The Nervous System - PowerPoint PPT Presentation

About This Presentation

The Nervous System


The Nervous System The human nervous system can be divided into two parts: the central nervous system (CNS) and the peripheral nervous system (PNS) – PowerPoint PPT presentation

Number of Views:842
Avg rating:3.0/5.0
Slides: 95
Provided by: JohnBu154
Learn more at:


Transcript and Presenter's Notes

Title: The Nervous System

The Nervous System
  • The human nervous system can be divided into two
    parts the central nervous system (CNS) and the
    peripheral nervous system (PNS)
  • http//

Central Nervous System
  • Drugs that affect the CNS can
  • Selectively relieve pain
  • Reduce fever
  • Suppress disordered movement
  • Induce sleep or arousal
  • Reduce appetite
  • Allay the tendency to vomit
  • Be used to treat anxiety, depression,
    schizophrenia, Parkinsons Disease, Alzheimers
    Disease, epilepsy, migraine, etc.

How do drugs work in the CNS?
  • A central underlying concept of
    neuropharmacology is that drugs that influence
    behavior and improve the functional status of
    patients with neurological or psychiatric
    diseases act by enhancing or blunting the
    effectiveness of specific combinations of
    synaptic transmitter actions.

Blood Brain Barrier (BBB)
  • A physiological mechanism that alters the
    permeability of brain capillaries, so that some
    substances, such as certain drugs, are prevented
    from entering brain tissue, while other
    substances are allowed to enter freely.
  • The separation of the brain, which is bathed in a
    clear cerebrospinal fluid, from the bloodstream.
    The cells near the capillary beds external to the
    brain selectively filter the molecules that are
    allowed to enter the brain, creating a more
    stable, nearly pathogen-free environment.

(No Transcript)
(No Transcript)
(No Transcript)
Diagram of a cerebral capillary enclosed in
astrocyte end-feet. Characteristics of the
blood-brain barrier are indicated (1) tight
junctions that seal the pathway between the
capillary (endothelial) cells (2) the lipid
nature of the cell membranes of the capillary
wall which makes it a barrier towater-soluble
molecules (3), (4), and (5) represent some of
the carriers and ion channels (6) the 'enzymatic
barrier'that removes molecules from the blood
(7) the efflux pumps which extrude fat-soluble
molecules that have crossed into the cells
  • Oxygen, glucose, and white blood cells are
    molecules that are able to pass through this
    barrier. Red blood cells cannot.

Blood Brain Barrier
  • The blood-brain barrier (abbreviated BBB) is
    composed of endothelial cells packed tightly in
    brain capillaries that more greatly restrict
    passage of substances from the bloodstream than
    do endothelial cells in capillaries elsewhere in
    the body.
  • Processes from astrocytes surround the epithelial
    cells of the BBB providing biochemical support to
    the epithelial cells.
  • The BBB should not be confused with the
    blood-cerebrospinal fluid barrier (BCB), a
    function of the choroid plexus.

(No Transcript)
(No Transcript)
History of the BBB
  • The existence of such a barrier was first noticed
    in experiments by Paul Ehrlich in the late-19th
    century. Ehrlich was a bacteriologist who was
    studying staining, used for many studies to make
    fine structures visible. Some of these dyes,
    notably the aniline dyes that were then popular,
    would stain all of the organs of an animal except
    the brain when injected. At the time, Ehrlich
    attributed this to the brain simply not picking
    up as much of the dye.

  • However, in a later experiment in 1913, Edwin
    Goldmann (one of Ehrlich's students) injected the
    dye into the spinal fluid of the brain directly.
  • He found that in this case the brain would become
    dyed, but the rest of the body remained dye-free.
    This clearly demonstrated the existence of some
    sort of barrier between the two sections of the

History of the BBB
  • At the time, it was thought that the blood
    vessels themselves were responsible for the
    barrier, as there was no obvious membrane that
    could be found.
  • It was not until the introduction of the scanning
    electron microscope to the medical research
    fields in the 1960s that this could be
    demonstrated. The concept of the blood-brain
    (then termed hematoencephalic) barrier was
    proposed by Lina Stern in 1921.

