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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

Cellular level
22 Cells are made up of
moleces 1 Chemical level
Atoms combine
to form molecules

Tissue level
3 Tissues consist
of similar types
of cells

Organismal level
6 The human
Connective organism is made
tissue up of many organ
systems
Organ level
4 Organs are made up Organ system level
of different types of 5 Organ systems consist of
tissues different organs that work Figure 1.1
together closely

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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%

Cellular level
Cells are the microscopic fundamental units of all living things. Every living thing
has cells: bacteria, protozoans, fungi, plants, and animals are the main groups
(Kingdoms) of living things. Some organisms are made up of just one cell (e.g.
bacteria and protozoans), but animals, including human beings, are multicellular.
An adult human body is composed of about 100 trillion cells! There are about
200 different kinds of specialized cells in the human body.

Specialized Cells of the Human Body

Nerve Cells: Also called Neurons, these cells are in the nervous system and
function to process and transmit information. They are the core components of
the brain, spinal cord and peripheral nerves. They use chemical and electrical
synapses to relay signals throughout the body.

Epithelial cells: Functions of epithelial cells include secretion, absorption,


protection, transcellular transport, sensation detection, and selective
permeability. Epithelium lines both the outside (skin) and the inside cavities and
lumen of bodies.

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Exocrine cells: These cells secrete products through ducts, such as mucus,
sweat, or digestive enzymes.

Endocrine cells: These cells are similar to exocrine cells, but secrete their
products directly into the bloodstream instead of through a duct. Endocrine cells
are found throughout the body but are concentrated in hormone-secreting glands
such as the pituitary.

Blood Cells: The most common types of blood cells are:

Red blood cells (erythrocytes). The main function of red blood cells is to
collect oxygen in the lungs and deliver it through the blood to the body
tissues.

White blood cells (leukocytes) they are produced in the bone marrow
and help the body to fight infectious disease and foreign objects in the
immune system. White cells are found in the circulatory system, lymphatic
system, spleen, and other body tissues.

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Cellular structure

Cell Membranes
The boundary of the cell, sometimes called the plasma membrane, separates
internal metabolic events from the external environment and controls the
movement of materials into and out of the cell. The plasma membrane is a
double phospholipid membrane, or a lipid bilayer.

Cytoplasm
The gel-like material within the cell membrane is referred to as the cytoplasm. It
is a fluid matrix, the cytosol, which consists of 80% to 90% water, salts, organic
molecules and many enzymes that catalyze reactions, along with dissolved
substances such as proteins and nutrients. The cytoplasm plays an important
role in a cell, serving as a "molecular soup" in which organelles are suspended
and held together by a fatty membrane.

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Cytoskeleton:
Threadlike proteins that make up the cytoskeleton continually reconstruct to
adapt to the cells constantly changing needs. It helps cells maintain their shape
and allows cells and their contents to move.

Nucleus

Controls the cell; houses the genetic material (DNA). The nucleus is the largest
of the cells organelles. Cells can have more than one nucleus or lack a nucleus
all together. Skeletal muscle cells contain more than one nucleus whereas red
blood cells do not contain a nucleus at all.
The nucleus contains the DNA, as mentioned above, the hereditary information
in the cell. Normally the DNA is spread out within the nucleus as a threadlike
matrix called chromatin. When the cell begins to divide, the chromatin condenses
into rod-shaped bodies called chromosomes, each of which, before dividing, is
made up of two long DNA molecules and various histone molecules. The
histones serve to organize the lengthy DNA, coiling it into bundles called
nucleosomes.

Ribosomes :
Ribosomes play an active role in the complex process of protein synthesis,
where they serve as the structures that facilitate the joining of amino acids.

Mitochondria:
Mitochondria are the organelles that function as the cell "powerhouse",
generating ATP, the universal form of energy used by all cells. It converts food
nutrients such as glucose, to a fuel (ATP) that the cells of the body can use.
Mitochondria are tiny saclike structures found near the nucleus.

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Endoplasmic Reticulum:

Endoplasmic means "within the plasma" and reticulum means "network".


A complex three dimensional internal membrane system of flattened sheets, sacs
and tubes, that play an important role in making proteins and responsible for
various activities, including the synthesis of lipids and hormones, especially in
cells that produce these substances for export from the cell.
Rough endoplasmic reticulum is the site where proteins not destined for the
cytoplasm are synthesized.
Smooth endoplasmic reticulum provides a variety of functions, including lipid
synthesis and degradation, and calcium ion storage.

Golgi Apparatus :

"Packages" cellular products in sacs called vesicles so that the products can
cross the cellmembrane and exit the cell. The Golgi apparatus is the central
delivery system for the cell.

Lysosomes :

Lysosomes are sac-like compartments that contain a number of powerful


degradative enzymes. They are built in the Golgi apparatus. They break down
harmful cell products and waste materials, cellular debris, and foreign invaders
such as bacteria, and then force them out of the cell.

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Cell Metabolism
Cell metabolism is the total energy released and consumed by a cell.
Metabolism describes all of the chemical reactions that are happening in the
body.

•Catabolism: The energy releasing process in which a chemical or food is used


(broken down) by degradation or decomposition, into smaller pieces.

•Anabolism: Anabolism is just the opposite of catabolism. In this portion of


metabolism, the cell consumes energy to produce larger molecules via smaller
ones.

.Your body is performing both anabolic and catabolic reactions at the same time
and around the clock, twenty four hours a day, to keep your body alive and
functioning. Even while you sleep, your cells are busy metabolizing.

Tissue level
Tissue is group of cells which are similar in structure and which perform
common or related functions.

Basic kinds of tissue

1. Epithelial Tissue: 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

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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

2. Connective Tissue:
Most abundant & widely distributed tissue.
 Connective Tissue Functions:
o Connects, binds and supports structures,((Tendons, ligaments,
etc.)
o Protects organs and tissues,
o Major site of energy storage.
o Transports substances (blood).
o Main site for immune response.

3. Muscle Tissue:
a. Muscle tissue consists of fibers that are specialized for contraction.
It provides motion & maintenance of posture.
b. Skeletal muscle tissue is attached to bones & its action is voluntary.

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c. Cardiac muscle tissue forms most of the heart & its action is
involuntary.

Muscle Tissue Functions:


i. Movement
ii. Maintains posture
iii. Produces heat
iv. Pumps blood
v. Peristalsis

4. 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.

Organ level
Organs are composed of the four kinds of tissues arranged in various proportions
and patterns: sheets,tubes, layers, bundles, strips, and so on. For example,the
kidneys consist of (1) a series of small tubes, each composed of a single layer of
epithelial cells; (2) blood vessels, whose walls contain varying quantities of
smooth muscle and connective tissue; (3) nerve-cell extensions that end near the
muscle and epithelial cells;(4) a loose network of connective-tissue elements that
are interspersed throughout the kidneys and also form enclosing capsules; and
(5) extracellular fluid andmatrix.

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Organ system
System Major Organs or Primary Functions
Tissues
Circulatory Heart, blood vessels, Transport of blood throughout the body’s
blood

Respiratory Nose, pharynx, Exchange of carbon dioxide and oxygen


larynx, trachea,
bronchi, lungs
Digestive Mouth, pharynx, Digestion and absorption of nutrients,
esophagus,Intestines
, salivary glands,
pancreas, liver
gallbladder
Urinary Kidneys, ureters, excretion of salts, water, and organic
bladder, urethra wastes
Musculoskeletal Cartilage, bone, Support, protection, and movement
ligaments, tendons,

Immune White blood cells, Defense against foreign invaders


lymph vessels and
nodes
Nervous Brain, spinal cord, states consciousness; learning; cognition
peripheral nerves

Endocrine All glands secreting Regulation and coordination of many


hormones: Pancreas, activities

Reproductive Male: Testes, penis, Production of sperm; transfer of sperm


and associated ducts Production of eggs; provision of a nutritive
Female: Ovaries, mammary glands environment for the
uterine tubes, uterus, developing embryo and fetus; nutrition of
vagina, the infant
Integumentary Skin, Nails, Hair Protection against injury and dehydration;
defense against foreign invaders;
regulation of
temperature

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What is Homeostasis?
Homeostasis in a general sense refers to stability, balance or equilibrium.
Maintaining a stable internal environment requires constant monitoring and
adjustments as conditions change. This adjusting of physiological systems within
the body is called homeostatic regulation.
Homeostatic regulation involves three parts or mechanisms: 1) the receptor, 2)
the control center and 3) the effector.

The receptor receives information that something in the environment is changing.


The control center or integration center receives and processes information from
the receptor. And lastly, the effector responds to the commands of the control
center by either opposing or enhancing the stimulus.

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Orientation and Directional Terms

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Pharmacology

Pharmacology is derived from Greek word. pharmakon, "drug"; and -logia is the
study of drug action. More specifically, it is the study of the interactions that occur
between a living organism and exogenous chemicals that alter normal
biochemical function. If substances have medicinal properties, they are
considered pharmaceuticals.

The field encompasses drug composition and properties, interactions, toxicology,


therapy, and medical applications and antipathogenic capabilities Pharmacology
deals with how drugs interact within biological systems to affect function.

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It is the study of drugs, of the body's reaction to drugs, the sources of drugs, their
nature, and their properties. In contrast, pharmacy is a medical science
concerned with the safe and effective use of medicines.

Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of
a living organism, alters normal bodily function.

In pharmacology, a drug is "a chemical substance used in the treatment, cure,


prevention, or diagnosis of disease or used to otherwise enhance physical or
mental well-being." Drugs may be prescribed for a limited duration, or on a
regular basis for chronic disorders.

Route of administration
A route of administration in pharmacology and toxicology is the path by which
a drug, fluid, poison, or other substance is brought into contact with the body.

A substance must be transported from the site of entry to the part of the body
where its action is desired to take place. The pharmacokinetic properties of a
drug (that is, those related to processes of uptake, distribution, and elimination)
are critically influenced by the route of administration.

Classification
Routes of administration can broadly be divided into:

• Topical: local effect, substance is applied directly where its action is


desired.
• Enteral: desired effect is systemic (non-local), substance is given via the
digestive tract.
• Parenteral: desired effect is systemic, substance is given by routes other
than the digestive tract.

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The U.S. Food and Drug Administration recognizes 111 distinct routes of
administration. The following is a brief list of some routes of administration.

Topical

• Epicutaneous (application onto the skin), e.g. allergy testing, typical local
anesthesia.
• Inhalational, e.g. asthma medications
• Enema, e.g. contrast media for imaging of the bowel
• Eye drops (onto the conjunctiva), e.g. antibiotics for conjunctivitis
• Ear drops - such as antibiotics and corticosteroids for otitis externa
• Intranasal route (into the nose), e.g. decongestant nasal sprays. Nasal
administration can also be used for systemic effect. This is related to the
transmucosal route through a mucous membrane via insufflation.
• Vaginal, e.g. topical estrogens, antibacterials

Enteral
Enteral is any form of administration that involves any part of the gastrointestinal
tract:

• By mouth (orally), many drugs as tablets, capsules, or drops


• By gastric feeding tube, duodenal feeding tube, or gastrostomy, many
drugs and enteral nutrition
• Rectally, various drugs in suppository or enema form

Parenteral by injection or infusion

• Intravenous (into a vein), e.g. many drugs, total parenteral nutrition


• Intraarterial (into an artery), e.g. vasodilator drugs in the treatment of
vasospasm and thrombolytic drugs for treatment of embolism
• Intramuscular (into a muscle

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• Intracerebral (into the cerebrum) direct injection into the brain


• Intracerebroventricular (into the cerebral ventricles) administration into the
ventricular system of the brain.
• Intracardiac (into the heart), e.g. adrenaline during cardiopulmonary
resuscitation (no longer commonly performed)
• Subcutaneous (under the skin), e.g. insulin,
• Intraosseous infusion (into the bone marrow
• Intradermal, (into the skin itself) is used for skin testing some allergens,
and also for mantoux test for Tuberculosis
• Intrathecal (into the spinal canal) is most commonly used for spinal
anesthesia and chemotherapy
• Intraperitoneal, (infusion or injection into the peritoneum) e.g. peritoneal
dialysis.
• Intravesical infusion is into the urinary bladder.
• Intracavernosal injection is into the base of the penis.

Advantages and disadvantages


There are advantages and disadvantages to each route of administration

Inhalation

Advantages

• Fastest method, 7–10 seconds for the drug to reach the brain
• User can titrate (regulate the amount of drug they are receiving)

Disadvantages

• Typically a more addictive route of administration because it is the fastest,


leading to instant gratification. In addition, drugs taken by inhalation do not
stay in the bloodstream for as long, causing the user to redose more

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quickly and intensifying the association between consuming the drug and
its effects.
• Difficulties in regulating the exact amount of dosage
• Patient having difficulties administering a drug via inhaler

Injection
Injection in compasses intravenous (IV), intramuscular (IM), and subcutaneous
(subcut)

Advantages

• Fast: 15–30 seconds for IV, 3–5 minutes for IM and subcutaneous
• 100% bioavailability.
• suitable for drugs not absorbed by the gut or those that are too irritant
(anti-cancer)
• One injection can be formulated to last days or even months, e.g., Depo-
Provera, a birth control shot that works for three months
• IV can deliver continuous medication, e.g., morphine for patients in
continuous pain, or saline drip for people needing fluids

Disadvantages

• Onset of action is quick, hence more risk of addiction when it comes to


injecting drugs of abuse
• Patients are not typically able to self-administer
• Belonephobia, the fear of needles and injection.
• If needles are shared, there is risk of HIV and other infectious diseases
• It is the most dangerous route of administration because it bypasses most
of the body's natural defenses, exposing the user to health problems such
as hepatitis, abscesses, infections, and undissolved particles or
additives/contaminants

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• If not done properly, potentially fatal air boluses (bubbles) can occur.
• Need for strict asepsis

Oral route

Advantage

• Oldest & commonest route


• 2. Safe, convenient, noninvasive, and often painless.
• 3. Medicament need not to be sterile hence economical.
• 4. Both solid and liquid can be given this route easily.

Disadvantage

• May cause nausea vomiting


• Cannot be used in unconscious and uncooperative patient.
• Action is slower hence not suitable for emergencies.
• Certain drugs destroyed by gastric juice in stomach

Dosage form

A dosage form (DF) is the physical form of a dose of a chemical compound used as a
drug or medication intended for administration or consumption.

Types

Oral

• Pill, tablet, or capsule


• Specialty tablet like buccal, sublingual, or orally-disintegrating
• Thin film (e.g., Listerine Pocket Paks)
• Liquid solution or suspension (e.g., drink or syrup)

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• Powder or liquid or solid crystals

Inhalational

• Aerosol
• Inhaler
• Nebulizer
• Vaporizer (usually to vaporize natural herbs like marijuana)

Parenteral Injection

• Intradermal (ID)
• Intramuscular (IM)
• Intraosseous (IR)
• Intraperitoneal (IP)
• Intravenous (IV)
• Subcutaneous (SC)

Topical

• Cream, gel, liniment or balm, lotion, or ointment, etc


• Ear drops (optic)
• Eye drops (ophthalmic)
• Skin patch (trans dermal)

Suppository

• Rectal (e.g., enema)


• Vaginal (e.g, douche, pessary, etc.)

Specialized dosage form

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Many tablets today are coated after being pressed. Coating is also performed for
the following reasons:

1. Controlling site of drug release


2. Providing controlled, continuous release or reduce the frequency of drug
dosing
3. Maintaining physical or chemical drug integrity
4. Enhancing product acceptance and appearance

Types of coating

1. Enteric coating: An enteric coating is a barrier applied to oral


medication that controls the location in the digestive system where it is
absorbed. Enteric refers to the small intestine, therefore enteric coatings
prevent release of medication before it reaches the small intestine.
2. Film coating: Film coated tablets are more durable, less bulky, and mask
the taste of tablet.
3. Sugar coating: Sugar coating is done by rolling the tablets in heavy
syrup, in a similar process to candy making. It is done to give tablets an
attractive appearance and to make pill-taking less unpleasant.

Pharmacokinetics
Pharmacokinetics (in Greek: “pharmacon” meaning drug and “kinetikos”
meaning putting in motion, the study of time dependency; sometimes abbreviated
as “PK”) is a branch of pharmacology dedicated to the determination of the fate
of substances administered externally to a living organism

Pharmacokinetics is often studied in conjunction with pharmacodynamics.


Pharmacodynamics explores what a “drug does to the body”, whereas
pharmacokinetics explores what the “body does to the drug”.

Pharmacokinetics includes the study of the:

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• Mechanisms of absorption and distribution of an administered drug,


• The rate at which a drug action begins and the duration of the effect,
• The chemical changes of the substance in the body (e.g. by enzymes) and
the effects and routes of excretion of the metabolites of the drug.

ADME
Pharmacokinetics is divided into several areas which includes the extent and rate
of Absorption, Distribution, Metabolism and Excretion. This is commonly referred
to as the ADME scheme. However recent understanding about the drug-body
interactions brought about the inclusion of new term Liberation. Now
Pharmacokinetics can be better described as LADME.

• Liberation is the process of release of drug from the formulation.


• Absorption is the process of a substance entering the body.
• Distribution is the dispersion or dissemination of substances throughout
the fluids and tissues of the body.
• Metabolism is the irreversible transformation of parent compounds into
daughter metabolites.
• Excretion is the elimination of the substances from the body. In rare
cases, some drugs irreversibly accumulate in a tissue in the body.

Pharmacokinetics describes how the body affects a specific drug after


administration. Pharmacokinetic properties of drugs may be affected by elements
such as the site of administration and the concentration in which the drug is
administered. These may affect the absorption rate.

Absorption
In pharmacokinetics, absorption is the movement of a drug into the
bloodstream.

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Absorption involves several phases. First, the drug needs to be administered via
some route of administration (oral, via the skin, etc.) and in a specific dosage
form such as a tablet, capsule, and so on.

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
Bioavailability is a measurement of the rate and extent of a therapeutically active
drug that reaches the systemic circulation and is available at the site of action. It
is denoted by the letter F.

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)

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Protein binding

Protein binding generally refers to the binding of a drug to proteins in blood


plasma. The interaction can also be between the drug and tissue membranes,
red blood cells, and other components of the blood.

The amount of drug bound to protein determines how effective the drug is in the
body. The bound drug is kept in the blood stream while the unbound components
of the drug may be metabolized or extracted, making them the active part of the
drug. So, if a drug is 95% bound to a binding protein and 5% is free, that means
that 5% of the drug is active in the system and causing pharmacological effects.

Metabolism
Metabolism is the set of chemical reactions that occur in living organisms to
maintain life. These processes allow organisms to grow and reproduce, maintain
their structures, and respond to their environments.

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.

Drug metabolism
The metabolism of a drug or toxin in a body is an example of a biotransformation.
Typically the body deals with a foreign compound by making it more soluble, to
increase the rate of its excretion through the urine. There are a number of
different process that can occur; the pathways of drug metabolism can be divided
into:

• phase І

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• phase II

Drugs can undergo one of four potential biotransformations: Active Drug to


Inactive Metabolite, Active Drug to Active Metabolite, Inactive Drug to Active
Metabolite, Active Drug to Toxic Metabolite (biotoxification).

Phase I reaction

• Includes oxidative, reductive and hydrolytic reactions.

• In these type of reactions, a polar group is either introduced or unmasked,


so the drug molecule becomes more water-soluble and can be excreted.

• Phase I reactions are Non-synthetic in nature & generally produce a more


water soluble & less active metabolite.

• The majority of Phase I metabolites are generated by a common


hydroxylating enzyme system known as cytochrome P450.

Phase II reaction

• These reactions involve covalent attachment of small polar endogenous


molecule such as glucuronic acid, sulfate, or glycine to form water-soluble
compounds.

• This is also known as a conjugation reaction.

• The final compounds have a larger molecular weight.

