2 diabetic

patients

• Combination therapy with metformin,

thiazolidinediones and insulin.
 Dosage
• The recommended starting dose is 1-2 mg
once daily with breakfast or the first main meal.

• Maximum dose is 8 mg. if patients do not

respond to maximum dose, add metformin.

• Attempts should be made to identify the

effective dose of each drug.
Adverse effects
• Hypoglycemia

• Vomiting, gastrointestinal pain & diarrhea

• Rare skin reactions like pruritus, erythema,

urticaria

• Agranulocytosis, thrombocytopenia, etc

Contraindications
• Hypersensitivity.

Warnings & Precautions

• Hypoglycemia may occur.
• Loss of control of blood glucose is seen
when patient is exposed to stress, infection
or surgery.
• Should not be used in pregnancy, nursing
mothers and children.
Drug Interactions
• Hypoglycemic action is potentiated with
NSAID’s, salicylates, sulfonamides,
chloramphenicol, & beta blockers.

• Drugs are thiazides, diuretics, corticosteroids,

phenothiazines, thyroid products, estrogens,
oral contraceptives, nicotinic acid may cause
hyperglycemia
Advantage over Glibenclamide
• Lower risk of hypoglycemia (due to quicker
dissociation from receptors).
• Faster onset of action (due to quicker
binding to receptors).
• Better protection during ischemia and better
myocardial preconditioning, hence better
cardioprotective effect.
• Less beta cell fatigue (due to quicker
dissociation from receptors, hence less
stimulation).
Advantage over
Glipizide
The efficacy of Glimepiride is similar to
that of glipizide, however, glimepiride
produced a more rapid lowering of
fasting plasma glucose levels than
glipizide.
Advantage over Gliclazide

In clinical trials efficacy were similar. However

Glimepiride has a genuine once a day dose
compared to gliclazide which has to be given
preferably bid.
 Overall Advantage of
Glimepiride
• Glimepiride is recommended as once a day
therapy. Whereas all other sulfonylureas are
recommended as bid at higher dosage.

• Glimepiride do not, at least in theory,

stimulate insulin secretion in the presence of
normoglycemia or when there is no food
intake.

• Glimepiride is the only sulfonylurea which is

USFDA approved to be used with insulin.

• Glimepiride appears to possess a greater

insulin-sparing property than other
sulfonylureas.
GLYTOP-SR
 GLYTOP-SR

COMPOSITION
Each tablet contains :
Glipizide 5 mg/10 mg in a SR form

INDICATION
• Type 2 Diabetes Mellitus
 GLYTOP-SR

RATIONALE
• Longer acting agents like
glibenclamide are efficacious but have
1) Higher rates of hypoglycemia

• Shorter acting agents like immediate

release glipizide are efficacious and
have low risk of hypoglycemia but have
2 disadvantages :
(i) Dosing more than OD
(ii) Greater excursions in plasma drug
levels
Ref : Simonson D, diabetes Care 1997; 20(4): 597-
606.
 What is the mechanism of
action of Glytop-SR?
• Like other SUs, stimulate insulin
release from pancreatic beta cells
by blocking potassium channels.
• Unlike other SUs, binds almost to
pancreatic K+ channels (140kDA &
65kDa protein)
 GLYTOP-SR

PHARMACOKINETICS

• Tmax : 6-12 h
• Steady state : 5th day
6-7 days in elderly
• Effect of food : None
• Metabolism : Liver (90%)
• Excretion : Urine and feces
 GLYTOP-SR
DOSAGE
Initial
No fixed dosage regimen
Recommended starting dose : 5mg OD with breakfast
Maximum : 20mg OD
Switch from conventional Glipizide
Nearest equivalent dose
Switch from other SUs
Start with 5mg OD
Type 2 DM Patients on Insulin
<20 units - discontinue insulin, start with 5mg OD Glytop-
SR
>20 units -Reduce insulin dosage by 50% and start
5mgOD Glytop-SR.
 GLYTOP-SR

COMPETITION
vs. Conventional Glipizide

1. Superior in lowering FBG

2. Less peak to trough
fluctuations
3. Incidence of hypoglycemia
comparable
 GLYTOP-SR

COMPETITION

vs. Glibenclamide

1. Lesser risk of hypoglycemia

2. Equieffective
3. Lower C-peptide
concentrations
 GLYTOP-SR
USPs
• Most frequently used sulfonylurea in US
(Skyler JS, Medical Clinics of N. America
1998)
• Potent and rapid acting - PPBG control
• 24 hour effect - Nocturnal and FBG control
• Better than IR Glipizide with respect to :
- FBS control
- Plasma insulin
• No effect on lipid profile, body weight and
exercise induced hypoglycemia