What is the purpose of the BBB?
  • The blood-brain barrier protects the brain from
    the many chemicals flowing around the body.
  • For example, many bodily functions are controlled
    by hormones, which are detected by receptors on
    the plasma membranes of targeted cells throughout
    the body.
  • The secretion of many hormones are controlled by
    the brain, but these hormones generally do not
    penetrate the brain from the blood, so in order
    to control the rate of hormone secretion
    effectively, there are specialized sites where
    neurons can "sample" the composition of the
    circulating blood.

  • At these sites, the blood-brain barrier is
    'leaky' these sites include three important
    'circumventricular organs', the subfornical
    organ, the area postrema and the organum
    vasculosum of the lamina terminalis (OVLT).
  • The blood-brain barrier is also an effective way
    to protect the brain from common infections. Thus
    infections of the brain are very rare however,
    as antibodies are too large to cross the
    blood-brain barrier, when infections of the brain
    do occur they can be very serious and difficult
    to treat.

How does the BBB affect the design of therapeutic
  • Mechanisms for drug targeting in the brain
    involve going either "through" or "behind" the
  • Modalities for drug delivery through the BBB
    entail disruption of the BBB by osmotic means,
    biochemically by the use of vasoactive substances
    such as bradykinin, or even by localized exposure
    to high intensity focused ultrasound (HIFU).
  • The potential for using BBB opening to target
    specific agents to brain tumors has just begun to
    be explored.

The Blood Brain Barrier
  • http//

Introduction to the CNS
  • http//
  • http//

Neurotransmitters found in the CNS
Its a balancing act!!
  • Current models of CNS diseases often attribute
    the physiological cause of the disease to an
    imbalance of neurotransmitters.

  • All ACh receptors in the CNS are nicotinergic.
    The stimulating effect of nicotine is due to the
    influence of these receptors.
  • Acetylcholine is transmitted within cholinergic
    pathways that are concentrated mainly in specific
    regions of the brainstem and are thought to be
    involved in cognitive functions, especially
    memory. Severe damage to these pathways is the
    probable cause of Alzheimers disease.

  • Most cell bodies of noradrenergic neurons are in
    the locus coeruleus, a center in the brain stem.
    These neurons send their axons to the limbic
    system (appetite inhibition), the subcortical
    centers and the cerebral cortex (arousal).
  • Noradrenaline is classed as a monoamine
    neurotransmitter and noradrenergic neurons? are
    found in the locus coeruleus?, the pons and the
    reticular formation in the brain. These neurons
    provide projections to the cortex, hippocampus?,
    thalamus? and midbrain. The release of
    noradrenaline tends to increase the level of
    excitatory activity within the brain, and
    noradrenergic pathways are thought to be
    particularly involved in the control of functions
    such as attention and arousal.

Locus ceruleus
  • The Locus ceruleus, also spelled locus caeruleus
    or locus coeruleus (Latin for 'the blue spot'),
    is a nucleus in the brain stem responsible for
    physiological responses to stress and panic.The
    locus ceruleus (or "LC") is located within the
    dorsal wall of the upper pons, under the
    cerebellum in the caudal midbrain, surrounded by
    the fourth ventricle. This nucleus is one of the
    main sources of norepinephrine in the brain, and
    is composed of mostly medium-sized neurons.
    Melanin granules inside the LC contribute to its
    blue color it is thereby also known as the
    nucleus pigmentosus pontis, meaning "heavily
    pigmented nucleus of the pons".

Locus ceruleus
  • Dopamine is also classed as a monoamine
    neurotransmitter and is concentrated in very
    specific groups of neurons collectively called
    the basal ganglia. Dopaminergic neurons are
    widely distributed throughout the brain in three
    important dopamine systems (pathways) the
    nigrostriatal, mesocorticolimbic, and the
    tuberohypophyseal pathways. A decreased brain
    dopamine concentration is a contributing factor
    in Parkinson?s disease, while an increase in
    dopamine concentration has a role in the
    development of schizophrenia.