First pass effect


The first-pass effect (also known as first-pass metabolism or presystemic
metabolism) is a phenomenon of drug metabolism whereby the concentration of
a drug is greatly reduced before it reaches the systemic circulation

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After a drug is swallowed, it is absorbed by the digestive system and enters the
hepatic portal system. It is carried through the portal vein into the liver before it
reaches the rest of the body. The liver metabolizes many drugs, sometimes to
such an extent that only a small amount of active drug emerges from the liver to
the rest of the circulatory system.

This first pass through the liver thus greatly reduces the bioavailability of the
drug. Alternative routes of administration like suppository], intravenous,
intramuscular, and sublingual avoid the first-pass effect because they allow drugs
to be absorbed directly into the systemic circulation.

The four primary systems that affect the first pass effect of a drug are the
enzymes of the gastrointestinal lumen, gut wall enzymes, bacterial enzymes, and
hepatic enzymes.

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 kinetics

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

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amount of drug eliminated is more, while at lower concentrations of drug: the


amount of drug eliminated is lower.

Zero order kinetics

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.

IV
AUC
Cmax

1/2 Cmax

Serum MEC
levels or MIC

Oral Tmax 1/2 life


AUC : Amount of drug absorbed along with rate of
absorption and time required to achieve maximum conc.
Significance - AUC directly proportional to efficacy or
action

Definitions

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 AUC - Area Under the Curve - it is the extent of absorption of drug in the
body
 MEC - Minmum Effective Concentration- it is the least concentration of
the drug in the plasma/blood required to produce therapeutic effect
 Tmax - it is the time required to achieve maximum concentration in
blood/tissues
 Cmax - it is the maximum concentration achieved by the drug in
blood/tissues.

Half life

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

Pharmacodynamics
Pharmacodynamics is the study of the physiological effects of drugs on the
body or on microorganisms or parasites within or on the body and the
mechanisms of drug action and the relationship between drug concentration and
effect.

Pharmacodynamics is often summarized as the study of what a drug does to the


body, whereas pharmacokinetics is the study of what the body does to a drug.
Pharmacodynamics is sometimes abbreviated as "PD", and when referred to in
conjunction with pharmacokinetics can be referred to as "PKPD".

Effects on the body


The majority of drugs either (a) mimic or inhibit normal physiological/biochemical
processes or inhibit pathological processes in animals or (b) inhibit vital
processes of endo- or ectoparasites and microbial organisms.

There are 5 main drug actions:

• depressing

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• stimulating
• destroying cells (cytotoxicity)
• irritation
• replacing substances

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


intracellular, that bind to drug and mediate pharmacological actions.

Drug + receptor Drug-receptor complex Effect

Agonist
An agonist is a drug that binds to a receptor of a cell and triggers a response by
the cell. An agonist often mimics the action of a naturally occurring substance.

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Types
Receptors can be activated or inactivated either by endogenous (such as
hormones and neurotransmitters) or exogenous (such as drugs) agonists and
antagonists, resulting in stimulating or inhibiting a biological response.

A physiological agonist is a substance that creates the same bodily


responses, but does not bind to the same receptor.

An endogenous agonist for a particular receptor is a compound naturally


produced by the body which binds to and activates that receptor. For example,
the endogenous agonist for serotonin receptors is serotonin, and the
endogenous agonist for dopamine receptors is dopamine.

A superagonist is a compound that is capable of producing a greater maximal


response than the endogenous agonist for the target receptor, and thus has an
efficacy of more than 100%.

Full agonists bind (have affinity for) and activate a receptor, displaying full
efficacy at that receptor. One example of a drug that acts as a full agonist is
isoproterenol which mimics the action of adrenaline at β adrenoreceptors.

Partial agonists (such as buspirone, aripiprazole, buprenorphine, or


norclozapine) also bind and activate a given receptor, but have only partial
efficacy at the receptor relative to a full agonist.

An inverse agonist is an agent which binds to the same receptor binding-site as


an agonist for that receptor and reverses constitutive activity of receptors.
Inverse agonists exert the opposite pharmacological effect of a receptor.

Antagonist

A receptor antagonist is a type of receptor drug that does not provoke a

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biological response itself upon binding to a receptor, but blocks or dampens


agonist-mediated responses.

In pharmacology, antagonists have affinity but no efficacy for their cognate


receptors, and binding will disrupt the interaction and inhibit the function of an
agonist or inverse agonist at receptors. Antagonists mediate their effects by
binding to the active site or to allosteric sites on receptors, or they may interact at
unique binding sites not normally involved in the biological regulation of the
receptor's activity.

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.

Therapeutic window

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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.

Additive Effect

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.

Synergistic effect

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.

Drug dosing

 OD - Once daily

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 BD - twice daily
 TD - Thrice daily
 QD – In a day
 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- 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

With the object of xxx its safety and/or efficacy

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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.

CARDIOVASCULAR SYSTEM

Introduction of cardiovascular system


Cardiovascular system comprises of:
1. Heart
2. Blood Vessels
3. Blood

What is the composition of blood?


The blood is composed of two parts:
• The plasma (liquid part, 55%)

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• The blood cells (45%)


A healthy adult has a blood volume of about 5 liters.

What is Plasma?
It is the liquid part of blood into which float different types of blood cells; i.e. RBC,
WBC & platelets;
• It contains several salts, glucose, amino acids, proteins, hormones, and
also digested and excretory products of food.
Serum is blood plasma from which the blood clotting protein called fibrinogen is
removed.

Which are the types of blood cells?


There are three types of blood cells:
1. Red blood cells or erythrocytes (RBCs)
• Approximate number in blood is 5 million cells/ cubic mm of blood.
Contain haemoglobin, which helps in carrying O2
2. White blood cells or Leucocytes (WBCs)
• Approximate number is 4000-11,000 cells / cubic mm of blood.
Function is to destroy bacteria, viruses and debris that enter the body
and form Special proteins, called antibodies that protect against
infection.
3. Platelets or thrombocytes
• Approximate number is between 1.5 lac-4.5 lac cells / cubic mm of
blood. Help in clotting.

What are the functions of blood?


The important functions of blood are as follows:
• Transports: Gases,waste products of metabolism (e.g. water, urea),
Hormones, Enzymes,

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• Nutrients (such as glucose, amino acids, micro-nutrients (vitamins &


minerals) etc.
• Maintains Body Temperature
• Controls pH
• Removes toxins from the body
• Toxins removed from the blood by the kidneys leave the body in the form
of urine & sweat
• Regulation of Body Fluid Electrolytes: Excess salt is removed from the
body in urine, which may contain around 10g salt per day
• To serve as defense against infections & injuries

What is haemoglobin and its function?


Haemoglobin is a complex protein that is rich in iron. It is found in RBCs. It
combines with oxygen to form oxy-haemoglobin and thus transports oxygen from
the lung to each and every cell. The carbon dioxide formed as a result of
metabolic reactions, binds with haemoglobin to form carboxyhaemoglobin and is
carried to the lungs for expulsion. Thus haemoglobin helps in carrying oxygen in
the body.

The normal haemoglobin levels in different age group.


Adults male - 14-18 g/dl
Adult female - 12-16 g/dl
Infants - 14-20 g/dl
Decrease in Haemoglobin concentration below normal is known as Anaemia,
where the oxygen carrying capacity of the blood is reduced.

Normal range of Hematological values

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What are the different types of blood vessels?


These are 3 types of Blood vessels
1. Arteries - Vessels which carries blood away from the heart. They carry
oxygenated blood with the exception of pulmonary artery. Arteries are
further subdivided into smaller vessels called arterioles, which further
subdivide into hairy thin capillaries at the cellular level.
2. Veins - Vessels which carry blood towards the heart. They carry
deoxygenated blood with the exception of pulmonary vein. Veins are
further subdivided into smaller vessels called venules.
3. Capillaries - These are the smallest blood vessels and many are not
visible through naked eyes. Exchange of O2, CO2, hormones, enzymes,
ions, glucose, etc with the cells, all takes place through the capillaries.

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Fig. Artery, capillaries and venules

Which are the layers of the walls of the arteries and veins?
Arteries and veins are made up of 3 layers -
• Tunica Externa, which is the outer most layer and is made of fibrous
Tissue.
• Tunica Media is the middle layer and the most important layer. This is
made of smooth muscle and elastic Tissues. The smooth muscles help
in contraction and dilation of the blood vessels, especially the arteries.
This helps in maintaining the tone of the blood vessels.
• Tunica Intima is the innermost layer. The intima is lined by a single
layer of cell called endothelium.

Fig. Artery, vein and capillary

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Capillaries are made of single layer of epithelial tissue called endothelium to


facilitate free exchange of essential materials.

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THE HEART

Introduction
Heart is located in the middle of the chest (a little towards the left) behind the
breastbone, between the lungs.

Anatomy of Heart

The heart is composed of 4 chambers -


• Two atria (left and right)
• Two ventricles (left and right)

The inter-ventricular septum is an internal wall that separates the right and left
ventricles.

Fig. Anatomy of the heart

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Four valves present in the heart to regulate the blood flow. They are -
1. Tricuspid Valve - Situated between right atrium and right ventricle.
2. Pulmonary Valve - Situated between right ventricle and beginning of
pulmonary artery.
3. Bicuspid valve (Mitral valve) - Situated between left atrium and left
ventricle.
4. Aortic Valve - Situated between left ventricle and the aorta.

Superior Vena Cava


Veins from the head and upper body drain the deoxygenated blood into the
superior vena cava, which empties into the right atrium of the heart.

Inferior Vena Cava


Veins from the legs and lower torso drain the deoxygenated blood into the
inferior vena cava, which empties into the right atrium of the heart.

Aorta
It is the largest blood vessel in body. It carries oxygen-rich blood from the left
ventricle to the various parts of the body.

Pulmonary Artery
It is the vessel transporting de-oxygenated blood from the right ventricle to the
lungs.
Pulmonary Vein It is the vessel transporting oxygen-rich blood from the lungs to
the left atrium.

Right Atrium
Receives de-oxygenated blood from the body through the superior vena cava
(head and upper body) and inferior vena cava (legs and lower parts).

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Right Ventricle
Receives de-oxygenated blood as the right atrium contracts, and sends blood to
lungs through pulmonary artery for oxygenation.

Left Atrium
The left atrium receives oxygenated blood from the lungs through the pulmonary
vein.

Left Ventricle.
The left ventricle receives oxygenated blood as the left atrium contracts.

What are the different layers of heart?


The heart is composed of 3 layers -
1. Pericardium - It is the outermost layer and covers the heart
2. Myocardium - This is the thickest layer of the heart and consists of special
muscle fibres called the cardiac muscles, which possess the property of
auto-rhythmic contraction and relaxation.
3. Endocardium -This forms a smooth inner surface to allow blood to flow
easily through the heart’s chambers.

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PHYSIOLOGY OF HEART

What is systole and diastole?

Systole - Contraction of the heart is called systole. Both atria and ventricle
contracts separately. Hence contraction of atria is called atrial systole and
contraction of ventricle is called ventricular systole.

Diastole - Relaxation of the heart is called diastole. Similarly there are atrial
diastole and ventricular diastole.

Fig. Systole and diastole

What is cardiac cycle?


Cardiac cycle - This is the duration of one systole and one diastole, i.e., one
heart beat. It is approximately 0.8 seconds. Duration of systole is 0.4 second and
diastole is 0.4 second.

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Atrial
systole
0.1 sec

Complete cardiac
diastole 0.4 sec
Ventricular
systole
0.3 sec

What is the conduction system of the heart?


The coordination of cardiac muscle contractions is made possible by the
conduction system of the heart. It is composed of-

• Sinoatrial node (S A node)


• Atrio-ventricular node (A V node)
• Bundle of His
• Purkinje Fibers

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After atrial systole, the electrical impulse that originated in the SA node travels
through the atrial walls to a relay point called the atrioventricular (AV) node
located in the wall between the right atrium and ventricle. Here, the signal is
delayed about 0.1s to ensure that the atria have finished contracting. After this
delay, the impulse travels though specialized cardiac muscle fibers in the
ventricular walls called Purkinje fibers. These fibers make up the AV bundle of
His. The AV bundle divides, sending a branch to each ventricle. When the
electrical impulse reaches the ends of the Purkinje fibers, it spreads through the
ordinary cardiac muscle, causing ventricular systole.

What are the various terminologies used in the hemodynamics of heart?

• Stroke volume (SV) is the amount of blood pumped by the heart per beat.
• End-diastolic volume is the amount of blood in ventricle at the end of its
diastole.
• End-systolic volume is the amount of blood remaining in ventricle after
systole.
• Stroke volume is determined by difference between end-diastolic volume
(EDV) and end-systolic volume (ESV)
SV = EDV (120ml) - ESV (50ml) = 70 ml/beat

• Ejection Fraction (EF) - It is the fraction of blood ejected by the ventricle


relative to its enddiastolic volume. Therefore, EF is calculated from:
EF = (SV / EDV) x 100

• EF helps in measuring the heart’s function. For e.g. in heart failure, EF


can become very small as SV decreases and EDV increases. Normal EF
is approximately 55% and in severe heart failure, EF may be only 5%.

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• Heart Rate (HR) - It is the number of times the heart beats per minute. It is
approximately equal to 72 times per minute in a normal healthy adult.
• Bradycardia - Heart beat less than 60/minute.
• Tachycardia - Heart beat more than 100/minute.
• Cardiac Output (CO) - It is the amount of blood pumped out by the heart in
1 minute.
CO = SV x HR = 5 liters (normal healthy adult)
• Arrhythmia - It is the irregular beating of the heart arising due to abnormal
electrical activity in the conduction system. It is a dangerous situation as
arrhythmia is one of the leading causes of sudden death.
• Peripheral resistance (PR) - It is the resistance offered by the walls of the
arteries to the flowing blood.
• Preload - It is the stretch on the ventricle wall due to the filling blood or the
venous return (EDV). Preload is directly proportional to the blood volume.
• Afterload (Back Pressure) - Afterload is the pressure which the ventricles
must overcome in order to eject blood. Thus, it is the pressure of the
pulmonary trunk and the aorta. Afterload is directly proportional to
peripheral resistance. Increased after load, means that ESV is increased;
thus, SV is reduced.

Which are the factors affecting cardiac output?

Following are the factors affecting cardiac output:


1. Force of Contraction - Cardiac output is directly proportional to FOC.
2. Heart Rate - Cardiac output is inversely proportional to heart rate. Greater
the heart rate, lower is the filling time and vice versa.
3. Preload - Cardiac output is directly proportional to preload.
4. Afterload - Cardiac output is inversely proportional to afterload. Greater is
the afterload, greater is the ESV and lesser is the SV.

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Which are the factors affecting peripheral resistance?


1. Diameter of Blood Vessels - PR is inversely proportional to diameter of
blood vessels. This is the major cause of increase in Blood Pressure of an
individual.
2. Elasticity of Blood Vessels - PR is inversely proportional to the elasticity of
blood vessels. With age elasticity decreases, hence blood pressure
increase.
3. Viscosity of Blood - PR is directly proportional to the viscosity of blood.

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BLOOD PRESSURE

What is blood pressure?


It is the lateral pressure exerted by the flowing blood on the walls of the arteries.
Blood pressure (BP) is of 2 types –

• Systolic blood pressure (SBP) - Blood pressure during contraction of the


heart. Optimal SBP is 120 mm Hg.
• Diastolic blood pressure (DBP) - Blood pressure during relaxation of the
heart. Optimal DBP is 80 mm Hg.

How is the blood pressure expressed?


Mathematically blood pressure is expressed as –
BP = CO x PR

Hence any increase or decrease in CO or PR or both will either increase or


decrease BP.
Blood pressure is measured by an instrument called Sphygmomanometer.
Blood pressure tends to vary considerably over the day even in a normal healthy
person.

Which are the physiological factors affecting BP?


• Circadian rhythm - It means the repetition of certain physiological
phenomenon on a 24 hour cycle. Example - Sleep, hunger, etc. Similarly,
blood pressure is minimum during sleep and maximum in the early
morning hour.
• Sex - Males generally have a little higher SBP than females.
• Age - BP increases with age

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• Exercise - Severe exercise can increase the SBP to as high as 150-170


mm Hg.
• Meal - BP may increase after a heavy meal, especially SBP.
• Posture - BP is maximum during standing and lowest while lying down.
• Emotion - During Stress BP may rise and may reduce during shock.
• Build - Person with larger built may have a little higher BP than a thin built.

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 -
1. Nervous System
2. Renin Angiotensin Aldosterone System or RAAS.

What is the nervous regulation?


Nervous regulation is of 2 types -
• Direct control
• Reflex control through baroreceptors.
Direct control - This is under the control of the higher centers in the brain.
During anger, excitement, ‘fright & flight’ situation, blood pressure increases.

Reflex control - Baroreceptors are finely branched nerve endings which monitors
blood pressure at different sites of the cardiovascular system. They can respond
to blood pressures above normal or blood pressures below normal.
Baroreceptors are present in the arch of aorta, carotid sinus and kidney. Now it
has been found to be present in most parts of the walls of the arteries.
• Increase in blood pressure, stretches the artery wall causing an increase
in impulse from the baroreceptors.

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• The discharge frequency is higher when the system is constantly changing


– pulsatile pressure instead of constant pressure.
• Output from baroreceptors sends signals to the cardiovascular center
causing a reduction in sympathetic output. The discharge frequency of the
baroreceptors then slowly decreases causing an increase in sympathetic
output - this is an example of a negative feedback loop that functions to
stabilize arterial blood pressure at a set point.
• Similarly decrease in blood pressure causes less stretch on the
baroreceptors which stimulate the sympathetic nerves, thereby increasing
the BP.

What is the center in the brain to control the blood pressure?


Cardiovascular center - These are interconnection of nerves present in the
medulla oblongata, which controls the function of heart and diameter of blood
vessels.
Schematic diagram of reflex control by nervous regulation

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Similarly when BP goes down, exactly the opposite happens

What is Renin-Angiotensin-Aldosterone System (RAAS)?


Specialized cells are located in the kidney which can sense the blood pressure.
These are called juxtaglomerular cells. When the blood pressure drops, the
amount of filtered Na+ also drops. The juxtaglomerular cells then release an
enzyme called renin.

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HYPERTENSION

What is hypertension?
Hypertension is defined as the sustained increase in blood pressure above
normal (120/80 mm Hg). This increase is either due to increase in cardiac output
or in peripheral resistance or both.
In majority of the cases it is increase in peripheral resistance.

What are the various types?


Hypertension is of 2 types -
Essential hypertension - This accounts for 90 - 95% of cases. In this case the
cause of essential hypertension is unknown.
Secondary Hypertension - This accounts for 5 - 10% of cases and is secondary
to a disease / drugs e.g.
• Kidney Disease
• Endocrine Disease
• Pregnancy
• Contraceptives
Once these disorders are cured hypertension is also cured.

How do different guidelines classify different grades of hypertension?


Classification of Hypertension as per JNC VII guidelines
Category SBP DBP
Normal < 120 and < 80
Pre-hypertension 120 - 139 80- 89
Hypertension
Stage 1 140 - 159 and/ or 90 - 99
Stage 2 > 160 and /or > 100

Hence as per JNC VII, hypertension can be more accurately defined as -

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“Sustained increase in Systolic Blood Pressure > 140 mmHg and / or Diastolic
Blood Pressure > 90 mm Hg.

Category Systolic blood Diastolic blood pressure


pressure (mm Hg) (mm Hg)
Optimal <120 <80
Normal <130 <85
High Normal 130-139 85-89
Hypertension
Grade 1 – mild 140-159 90-99
Grade 2 – moderate 160-179 100-109
Grade 3 - severe >_180 > 110
Isolated systolic
hypertension
Grade 1 140-159 <90
Grade 2 <_160 <90

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 -


1. Heart and blood vessels, leading to -
a. Ischemic heart Disease (atherosclerosis)
b. Left Ventricular Hypertrophy
c. Heart Failure
d. Arrhythmia
e. Peripheral vascular disease
2. Kidney (Nephropathy) - May lead to kidney (renal) failure.
3. Brain - May lead to stroke.
4. Eye (Retinopathy) - May lead to blindness.