Biosynthesis of Epinephrine
  • Although dopamine is synthesized by only several
    hundred thousand cells, it fulfils an exceedingly
    important role in the higher parts of the CNS.
    These dopaminergic neurons can be divided into
    three subgroups with different functions. The
    first group regulates movements a deficit of
    dopamine in this (nigrostriatal) system causes
    Parkinson's disease which is characterized by
    trembling, stiffness and other motor disorders,
    while in the later phases dementia can also set
    in. ?The second group, the mesolimbic, has a
    function in regulating emotional behavior. The
    third group, the mesocortical, projects only to
    the prefrontal cortex. This area of cortex is
    involved with various cognitive functions,
    memory, behavioral planning and abstract
    thinking, as well as in emotional aspects,
    especially in relation to stress. The earlier
    mentioned reward system is part of this last
    system. ?The nucleus accumbens is an important
    intermediate station here. Disorders in the
    latter two systems are associated with

Dopamine and Parkinsons Disease
  • In patients with Parkinsons disease, there is
    disease or degeneration of the so-called basal
    ganglia in the deeper grey matter of the brain,
    particularly of that part known as the substantia

Parkinsons Disease
  • The substantia nigra, which connects with the
    striatum (caudate nucleus and globus pallidus),
    contains black pigmented cells and, in normal
    individuals, produces a number of chemical
    transmitters, the most important of which is
    dopamine. Transmitters are chemicals that
    transmit, that is, pass on, a message from one
    cell to the next, either stimulating or
    inhibiting the function concerned it is like
    electricity being the transmitter of sound waves
    in the radio. Other transmitters include
    serotonin, somatostatin and noradrenaline. In
    Parkinson?s disease, the basal ganglia cells
    produce less dopamine, which is needed to
    transmit vital messages to other parts of the
    brain, and to the spinal cord, nerves and muscles.

In Parkinsons disease, there is degeneration of
the substantia nigra which produces the chemical
dopamine deep inside the brain
Parkinsons Disease
  • The basal ganglia, through the action of
    dopamine, are responsible for planning and
    controlling automatic movements of the body, such
    as pointing with a finger, pulling on a sock,
    writing or walking. If the basal ganglia are not
    working properly, as in Parkinsons disease
    patients, all aspects of movement are impaired,
    resulting in the characteristic features of the
    disease ? slowness of movement, stiffness and
    effort required to move a limb and, often,
  • Dopamine levels in the brains substantia nigra
    do normally fall with ageing. However, they have
    to fall to one-fifth of normal values for the
    symptoms and signs of parkinsonism to emerge.

Parkinsons Disease
  • http//
  • http//

  • James Parkinson (1755-1824), while best
    remembered for the disease state named after him
    by Charcot, was a man of many talents and
    interests. Publishing on chemistry, paleontology
    and other diverse topics, he was, early in his
    career, a social activist championing the rights
    of the disenfranchised and poor. His efforts in
    this area were enough to result in his arrest and
    appearance before The Privy Council in London on
    at least one occasion. In collaboration with his
    son, who was a surgeon, he also offered the first
    description, in the English language, of a
    ruptured appendix.

History of Parkinsons Disease
  • His small but famous publication, "Essay on the
    Shaking Palsy", appeared in 1817, 7 years before
    his death in 1824. The clinical description of 6
    patients was a remarkable masterpiece testifying
    to his prodigious powers of observation for most
    of the 6 were never actually examined by
    Parkinson himself rather, they were simply
    observed walking on the streets of London.

Treatment of Parkinsons Disease
  • Since PD is related to a deficiency of dopamine,
    it would be appropriate to administer dopamine
  • Problem Dopamine does not cross BBB, since it
    is too polar

History of Treatment of PD
  • Arvid Carlsson (b. January 25, 1923) is a Swedish
    scientist who is best known for his work with the
    neurotransmitter dopamine and its effects in
    Parkinson's disease. Carlsson won the Nobel Prize
    in Physiology or Medicine in 2000 along with
    co-recipients Eric Kandel and Paul
    Greengard.Carlsson was born in Uppsala, Sweden,
    son of Gottfrid Carlsson, historian and later
    professor of history at the Lund University,
    where he began his medical education in 1941.
    Although Sweden was neutral during World War II,
    Carlsson's education was interrupted by several
    years of service in the Swedish Armed Forces. In
    1951, he received his M.L. degree (the equivalent
    of the American M.D.) and his M.D. (the
    equivalent of the American Ph.D.). He then became
    a professor at the University of Lund. In 1959 he
    became a professor at the G?eborg University.In
    the 1950s, Carlsson demonstrated that dopamine
    was a neurotransmitter in the brain and not just
    a precursor for norepinephrine, as had been
    previously believed. He developed a method for
    measuring the amount of dopamine in brain tissues
    and found that dopamine levels in the basal
    ganglia, a brain area important for movement,
    were particularly high. Carlsson then showed that
    giving animals the drug reserpine caused a
    decrease in dopamine levels and a loss of
    movement control. These effects were similar to
    the symptoms of Parkinson's disease. By
    administering to these animals L-Dopa, a
    precursor to dopamine, he could alleviate the
    symptoms. These findings led other doctors try
    L-Dopa with human Parkinson's patients and found
    it to alleviate some of the symptoms in the early
    stages of Parkinson's. L-Dopa is still today the
    cornerstone of Parkinson therapy.

Biosynthesis of Epinephrine
Wait a minute!
  • If dopamine is too polar to cross the BBB, how
    can L-DOPA cross it?

  • L-DOPA is transported across the BBB by an amino
    acid transport system (same one used for tyrosine
    and phenylalanine)
  • Once across, L-DOPA is decarboxylated to dopamine
    by Dopa Decarboxylase (DDC).

  • This is an example of a prodrug, that is, a
    molecule that is a precursor to the drug and is
    converted to the actual drug at an appropriate
    place in the body.

  • In actual practice, L-DOPA is almost always
    coadminstered together with an inhibitor of
    aromatic L-amino acid decarboxylase, so it
    doesnt get converted to dopamine before it
    crosses the BBB.
  • The inhibitor commonly used is carbidopa, which
    does not cross the BBB itself.
  • The inhibitor also prevents undesirable side
    effects of dopamine release into the PNS,
    including nausea.

(Carbidopa-Levodopa) is a combination of
carbidopa and levodopa for the treatment of
Parkinson's disease and syndrome.
  • http//

  • Endorphins (or more correctly Endomorphines) are
    endogenous opioid biochemical compounds. They are
    peptides produced by the pituitary gland and the
    hypothalamus in vertebrates, and they resemble
    the opiates in their abilities to produce
    analgesia and a sense of well-being. In other
    words, they might work as "natural pain killers."
    Using drugs may increase the effects of the

  • Although the CNS contains less than 2 of the
    total serotonin in the body, serotonin plays a
    very important role in a range of brain
    functions. It is synthesised from the amino acid
    tryptophan.Within the brain, serotonin is
    localised mainly in nerve pathways emerging from
    the raphe nuclei, a group of nuclei at the centre
    of the reticular formation in the?Midbrain?,
    pons? and medulla. These serotonergic pathways
    spread extensively throughout the brainstem?, the
    cerebral cortex? and the spinal cord?. In
    addition to mood control, serotonin has been
    linked with a wide variety of functions,
    including the regulation of sleep, pain
    perception, body temperature, blood pressure and
    hormonal activity.Outside the brain, serotonin
    exerts a number of important effects,
    particularly involving the gastrointestinal and
    cardiovascular systems.

(No Transcript)
(No Transcript)
(No Transcript)
(No Transcript)
(No Transcript)
What is serotonin?
In the central nervous system, serotonin is
believed to play an important role in the
regulation of body temperature, mood, sleep,
vomiting, sexuality, and appetite. Low levels of
serotonin have been associated with several
disorders, namely clinical depression,
obsessive-compulsive disorder (OCD), migraine,
irritable bowel syndrome, tinnitus, fibromyalgia,
bipolar disorder, and anxiety disorders.citation
needed If neurons of the brainstem that make
serotoninserotonergic neuronsare abnormal,
there is a risk of sudden infant death syndrome
(SIDS) in an infant.1
Understanding Serotonin
  • The pharmacology of 5-HT is extremely complex,
    with its actions being mediated by a large and
    diverse range of 5-HT receptors. At least seven
    different receptor "families" are known to exist,
    each located in different parts of the body and
    triggering different responses. As with all
    neurotransmitters, the effects of 5-HT on the
    human mood and state of mind, and its role in
    consciousness, are very difficult to ascertain.

Understanding Serotonin
  • Serotonergic action is terminated primarily via
    uptake of 5-HT from the synapse. This is through
    the specific monoamine transporter for 5-HT, 5-HT
    reuptake transporter, on the presynaptic neuron.
    Various agents can inhibit 5-HT reuptake
    including MDMA (ecstasy), cocaine, tricyclic
    antidepressants (TCAs) and selective serotonin
    reuptake inhibitors (SSRIs).Recent research
    suggests that serotonin plays an important role
    in liver regeneration and acts as a mitogen
    (induces cell division) throughout the body.