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MANAGEMENT OF HYPERTENSION

What are the different modalities used for THE MANAGEMENT of


hypertension?
1. Life style modifications.

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2. Drug therapy.

What are the life style modifications?


Life style modifications
• Weight reduction
• Exercise
• Reduce Salt intake
• Moderate alcohol intake
• Smoking cessation
• Stress management
• Reduce fat intake
• Control sugar

What is the pharmacological treatment?


Drug therapy
• Commonly used Drugs
o Beta blockers
o Diuretics
o Calcium Channel Blockers
o Angiotensin Converting Enzyme Inhibitors
o Angiotensin Receptor Blockers.
• Less used drugs
o Alpha Blockers
o Vasodilators

ISCHEMIC HEART DISEASE

What is Ischemic heart disease (IHD)?

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Ischemic heart disease (IHD) is also known as Coronary artery disease (CAD) or
coronary heart disease (CHD). The word ischemia means “lack of blood supply.”
It occurs as a consequence of obstruction to the blood flow to the heart muscles.

What are the causes of obstruction?


Causes of obstruction -
1. Atheroma - Deposition of fatty materials in the walls of the arteries
2. Thrombosis - Formation of a clot.
3. Spasm - Sudden constriction of a portion or multiple portion of artery
4. Embolism - A moving clot or atheroma.

Fig. Thrombosis and Embolism


What are the symptoms of IHD?
Symptoms of IHD

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Heartburn, nausea, vomiting, shortness of breath, and heavy sweating.

What are the most common presentations of IHD?


The most common presentations of IHD are -
1. Angina Pectoris.
2. Acute Myocardial Infarction (heart attack)

What is angina and what are the various types?


Angina pectoris
Angina pectoris is the medical term for chest pain or discomfort due to coronary
heart disease.
Typical angina is discomfort, fullness, squeezing or pain in the center of the
chest. The pain also may be felt in the neck, jaw, shoulder, back or arm.

Types of Angina
1. Stable angina
• A feeling of tightness, heavy pressure, or squeezing or crushing chest
pain that:
• Is mid-sternal (under the breastbone) or slightly to the left
• Is not clearly localized
• May radiate to shoulder, arm, jaw, neck, back, or other areas
• May feel similar to gas or indigestion.
• Is precipitated by activity, stress, or exertion
• Lasts for 1 to 15 minutes
• Is usually relieved by rest and/or nitroglycerin

Chest pain or heaviness that is not relieved by more than 1 nitroglycerin tablet
taken 5 minutes apart, and that lasts longer than 15 minutes may represent
unstable angina or even a heart attack.

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2. Unstable angina
Unstable angina describes a syndrome that is intermediate between stable
angina and myocardial infarction: an accelerating chest pain that lasts longer
than stable angina, occurs with less exertion or at rest, or is less responsive to
medication.
Unstable angina and myocardial infarction are considered acute coronary
syndromes, while stable angina is a chronic condition.
Unstable angina is differentiated from stable angina in that the pain may:
• Occur at rest
• Be new in conditions of onset or last longer than previous anginal attacks
• Be less responsive to medication

Fig : Lumen of an artery in various types of angina

3. Prinzmetal or Variant angina


• Always occurs when a person is at rest.
• It doesn’t follow physical exertion or emotional stress. Attacks can be
very painful and
• usually occur between midnight and 8 a.m. Caused due to coronary
artery spasm.
What is Myocardial Infarction (MI)?
Myocardial Infarction (MI)

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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.

What are the symptoms?


Chest pain behind the sternum (breastbone) is a major symptom of heart attack,
but in many cases the pain may be subtle or even completely absent (called a
“silent heart attack”), especially in the elderly and diabetics. Often, the pain
radiates from your chest to your arms or shoulder; neck, teeth, or jaw; abdomen
or back. Sometimes, the pain is only felt in one of these or other location.

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

What are the other symptoms?


Other symptoms you may have either alone or along with chest pain include:
• Shortness of breath
• Cough
• Lightheadedness - dizziness
• Fainting
• Nausea or vomiting
• Sweating, which may be profuse
• Feeling of “impending doom”
• Anxiety

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What is Silent angina?


Not everyone with coronary heart disease experiences angina. Sometimes the
heart is short of blood supply, (ischemic) but there is no warning chest pain or
tightness. The diseased arteries cannot deliver sufficient blood to the heart,
leading to Silent Ischaemia, another form of angina. This condition can occur with
no symptoms. Up to 20 percent of people experience “silent” heart attacks that
have no symptoms. An electrocardiogram (ECG or EKG), a measurement of
electrical impulses produced by the heart, may indicate silent ischaemia.
Diabetics are prone to this condition.

Fig : Site of infarct in heart


What are the Treatment options?
Following are the treatment options
• Life style modifications
• Drug therapy
• Surgical procedures
What are the Life style modifications?
Life style modifications (to remove the risk factors)
• Control blood sugar
• Stop smoking

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• Exercise slowly and regularly


• Avoid outdoor activity in very hot or very cold temperatures
• Lose weight
• Blood pressure control
• Lower cholesterol

What is the pharmacological therapy?


Drug therapy
The objective of therapy is to either -
• Increase oxygen supply
• Decrease oxygen demand
• Or both.

Which are the commonly used drugs?


Drugs frequently used are
1. Nitrates - Causes profound vasodilatation, thus increasing O2 supply.
E.g., Isosorbide dinitrate.
2. Beta blockers - Decrease force of contraction of heart and hence
decrease O2 demand. E.g., Atenolol, Propranolol, Metoprolol.
3. Calcium channel blockers - Causes vasodilatation, thus increasing O2
supply. E.g., Nifedipine, Diltiazem, Amlodipine.
4. Potassium channel openers - Cause vasodilatation hence increase O2
supply. E.g., Nicorandil.
5. Metabolic modifier - Causes shift of energy generation of heart tissues
from aerobic to anerobic respiration. Thus reducing O2 requirement. E.g.,
Trimetazidine.

Which are the various surgical procedures in use?

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1. CABG ( coronary artery bypass grafting, Bypass Surgery).When one or


more of the coronary arteries becomes partially or totally blocked, the
heart does not get an adequate blood supply. Heart bypass surgery
creates a detour or “bypass” around the blocked part of a coronary
artery to restore the blood supply to the heart muscle.
2. Angioplasty (Percutaneous Transluminal Coronary Angioplasty,
PTCA) Angioplasty is a medical procedure in which a balloon is used
to open narrowed or blocked blood vessels of the heart (coronary
arteries). It is not considered to be a type of surgery.

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STROKE

What is stroke?
When blood supply to any part of the brain is interrupted, resulting in tissue death
and loss of brain function.

Fig: Stroke

Which are the 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,
depending on which part of the brain is affected.
The most common cause of stroke is emboli from heart (thrombus from
atherosclerotic plaque.

What is 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.

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HEART FAILURE

What is heart failure?

Heart failure (HF) or Congestive Heart Failure (CHF) is an inability of the heart to
pump sufficient blood to meet the body’s metabolic requirement.

What are the types of Heart Failure?


Heart Failure is of 2 types –
• Systolic heart failure. This is caused by impairment of myocardial
contraction leading to weakened systolic contraction, thus reducing stroke
volume and cardiac output. Major causes are MI, Cardiomyopathy.
• Diastolic heart failure. In this case the ventricle does not relax properly
during diastole; hence there is improper feeling of the heart with blood. For
example, chronic high blood pressure can cause your heart muscle to
become stiff or thickened so that it can’t relax properly, which limits how
much blood fills the left ventricle.
Generally in a normal person ejection fraction is around 60% or more. But in HF
patients the EF can be less than 60%, sometimes as less as 10-15%. The EF is
less in systolic HF but may remain normal in diastolic HF.
Sometimes heart failure is also classified depending on which side of the heart is
failing to pump properly. They are A) Left sided heart failure and b) Right sided
heart

What is left-sided heart failure?


Left-sided heart failure is a disorder in which the left side of the heart loses its
ability to pump blood efficiently, thereby failing to meet the demands of the body.
As the ability to pump blood forward from the left side of the heart is decreased,

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the remainder of the body does not receive enough oxygen especially when
exercising. This results in fatigue.
In addition, the pressure in the veins of the lung increases, which may cause fluid
accumulation in the lung. This results in shortness of breath and pulmonary
edema.
Common causes of left-sided failure include the following:
• Heart attack
• Chronic blockages of the heart arteries
• High blood pressure
• Excessive alcohol consumption
• Leaking or narrow heart valves
• Hypothyroidism
• Heart muscle infections
• Any other disease that damages the heart muscle

In children, common causes include heart birth defects such as abnormal heart
valves, abnormal blood vessel connections, or viral infections.

What is right-sided heart failure?


In right-sided heart failure, the right side of the heart loses its pumping action and
blood may back up into other areas of the body, producing congestion.
Congestion affects the liver, the gastrointestinal tract, and the limbs.
In addition, the heart may be unable to pump blood efficiently to the lungs.
Causes of right-sided heart failure include left-sided heart failure and chronic lung
diseases (such as emphysema). Other causes include congenital heart disease,
primary pulmonary hypertension (PPH), and heart valve disease.

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What causes heart failure?


Heart failure is caused by many conditions that damage the heart muscle,
including:
• Coronary artery disease – the most common cause of HF is CAD. This
occurs when a coronary artery becomes suddenly blocked, stopping the
flow of blood to the heart muscle and damaging it. All or part of the heart
muscle becomes cut off from its supply of oxygen. A heart attack can
damage the heart muscle, resulting in a scarred area which does not
function.
• Arrhythmias – One of the most common causes of HF.
o Tachyarrhythmias reduce the time of ventricular filling resulting
mainly in diastolic HF.
o Bradyarrhythmia reduces the cardiac output.
• Cardiomyopathy — damage to the heart muscle from causes other than
artery or blood flow problems. Causes include infections, alcohol or drug
abuse.

Heart failure is also caused by conditions that overwork the heart muscle,
including:
• High blood pressure (hypertension) — Blood pressure is the force of blood
pushing against blood vessel walls. High blood pressure means the
pressure in the arteries is above the normal range.
• Valve disease — a heart valve that is not working properly and is either
leaking or blocking the normal flow of blood.
• Heart defects present at birth
• Diabetes Mellitus
• Chronic kidney disease

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How Heart failure develops or pathogenesis of heart failure


Whenever there is heart failure the output is hampered. But the body always
tries to maintain homeostasis that is normal output. This is done by activation of
various systems. These are-
1. Sympathetic nervous system (SNS)
2. Renin-Angiotensin Aldosterone System (RAAS)
3. Natriuretic peptides. (ANP & BNP)

Sympathetic nervous system – The decreased stroke volume and leads to


activation of the baroreceptors thus stimulating the SNS. This causes increase in
plasma concentration of norepinephrine. NE increases the force of contraction
and heart rate thus tries to ensure normal cardiac output. But in the long run NE
have toxic effect on the heart by causing myocardial hypertrophy (cardiac
remodeling) thus worsening cardiac dysfunction.

Renin-Angiotensin System – In heart failure increased SNS activity causes


activation of rennin angiotensin system. This leads to –
1. Increased vasoconstriction and increase sodium and water retention due
to stimulation of aldosterone. All these tries to maintain normal BP as well
as increased blood volume to ensure proper blood flow to all tissues. But
ultimately it adversely affects the patient as increased blood volume
worsens the edema which is already there.
2. Further more increased vasoconstriction increases the afterload on the
already failing heart and has adverse effects.
3. Angiotensin II also mediates cellular hypertrophy and contributes to
progressive loss of myocardial function.

Natriuretic peptides – Atrial natriuretic peptides (ANP) and b-type natriuretic


peptide (BNP) are endogenously generated peptides which are secreted when

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there is increased atrial and ventricular volume due to increase in blood volume.
They are released from atrial and ventricle and increases the excretion of sodium
and water and decrease the pressure on the ventricle by decreasing preload and
afterload. Thus they are helpful. But in heart failure their effect is not as powerful
as the SNS and RAAS.

What are the causes of Heart Failure?


The main causes of HF are -
1. Increase Afterload
2. Increase Preload
3. Damage to myocardium

How does heart failure develop?


This can arise due to –
• 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 are the symptoms?


The most common symptoms of HF are -
• Decrease in cardiac output (Fatigue, decrease in exercise capacity

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• Pulmonary congestion (Breathlessness)


• Systemic venous congestion (Liver enlargement, peripheral edema)
• Sudden weight gain due to accumulation of excess fluid.

What is the classification of heart failure?

NHYA classification of Heart Failure


Class I. Patients with cardiac disease but without resulting limitation of physical
activity. Ordinary physical activity does not cause undue fatigue, palpitation,
dyspnea or anginal pain.
Class II. Patients with cardiac disease resulting in slight limitation of physical
activity. They are comfortable at rest. Ordinary physical activity results in fatigue,
palpitation, dyspnoea or anginal pain.
Class III. Patients with cardiac disease resulting in marked limitation of physical
activity. They are comfortable at rest. Less than ordinary activity causes fatigue,
palpitation, dyspnoea or anginal pain.
Class IV. Patients with cardiac disease resulting in inability to carry on any
physical activity without discomfort. Symptoms of heart failure or the anginal
syndrome may be present even at rest. If any physical activity is undertaken,
discomfort increases.

What are the various treatment options?


1. Life style modifications - Bed rest, Exercise, Diet
2. Drug therapy
a. ACE –Inhibitors/ ARBs in selected patients
b. Diuretics
c. Beta blockers
d. Digoxin
3. Surgical procedures - Replacements of valves, etc.

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Clinical trial and guideline basis for compelling indications for individual
drug classes

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NERVOUS SYSTEM

The nervous system is a network of specialized cells that communicate


information about an organism's surroundings and itself. It processes this
information and causes reactions in other parts of the body. It is composed of
neurons and other specialized cells called glial cells (plural form glia) that aid in
the function of the neurons.

The nervous system is divided broadly into two categories: the peripheral
nervous system and the central nervous system.

Central Nervous System


The central nervous system (CNS) is the largest part of the nervous system, and
includes the brain and spinal cord. The spinal cavity holds and protects the spinal
cord, while the head contains and protects the brain. The CNS is covered by the
meninges, a three layered protective coat.

Central nervous system


nervous system

Brain
Spinal cord

Fore Brain Mid Brain Hind Brain


Cerebrum,
Thalamus Pons Medulla
Hypothalamus Cerebellum

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Cereberum - Cereberum is considered as seat of intelligence & develop into


the left and right cerebral hemispheres.

• left side controls right side of body


• right side controls left side of body

Cereberum has four lobes. They are:


1. Frontal lobe: Memory Formation, Emotions, Decision making Reasoning
& Personality.
2. Occipital lobe: Its primary function is the processing,
integration,Interpretation of VISION and visual stimuli.
3. Parietal lobe: Senses and integrates sensations) Spatial awareness and
Perception.(Awareness of body in space and in relation to each other)
4. Temporal lobe: Hearing, Organization of language. Information Retrieval
(Memory and Memory Formation)

Functional area of Cerebrum:

Basal Ganglia:
The basal ganglia (or basal nuclei) are a group of nuclei in the brains of
vertebrates, situated at the base of the forebrain and strongly connected with the
cerebral cortex, thalamus and other areas.
The basal ganglia are associated with a variety of functions, including motor
control and learning.
The main components of the basal ganglia are the striatum, pallidum, substantia
nigra, and subthalamic nucleus.
The largest component, the striatum, receives input from many brain areas but
sends output only to other components of the basal ganglia. The pallidum
receives its most important input from the striatum (either directly or indirectly),
and sends inhibitory output to a number of motor-related areas, including the part

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of the thalamus that projects to the motor-related areas of the cortex. The
substantia nigra consists of two parts, one that functions similarly to the pallidum,
and another that provides the source of dopamine input to the striatum.

Thalamus:

The thalamus is a midline paired symmetrical structure within the brains of


vertebrates, including humans. It is situated between the cerebral cortex and
midbrain, both in terms of location and neurological connections.
Its function includes relaying sensation, special sense and motor signals to the
cerebral cortex, along with the regulation of consciousness, sleep and alertness.
Hypothalamus:

The hypothalamus is a portion of the brain that contains a number of small


nuclei with a variety of functions. One of the most important functions of the
hypothalamus is to link the nervous system to the endocrine system via the
pituitary gland (hypophysis).

The hypothalamus is located below the thalamus, just above the brain stem.The
hypothalamus is responsible for certain metabolic processes and other activities
of the Autonomic Nervous System. It synthesizes and secretes neurohormones,
often called hypothalamic-releasing hormones, and these in turn stimulate or
inhibit the secretion of pituitary hormones. The hypothalamus controls body
temperature, hunger, thirst, fatigue, and circadian cycles.

Mid Brain:

Pons:

The pons is a structure located on the brain stem. It is cranial to (up from) the
medulla oblongata, caudal to (down from) the midbrain, and ventral to (in front of)
the cerebellum. In humans and other bipeds this means it is above the medulla,

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below the midbrain, and anterior to the cerebellum. Its white matter includes
tracts that conduct signals from the cerebrum down to the cerebellum and
medulla, and tracts that carry the sensory signals up into the thalamus.

Hind Brain:

Medulla:

The medulla oblongata is the lower half of the brainstem. The medulla contains
the cardiac, respiratory, vomiting and vasomotor centers and deals with
autonomic functions, such as breathing, heart rate and blood pressure.

Functions
The medulla oblongata controls autonomic functions, and relays nerve signals
between the brain and spinal cord. It is also responsible for controlling several
major points and autonomic functions of the body:

• respiration, blood pressure


• swallowing, vomiting
• defecation, urination
• reflexes

Cerebellum:

The cerebellum (Latin for little brain) is a region of the brain that plays an
important role in motor control.. The cerebellum does not initiate movement, but it
contributes greatly to coordination, precision, and accurate timing. There are
neural pathways linking the cerebellum with the motor cortex (the part of the
cerebral cortex involved in motor control) and other movement-generating brain
areas; it receives input from many sensory systems and many other parts of the
brain and spinal cord.

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Because of this 'fine-tuning' function of the cerebellum, damage to it does not


cause paralysis, but instead produces disorders in fine movement, equilibrium,
posture, and motor learning.

Motor control system:

Pyramidal system:
The pyramidal system is a major motor system comprised of the axons that run
through the corticospinal and corticobulbar tracts. The corticospinal neurons are
involved with the movement of fingers, hands, arms torso, legs, and feet. The
corticobulbar neurons are involved with the movement of the neck, face, oral
cavity, and larynx. Damage to either the corticospinal or corticobulbar tracts
above the level of efferent cranial nerve nuclei will result in problems with the
motor activity on the opposite side.

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Extrapyramidal system:

In human anatomy, the extrapyramidal system is a neural network located in the


brain that is part of the motor system involved in the coordination of
movement. The system is called "extrapyramidal" to distinguish it from the
tracts of the motor cortex that reach their targets by traveling through the
"pyramids" of the medulla.

The pyramidal pathways (corticospinal and some corticobulbar tracts) may


directly innervate motor neurons of the spinal cord or brainstem (anterior
(ventral) horn cells or certain cranial nerve nuclei), whereas the
extrapyramidal system centers around the modulation and regulation
(indirect control) of anterior (ventral) horn cells.

Extrapyramidal tracts are chiefly involved in reflexes, locomotion, complex


movements, and postural control.

Limbic system: The limbic system is a set of brain structures including the
hippocampus, amygdala, anterior thalamic nuclei, and limbic cortex, which
support a variety of functions including emotion, behavior, long term memory,
and olfaction.

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The limbic system includes many structures in the cerebral cortex and sub-cortex
of the brain. The following structures are, or have been considered to be, part of
the limbic system:

• Amygdala: Involved in signaling the cortex of motivationally significant


stimuli such as those related to reward and fear in addition to social
functions such as mating.
• Hippocampus: Required for the formation of long-term memories and
implicated in maintenance of cognitive maps for navigation.
• Parahippocampal gyrus: Plays a role in the formation of spatial memory
• Cingulate gyrus: Autonomic functions regulating heart rate, blood pressure
and cognitive and attentional processing
• Fornix: carries signals from the hippocampus to the mammillary bodies
and septal nuclei.

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• Hypothalamus: Regulates the autonomic nervous system via hormone


production and release. Affects and regulates blood pressure, heart rate,
hunger, thirst, sexual arousal, and the sleep/wake cycle.

Histology of Nervous tissue:

All living cells have the ability to react to stimuli. Nervous tissue is specialised to
react to stimuli and to conduct impulses to various organs in the body which bring
about a response to the stimulus. Nerve tissue (as in the brain, spinal cord and
peripheral nerves that branch throughout the body) are all made up of
specialised nerve cells called neurons. Neurons are easily stimulated and
transmit impulses very rapidly. A nerve is made up of many nerve cell fibres
(neurons) bound together by connective tissue.

Functions of Nerve Tissue

• Nervous tissue allows an organism to sense stimuli in both the internal


and external environment.
• The stimuli are analysed and integrated to provide appropriate, co-
ordinated responses in various organs.
• The afferent or sensory neurons conduct nerve impulses from the sense
organs and receptors to the central nervous system.
• Internuncial or connector neurons supply the connection between the
afferent and efferent neurons as well as different parts of the central
nervous system.
• Efferent or somatic motor neurons transmit the impulse from the central
nervous system to a muscle (the effector organ) which then react to the
initial stimulus.
• Autonomic motor or efferent neurons transmit impulses to the involuntary
muscles and glands.

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Neuron

A neuron is an excitable cell in the nervous system that processes and transmits
information by electrochemical signaling. Neurons are the core components of
the brain, the spinal cord, and the peripheral nerves.

Sensory neurons respond to touch, sound, light and numerous other stimuli
affecting cells of the sensory organs that then send signals to the spinal cord and
brain.

Motor neurons receive signals from the brain and spinal cord and cause muscle
contractions and affect glands.

Anatomy and histology

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The soma is the central part of the neuron. It contains the nucleus of the cell, and
therefore is where most protein synthesis occurs.

The dendrites of a neuron are cellular extensions with many branches, and
metaphorically this overall shape and structure is referred to as a dendritic tree.
This is where the majority of input to the neuron occurs. The dendrites carries
nerve signals toward the soma.

The axon is a finer, cable-like projection which can extend tens, hundreds, or
even tens of thousands of times the diameter of the soma in length. The axon
carries nerve signals away from the soma (and also carries some types of
information back to it).

The axon terminal contains synapses, specialized structures where


neurotransmitter chemicals are released in order to communicate with target
neurons.

Myelin

Myelin is a dielectric (electrically insulating) material that forms a layer, the


myelin sheath, usually around only the axon of a neuron. It is essential for the
proper functioning of the nervous system. Schwann cells supply the myelin for
peripheral neurons, whereas oligodendrocytes, specifically of the interfascicular
type, myelinate the axons of the central nervous system.

Function of myelin layer

The main purpose of a myelin layer (or sheath) is to increase in the speed at
which impulses propagate along the myelinated fiber. Along unmyelinated fibers,
impulses move continuously as waves, but, in myelinated fibers, they hop or
"propagate by saltation."

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White matter

White matter is one of the two components of the central nervous system and
consists mostly of myelinated axons. White matter tissue of the freshly cut brain
appears pinkish white to the naked eye because myelin is composed largely of
lipid tissue veined with capillaries. Its white color is due to its usual preservation
in formaldehyde

The white matter is the tissue through which messages pass between different
areas of gray matter within the nervous system. Using a computer network as an
analogy, the gray matter can be thought of as the actual computers themselves,
whereas the white matter represents the network cables connecting the
computers together.

Grey matter

Grey matter is a major component of the central nervous system, consisting of


neuronal cell bodies, neuropil (dendrites and both unmyelinated axons and
myelinated axons), glial cells (astroglia and oligodendrocytes) and capillaries.

The function of grey matter is to route sensory or motor stimulus to interneurons


of the CNS in order to create a response to the stimulus through chemical
synapse activity.

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Neurotransmitters

Neurotransmitters are endogenous chemicals which relay, amplify, and


modulate signals between a neuron and another cell.

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.

2. Biogenic Amines- Certain amino acids are modified & decarboxylated to


produce Biogenic amine. They are also known as catecholamine.

1. Nor epinephrine- plays role in arousal, dreaming & regulating the


mood.
2. Dopamine- plays role in emotional responses, addictive behavior &
pleasure experience. Dopamine also help in maintaining the muscle
tone.

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Neurotransmitter & behavior:

Dopamine: dopamine is a neurotransmitter and is found in several areas of


brain, including the substantia nigra & the ventral tegmental area. Dopamine is a
neurohormone released by the hypothalamus and inhibits prolactin.

Dopamine has many function in the brain, including important roles in behavior
and cognition, voluntary movement, motivation & reward, inhibition of prolactin,
production of sleep, mood, attention,and learning.

What dopamine does?

– Dopamine in Basal Ganglia helps in movement ( decreased 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 Receptor Data

Receptor D1 D2 D3 D4 D5
Subtype
Localisation Caudate, Caudate, Nucleus Frontal cortex, Hippocampus,
accumbens,

putamen, putamen, olfactory tubercle, midbrain, hypothalamus

nucleus nucleus islands of Calleja amygdala,


accumbens, accumbens,
olfactory olfactory tubercle cardiovascular
tubercle system

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Likely Locomotion, Locomotion, Locomotion, Mostly unknown - Learning and


Physiological memory
Roles
reward, reward, possible role in possible role in
reinforcement, reinforcement, cognition and cognition and
emotion emotion,

learning and learning and hypertension


memory, memory,

renin secretion renin secretion

Effects of dopamine level:


Decreased level Increased level
– PD
– Muscle rigidity – Addiction
– Unstable posture – Suspicious & prone to
(stooped) misinterpret.
– Loss of balance – More intense
– Mask like facial suspiciousness.
expression. – Sense organ will get
– Impairment in intllectual affected.
activity – Hallucination.
– Impair ability to focus – Delusions
(ADHD)

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Dopamine & mental disorder

Increased level in meolimbic system causes hallucination & delusion.


Decreased level in mesocortical region can cause apathy & social withdrawl.
Decreased level in nigrostriatal tract will cause EPS.
Decreased level in tubero infundibular tract will cause gynaecomstia.

Serotonin:
Serotonin is the calming neurotransmitter important to the maintenance of good
mood. It promotes contentment and is responsible for normal sleep. In addition to
the central nervous system, serotonin is also found in the walls of the intestine
(the enteric nervous system) and in platelet cells that promote blood clotting.
Serotonin plays an important role in regulating memory, learning, and blood
pressure, as well as appetite and body temperature. Low serotonin levels
produce insomnia and depression, aggressive behavior, increased sensitivity to
pain, and are associated with obsessive-compulsive eating disorders.

Effects of serotonin level:


Moderately low level Severely low

Sleep disturbance Thinking speed will increase


Appetite disturbance Focus more on torturing memories
Reduced libido Emotionally numb
Social withdrawal Outbursts will begin
Frequent crying spells Evil thought
Low self-esteem
Loss of personality

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Serotonin receptors classification

5-HT agonists

• 5-HT1A receptor
– Azapirones such as buspirone, gepirone, and tandospirone are 5-
HT1A agonists marketed primarily as anxiolytics, but also recently
as antidepressants.
• 5-HT1B receptor
– Triptans such as sumatriptan, rizatriptan, and naratriptan, are 5-
HT1B receptor agonists that are used to abort migraine and cluster
headache attacks.
• 5-HT1D receptor
– In addition to being 5-HT1B agonists, triptans are also agonists at
the 5-HT1D receptor, which contributes to their antimigraine effect.
• 5-HT1F receptor

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– LY-334,370 was a selective 5-HT1F agonist used for the treatment


of migraine and cluster headaches.
• 5-HT2A receptor
– Psychedelic drugs such as LSD, mescaline, psilocin, DMT, and 2C-
B act as 5-HT2A agonists. Their action at this receptor is
responsible for their hallucinogenic effects.

• 5-HT2C receptor
– Lorcaserin is a thermogenic and anorectic weight-loss drug which
acts as a selective 5-HT2C agonist.
• 5-HT4 receptor
– Cisapride is a 5-HT4 receptor agonist that has been used to treat
disorders of gastrointestinal motility.

5 HT2 antagonists
• 5 HT2 antagonists: antipsychotics
– 5-HT2A and 5-HT2C receptor antagonists which cross the blood-
brain barrier have antipsychotic properties and are called atypical
neuroleptic or atypical antipsychotic agents. In addition to their
5HT2A antagonist effect, they inhibit dopaminergic receptors.
– Atypical neuroleptic agents with 5-HT2A antagonist effect improve
the positive and negative symptoms of psychosis probably better
than classical neuroleptic agents but these latter were often
prescribed in too large doses.
• 5-HT3 antagonists
– This class includes drugs such as ondansetron, palonosetron and
others. These agents are particularly useful in the treatment of
chemotherapy induced nausea and vomiting (CINV).

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– The principal effect of 5-HT3 receptor antagonists is to inhibit


vomiting induced by antineoplastic drugs, such as cisplatin and
doxorubicin, which are cytotoxic and release serotonin from the
digestive tract. Serotonin released stimulates 5-HT3 receptors
localized on vagal terminations in the digestive tract leading to
ascending impulses and on Area postrema, both stimulations
leadind to hyperemesis. The specific antagonists of 5-HT3
receptors inhibit vomiting and are classified among antiemetic
agents.
– Drugs used are ondansetron, granisetron, tropisetron and
dolasetron

The best food sources of tryptophan include brown rice, cottage cheese, meat,
peanuts, and banana and sesame seeds.

Acetylcholine

Acetylcholine is the primary chemical carrier of thought and memory. This


excitatory neurotransmitter is essential for both the storage and recall of memory,
and partly responsible for concentration and focus. It also plays a significant role
in muscular coordination . A deficit in acetylcholine is directly related to memory
decline and reduced cognitive capacity.

Unlike other key neurotransmitters, acetylcholine is not made from amino acids.
Its primary building block is choline, which doesn't have to compete for entry into
your brain. Therefore, the more choline you consume, the more acetylcholine you
can produce.

Choline belongs to the B family of vitamins and is a fat-like substance that's


necessary to metabolize fats. It is found in lecithin as phosphatidyl choline.

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Foods high in lecithin include egg yolks, wheat germ, soybeans, organ meats,
and whole wheat products.

You can boost your acetylcholine levels by taking supplements of phosphatidyl


choline, which is also the form of choline most important to the structure of your
neural membranes. Vitamin C and B5 are needed for your brain to synthesize
acetylcholine, in the presence of choline acetyltransferase, a key brain enzyme.

Acetylcholine levels tend to decline with age, in part because of a decreased


ability to synthesize this enzyme. There also may be an increase in
acetylcholinesterase, the enzyme that breaks down acetylcholine.

Norepinephrine

Norepinephrine, also called noradrenalin, is the primary excitatory


neurotransmitter needed for motivation, alertness, and concentration. Like a
hormone, it travels in the bloodstream to arouse brain activity with its adrenalin-
like effects.

Your brain requires norepinephrine to form new memories and to transfer them to
long-term storage. This neurotransmitter also influences your metabolic rate.

Both norepinephrine and dopamine are manufactured from the amino acids
tyrosine or phenylalanine in the presence of adequate oxygen, vitamins B3, B6,
and C, folic acid, iron, and copper. Food sources of tyrosine include almonds,
avocados, bananas, dairy products, lima beans, pumpkin seeds, and sesame
seeds

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Neurotransmitter Information

Neuro Deficiencies May Supplement Present In


Produce
Transmitter Cause Required Foods

Lack of rational emotion, 5HTP or L-


Emotional feelings of irritability, tryptophan from Turkey Ham
Serotonin
Stability sudden unexplained food, Calcium Milk Cheese
tears, sleep problems and Magnesium

Pleasure, reward, Anhedonia - No


good feelings pleasure, world looks Lean beef
L-phenylalanine
Dopamine toward others, colorless, inability to Shellfish Fowl
Vitamin B6
maternal/ "love", no remorse about Soy products
paternal love personal behavior

Lean beef
Arousal, energy, Lack of ambition, lack of L-phenylalanine
Norepinephrine Shellfish Fowl
drive drive, depression Vitamin B6
Soy products

Lean beef &


Free floating anxiety,
pork Sesame
feelings that things are L-glutamine
GABA Staying calm seeds Fowl
closing in around you, Vitamin B6
Sunflower
unexplained panic
seeds

Feelings of
incompleteness, lack of
fulfillment, feelings of D-phenylalanine Seafood Fowl
Psychological
Enkephalins inferiority, feelings of Vitamin B6 Folic Lima beans
pain relief
inadequacy, never feels Acid Ham
"equal," fearful, insecure
feelings

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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.

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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.

Psychiatric Disorders

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,
delusions, or thought disorder, as described below.

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Hallucination
A hallucination, in the broadest sense, is a perception in the absence of a
stimulus. In a stricter sense, hallucinations are defined as perceptions in a
conscious and awake state in the absence of external stimuli which have
qualities of real perception, in that they are vivid, substantial, and located in
external objective space.

Hallucinations can occur in any sensory modality — visual, auditory, olfactory,


gustatory, tactile, proprioceptive, equilibrioceptive, nociceptive, and
thermoceptive.

Types of hallucinations
Hallucinations may be manifested in a variety of forms. Various forms of
hallucinations affect the different senses, sometimes occurring simultaneously,
creating multiple sensory hallucinations for the patient.

Auditory hallucinations
Auditory hallucinations (also known as Paracusia), particularly of one or more
talking voices, are particularly associated with psychotic disorders such as
schizophrenia or mania, and hold special significance in diagnosing these
conditions, although many people not suffering from diagnosable mental illness
may sometimes hear voices as well.

Other types of auditory hallucination include exploding head syndrome and


musical ear syndrome. In the latter, people will hear music playing in their mind,
usually songs they are familiar with.

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. Phantosmia often results from damage to the nervous tissue

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in the olfactory system. The damage can be caused by viral infection, brain
tumor, trauma, surgery, and possibly exposure to toxins or drugs.

Hypnagogic hallucination
These hallucinations occur just before falling asleep, and affect a surprisingly
high proportion of the population. The hallucinations can last from seconds to
minutes, all the while the subject usually remains aware of the true nature of the
images.

Delirium tremens
One of the more enigmatic forms of visual hallucination is the highly variable,
possibly polymodal delirium tremens. Individuals suffering from delirium tremens
may be agitated and confused, especially in the later stages of this disease.
Insight is gradually reduced with the progression of this disorder. Sleep is
disturbed and occurs for a shorter period of time, with Rapid eye movement
sleep.

Delusion
A delusion, in everyday language, is a fixed belief that is either false, fanciful, or
derived from deception. Psychiatry defines the term more specifically as a belief
that is pathological (the result of an illness or illness process). As a pathology, it
is distinct from a belief based on false or incomplete information, apperception,
illusion, or other effects of perception.

Delusions typically occur in the context of neurological or mental illness, although


they are not tied to any particular disease and have been found to occur in the
context of many pathological states (both physical and mental).

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Types
. Some of the more common delusion themes are

• 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. A person may describe, for instance, the experience that aliens
actually make him or her move in certain ways and that the person
affected has no control over the bodily movements. Thought broadcasting
(the false belief that the affected person's thoughts are heard aloud),
thought insertion, and thought withdrawal (the belief that an outside force,
person, or group of people is removing or extracting a person's thoughts)
are also examples of delusions of control.
• 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. This
delusion stems from pathological jealousy, and the person often gathers
"evidence" and confronts the spouse about the nonexistent affair.
• Delusion of guilt or sin (or delusion of self-accusation): This is a false
feeling of remorse or guilt of delusional intensity. A person may, for
example, believe they have committed some horrible crime and should be
punished severely. Another example is a person who is convinced they
are responsible for some disaster (such as fire, flood, or earthquake) with
which there can be no possible connection.
• Delusion of mind being read: The false belief that other people can
know one's thoughts. This is different from thought broadcasting in that the
person does not believe their thoughts are heard aloud.

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• 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.
• Erotomania is a delusion in which one believes that another person is in
love with him or her. They believe that this other person was the first to
declare his or her affection, often by special glances, signals, telepathy, or
messages through the media.
• 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).
More commonly, a person with this delusion may believe they have
accomplished some great achievement for which they have not received
sufficient recognition (for example, the discovery of a new scientific
theory).
• 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. Sometimes the delusion is isolated and fragmented (such
as the false belief that co-workers are harassing), but sometimes are well-
organized belief systems involving a complex set of delusions
("systematized delusions"). People with a set of persecutory delusions
may believe, for example, they are being followed by government
organizations because the "persecuted" person has been falsely identified
as a spy. These systems of beliefs can be so broad and complex that they
can explain everything that happens to the person.
• Religious delusion: Any delusion with a religious or spiritual content.
These may be combined with other delusions, such as grandiose
delusions (the belief that the affected person was chosen by God, for
example), delusions of control, or delusions of guilt. Beliefs that would be

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considered normal for an individual's religious or cultural background are


not necessarily delusions.
• 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".

It describes a persistent underlying disturbance to conscious thought and is


classified largely by its effects on speech and writing. Affected persons may
show pressure of speech (speaking incessantly and quickly), derailment or flight
of ideas (switching topic mid-sentence inappropriately), thought blocking,
rhyming, punning, or 'word salad' when individual words may be intact but
speech is incoherent.

Types:

• Pressure of speech - An increase in the amount of spontaneous speech


compared to what is considered customary.
• Distractible speech - During mid speech, the subject is changed in
response to a stimulus. e.g. "Then I left San Francisco and moved to...
where did you get that tie?"
• Tangentiality- Replying to questions in an oblique, tangential or irrelevant
manner. e.g:

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Q: "What city are you from?"


A: "Well, that's a hard question. I'm from Iowa. I really don't know where
my relatives came from, so I don't know if I'm Irish or French."

• Derailment (also Loose Association and Knight's Move thinking) -


Ideas slip off the track on to another which is obliquely related or
unrelated. e.g. "The next day when I'd be going out you know, I took
control, like uh, I put bleach on my hair in California."
• Incoherence (word salad) - Speech that is unintelligible because, though
the individual words are real words, the manner in which they are strung
together results in incoherent gibberish, e.g. the question "Why do people
comb their hair?" elicits a response like "Because it makes a twirl in life,
my box is broken help me blue elephant. Isn't lettuce brave? I like
electrons. Hello, beautiful."
• Illogicality - Conclusions are reached that do not follow logically (non
sequiturs or faulty inferences). e.g. "Do you think this will fit in that box?"
draws a reply like "Well duh; it's brown, isn't it?"
• Clanging - Sounds, rather than meaningful relationships, appear to
govern words. e.g. "I'm not trying to make noise. I'm trying to make sense.
If you can't make sense out of nonsense, well, have fun."
• Neologisms - New word formations. e.g. "I got so angry I picked up a dish
and threw it at the geshinker."
• Word approximations - Old words used in a new and unconventional
way. e.g. "His boss was a seeover."
• Evasive Interaction - Attempts to annunciate ideas and/or feelings about
another individual comes out as evasive or in a diluted form. e.g. "I... er
ah... you are uh... I think you have... uh-- acceptable erm... uh... hair."
• Circumstantiality - Speech that is very delayed at reaching its goal.
Excessive long windedness. e.g. "What is your name?" "Well, sometimes
when people ask me that I have to think about whether or not I will answer

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because some people think it's an odd name even though I don't really
because my mom gave it to me and I think my dad helped but it's as good
a name as any in my opinion but yeah it's Tom."
• Loss of goal - Failure to show a train of thought to a natural conclusion.
e.g. "Why does my computer keep crashing?", "Well, you live in a stucco
house, so the pair of scissors needs to be in another drawer."
• Perseveration - Persistent repetition of words or ideas. e.g. "It's great to
be here in Nevada, Nevada, Nevada, Nevada, Nevada."
• Echolalia - Echoing of one's or other people's speech that may only be
committed once, or may be continuous in repetition e.g. "What would you
like for dinner?", "That's a good question. That's a good question. That's a
good question. That's a good question."
• Blocking - Interruption of train of speech before completion. e.g. "Am I
early?", "No, you're just about on-"
• Stilted speech - Speech excessively stilted and formal. e.g. "The attorney
comported himself indecorously."
• Self-reference - Patient repeatedly and inappropriately refers back to self.
e.g. "What's the time?", "It's 7 o'clock. That's my problem."
• Phonemic paraphasia - Mispronunciation; syllables out of sequence. e.g.
"I slipped on the lice broke my arm."
• Semantic paraphasia - Substitution of inappropriate word. e.g. "I slipped
on the coat, on the ice I mean, and broke my book."