Anatomy of the Brain(seizures)
  • http//

The action of drugs to treat mental illness
  • Serotonin, noradrenaline and dopamine are
    involved in the control of many of our mental
    states, sometimes acting on their own and at
    other times acting together (illustrated in the
    following diagram). These and other
    neurotransmitters are likely to play a pivotal
    role in the pathological basis of mental illness
    and diseases of the brain. Much of the evidence
    for this stems from the fact that most of the
    effective antidepressant drugs are thought to
    work by changing either serotonin and/or
    noradrenaline metabolism, or receptor sensitivity
    to these neurotransmitters

(No Transcript)
  • Ergotropic Energy expending systems (sympathetic
    division of the PNS) Fight or flight
  • Trophotropic Nutrient accumulating systems
    (parasympathetic division of the PNS) Rest and

  • http//
  • http//

Historical Drugs to treat schizophrenia
  • http//

  • Histamine is a biogenic amine chemical involved
    in local immune responses as well as regulating
    physiological function in the gut and acting as a
    neurotransmitter (Marieb, 2001, p.414). New
    evidence also indicates that histamine plays a
    role in chemotaxis of white blood cells.

  • Histamine is released as a neurotransmitter. The
    cell bodies of neurons which release histamine
    are found in the posterior hypothalamus, in
    various tuberomammillary nuclei. From here, these
    histaminergic neurons project throughout the
    brain, to the cortex through the medial forebrain
    bundle. Histaminergic action is known to modulate
    sleep. Classically, antihistamines (H1 histamine
    receptor antagonists) produce sleep. Likewise,
    destruction of histamine releasing neurons, or
    inhibition of histamine synthesis leads to an
    inability to maintain vigilance. Finally, H3
    receptor antagonists (which stimulate histamine
    release) increase wakefulness.It has been shown
    that histaminergic cells have the most
    wakefulness-related firing pattern of any
    neuronal type thus far recorded. They fire
    rapidly during waking, fire more slowly during
    periods of relaxation/tiredness and completely
    stop firing during REM and non-REM sleep.
    Histaminergic cells can be recorded firing just
    before an animal shows signs of waking.

  • Sexual response
  • Research has shown that histamine is released as
    part of the human orgasm from mast cells in the
    genitals, and the histamine release has been
    connected to the sex flush among women. If this
    response is lacking while a woman also has
    trouble achieving orgasm, this may be a sign of
    histapenia. In such cases, a doctor may prescribe
    diet supplements with folic acid and niacin
    (which used in conjunction can increase blood
    histamine levels and histamine release), or
    L-histidine. Conversely, men with high histamine
    levels may suffer from premature ejaculations.

Antibodies and the Immune Response
  • Antibodies are manufactured by the lymph system.
    Antibodies are specialized proteins that the body
    produces in response to invasion by a foreign
    substance. The process of antibody formation
    begins when an antigen stimulates specialized
    lymphocytes, called B cells, into action.
    Antibodies then counteract invading antigens by
    combining with the antigen to render it harmless
    to the body.
  • Production of white blood cells and antibodies in
    reaction to an invading disease organism is
    called an immune response. This response is one
    of the body's primary and most efficient lines of
    defense. In most cases, once antibodies have been
    produced to fight a certain organism, it no
    longer poses a great threat to the body. That is
    why one attack of a disease often prevents that
    same disease from infecting the body again -- the
    first attack causes production of antibodies that
    protect the body against subsequent attacks. With
    measles, for example, antibodies are produced as
    a result of having the disease or of being
    immunized with the measles vaccine. These
    antibodies are able to resist a second attack of
    the disease.

Antibodies and the Immune Response
  • Antibodies are not always beneficial. For
    example, when tissue from another body, such as a
    transplanted heart, is introduced, antibodies are
    produced to destroy the "invader." Transplants
    usually are made possible only by means of drugs
    that act against the body's natural immune
    response. Also, when blood is transfused from one
    person to another, it must be of a matching type
    otherwise, the recipient's immune system will
    manufacture antibodies to destroy the transfused
  • Sometimes, the immune system causes reactions
    that make the body unusually sensitive to foreign
    material. When the immune response is disruptive
    to the body in this way, it is called an allergic
    reaction. Let's look at this important mechanism,
    and the types of allergens, in the next section.