Delirium
Delirium is an acute and debilitating decline in attention-focus, perception, and
cognition that produces an altered form of semi-consciousness. It is a systemic
syndrome caused by a chemical or disease-process which is disrupting the
neurons of the cerebral cortex. Though hallucinations and delusions are often
present, the symptoms of delirium are clinically distinct from those induced by
psychosis or hallucinogens.

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Delirium is not the same as dementia (the two entities have different diagnostic
criteria), though it commonly occurs in demented patients.

Delirium may be of a hyperactive variety manifested by 'positive' symptoms of


agitation or combativeness, or it may be of a hypoactive variety (often referred to
as 'quiet' delirium) manifested by 'negative' symptoms such as inability to
converse or focus attention or follow commands. While the common non-medical
view of a delirious patient is one who is hallucinating, most people who are
medically delirious do not have either hallucinations or delusions. Delirium is
commonly associated with a disturbance of consciousness (e.g., reduced clarity
of awareness of the environment). The change in cognition (memory deficit,
disorientation, language disturbance) or the development of a perceptual
disturbance, must be one that is not better accounted for by a pre-existing,
established, or evolving dementia.

Depression (mood)
.
Depression is a state of low mood and aversion to activity. While often
described as a dysfunction, there are also strong arguments for seeing
depression as an adaptive defense mechanism.

The Diagnostic and Statistical Manual of Mental Disorders defines a depressed


person as experiencing feelings of sadness, helplessness and hopelessness. In
traditional colloquy, feeling "depressed" is often synonymous with feeling "sad",
but both clinical depression and non-clinical depression can also refer to a
conglomeration of more than one feeling.

Symptoms

• never seem to be enough


• dullness

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• chronic sadness never seeming to end


• obsessions
• shakiness when feeling most down
• mood swings

Types of psychological depression

Unipolar depression
Individuals with unipolar depressive disorders may experience extreme and
profound painful sadness that persists for a period of weeks or even years. A
loss of interest in activities such as work, hobbies, or spending time with family is
common, and the individual may not be able to experience enjoyment or
pleasure in activities they once enjoyed. The feelings of sadness and loss of
interest may cause a depressed individual to have trouble functioning in
occupational, social, or academic settings.

The unipolar depressive disorders include major depressive disorder, dysthymia,


seasonal affective disorder, and other similar depressive illnesses.

Major depression
A major depressive episode is characterized by either feelings of sadness or a
loss of interest that persists for at least two weeks and causes difficulties in an
individual's functioning at work, school, home, or in relationships with friends or
family. Other common symptoms that might be present include:

• A low • Changes in • Loss of energy or


mood for appetite/weight loss feeling fatigued
most of the or gain • Unexplained
day • Irritability or physical symptoms
• Feelin agitation • Frequently
gs of guilt • Trouble sleeping or experiencing

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• Feelin sleeping too much breakdowns or


gs of • Decreased libido crying
worthlessnes
• Having trouble with • Thoughts of suicide
s
concentration or or thoughts or
• Feelin
memory wishes of death
g nervous or
anxious

• Feelin
g slow and
sluggish

Dysthymia

Dysthymia (also referred to as Dysthymic Disorder) is a chronic low grade


depression that is less severe than a major depressive episode but that persists
for at least two years during which the individual is not without the depressive
symptoms for more than two months. Dysthymia is often characterized by a
disinterest in activities, an inability to feel enjoyment or pleasure, and/or feelings
of chronic sadness.

Seasonal affective disorder


Seasonal affective disorder (SAD) is a type of unipolar depression that develops
annually, usually in the winter when the sun's light is less intense and the length
of the day is shorter. People who live at higher latitudes tend to have less
sunlight exposure in the winter and therefore experience higher rates of SAD.
SAD is also more prevalent in people who are younger and typically affects more
females than males.

According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV),


the criteria for seasonal affective disorder include:

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• The person experiences a regular pattern of depressive


episodes, which begin at a certain time of the year
• The depressed mood also stops or changes at a regular time
each year
• It has lasted longer than 2 years
• The person has experienced more seasonal types of
depression than other types (major depression for example)

Bipolar depression
Bipolar disorders (previously known as manic depression) are characterized by
alternating periods of depressed mood and extremely elevated mood. A manic
episode is a period of elevated mood that is often characterized by feelings of
elation, increased energy, and racing thoughts. Some manic episodes are also
accompanied by psychotic symptoms such as hallucinations or delusions,
particularly delusions of grandeur.

Individuals with bipolar disorders experience both poles of mood—the extreme


highs and the extreme lows. The bipolar disorders include bipolar I disorder,
bipolar II disorder, and cyclothymia ("cycling mood" in Latin).

Bipolar I disorder
People with bipolar I disorder have periods where they meet the classification for
major depression, then eventually their mood alters and they begin to experience
the extreme opposite - increased energy and feelings of wellbeing.

Possible major depression phase Possible manic phase symptoms


symptoms:
• A distinct increase in energy and
• Loss of interest and activity
enjoyment • Impaired judgement
• Reduced energy • Lack of insight

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• Fatigue • Distractability
• Lethargy • Hostile behaviour
• Apathy • Disjointed thinking
• Lowered • Feelings of wellbeing
concentration and attention • Physical efficiency
• Reduced self-
• Mental efficiency
esteem and self-
confidence
• Guilt
• Unworthiness
• Becoming pessimistic
• Diminished sleep and
appetite

• Ideas or acts of self-


harm or suicide
While a person experiencing mania may appear more sociable and talkative,
they may feel like they are losing control with all these extreme feelings. With
bipolar I, the person may also experience paranoia and hallucinations which
modify their perceptions of the world around them.

Bipolar II disorder
A person with bipolar II disorder will experience both ups and downs such as
those with Bipolar I, and feel the same sense of depression. However, the
important difference between Bipolar I and II is that the person experiences
hypomania, not mania. Hypomanic symptoms include becoming more sociable,
feeling the constant need to talk, being extremely friendly, experiencing a
decrease in the amount of sleep needed.

A person with bipolar II disorder will not have hallucinations or paranoid ideas.
The manic feelings are less extreme in this type of Bipolar Disorder, however the
impact on the person can be similar. The depression phase of both conditions is

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what causes the most impairment to life. This phase lasts longer than the manic
or hypomanic phases and is considered to be the most distressing feature of
Bipolar Disorder.

Cyclothymia

Cyclothymia is a related condition to bipolar disorder; however, bipolar disorder


can improve within a number of years, while cyclothymia is a chronic condition
that can last for a longer time. The symptoms of bipolar II disorder do not
necessarily lead to a disruption in social or occupational environments, although
they have the potential to negatively impact the life of those affected.

Schizophrenia

Schizophrenia is a psychiatric diagnosis that describes a neuropsychiatric


abnormality and mental disorder characterized by abnormalities in the perception
or expression of reality. It most commonly manifests as auditory hallucinations,
paranoid or bizarre delusions, or disorganized speech and thinking with
significant social or occupational dysfunction.

People with schizophrenia may not make sense when they talk. They may sit for
hours without moving or talking. Sometimes people with schizophrenia seem
perfectly fine until they talk about what they are really thinking.

What are symptoms of schizophrenia?


The symptoms of schizophrenia fall into three broad categories: positive
symptoms, negative symptoms, and cognitive symptoms

Positive symptoms

Positive symptoms are psychotic behaviors not seen in healthy people. People
with positive symptoms often "lose touch" with reality. These symptoms can

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come and go. Sometimes they are severe and at other times hardly noticeable,
depending on whether the individual is receiving treatment. They include the
following:

Hallucinations are things a person sees, hears, smells, or feels that no one else
can see, hear, smell, or feel

Delusions are false beliefs that are not part of the person's culture and do not
change. The person believes delusions even after other people prove that the
beliefs are not true or logical. People with schizophrenia can have delusions that
seem bizarre, such as believing that neighbors can control their behavior with
magnetic waves.

Thought disorder are unusual or dysfunctional ways of thinking. One form of


thought disorder is called "disorganized thinking." This is when a person has
trouble organizing his or her thoughts or connecting them logically. They may talk
in a garbled way that is hard to understand. Another form is called "thought
blocking." This is when a person stops speaking abruptly in the middle of a
thought. When asked why he or she stopped talking, the person may say that it
felt as if the thought had been taken out of his or her head. Finally, a person with
a thought disorder might make up meaningless words, or "neologisms."

Movement disorders may appear as agitated body movements. A person with a


movement disorder may repeat certain motions over and over. In the other
extreme, a person may become catatonic. Catatonia is a state in which a person
does not move and does not respond to others. Catatonia is rare today, but it
was more common when treatment for schizophrenia was not available.

Negative symptoms

Negative symptoms are associated with disruptions to normal emotions and


behaviors. These symptoms are harder to recognize as part of the disorder and

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can be mistaken for depression or other conditions. These symptoms include the
following:

• "Flat affect" (a person's face does not move or he or she talks in a dull or
monotonous voice)
• Lack of pleasure in everyday life
• Lack of ability to begin and sustain planned activities
• Speaking little, even when forced to interact.

People with negative symptoms need help with everyday tasks. They often
neglect basic personal hygiene. This may make them seem lazy or unwilling to
help themselves, but the problems are symptoms caused by the schizophrenia.

Cognitive symptoms

Cognitive symptoms are subtle. Like negative symptoms, cognitive symptoms


may be difficult to recognize as part of the disorder. Often, they are detected only
when other tests are performed. Cognitive symptoms include the following:

• Poor "executive functioning" (the ability to understand information and use


it to make decisions)
• Trouble focusing or paying attention
• Problems with "working memory" (the ability to use information
immediately after learning it).

Cognitive symptoms often make it hard to lead a normal life and earn a living.
They can cause great emotional distress.

How is schizophrenia diagnosed?

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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)

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).

Management of Psychosis

Antipsychotics (also called neuroleptics) are a group of psychoactive drugs


commonly but not exclusively used to treat psychosis. Antipsychotics are also

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referred to as neuroleptic drugs. The word neuroleptic is derived from Greek: "
(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
antipsychotic and the atypical or second-generation antipsychotic.

The typical antipsychotics are classified according to their chemical structure


while the atypical antipsychotics are classified according to their pharmacological
properties. These include serotonin-dopamine antagonists, multi-acting receptor-
targeted antipsychotics (MARTA), and dopamine partial agonists, which are often
categorized as atypicals.

Typical antipsychotics are also sometimes referred to as the major tranquilizers,


because some of them can tranquilize and sedate. As with the term
"neuroleptics," the term "major tranquilizers" is falling out of common and
scientific use. The term "tranquilizers" now generally refers to drugs that are
primarily intended to sedate—mostly the barbiturates and benzodiazepines,
which were once referred to as the "minor tranquilizers."

Typical antipsychotic/ First generation antipsychotics:

The typical antipsychotics are classified according to their chemical structure. It is


sometime referred as major tranquilizers.

They acts by D2 receptor antagonism.

• Butyrophenones
– Haloperidol
– Droperidol (Droleptan)
• Phenothiazines
– Chlorpromazine
– Fluphenazine
– Perphenazine

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– Prochlorperazine
• Thioxanthenes
– Chlorprothixene
– Flupenthixol
– Thiothixene

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Atypical / second generation antipsychotic:

Atypical / second generation antipsychotics are classified based on


pharmacological property. They act on both 5-HT & D-receptor. They are
used to treat schizophrenia, acute mania, bipolar mania, psychotic agitation.

– Clozapine, Olanzapine, Quetapine, Resperidone, Ziprasidone ,


Sertindole, Amisulpride

Third generation antipsychotics

• Aripiprazole - The extent to which these effects differ from other atypical
antipsychotics is debated..
• Under clinical development - Bifeprunox; norclozapine (ACP-104).

Selective serotonin reuptake inhibitor


Selective serotonin reuptake inhibitors or serotonin-specific reuptake
inhibitor (SSRIs) are a class of compounds typically used as antidepressants in
the treatment of depression, anxiety disorders, and some personality disorders.
They are also typically effective and used in treating premature ejaculation
problems as well as some cases of insomnia.

SSRIs increase the extracellular level of the neurotransmitter serotonin by


inhibiting its reuptake into the presynaptic cell, increasing the level of serotonin
available to bind to the postsynaptic receptor. They have varying degrees of
selectivity for the other monoamine transporters, with pure SSRIs having only
weak affinity for the noradrenaline and dopamine transporter.

The first class of psychotropic drugs to be rationally designed, SSRIs are the
most widely prescribed antidepressants in many countries.[2]

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List of SSRIs
Drugs in this class include :

• citalopram
• dapoxetine
• escitalopram
• fluoxetine
• fluvoxamine
• paroxetine
• sertraline
• zimelidine

Tricyclic antidepressant
Tricyclic antidepressants (TCAs) are a class of psychoactive drugs used
primarily as antidepressants. They are named after their chemical structure,
which contains three rings of atoms, and are closely related to the tetracyclic
antidepressants (TeCAs), which contain four rings of atoms.

In recent times, the TCAs have been largely replaced in clinical use in most parts
of the world by newer antidepressants such as the selective serotonin reuptake
inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs),
among others, though they are still sometimes prescribed for certain indications.

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List of TCAs
The TCAs include the following agents:

• Tertiary Amines
o Amitriptyline, Butriptyline , Clomipramine , Dosulepin / Dothiepin
o Doxepin , Imipramine , Lofepramine , Trimipramine
• Secondary Amines
o Desipramine, Nortriptyline , Protriptyline
• Unclassified/Unsorted
o Demexiptiline, Dibenzepin, Dimetacrine, Iprindole, Melitracen
• Research Chemicals
o Cianopramine (Ro-11-2465)
o Cyanodothiepin (BTS-56,424)
o Fluotracen (SKF-28,175)

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PSYCHIATRIC DISORDERS

What causes psychiatric disorders?


Psychiatric disorders are the result of disturbance of:
• Thinking (Cognition)
• Emotion (Feelings/Affect)
• Behaviour (Action/Conation)
• Perception
• Memory

Thinking (Cognition): It involves Orientation, Level of awareness, Thought,


Attention, Language, Judgement and Insight.

Emotion: Disturbance of emotion leads to Depression (sadness or grief), Elation


(joy or mania), Anxiety (fear or panic) and Anger (irritation or rage).

Behaviour: Disturbance leads to motor behavioural disturbances and


interpersonal behavioural disturbances.

Perception: Disturbance in perception leads to Hallucination, Delusion and


Illusion.

Memory: Impairment of memory occurs in dementia.

What is hallucination, illusion and delusion?


Hallucination
False sensory perception without a real external stimulus. Seeing or hearing
things which do not exist.

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Delusion
False beliefs which cannot be corrected by reason; argument; or persuasion

Illusion
False interpretation of a real sensory image

What are different types of psychiatric disorders?


Major Disorders Minor Disorders
(Psychoses) (Neuroses)
Organic Functional - Psychoneuroses
Acute Chronic - Major Depressive
(e.g. Anxiety, Phobias)
Illness
Delirium Dementia - Personality
- Bipolar Affective
Disorders
Disorder (Manic
- Alcoholism and Drug
Depressive
Dependence
Disorder)
- Psychosexual
- Schizophrenia
Disorders

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SCHIZOPHRENIA

What is schizophrenia?
It is a chronic, severe and disabling mental illness. The term schizophrenia was
first used in 1911 by Eugen Bleuler, a Swiss psychiatrist to categorize patients
whose though processes, emotional responses and behavioural responses
seemed disconnected. The term schizophrenia literally means split mind.

Definition
A disturbance that lasts for at least 6 months and includes a month of active
phase symptoms (two or more) of the following: Delusions, hallucinations,
disorganized speech, grossly disorganized or catatonic behaviour, negative
symptoms.
Schizophrenia conceptualises the presence of Schism (division) between
thought, emotion and behaviour.

Thought

Emotion Behavior

Epidemiology
• It affects 1% of the earth’s population.
• Lifetime risk: 1-15%
• Schizophrenic patients occupy 20-25% of all beds available for psychiatric
care
• Between 10-20% of all patients commit suicide.

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• Age and Sex:


o Equally prevalent in men and women
o Men more likely to be impaired with negative symptoms
• Schizophrenia, though discussed alone is almost always accompanied by
other disorders
• Environmental component:
o Biological (e.g. infection)
o Psychological (stressful family or death)
• Biological component influenced by substance abuse, stress, trauma.

General symptoms
No clinical sign or symptom is unique in Schizophrenia and can be seen in other
psychiatric and neurological disorders. Patients symptoms change with time.
Clinicians must consider patients' educational level, intellectual ability and
cultural background.
• Paranoid feelings and delusions
• Blunted affect
• Excessive motor activity
• Maintaining bizarre postures for prolonged periods

What are positive and negative symptoms of schizophrenia?

Positive symptoms

• Agitation
• Hallucinations (seeing or hearing things which do not exist)
• Thought insertion (the experience of thoughts being placed into one's
mind)
• Thought broadcasting (the experience of one's thoughts being available to
others)

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• Delusions (false beliefs)

Negative symptoms (decrease in function / loss of ability)


• Withdrawal from surroundings
• Blunting or lack of emotion (severe reduction in emotional expressiveness)
• Colourless speaking tones.
• General loss of interest in life and ability to experience pleasure .
• Inappropriate affect (a condition in which the patient displays
inappropriate reactions to an event, such as laughing hysterically over a
loss).
• Lack of responsiveness.

What causes schizophrenia?


No single cause can account for all cases of schizophrenia. Rather it appears to
be the result of multiple “hits” from genetic factors, environmental, psychological
etc.

Genetic Factors
Schizophrenia undoubtedly has a genetic component. The risk for inheriting
schizophrenia is 10% in those who have one immediate family member with the
disease and about 40% if the disease affects both parents or an identical twin. It
should be noted that heredity does not explain all cases of the disease. About
60% of people with schizophrenia have no close relatives with the illness.

Infectious Agents
Viruses – The case for viruses as a cause of this disease rets mainly on
circumstantial evidence, such as living in crowded conditions. The following are
some studies suggesting an association.

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• Winter and Spring Births. The risk for schizophrenia worldwide is 5% to


8% higher for those born during winter and spring, when colds and
viruses are more prevalent.
• The risk is higher for people who are born in cities than in the country.
The longer one lives in the city, the higher the risk.
• Large Families. The risk for schizophrenia is also greater in large families
in which there are short intervals between siblings (two or fewer years).
Such observations suggest that exposure to infectious agents early in
infancy may help set the stage for development of the disease.
• Pregnant Mother’s Exposure to Viruses. The mother’s exposure to viral
infections such as rubella, measles, chicken pox, or others while the
infant is in the womb has also been associated with a higher risk for
schizophrenia her child.
• Researchers are trying to identify specific viruses that may be
responsible for some cases. Of particular interest is research finding
evidence of a virus that belongs to the HERV-W retrovirus family in 30%
of people with acute schizophrenia.