Allergic Reaction
  • An allergy is a state of special sensitivity to a
    particular environmental substance, or allergen.
    An allergic reaction is the body's response to
    exposure to an allergen.
  • Although an allergy can be present almost
    immediately after exposure to an allergen, it
    usually develops over time, as the immune system
    forms antibodies against the foreign substance.
    Under normal conditions, such antibodies work to
    protect the body from further attack. In the case
    of an allergy, however, the antibodies and other
    specialized cells involved in this protective
    function trigger an unusual sensitivity, or
    overreaction, to the foreign substance.
  • The antibodies stimulate specialized cells to
    produce histamine, a powerful chemical. Histamine
    causes the small blood vessels to enlarge and the
    smooth muscles (such as those in the airways and
    the digestive tract) to constrict. Histamine
    release can also cause other reactions, such as

Allergic Reaction
  • No one knows why allergies develop, but it is
    known that an allergy can appear, disappear, or
    reappear at any time and at any age. Allergic
    reactions rarely occur during the first encounter
    with the troublesome allergen because the body
    needs time to accumulate the antibodies. Also, an
    individual's sensitivity to certain allergens
    seems to be related to a family history of
    allergies. People who have a tendency to develop
    allergies are referred to as atopic.
  • An allergic reaction can be so mild that it is
    barely noticeable or so severe that it is
    life-threatening. An extremely severe allergic
    reaction, called anaphylactic shock, is marked by
    breathing difficulties (from swelling of the
    throat and larynx and narrowing of the bronchial
    tubes), itching skin, hives, and collapse of the
    blood vessels, as well as by vomiting, diarrhea,
    and cramps. This condition can be fatal if not
    treated immediately.

Allergic reaction Histamine and Antihistamines
  • http//
  • http//

Antihistamines to Antipsychotics?
  • In the late 1930s, such dicyclic antihistamines
    as phenbenzamine, diphenhydramine, and mepyramine
    were in wide clinical use. The antihistamines'
    most striking clinical side-effect was CNS
    depression -- drowsiness.

Antihistamines to Antipsychotics?
  • In common use, the term antihistamine refers only
    to H1-receptor antagonists, also known as
    H1-antihistamines. It has been discovered that
    these H1-antihistamines are actually inverse
    agonists at the histamine H1-receptor, rather
    than antagonists per se.

Antihistamines to Antipsychotics?
  • In the late 1930s, Paul Charpentier had
    synthesized the first tricyclic antihistamine,
    promethazine, which had a strong sedative effect.
    He then synthesized a variety of promethazine
    analogues, including chiorpromazine.

Antihistamines to Antipsychotics?
  • http//

Antihistamines to Antipsychotics?
  • Chlorpromazine was the first antipsychotic drug,
    used during the 1950s and 1960s. Used as
    chlorpromazine hydrochloride and sold under the
    tradenames Largactil? and Thorazine?, it has
    sedative, hypotensive and antiemetic properties
    as well as anticholinergic and antidopaminergic
    effects. It also has anxiolytic (alleviation of
    anxiety) properties. Today, chlorpromazine is
    considered a typical antipsychotic.

Antihistamines to Antipsychotics?
  • The drug had been developed by Laboratoires
    Rh?e-Poulenc in 1950 but they sold the rights in
    1952 to Smith-Kline French (today's
    GlaxoSmithKline). The drug was being sold as an
    antiemetic when its other use was noted.
    Smith-Kline was quick to encourage clinical
    trials and in 1954 the drug was approved in the
    US for psychiatric treatment. The effect of this
    drug in emptying psychiatric hospitals has been
    compared to that of penicillin and infectious
    diseases.1 Over 100 million people were treated
    but the popularity of the drug fell from the late
    1960s as the severe extrapyramidal side effects
    and tardive dyskinesia became more of a concern.
    From chlorpromazine a number of other similar
    neuroleptics were developed (e.g.
    triflupromazine, trifluoperazine).

Antihistamines to Antipsychotics?
  • Previously used as an antihistamine and
    antiemetic its effects on mental state were first
    reported by the French doctor Henri Laborit in
    1951 or 1952 (different sources) as sedation
    without narcosis. It became possible to cause
    'artificial hibernation' in patients, if used as
    a cocktail together with pethidine and hydergine.
    Patients with shock, severe trauma or burns,
    become, if treated so, sedated, without anxiety
    and unresponsive/indifferent to painful external
    stimuli like minor surgical interventions. The
    first published clinical trial was that of Jean
    Delay and Pierre Deniker at Ste. Anne H?pital in
    Paris in 1952, in which they treated 38 psychotic
    patients with daily injections of
    chlorpromazine.1 Drug treatment with
    chlorpromazine went beyond simple sedation with
    patients showing improvements in thinking and
    emotional behaviour. Ironically, the
    antipsychotic properties of chlorpromazine appear
    to be unrelated to its sedative properties.
    During long term therapy some tolerance to the
    sedative effect develops.
  • Chlorpromazine substituted and eclipsed the old
    therapies of electro and insulin shocks and other
    methods such as psychosurgical means (lobotomy)
    causing permanent brain injury. Before the era of
    neuroleptics, starting with chlorpromazine,
    positive long-term results for psychotic patients
    were only 20.

  • Neuroleptic A term that refers to the effects of
    antipsychotic drugs on a patient, especially on
    his or her cognition and behavior.
  • Neuroleptic drugs may produce a state of apathy,
    lack of initiative and limited range of emotion.
    In psychotic patients, neuroleptic drugs cause a
    reduction in confusion and agitation and tend to
    normalize psychomotor activity.The term comes
    from the Greek "lepsis" meaning a taking hold.

  • Extrapyramidal side effects Physical symptoms,
    including tremor, slurred speech, akathesia,
    dystonia, anxiety, distress, paranoia, and
    bradyphrenia, that are primarily associated with
    improper dosing of or unusual reactions to
    neuroleptic (anti-psychotic) medications.

Reward pathways in the CNS
  • The most important reward pathway in brain is the
    mesolimbic dopamine system. This circuit
    (VTA-NAc) is a key detector of a rewarding
    stimulus. Under normal conditions, the circuit
    controls an individual?s responses to natural
    rewards, such as food, sex, and social
    interactions, and is therefore an important
    determinant of motivation and incentive drive. In
    simplistic terms, activation of the pathway tells
    the individual to repeat what it just did to get
    that reward. It also tells the memory centers in
    the brain to pay particular attention to all
    features of that rewarding experience, so it can
    be repeated in the future. Not surprisingly, it
    is a very old pathway from an evolutionary point
    of view. The use of dopamine neurons to mediate
    behavioral responses to natural rewards is seen
    in worms and flies, which evolved 1-2 billion
    years ago.
  • http//

Norepinephrine Reuptake Inhibitors as
  • Norepinephrine reuptake inhibitors (NRIs), also
    known as noradrenaline reuptake inhibitors
    (NARIs), are compounds that elevate the
    extracellular level of the neurotransmitter
    norepinephrine in the central nervous system by
    inhibiting its reuptake from the synaptic cleft
    into the presynaptic neuronal terminal. The drugs
    inhibit the class of neurotransmitter
    transporters known as norepinephrine
    transporters. They have virtually no action at
    other monoamine transporters.

  • http//
  • http//
  • http//
  • http//

Norepinephrin Reuptake Inhibitors for Depression
  • Atomoxetine is classified as a norepinephrine
    reuptake inhibitor, and is approved for use in
    children, adolescents, and adults.
  • Atomoxetine is the first non-stimulant drug
    approved for the treatment of attention-deficit
    hyperactivity disorder (ADHD). It is sold in the
    form of the hydrochloride salt of atomoxetine. It
    is manufactured and marketed under the brand name
    Strattera? by Eli Lilly and Company as a generic
    Attentin by Torrent Pharmaceuticals. There is
    currently no generic available within the United
    States due to patent restrictions.

  • Strattera was originally intended to be a new
    antidepressant drug however, in clinical trials,
    no such benefits could be proven. Since
    norepinephrine is believed to play a role in
    ADHD, Strattera was tested and subsequently
    approved as an ADHD treatment.

  • Reboxetine is an antidepressant drug used in the
    treatment of clinical depression, panic disorder
    and ADD/ADHD. Its mesilate (i.e.
    methanesulfonate) salt is sold under tradenames
    including Edronax?, Norebox?, Prolift?, Solvex?
    or Vestra?.
  • Unlike most antidepressants on the market,
    reboxetine is a noradrenaline reuptake inhibitor
    (NARI) it does not inhibit the reuptake of
    serotonin, therefore it can be safely combined
    with an SSRI.