Loss of Oxygen around the Time of Birth


Many studies have reported an association between schizophrenia and problems
surrounding birth, particularly those that cause oxygen deprivation, which could
affect the nerve growth or structure in the developing brain. Specific
complications that have been associated with such a higher risk include the
following :
• Prolonged labor.
• Bleeding during pregnancy
• A short gestation period and low birth weight.

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Psychological Factors
Although parental influence is no longer believed to play a major role in the
development of schizophrenia. It would be irresponsible to ignore outside
pressures and influences that may exacerbate or trigger symptoms. The
prefrontal lobes of the brain. Which are the brain areas often though to lead to
this disease, are extremely responsive to environmental stress. Given the fact
that schizophrenic symptoms naturally elicit negative responses from the
sufferer’s circle of family and acquaintances, it is safe to assume that negative
feedback can intensify deficits in a vulnerable brain and perhaps even trigger
and exacerbate existing symptoms.

One study to support this indicated that early parental loss, either from death or
separation, increase the risk for psychiatric disorders, including schizophrenia. In
another interesting 200 study, criticism by family members was significantly
correlated with the onset of disorganized thinking in patients with impaired
working memory.

What are the signs and symptoms of schizophrenia ?


Schizophrenia is characterized by a cluster of symptoms that typically include the
following :
• Delusions
• Hallucinations
• Disordered thinking
• Emotional unresponsiveness.

Consequences of schizophrenia
The disease has a devastating effect on all aspects of human thought, emotion
and expression. Only about 20% reach full recovery after a first episode, but new
drugs are offering significant hope for improving the patient’s life.

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Medical illnesses – More serious health problems than those without mental
disorders.
Depression – Common in later adulthood.

Effect on Social Status – Half of schizophrenic patients are able to take care for
themselves, work and precipitate socially.
Effect on intelligence – About half of patients experiences some decline in IQ.
Suicide and Self Destructive behaviours - Suicide - About 20% and 50% of
patients with schizophrenia attempt suicide and an estimated 9% to 13% of
schizophrenia succeed. Smoking and other Addictions – A large majority of
people with schizophrenia abuse nicotine, alcohol and other substances.
Effect on Family members – Family members suffer from grief, long term guilt
and many emotional issues when faced with a schizophrenic loved one.

How is Schizophrenia diagnosed?


Verbal screening tests to help determine whether a patient’s symptoms meet the
criteria for schizophrenia. Because no single symptom is specific to
schizophrenia, a diagnosis may be made when one or more of the following
conditions is present :
• If a patient has at lease one active flare-up lasting a month or less. The
flare-up consists of at least two characteristic symptoms (e.g.
hallucinations, delusions, evidence of disorganized thinking and
emotional unresponsiveness with a flat speaking tone).
• If the patient has particularly bizarre delusions or hallucinations even in
the absence of other characteristic symptoms.
• If certain symptoms are present for at least six month even in the
absence of active flare-ups. Such symptoms include marked social
withdrawal, peculiar behaviour (talking to oneself, severe

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superstitiousness), vague and incoherent speech, or other indications of


disturbed thinking. The patient’s social and person relationships would
also have deteriorated since the onset of symptoms.

What are the general guidelines for treating schizophrenia?


Integrated Approach – Schizophrenia is now officially categorized as a brain
disease not a psychologic disorder and drug treatment is the primary therapy.
The treatment approach involves the following:
• Motivational interviewing to encourage the patients’ commitment to
change.
• Use of antopsychotic medications (generally atypical or novel
antipsychotics) with monitoring.
• Community based rehabilitation
• Cognitive-behavioural therapy, which aims to reduce delusions and
hallucinations.
• Family interventions.

Classes of drugs used in schizophrenia


Most drugs that treat schizophrenia work by blocking receptors of the
neurotransmitter dopamine, which is though to play a major role in psychotic
symptoms. The following drug classes are generally used for schizophrenia :
• Antipsychotic agents also called neuroleptic agents –
They include haloperidol (Serenace). Others include chlorpromazine,
perphenazine, thioridazine, meoridazine, trifluoperazine and fluphenazine.

• The atypical or novel antipsychotics - include clozapine, risperidone,


olanzapine, quetiapine, ziprasidone.

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MOOD DISORDERS

What is mood disorder ?


Mood disorders are characterized by a disturbance in the regulation of mood,
behaviour and affect.

What are the types of mood disorders ?


Mood disorders are sub-divided into
1. Depressive disorders
2. Bipolar disorders
3. Depression in association with medical illness or alcohol and substance
abuse.

What is major depression?


• Major depression is defined as depressed mood on a daily basis for a
minimum duration of 2 weeks.
• An episode may be characterised by sadness, indifference or apathy or
irritability and is usually associated with change in a number of
neurovegetative functions, including sleep patters and appetite and
weight, motor agitation or retardation, fatigue, impairment in concentration
and decision making, feeling of shame or guilt and thoughts of death or
dying.

What is the incidence of major depression?


• Approximately 15% of the general population experiences a major
depressive episode at some point in life and 6 to 8% of all outpatients in
primary care settings satisfy diagnostic criteria for the disorder.

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• Incidence of depression increases with age; the disorder in approximately


twice as prevalent in women as in men, regardless of age.
• Unipolar depressive disorders usually have their onset in early adulthood
and recurrences over the course of a lifetime are likely. 50 to 60% of
patients who have first episode have at least one or two more episodes.

What are the criteria for diagnosis of major depression?

Symptoms criteria for major depressive disorder (unipolar depression).


At least five of the following symptoms must be present within a 2-week period*
• Depressed mood most of the day
• Diminished interest or loss of pleasure (anhedonia)
• Significant weight loss or weight gain
• Insomnia or hypersomnia
• Psychomotor retardation or agitation
• Loss of energy
• Feelings of worthlessness or excessive guilt
• Difficulty in thinking or concentrating
• Suicidal ideation or attempt

*Depressed mood or anhedonia must be one of the five symptoms. In addition to


these criteria, symptoms include a significant drop in social or occupational
function, and they are not better accounted for by other factors, such as
substance abuse or a general medical condition”
Data from Diagnostic and Statistical Manual for mental Disorders, 4th edition.

What is the etiology (cause) of major depression?


Etiology - poorly understood.

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• Monozygotic twins have a higher concordance rate (46%) than


dizygotic
• Siblings (20%).
• Involvement of the serotonin (5-Hydrozytryptophan) system is
suggested by findings of lower plasma tryptophan levels, a decreased
cerebrospinal fluid level of 5-hydroxyinsolacetic acid (the principal
metabolite of serotonin in brain).
• An increase in brain 5-HT receptors.
• Neuroendocrine abnormalities consist of :
• Increased cortisol secretion
• An increase in adrenal size
• A decreased inhibitory response of glucorticoids to
dexamethasone.

What is the management of major depression?


Treatment – Treatment planning requires co-ordination of short term symptom
remission with longer term continuation and maintenance strategies designed to
prevent relapse and recurrence.

• Medication (anti-depressants).
• Psychotherapy to help the patient cope with decreased self-esteem
and demovalization , demonstrably improves outcome.
• Electro-convulsive therapy (ECT)
What are the commonly used anti-depressants?

Classification
1. Tricyclic Antidepressants – Imipramine, Amitriptyline, Trimipramine,
Doxepin, Clomipramine, Dothoepin.
2. Moradrenaline reuptake inhibitors (NA > 5HT) - Nortriptyline,
Desipramine, Protriptyline, Amoxapine.

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3. Selective Serotonin (5 HT) reuptake inhibitors : Fluoxetine, Fluvoxamine,


Paroxetine, Citalopram, S-Citalopram.
4. Atypical antidepressants – Bupropion, Tianeptine.

BIPOLAR DISORDER

What are the Clinical manifestations of Bipolar disorders?


• It is characterized by unpredictable swings in mood from mania/or
hypomania) to depression.
• Some patients suffer only from recurrent attacks of mania, which in its
pure form is associated with increased psychomotor activity, excessive
social extroversion, decreased need for sleep, impulsivity and impairment
in judgement and expansive, grandiose and some time irritable mood.

What is the etiology of Bipolar disorders?


Etiology – Genetic predispositions to bipolar disorder is significant. The
concordance rate for monosygotic twin pairs approaches 80%.
• Autosomal dominant transmission
• The pathophysiological mechanisms underlying the profound and
recurrent mood swings of bipolar disorders remain uncommon. Cellular
models of changes in membrane Na+ and K+ activated ATPase and
proposals of disordered signal transduction mechanisms involving either
the phosphoinositol system or guaine nucleotide binding proteins have
received the most attention.

What are the criteria for diagnosis of Bipolar disorders?


Symptoms criteria for bipolar disorder
Abnormally expensive and elevated mood or irritability that lasts longer than 1
week, less if hospitalised and three or more of the following symptoms:

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• Inflated self esteem or grandiosity.


• Diminished need for sleep (eg. Up for several consecutive
nights without feeling tired).
• Pressured need to keep talking.
• Racing thoughts.
• Distracted attention.
• Increase in goal directed activity (eg. Socially, professionally or
sexually).
• Indulgence in pleasurable activities to the detriment of the
patient’s welfare.
In addition to these criteria, symptoms include a significant drop in social or
occupation function. They may be associated with psychosis and may lead to
hospitalization to prevent harm to self or others. Symptoms are not better
accounted for by other factors, such as substance abuse or a general medical
condition
Data from Diagnostic and Statistical Manual for Mental disorders, 4th Edn.

What is the management of Bipolar disorders ?

Treatment
Lithium carbonate remains the mainstay of treatment in bipolar disorder, although
sodium valproate is equally effective in acute mania. Carbamazepine is also
efficacious.

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PSYCHOTHERAPY

Anxiety Disorders
a. Definition of anxiety. Unpleasant and unwarranted feelings of
apprehension sometimes accompanied by physiologic symptoms.

b. Types of anxiety disorders: Generalized anxiety disorder,


panic disorder, agoraphobia, social or simple phobias, obsessive
compulsive disorder, posttraumatic stress disorder

c. Differential diagnosis of anxiety disorders

i. Psychiatric: Anxious depression, drug abuse or withdrawal


(alcohol, benzodiazepines), stimulant use (caffeine,
amphetamines), some personality disorders, akathisia in
patients on antipsychotic medications,

ii. Medical

1. Cardiovascular (such as angina, cardiac arrhythmias,


MI, CHF, HTN, mitral valve prolapse).

2. Respiratory (such as asthma, COPD,


hyperventilation, hypoxia, PE).

3. Endocrine (such as hypoglycemia, hyperthyroidism,


menopause, pheochromocytoma, Cushing's syndrome).

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4. Neurologic (such as delirium, multiple sclerosis,


partial complex seizures, postconcussion syndrome,
vestibular dysfunction).

5. Drugs (such as theophylline, bronchodilators,


steroids, calcium-channel blockers, neuroleptics,
anticholinergics).

6. Gastroesophageal reflux.

II. Generalized Anxiety Disorder (GAD).


a. Overview. Probably the most common anxiety disorder in primary
care with lifetime prevalence of 5%. Gradual onset with peak on-
set in the teen years. High risk for other comorbid psychiatric
disorders

b. DSM-IV diagnosis.

i. Excessive anxiety and worry on most days for at least 6


months, about a number of issues.

ii. Difficulty controlling the worry.

iii. The anxiety and worry are associated with at least 3 of the
following 6 symptoms for the past 6 months:

1. Restlessness or feeling on edge

2. Irritability

3. Being easily fatigued

4. Difficulty concentrating

5. Muscle tension

6. Sleep disturbance

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iv. Focus of the anxiety and worry does not relate to another
major emotional disorder (for example, worry is not about
having a panic attack as in panic disorder).

v. Anxiety causes significant distress or impairment in


functioning.

vi. The symptoms are not attributable to substance use or a


medical condition and are not present only during the course
of a mood, psychotic, or developmental disorder.

c. Treatment.

i. Therapy.

1. Psychotherapy. Most patients with mild symptoms


can be treated with supportive counseling and
education without need for medication.

2. Other therapies. Relaxation training and cognitive


therapy.

ii. General measures. Regular exercise, adequate amounts of


sleep, avoidance of caffeine and alcohol.

iii. Medications.

1. SSRIs. Several have received FDA approval for


treatment of GAD, all are probably effective. Use in
doses similar to those for panic disorder (see below).
In select patients may add a benzodiazepine for first
several weeks of treatment, since it has a quicker
onset of action and avoids potential initial side effect
of increased anxiety with SSRIs.

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2. Benzodiazepines. Usually of short-term use with no


long-term efficacy proved. Use lowest dose that
alleviates anxiety. Longer half-life drugs may be
easier to taper and reduce incidence of
dependence. May cause rebound anxiety with
taper or withdrawal. Examples: clonazepam,
alprazolam, diazepam, lorazepam.

3. Haloperidol (Serenace) - 0.25 mg. A better


alternative to Alprazolam. Relives anxiety rapidly, no
sediation, no drug dependence and preferred when
mental altertness is essential.

4. Venlafaxine (Effexor). FDA approved for GAD,


considered as an alternative to SSRIs.

5. TCAs. Imipramine 25 to 150 mg/day. Does not


become effective for 2 to 3 weeks. Most beneficial in
patients with comorbid depression or sleep
disturbance.

6. Beta-blockers. Propranolol may help physical


symptoms such as racing heart, akathisia (not FDA
approved) but has no effect on psychic component of
anxiety. Can also be used for performance anxiety.

7. Antihistamines. Hydroxyzine 50 to 100 mg QID may


be used PRN, as an adjunct to other medications, or
as an alternative therapy for patients with addiction
potential.

8. Buspirone. Clinically appears less effective than


other agents. Start 5 mg PO TID and increase to

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typical dose of 20 to 30 mg/day. Takes 2 weeks to be


effective. Non-sedating with little abuse potential.

III. Panic Disorder


a. Overview. Estimated lifetime prevalence is greater than 3%.

b. DSM-IV diagnosis. Recurrent unexplained panic attacks (discrete


periods of intense fear).

i. At least one of the attacks has been followed by 1 month (or


more) of one (or more) of the following:

1. Concern about having future attacks

2. Worry about consequences of the attack

3. Change in behavior related to the attacks

ii. Panic attacks are not substance induced, related to a


general medical condition, or better accounted for by another
mental illness.

iii. During the attack at least 4 of the following symptoms


develop quickly and peak within 10 minutes:

c. Treatment.

i. Medications.

1. SSRIs are the drugs of choice (Zoloft and Paxil are


FDA-approved for this indication). Recommended
dosage ranges: Zoloft (sertraline) 50 to 100 mg/day,
Paxil (paroxetine) 20 to 50 mg/day, Celexa
(citalopram) 20 to 40 mg/day, Luvox (fluvoxamine) 50
to 300 mg/day, and Prozac (fluoxetine) 10 to 60
mg/day. Start at lowest dose and may increase after
first week as tolerated (such as Prozac 10 mg PO
QOD for week 1, 10 mg QD for week 2, and then 20

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mg QD for week 3). Monitor for initial paradoxical


anxiety secondary to drug side effect, which usually
resolves with time.

2. Tricyclic antidepressants. For example, start


imipramine at 10 to 25 mg QHS and increase by 10 to
25 mg Q3 or 4 days until effective, side effects
predominate, or initial target dose of 150 to 200 mg
QHS is reached. If no response after 4 to 6 weeks at
target dose, may increase to maximum dose of 300 to
400 mg QHS as tolerated. Clinical experience has
shown that serotonergic TCAs are more effective than
noradrenergic TCAs.

3. Benzodiazepines have a quicker onset of action than


other drugs; may use as a short-term adjunct to
SSRIs if initial paradoxical anxiety arises. They may
be used long term if patients fail treatment or are
unable to tolerate SSRIs or TCAs.

4. Haloperidol (Serenace 0.25mg ) relieves anxiety


rapidly, no sedation, no drug dependence, and
preferred when mental alertness is required.

5. MAOIs are reserved for patients who do not respond


to SSRIs or TCAs because of serious adverse drug
reactions. Before starting, consider consulting a
psychiatrist.

6. Propanolol is not a first-line agent for panic disorder


but is very effective for physical symptoms of panic
attacks associated with performance anxiety.

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7. Buspirone (Buspar) has demonstrated little efficacy


in patients with panic disorders.

ii. Psychotherapy.

1. Supportive therapy is always included.

2. Addition of cognitive therapy may be beneficial.

IV. Agoraphobia
a. Overview. Age of onset most often in 20s and 30s. More common
in women. Often occurs with panic disorders.

b. DSM-IV diagnosis criteria require:

i. Fear of being in place or situations from which escape might


be difficult or embarrassing in the event of suddenly
developing a panic attack or panic-like symptoms.

ii. The situations are avoided, or else endured with


considerable anxiety about having panic-attacks symptoms,
or require a companion.

iii. Anxiety and avoidance are not better accounted for by


another mental disorder.

c. Treatment

i. Agoraphobia with panic attacks. Choices include SSRIs,


TCAs, benzodiazepines, or MAOIs. See section on panic
disorder above. Medications in combination with behavioral
therapy most beneficial.

ii. Agoraphobia alone. Systematic desensitization with


exposure to real-life feared situations is the treatment of
choice. Consult a psychologist.

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V. Social Phobias and Other Phobias


a. Overview. Social phobia has a lifetime prevalence of 13% with
onset most common in the mid-teens. Other specific phobias are
more common in females, and impairment is usually minimal.

b. DSM-IV criteria.

i. Persistent fear of humiliation or embarrassment in certain


social situations (social phobia) or irrational fear of other
circumscribed stimuli (specific phobia).

ii. Exposure to the particular stimulus provokes anxiety, which


may include a situationally bound panic attack.

iii. The person usually realizes that the fear is excessive.

iv. The fear results in avoidance of the stimulus that interferes


with patient's social environment or produces significant
distress.

v. The fear or avoidance is not attributable to substance use, a


general medical condition, or another mental disorder.

c. Treatment.

i. Systematic desensitization and exposure (for specific


phobias) and cognitive behavioral therapy (for social
phobias).

ii. Beta-blockers may be effective in treating performance-


anxiety symptoms.

iii. Drugs used in generalized social phobias include SSRIs


(only Paxil currently has the FDA-approved indication, start
at 20 mg/day, increase up to 60 mg/day) or an MAOI (such
as phenelzine).

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VI. Obsessive-Compulsive Disorder (OCD)


a. Overview. Lifetime prevalence of 2.5%. Onset usually in
adolescence or early adulthood.

b. DSM-IV diagnosis. Obsessions or compulsions that significantly


interfere with daily functioning because of distress or time
consumption.

i. Obsessions. Recurrent, persistent thoughts that are


experienced as intrusive and inappropriate. Examples
include fear of contamination, constant worry about
performing inappropriate or dangerous acts. The person
recognizes the thoughts as a product of his or her own mind
and attempts to ignore or suppress them.

ii. Compulsions. Repetitive, purposeful behaviors performed


in response to an obsession or according to certain rules.
Includes repetitive handwashing, checking rituals,
organization rituals, ritualistic counting. These are designed
to neutralize or prevent discomfort. In general, recognized by
the patient as unreasonable.

c. Treatment. Generally not curative but can obtain significant


improvement.

i. Behavior therapy uses exposure and response prevention


to limit the dysfunction that results from the obsessions or
compulsions.

ii. Medications.

1. SSRIs. Start at low dose and titrate to doses higher


than those used for depression (such as fluoxetine

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[Prozac] start 20 mg daily; usual daily dose 40 to 80


mg). If a therapeutic trial with one SSRI fails, another
one may be efficacious.

2. Clomipramine (Anafranil). Start with 25 mg, and


titrate up to 150 to 250 mg daily. Give in divided
doses with meals to minimize GI side effects, or at
bedtime to minimize sedation.

iii. Cingulotomy. A last resort for severe treatment-resistant


patients. May benefit up to 80% of patients receiving the
surgery, but results may be inconsistent.

VII. Posttraumatic Stress Disorder (PTSD)


a. Overview. Lifetime prevalence 1% to 14%. PTSD can occur at any
age. Symptoms usually begin within 3 months after the inciting
trauma.

b. DSM-IV diagnosis criteria. PTSD occurs in individuals who


experienced an extraordinarily distressing event (combat, sexual
abuse or rape, natural disasters) involving self or others. In
addition, the person's response includes intense fear or
helplessness.

i. Characterized by persistent re-experiencing of the event in at least


one of the following ways:

1. Intrusive, recurrent recollections of the event

2. Recurrent distressing dreams of the event

3. Sudden sense of reliving the experience (flashbacks,


hallucinations)

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4. Intense distress with exposure to symbols or representations


of the event (such as anniversaries)

ii. Results in avoidant behavior of stimuli associated with the


trauma or decreased responsiveness to the external world
(psychic numbing).

iii. Associated with 2 or more symptoms of increased arousal


(insomnia, irritability, anger, poor, concentration, hypervigilance, or
exaggerated startle).

iv. The disturbance lasts more than 1 month and causes


significant distress or functional impairment.

c. Treatment.

i. Supportive therapy that is appropriate for grief reaction.

ii. Group therapy may be helpful.

iii. Individuals may benefit from medical treatment (such as


treating depressive or anxiety symptoms). Zoloft (sertraline)
has FDA approval for this indication, any of the SSRIs may
be beneficial.

iv. Some evidence indicates that the use of beta-blockers soon


after the event may prevent the disorder by blocking the
negative physical response but this is still preliminary.

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GLOSSARY

• Agoraphobia—fear of having a panic attack (intense and overwhelming


anxiety) in a place where there is no one who can help you and you
cannot easily escape. This fear often keeps people from leaving home or
traveling.
• Anorexia nervosa- an illness in which a person cannot maintain normal
weight, is very afraid of gaining weight, sees oneself as heavy or fat even
though the person is significantly underweight, and refuses to eat enough
to maintain a normal body weight.
• Anxiety disorder- one in a group of illnesses in which the most important
symptom is anxiety. This group includes Obsessive-Compulsive Disorder,
Panic Disorder, Posttraumatic Stress Disorder, Social Phobia and Specific
Phobia.
• Attention-deficit hyperactivity disorder (ADHD) - an illness in which
children, teens or adults cannot pay attention, sit quietly, remember

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instructions, wait for a turn or keep from speaking out when it's not time to
speak.
• Avoidant personality disorder- a persistent and rigid pattern of avoiding
social situations, low self-esteem, fear of criticism, fear of being foolish,
and fear of embarrassment.
• Bipolar disorder - another term for manic-depression, an illness in which
there are cycles of depression and mania.
• Borderline personality disorder - a persistent and rigid pattern of losing
control of feelings and impulses, and extreme instability in relationships
and self-image. Behaviors often include rage, self-mutilation, suicide
attempts or threats, and intense, stormy relationships.
• Bulimia nervosa - an illness in which there is frequent binge-eating (that
is, eating large amounts of high-calorie food in a short period of time). The
binges are followed by attempts to make up for eating so much by
vomiting, using diuretics or laxatives, strict dieting, fasting or vigorous
exercise.
• Dementia - a brain disorder where there is loss of memory and other
important functions of the brain (for example, the ability to speak, the
ability to recognize ordinary things, the ability to plan or organize).
• Dependent personality disorder - a personality problem in which a
person is unable to cope because of extreme lack of self-confidence, a
wish to have others assume responsibility for one's life, and consistently
putting the needs of another person before one's own needs.
• Depression - an illness in which there is a long-lasting mood of sadness,
despair or discouragement in which a person has trouble functioning at
home, at work or at school. Symptoms may include slowed thinking, lack
of pleasure, guilt, hopelessness, and problems with eating and sleeping.

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• Dissociative disorders - illnesses that involve dissociation (splitting off of


groups of mental processes from consciousness), for example, amnesia,
or multiple personality disorder.
• Eating disorder - severe trouble with eating behaviors. Examples are
anorexia and bulimia.
• Factitious disorders (Munchausen) - an illness in which there are
physical or psychological symptoms that are intentionally produced in
order to assume the sick role.
• Generalized anxiety disorder (GAD) - an illness in which a person has
unrealistic or excessive anxiety about one or more problems.
• Insomnia - trouble falling asleep or staying asleep.
• Mood disorders - psychiatric illnesses in which the most important
symptoms are problems with mood.
• Narcissistic personality disorder - a psychiatric problem in which a
person behaves consistently with an exaggerated sense of self-
importance and specialness, uses other people, and lacks genuine
feelings for other people. People with this disorder often lack self-esteem
and need excessive admiration from others.
• Obsessive-compulsive (OCD) - one of the anxiety disorders in which a
person has obsessions (insistent thoughts, impulses or images that
cannot be dismissed) and/or compulsions (persistent urges to perform a
ritual, such as hand-washing or checking things)
• Obsessive-compulsive personality disorder - a persistent
preoccupation with orderliness, perfectionism, and mental and
interpersonal control, at the expense of flexibility, openness, and
efficiency.
• Oppositional defiant disorder - a childhood disorder in which there is
uncontrollably negative and hostile behavior.

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• Panic disorder - an illness in which a person has panic attacks (sudden


episodes of intense and overwhelming anxiety)
• Paranoia - suspiciousness caused by misinterpretation of actual events
• Pervasive development disorder (PDD) - one of several disorders that
begin in infancy, childhood or adolescence, causing severe and pervasive
problems in several areas: social interaction, communication, or the
presence of stereotyped behavior, interest and activities. Includes autism
and Asperger's Disorder.
• Posttraumatic stress disorder (PTSD) - an anxiety disorder in which
living through an overwhelming mental or physical stress is followed by
persistent symptoms of reexperiencing the event in the person's mind,
avoiding things that remind the person of the event, numbness, and
severe anxiety or irritability.
• Psychotic disorders - psychiatric disorders that causes loss of touch with
reality
• Schizoaffective disorder - a disorder in which there are problems both
with psychotic symptoms and with mood symptoms (mania or depression).
• In schizoaffective disorder there must be a period of time in which
psychotic symptoms are experienced with an abnormal mood.
• Schizophrenia - a disorder that includes psychotic symptoms such as
delusions and hallucinations which interfere with one's ability to function.
• Seasonal affective disorder - a disorder in which mood is strongly
affected by the season of the year.
• Sleep apnea - a sleep disorder in which a person gets very poor quality
sleep because he or she stops breathing repeatedly during the night,
causing the person to repeatedly wake up gasping for air.
• Sleep disorders - disorders in which people have problems with sleep

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• Social phobia - a disorder in which a person experiences severe and


overwhelming fear of all social situations or of specific social situations,
e.g. eating in public or using a public bathroom.
• Specific phobia - an illness in which there is extreme fear caused by a
specific object or situation, e.g. spiders, dogs, high places, closed-in
places. This happens even though the person knows the fear is excessive
or unreasonable.
• Substance abuse - using a substance (usually a street drug) excessively,
even when it hurts relationships with other people, prevents doing well at
work or school, ruins a person's health or creates trouble with the law.
• Substance dependence - addiction; needing to use a substance (usually
a street drug) so much that if the substance is stopped abruptly, there are
dangerous physical symptoms, like fever, shaking, sweating, or seizures.
Needing to use the substance/drug so much that it keeps a person from
working, going to school, having good relationships and obeying the law.
• Substance related disorders - a group of illnesses including problems
with substance (usually street drugs) abuse and dependence.

CARBOHYDRATE METABOLISM

Energy - Sources, Storage & Uses


To sustain life human being needs energy. Energy is obtained from three nutritional
sources –

1. Carbohydrate.
2. Fats.
3. Proteins.

Out of this human body mainly utilizes carbohydrate and fats. Proteins are used only
when there is a crisis of carbohydrate and fats in the body.

Human being obtains energy from 2 major fuels –

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1. Glucose obtained from carbohydrates.


2. Fatty acids obtained from fats.

Proteins can also provide energy. Proteins break down into amino acids, which are
converted to glucose and can be used as energy.

What is a Carbohydrate?

Carbohydrates are compounds which have the following basic composition:

Carbohydrate can be further classified as –

1. Monosaccharides
2. Disaccharides
3. Oligosaccharides
4. Polysaccharides

Monosaccharides have single sugar unit. E.g.

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 have linked sugar units

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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

Oligosaccharides

Dried beans, peas, lentils

• Rafinose (gal-glu-fru)
• Stachyose (gal-gal-gal-fru)
• Metabolized by intestinal bacteria
• Produces gaseous effects

Polysaccharides

Contain 100’s or 1000’s of monosaccharide units

Starch-digestible, fiber-indigestible

Glycogen

• Stored form of glucose


• .Major sites – Muscles and Liver; 75% is stored in muscles.
• Liver: major site for glycogen synthesis.
o ~10% of wet weight of liver
• Muscles
o Glycogen < 1% weight
o Used as energy when body requires
o Important for “instant” energy

Functions of glycogen –

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Glycogen stored in skeletal muscle serves as fuel reserve for synthesis of ATP during
muscle contraction Glycogen stored in liver helps in maintaining 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

Synopsis of carbohydrate digestion

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Glucose is the primary energy source for the human body

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1. Brain is the most important glucose consumer (50%)

2. Metabolism results in:

• Energy (ATP) production (conversion to CO2 + H2O)


• Storage as glycogen in liver or triglyceride in adipose tissue
• Conversion to amino acids, proteins, etc.

Regulation of Blood Glucose Concentration


What is Glycolysis?

1. Derived from the Greek stem glyk-, “sweet,” and the word lysis, “dissolution.”
2. It is the sequence of reactions that metabolizes one molecule of glucose to 2
molecules of pyruvic acid with the generation of 2 molecules of ATP
3. In anaerobic condition pyruvic acid is converted to lactic acid
4. In aerobic condition pyruvic acid is converted to acetyl-CoA.

What is Gluconeogenesis?

1. 1 It is the process of synthesis of glucose from noncarbohydrate sources


(pyruvate, amino acids, lactic acid)
2. 2 Converts lactate or amino acids to glucose in starvation or stress.
3. 3 Opposite of glycolysis
4. 4 Helps in maintaining normal glucose level during fasting.

What is Glycogenesis?

1. 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. This
process is called glycogenesis.
2. Glycogen is synthesized depending on the demand for glucose and ATP (energy)
3. If both are present in relatively high amounts, then the excess glucose is converted
into glycogen for storage in liver and muscle cells.

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What is Glycogenolysis?

1. When blood glucose concentration drops, there is a breakdown of glycogen to


make glucose
2. Mobilizes stored glycogen in liver & skeletal muscle.
3. Helps in maintaining normal glucose level during fasting.

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HORMONES AND GLUCOSE CONTROL


Blood glucose is very tightly maintained between 70 mg/dl to 110 mg/dl in order to
ensure adequate glucose to various tissues especially brain. Both high and low glucose
level can be harmful. Low glucose can result in irreversible brain damage and high
glucose can lead to a chronic disease – Diabetes Mellitus.

Glucose metabolism is under the control of various hormones.

Most common are :

■ Insulin ■ Glucagon
■ Epinephrine ■ Somatostatin

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INSULIN - SYNTHESIS, SECRETION AND MODE OF


ACTION
First hormone identified (1920’s) by Banting and Best

Released when glucose is abundant (elevated plasma glucose)

How insulin is synthesized ?

Synthesis of insulin starts from preproinsulin.

What is the role of C-peptide?

1. Insulin is difficult to measure


2. Half-life is only 5 mins
3. Rapidly inactivated by various enzymes.
4. C-Peptide has 30 mins half life
5. Synthesized in equimolar conc to that of insulin
6. Determines amount of insulin secreted from β-cell

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How insulin is secreted?

1. Insulin is secreted in 2 phases –

First phase

• Sharp peak within 3-5 mins of glucose


intake
• Completed within 10 mins
• Release of stored insulin

The first phase is very important as it –

• Promotes peripheral utilization of the prandial nutrient load.


• Suppresses hepatic glucose output.
• Limits post prandial glucose elevation

Second phase

• Release of newly synthesize insulin.


• Second phase helps to attain normoglycemia.

What does insulin do?

1. Increases glucose uptake by muscle and adipose cells.


2. Helps in increasing cells to breakdown glucose, releasing energy in the form of
ATP.
3. Helps the liver and muscle to store glucose as glycogen (short-term energy
reserve).
4. Decreases glucose production from liver.
5. Adipose tissue to store glucose as fat (long-term energy reserve).
6. Increases glycogen synthesis and protein synthesis.

Insulin is the ONLY hormone that lowers circulating glucose level!

What is “Glucagon” and what is its role in glucose metabolism?

1. Secreted from α-cells of pancreas.

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2. Major target organ: liver.


3. Stimulates production of glucose by glycogenolysis and gluconeogenesis.
4. Glucagon prevents hypoglycemia by increasing cell production of glucose.
5. Principal hormone for producing a rapid increase in plasma glucose
concentration.
6. Secretion is suppressed in hyperglycemia.

What is the role of the hormone “Epinephrine in glucose metabolism?

1. It’s a catecholamine secreted by the adrenal medulla and helps in “fight and
flight” situation.
2. Serves as a backup for glucagon
3. Stimulates glucagon secretion and inhibits insulin secretion by pancreas
4. Stimulates glycogen breakdown (glycogenolysis) and decreases glucose use
5. Helps to maintain glucose level to brain during conditions of stress.

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What is the role of “Somastostatin”?

1. Secreted by γ-cells of pancreas

2. Primary act is to inhibit secretion of insulin and glucagon.

What are Glucose Trasporters (GLUT)?

Glucose been water soluble can’t readily enter through the cell membrane. Special
proteins called “Glucose Transporters” or “GLUT” helps in the entry of glucose to
various cells. Till now 6 types of GLUT has been identified. The following table shows
the various GLUT present, their locations and relation to insulin –

Insulin
Transporter Tissue
dependent?
GLUT1 RBCs, brain, kidney No
GLUT2 β-cells of pancreas, small intestine, kidney No
GLUT3 Neurons , placenta No
GLUT4 Skeletal and cardiac muscle, adipose tissue Yes
GLUT5 small intestine, kidney, brain, adipose tissue No
GLUT7 Some liver cells No

How insulin is secreted from β-cells?

1. Insulin is secreted in the following steps


2. High blood glucose causes opening of large number of GLUT-2 present on the β-
cell membrane.
3. Glucose enters in high concentration and generates excess ATP.High
concentration of ATP binds with the K+ channels present on the β-cell membrane
and causes closure of the channels.
4. Thus K+ is not able to move out of the cell which is the normal ionic movement.
5. This results in charge imbalance leading to a condition called “Depolarization”
6. This results in opening of Ca++ channels and excess Ca++ enters the beta cell.
7. The excess Ca++ binds with the secretary granules which synthesizes and stores
insulin.

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8. The binding of Ca++ results in movement of the secretary granules to the cell
membrane and insulin is released in the blood.

How insulin increases glucose uptake in the storage cells?

Insulin acts in the following way –

1. Insulin binds with the insulin receptor present on the muscles (& adipose) cells
and stimulates it.
2. This result in stimulation of series of enzymatic reaction inside the muscle (&
adipose) cells.
3. Most of the GLUT-4 present in these cells is generally located inside the cells and
not on the membrane.
4. These enzymes results in movement of the GLUT-4 to the cell membrane – a
process called “Translocation”.
5. Now more glucose can enter these muscle cells.
6. Once inside, the glucose are either utilized through the process of glycolysis to
generate ATP or stored as glycogen for future use.

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Meanwhile –

• Insulin also binds with receptors in the liver and reduces glucose production by
inhibiting the process of gluconeogenesis and glycogenolysis.
• Thus glucose concentration comes back to normal.

What happens when glucose level becomes normal?

1. Once normal glucose level is restored, stimulation on beta cells are removed and
insulin secretion decreases.
2. Thus concentration of insulin comes back to basal (normal) level.
3. Glucagon concentration which was reduced during high glucose level now comes
back to normal level.
4. Inhibiting action of insulin from liver is removed.
5. Normal glucagons level and low insulin level now helps the liver to produce
adequate amount of glucose (gluconeogenesis & glycogenolysis) and helps in
maintaining normal glucose level during post absorptive state.

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What do you mean by the terms, hyperglycemia and hypoglycemia ?

Hyperglycemia – excess glucose in the blood (> 110 mg/dl).

Hypoglycemia – too little glucose in the blood, (< 60 mg/dl). This is very important as
during treatment of diabetes hypoglycemia is often seen which can be life threatening.
Common symptoms of hypoglycemia includes increase in heart rate, confusion, sweating,
giddiness etc. Prolonged hypoglycemia can lead to irreversible brain damage.

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What is the role of insulin on lipid metabolism?

Triglycerides are the stored form of fats present in the adipose tissues which serves to
provide energy when glucose is used up.

Insulin inhibits the conversion of triglycerides to FFA (a process called lipolysis) or in


other words insulin helps in conversion of FFA to triglycerides (a process called
lipogenesis)

In some conditions where there is less insulin FFA can be converted to another
compound called ketone bodies leading to ketoacidosis a life threatening condition in
diabetes mellitus.

What is the role of insulin on protein metabolism?

Insulin helps in –

1. Protein synthesis
2. Inhibits proteolysis (breakdown of proteins)

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Summary of insulin action

Increases –

• Glucose uptake
• Glycolysis
• Glycogenesis
• Lipogenesis
• Protein synthesis

Decreases –

• Gluconeogenesis
• Glycogenolysis
• Lipolysis
• Ketogenesis
• Proteolysis

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Negative feedback mechanism of insulin

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DIABETES MELLITUS - DEFINITION, PATHOGENESIS


AND MANAGEMENT
Diabetes mellitus is defined as 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.

What are the various risk factors for diabetes?

1. Family history of diabetes.


2. Obesity (> 20% over desired body weight or BMI > 27 kg/m23.
3. Age > 45 years.
4. Sedentary life style.
5. Some ethnic groups (Indians, African-Americans and Native Americans, Asian
Americans).
6. Gestational diabetes or delivering a baby weighing more than 9 pounds (4 kg or
more)
7. High blood pressure (> 140/90mmHg).
8. High blood levels of triglycerides (> 250 mg/dl).
9. Low HDL cholesterol level (<35 mg/dl)

What are the common symptoms of diabetes mellitus?

1. Frequent urination - Polyuria


2. Excessive thirst - Polydypsia
3. Excessive hunger - Polyphagia
4. Fatigue
5. Weight loss
6. Blurred vision

But the symptoms are more prominent in Type-1 DM

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What are the types of diabetes mellitus?

Most common types are –

• Type-1 Diabetes mellitus


• Type-2 Diabetes mellitus

What is type-1 Diabetes mellitus?

1. This disease is caused due to total destruction of β-cells of the pancreas.

2. The dsetruction is due to autoimmune destruction of islets

3. Most prominent during childhood

4. Therapy involves Insulin injection

What is type-2 diabetes mellitus?

1. This is the most common type of diabetes (>90%)


2. Related to genetic defect and life style and food habits.
3. Consists of 2 common defects –
a. Insulin resistance
b. β-cell impairment or impaired insulin secretion.

What is insulin resistance?

1. This is the decreased ability of normal insulin to act effectively on peripheral


tissues (muscle & adipose tissues) and liver.
2. Hence β-cell has to secrete more insulin to maintain normal glucose level.

What are the various causes of insulin resistance?

As per various clinical studies available plasma free fatty acids (FFA) has been found to
be one of the major culprit.

1. Central or visceral obesity is the major cause


2. Adipocytes secretes high conc of FFA.

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3. FFA enters muscle cells and interferes with insulin signaling system
4. Thus there is less GLUT 4 translocation
5. Leads to decreased glucose uptake
6. Adipocytes also secretes various biochemicals like resistin, leptin, TNF-α &
adiponectin
7. Low adiponectin level or high conc of resistin, leptin, TNF-α has been associated
with insulin resistance

What is hyperinsulinemia?