  • Viloxazine (Emovit, Vivalan, Vivarint, Vicilan)
    is a bicyclic antidepressant morpholine
    derivative that inhibits the reuptake of
  • In 1976, Lippman and Pugsley reported that
    viloxazine, like imipramine, inhibited
    norepinephrine reuptake in the hearts of rats and
    mice unlike imipramine, (or desipramine or
    amitriptyline, for that matter) it did not block
    reuptake of norepinephrine in neither the
    medullae nor the hypothalami of rats.

Further tinkering with the structure of the
antipsychotic drugs led to a drug which was
useful in treating depression
  • Imipramine was, in the late 1950s, the first
    tricyclic antidepressant to be developed (by
    Ciba-Geigy). Initially, it was tried against
    psychotic disorders (e.g. schizophrenia), but
    proved insufficient.
  • During the clinical studies its antidepressant
    qualities, unsurpassed until the advent of SSRIs,
    became evident. Subsequently it was extensively
    used as standard antidepressant and later served
    as a prototypical drug for the development of the
    later released tricyclics.
  • It is not as commonly used today but sometimes
    used to treat major depression as a second-line

Tricyclic Antidepressants
  • The tricyclic antidepressants share the common
    structural feature of fused 6-7-6 membered rings,
    as shown below.

Tricyclic Antidepressants
Tricyclic antidepressants
  • Tricyclic antidepressants are a class of
    antidepressant drugs first used in the 1950s.
    They are named after the drugs' molecular
    structure, which contains three rings of atoms
    (compare tetracyclic antidepressant). The term
    'tricyclic antidepressant' is sometimes
    abbreviated to TCA.
  • The exact mechanism of action is not well
    understood, however it is generally thought that
    tricylic antidepressants work by inhibiting the
    re-uptake of the neurotransmitters
    norepinephrine, dopamine, or serotonin by nerve
    cells. Tricyclics may also possess an affinity
    for muscarinic and histamine H1 receptors to
    varying degrees. Although the pharmacologic
    effect occurs immediately, often the patient's
    symptoms do not respond for 2 to 4 weeks.1
  • Tricyclic antidepressants are used in numerous
    applications mainly indicated for the treatment
    of clinical depression, pain, nocturnal enuresis,
    and ADHD, but they have also been used
    successfully for headache, bulimia nervosa,
    interstitial cystitis, irritable bowel syndrome,
    narcolepsy, persistent hiccups, pathological
    crying or laughing, smoking cessation, as an
    adjunct in schizophrenia, and in ciguatera

  • Narcolepsy is a neurological condition most
    characterized by Excessive Daytime Sleepiness
    (EDS). A narcoleptic will most likely experience
    disturbed nocturnal sleep, confused with
    insomnia, and disorder of REM or rapid eye
    movement sleep. It is a type of dyssomnia. A
    person with narcolepsy is likely to become drowsy
    or to fall asleep, often at inappropriate times
    and places.
  • While the cause of narcolepsy has not yet been
    determined, scientists have discovered conditions
    that may increase an individual's risk of having
    the disorder. Specifically, there appears to be a
    strong link between narcoleptic individuals and
    certain genetic conditions. One factor that may
    predispose an individual to narcolepsy involves
    an area of Chromosome 6 known as the HLA (human
    leukocyte antigen) complex.
  • Certain variations in the HLA complex are thought
    to increase the risk of an auto-immune response
    to protein producing neurons in the brain. The
    protein produced, called hypocretin or orexin, is
    responsible for controlling appetite and sleep
    patterns. Individuals with narcolepsy often have
    reduced numbers of these protein-producing
    neurons in their brains.

Attention Deficit Hyperactivity Disorder (ADHD)
  • Attention-Deficit/Hyperactivity Disorder (ADHD)
    (sometimes referred to as ADD when only
    inattentiveness and distractibility are
    problematic) is a neurological disorder initially
    appearing in childhood which manifests itself
    with symptoms such as hyperactivity,
    forgetfulness, poor impulse control, and
  • Research suggests that ADHD arises from a
    combination of various genes, many of which
    affect dopamine transporters.27 Suspect genes
    include the 10-repeat allele of the DAT1
    gene,28 the 7-repeat allele of the DRD4
    gene,28 and the dopamine beta hydroxylase gene
    (DBH TaqI).29 Additionally, SPECT scans found
    people with ADHD to have reduced blood
    circulation,30 and a significantly higher
    concentration of dopamine transporters in the
    striatum which is in charge of planning ahead.

(No Transcript)
Write a Comment
User Comments (0)