1. Persons with insulin resistance, requires higher insulin level to bring glucose back
to normal.
2. β-cells secretes additional insulin to compensate. Thus these persons have higher
insulin level in the plasma. This condition is called hyperinsulinemia.
3. This puts additional stress on β-cells
4. Person may be normal or diabetic depending on the proper functioning of β-cells.
5. Hyperinsulinemia is a major risk factor for various cardiovascular disease.

What do you mean by β-cell impairment?

1. This is the condition where the beta cells are unable to produce sufficient insulin
as per rise in bloodglucose level due to both reduced β-cell mass and functional
abnormalities of the β-cell.

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2. These reduced β-cells works hard to compensate for the synthesis of adequate
insulin.
3. Continuous stress on the β-cell may lead to β-cell fatigue.
4. Gradually there is development of progressive rise in glucose level.
5. Ultimately the patient progresse to development of frank diabetes type-2.

What is the consequence of insulin resistance and β-cell impairment?

The presence of both these pathological disorder causes –

1. Decrease glucose uptake in storage cells


2. Increased glucose production from liver

Thus there is a progressive increase in hyperglycemia.

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What are types of Type-2 Diabetes Mellitus?

Type-2 Diabetes mellitus is of 2 types –

Obese (> 90%)

• These patients have very high degree of insulin resistance compared to β-cell
impairment.

Non-obese

• These patients have very high degree of β-cell impairment compared to insulin
resistance.

How Type-2 Diabetes Mellitus is diagnosed?

Type-2 Diabetes mellitus is diagnosed by the following blood test –

1. Fasting plasma glucose test (FPG).


2. Oral glucose tolerance test (OGTT).

Fasting glucose test – A sample of blood is taken 8-10 hours after the last mean,
particularly early in the morning and analyzed.

Category FPG (mg/dl)


Normal <100
Impaired Fasting Glucose Tolerance (IFG) 100-125
Diabetes >126

Oral glucose tolerance test – This is done along with the fasting glucose test. After the
fasting glucose sample is taken, the patient is given 75-100 gm of glucose solution. A
second sample is taken after 2 hours.

Category PPG (mg/dl)


Normal <140
Impaired Fasting Glucose Tolerance (IFG) 140-199
Diabetes >200

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What is glycosylated hemoglobin or HbA1c?

1. Glucose can form irreversible complex with plasma proteins, like hemoglobin.
These complexes are called glycosylated hemoglobin or HbA1c.
2. Normal laboratory values are 4 - 6%
3. Used to monitor glucose level during treatment of diabetes mellitus.
4. Since the life span of RBC are 120 days or 4 months this test gives a good
indication of average blood glucose during the previous 3 - 4 months.
5. Target level of less than 7.0 % indicates good control.

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HYPERGLYCEMIA & TISSUE DAMAGE - PIECES OF


THE PUZZLE

The general features of hyperglycemia-induced tissue damage are shown schematically


below. The DCCT (Diabetes Control and Complications Trial) and the UKPDS (U.K.
Prospective Diabetes Study) established that hyperglycemia, shown on the far left of the
figure, is the initiating cause of the diabetic tissue damage that we see clinically, shown
on the far right.

The tissue-damaging effects of hyperglycemia can damage 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 make them so vulnerable to hyperglycemia? We know that in diabetes,
hyperglycemia is bathing all the cells of every tissue. 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

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causes complications must involve mechanisms going on inside these cells, rather than
outside.
The first such mechanism that was discovered was the polyol pathway and increased
polyol pathway flux.This was the first piece of the puzzle. Then, ~10 years later, in the
late 1970s, a second piece of the puzzle emerged: increased formation of advanced
glycation end products (AGEs). In the late 1980s and early 1990s, a third piece of the
puzzle was discovered: hyperglycemia-induced activation of protein kinase C (PKC)
isoforms. And in the late 1990s, a fourth piece of the puzzle was discovered: increased
hexosamine pathway flux and consequent overmodification of proteins by N
-acetylglucosamine.

Increased Flux Through the Polyol Pathway


The polyol pathway, shown schematically in Fig. 2, focuses on the enzyme aldose
reductase. Aldose reductase normally has the function of reducing toxic aldehydes in the
cell to inactive alcohols, but when the glucose concentration in the cell becomes too high,
aldose reductase also reduces that glucose to sorbitol, which is later oxidized to fructose.
In the process of reducing high intracellular glucose to sorbitol, the aldose reductase
consumes the cofactor NADPH. But as shown in Fig. 2, NADPH is also the essential
cofactor for regenerating a critical intracellular antioxidant, reduced glutathione. By
reducing the amount of reduced glutathione, the polyol pathway increases susceptibility
to intracellular oxidative stress.

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Intracellular Production of AGE Precursors


Intracellular production of AGE precursors as shown schematically in Fig. 3, appear to
damage cells by three mechanisms. The first mechanism, shown at the top of the
endothelial cell, is the modification of intracellular proteins including, most importantly,
proteins involved in the regulation of gene transcription .The second mechanism, shown
on the left, is that these AGE precursors can diffuse out of the cell and modify
extracellular matrix molecules nearby, which changes signaling between the matrix and
the cell and causes cellular dysfunction. The third mechanism, shown on the right of Fig.
3, is that these AGE precursors diffuse out of the cell and modify circulating proteins in
the blood such as albumin. These modified circulating proteins can then bind to AGE
receptors and activate them, thereby causing the production of inflammatory cytokines
and growth factors, which in turn cause vascular pathology. Again, how do we know that
this piece of the puzzle is really important? From many animal studies such as one done
by Hans-Peter Hammes, showing that that pharmacologic inhibition of AGEs prevents
late structural changes of experimental diabetic retinopathy.

PKC Activation
The third mechanism on my "pieces of the puzzle" list was the PKC pathway. In this
pathway, shown schematically in Fig. 4, hyperglycemia inside the cell increases the

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synthesis of a molecule called diacylglycerol, which is a critical activating cofactor for


the classic isoforms of protein kinase-C, -β, -δ, and -α. When PKC is activated by
intracellular hyperglycemia, it has a variety of effects on gene expression, examples of
which are shown in the row of open boxes in Fig. 4. In each case, the things that are good
for normal function are decreased and the things that are bad are increased. For example,
starting from the far left of Fig. 4, the vasodilator producing endothelial nitric oxide
(NO) synthase (eNOS) is decreased, while the vasoconstrictor endothelin-1 is
increased. Transforming growth factor-β and plasminogen activator inhibitor-1 are
also increased. At the bottom of the figure, the row of black boxes lists the pathological
effects that may result from the abnormalities in the open boxes. Again, how do we know
that this piece of the puzzle is really important? We know that this is important from
many animal studies such as several published by George King, showing that inhibition
of PKC prevented early changes in the diabetic retina and kidney.

Increased Hexosamine Pathway Activity


The last mechanism on the "pieces of the puzzle" list was increased flux through the
hexosamine pathway. As shown schematically in Fig. 5, when glucose is high inside a
cell, most of that glucose is metabolized through glycolysis, going first to glucose-6
phosphate, then fructose-6 phosphate, and then on through the rest of the glycolytic
pathway. However, some of that fructose-6-phosphate gets diverted into a signaling
pathway in which an enzyme called GFAT (glutamine:fructose-6 phosphate
amidotransferase) converts the fructose-6 phosphate to glucosamine-6 phosphate and
finally to UDP (uridine diphosphate) N -acetyl glucosamine.

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What happens after that is the N -acetyl glucosamine gets put onto serine and threonine
residues of transcription factors, just like the more familiar process of phosphorylation,
and overmodification by this glucosamine often results in pathologic changes in gene
expression. For example, in Fig. 5, increased modification of the transcription factor Sp1
results in increased expression of transforming growth factor-β1 and plasminogen
activator inhibitor-1, both of which are bad for diabetic blood vessels. Again, how do
we know that this piece of the puzzle is really important? Although this piece of the
puzzle is the most recent to be recognized as a factor in the pathogenesis of diabetic
complications, it has been shown to play a role both in hyperglycemia-induced
abnormalities of glomerular cell gene expression and in hyperglycemia-induced
cardiomyocyte dysfunction in cell culture. In carotid artery plaques from type 2 diabetic
subjects, modification of endothelial cell proteins by the hexosamine pathway is also
significantly increased.

Unifying Mechanism

Increased levels of the upstream glycolytic metabolite glyceraldehyde-3-phosphate


activates two of the four pathways. It activates the AGE pathway because the major
intracellular AGE precursor methylglyoxal is formed from glyceraldehyde-3 phosphate.
It also activates the classic PKC pathway, since the activator of PKC, diacylglycerol, is
also formed from glyceraldehyde-3 phosphate. [reactive oxygen species (ROS).]

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COMPLICATIONS OF DIABETES MELLITUS


Complications in Diabetes mellitus are of 2 types –

1. Acute complications

● Diabetes Ketoacidosis (DKA)

● Non-ketotic hyperosmolar state (NKHS)

2. Chronic complications

● Vascular

● Non-vascular

What is Diabetes Ketoacidosis (DKA) and how it happens?

This is a Life threatening complication mainly in Type-1 DM or patients with lack of


insulin.

• Inadequate insulin causes excess lipolysis leading to increased FFA


• Increases ketone bodies leading to ketoacidosis
• May even cause coma or death

What are the various symptoms of DKA?

Symptoms are –

1. Nausea and vomiting.


2. Thirst / polyuria.
3. Abdominal pain.
4. Altered mental function.
5. Shortness of breath.

Treatment includes immediate injection of insulin.

What is Non-Ketotic Hyperosmolar State (NKHS)?

1. This is another life threatening complication reported in all age groups, but it most
frequently affects older patients with type 2 diabetes
2. Initiating event in hyperosmolar hyperglycemic state is glucosuric diuresis

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3. Decreased intravascular volume or underlying renal disease decreases the


glomerular filtration rate, causing the glucose level to increase.
4. The loss of more water than sodium leads to hyperosmolarity

What are the symptoms and treatment of NKHS?

Symptoms are –

1. Polyuria.
2. Orthostatic hypotension.
3. Neurological symptoms like - altered mental status, lethargy, seizure and possibly
coma.

Treatment includes

1. Vigorous intravenous rehydration,


2. Electrolyte replacement
3. Administration of intravenous insulin

What are the various chronic complications?

Chronic complications are of 2 types –

• Vascular
• Non-vascular.

What are the various types of vascular complications?

Vascular complications are of two types:

■ Microvascular

• Retinopathy
• Neuropathy
• Nephropathy

■ Marcovascular

• Cardiovascular disease
• Cerebrovascular disease
• Peripheral vascular disease

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MICROVASCULAR COMPLICATIONS
What is retinopathy?

1. This is one of leading cause of blindness.


2. It starts with small areas of balloon-like swelling in the
retina’s tiny blood vessels.
3. As the disease progresses, blood vessels that nourish
the retina are blocked.
4. At this advanced stage, the signals sent by the retina for
nourishment trigger the growth of new blood vessels.
5. These new blood vessels are abnormal and fragile.
6. If they leak blood, severe vision loss and even blindness can result.

What is peripheral neuropathy?

Neuropathy is damage to the nerves that helps to feel sensations such as pain. It is of 2
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

2. Autonomic Neuropathy

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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

What are the various stages of Diabetic nephropathy?

Diabetic nephropathy is the most common cause of kidney failure. Scientist have
suggested 5 stages in the progression to kidney failure in people with diabetes –

1. Stage 1 (very early diabetes) Increased demand upon the kidneys is indicated by
an above-normal glomerular filtration.
2. Stage 2 (developing diabetes) The GFR remains elevated or has returned to
normal; development of microalbuminuria.
3. Stage 3 (overt, or dipstick-positive diabetes or macroalbuminuria);
Hypertension may develop.
4. Stage 4 (late-stage diabetes). “advanced clinical nephropathy.” GFR < 75
milliliters per minute. Almost all patients have hypertension at stage 4.
5. Stage 5 (end-stage renal disease, ESRD) - GFR <10 mL/min) and renal
replacement therapy (i.e., hemodialysis, peritoneal dialysis, kidney
transplantation) is needed.

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MACROVASCULAR COMPLICATIONS
What are the various cardiovascular complications in Diabetes
patients?

More than 60% of DM patients die due to CAD. Most common CVD includes –

• Hypertension
• CAD
• Heart Failure

Hypertension –

As per JNC VII, hypertension is defined as sustained increase in “Systolic “ Blood


Pressure > 140 mmHg and / or “Diastolic” Blood Pressure > 90.

How hypertension is classified?

In Type-2 Diabetes mellitus hypertension is closely associated with hyperinsulinemia.


The probably mechanism involved Na+ & H2O retention by high concentration of
insulin. Diabetes patients have 3-4 higher risk of developing hypertension than normal
persons.

Category SBP DBP


Normal < 120 and <80
Pre hypertension 120-139 and /or 80-89
Hypertension
Stage I 140-159 and /or 90-99
Stage II ≥ 160 and /or ≥ 100

How hypertension is managed in Type-2 Diabetes Mellitus?

The most common drug of choice as per various clinical studies are –

In Type-1 Diabetes mellitus – ACEI (Angiotensin converting enzyme inhibitors).

In Type-2 Diabetes mellitus – ARBs (Angiotensin receptor blockers).

Depending on various co-morbid conditions or in uncontrolled hypertension combination


therapy is used which consists of addition of other classes of drugs like - diuretics,
calcium channel blockers, β-blockers etc

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What is Coronary Artery Disease (CAD)?

CAD is the consequence of inadequate supply of blood (oxygen) to the areas of heart
muscles. That is when supply of blood is less than the demand.

What cause decrease in blood supply?

The various causes of obstruction are –

1. Atheroma (Atherosclerosis) – deposition of fatty substances in the coronary


artery..
2. Thrombosis – clot formation
3. Embolism – a moving clot or atheroma.
4. Spasm – sudden constriction of a portion or multiple portion of a coronary artery.

What are the major presentations of CAD?

The 2 most common presentations of CAD are –

1. Angina pectoris.
2. Myocardial infarction.

What are the various types of angina?

• Stable – the pain is mild in nature. In this case patients get pain when he exerts
more than his normal routine work. The pain subsides when he takes rest. The
cause of abstruction is atherosclerosis.

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• Unstable - the pain is severe caused by almost complete blocked of the coronary
artery due to atherosclerosis. The pain can take place even during minimal
exertion and doesn’t subside on rest.
• Variant or Prinzmetal’s – the pain is very severe and can take place anytime of the
day, even during rest. Incidences of variant angina are seen sometimes during
sleep also. Here the cause is spasm of the coronary arteries.

What is Myocardial infarction?

This is also called “heart attack” in lay man’s language. An MI occurs when there is
death of muscle tissue due to lack of oxygen.

How CAD is treated?

The treatment options of CAD includes

1. Life Style Modifications

• Diet
• Reduce weight, if obese.
• Reduce salt intake.
• Moderate or limit alcohol intake.
• Exercise - vigorous exercise should be avoided as diabetics may have –
o Silent heart disease: a condition where the signs and symptoms of typical
heart disease like breathlessness, fatigue etc may not be evident.
o May cause hypoglycemia.
o Weaken blood vessels and may lead to injury in eye and feet.

2. Drug Therapy

The basis of drug treatment is to increase oxygen supply or decrease oxygen demand or
both. The most common drugs used are –

• Nitrates – Isosorbide dinitrate.


• Beta blockers – Atenolol, Metoprolol.

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• Calcium channel blockers – Amlodipine, Nifedipine


• Potassium channel openers - Nicorandil.
• Metabolic modifier – Trimetazidine.

What is heart failure?

It is the inability of the heart to pump sufficient blood to meet the body’s metabolic
requirement. Major cause of heart failure is CAD.

How heart failure is classified?

HF is classified as per NYHA (New York Heart Association) classification.

1. Class I : Heart disease with no limitations in physical activity


2. Class II: Heart disease with slight limitations in physical activity. Comfortable at
rest
3. Class III: Heart disease with marked limitations in physical activity. May present
at rest
4. Class IV: Heart disease with discomfort at any activity.

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WHAT IS STROKE AND TIA (TRANSIENT ISCHEMIC ATTACK)?

Stroke is said to occur when blood supply is interrupted to areas of brain, resulting in
tissue death and loss of brain function. This may include loss of speech, vision, paralysis,
etc depending on the part of the brain damage.

TIA is a brain disorder caused by temporary disturbance of blood supply to an area of the
brain, resulting in a sudden, brief decrease in brain functions.

What is peripheral vascular disease?

Peripheral vascular disease is caused due to blocking of an artery in the peripheral region
of the body. Major cause of blockade is atherosclerosis and clot formation.

What are the various non-vascular complications?

The major non-vascular complications are-

1. Galucoma, Cataract – Increase in intraocular pressure or formation of a opaque


layer on the cornea of the eyes.
2. Diabetic foot ulcer – progressive life threatening infection which is one of the
major causes of amputation.
3. Gastroparesis – partial paralysis of the stomach due to neuropathy in the nerves
connecting the nerves.
4. Sexual dysfunction – erectile dysfunction etc.
5. Skin changes – abnormal lesions seen in the skins.

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MANAGEMENT OF TYPE-2 DIABETES MELLITUS


What are the goals in management of Type-2 Diabetes mellitus?

Immediate Goals: To stabilize the blood sugar

Long-term goals:

 To prolong life
 Relieve symptoms and
 Prevent long-term complications

What are the treatment options?

1. Life style modifications

● Diet and Exercise

2. Pharmacological therapy.

What are the various studies which shows the importance of tight
glycemic control?

Some of the landmark studies are -

■ 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.

Results: Each 1% reduction in mean HbA1c was associated with reductions in risk of -

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• 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

1. Clinical study conducted from 1983 to 1993 by the National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK)
2. 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.
3. They also were required to have no, or only early signs of, diabetic eye disease.
4. The study compared the effects of two treatment regimens—standard therapy and
intensive control— on the complications of diabetes.
5. Result : Lowering blood glucose reduces risk
6. Eye disease (Retinopathy) - 76% reduced risk
7. Kidney disease (Nephropathy) - 50% reduced risk
8. Nerve disease (Neuropathy) - 60% reduced risk
9. Cardiovascular disease – 35 %

United States Diabetes Prevention Program

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Kumamoto Study

1. Objective — To examine whether intensive glycemic control could decrease the


frequency or severity of diabetic microvascular complications.
2. 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.
3. Results — the cumulative percentages of worsening in retinopathy and
nephropathy were significantly lower in the MIT group than in the CIT group.
4. 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.

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TREATMENT OF TYPE-2 DIABETES MELLITUS


Following are the various pharmacological treatment options in the management of
Type 2 Diabetes –

1. Oral Hypoglycemic agents.

• Sulfonylureas – e.g., Glibenclamide, Gliclazide, Glipizide and


Glimepiride.
• Non-sulfonylureas (Magletinides) – e.g., Repaglinide and Nateglinide.

2. Anti-hyperglycemic agents.

■ Insulin sensitizers –

• Biguanides – e.g., Metformin.


• Thiazolidinediones – e.g., Rosiglitazone and Pioglitazone.
• α-Glucosidase inhibitors – e.g., Acarbose, Miglitol.

3. Insulin analogoues – e.g., Bovine, porcine and human.

4. Newer agents –

• Aldolase reductase inhibitors – e.g., Aminoguanidine.


• Insulin mimetic agents – e.g., Vanadium salts.
• Glucagon antagonists – e.g., β3-adrenergic agonists.
• Potentiators of insulin secretion – e.g., Glucagon like peptide amide.

In most cases single drugs fails to achieve the target HbA1c goal, in such cases
combination therapies are used like –

Commonly used combinations are:

• Sulfonylurea and metformin


• A glitazone and a sulfonylurea or insulin
• Non- SU and metformin

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• Sulfonylurea and insulin


• Any other drug mentioned above and insulin

Now the use of a glitazone in combination with metformin and a sulfonylurea (Triple
drug combination) in patients who have not responded to monotherapy or with
combination of two oral agents have also been approved by FDA.

What do you mean by Primary and Secondary failure of treatment?

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.

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