The action of drugs to treat mental illness

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The action of drugs to treat mental illness

• Serotonin (5-HT), 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.
• 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

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Definitions

• Ergotropic Energy expending systems (sympathetic
  division of the PNS) Fight or flight
• Trophotropic Nutrient accumulating systems
  (parasympathetic division of the PNS) Rest and
  digest

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Dopamine
Acetylcholine
Serotonin (5-Hydroxytryptamine) (5-HT)
Norepinephrine
GABA (?-aminobutyric acid)
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Schizophrenia
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Schizophrenia

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Historical Drugs to treat schizophrenia

• The discovery of the first drugs to treat
  schizophrenia resulted from the proper
  application of a side effect of antihistamines.
• http//www.pbs.org/wgbh/aso/databank/entries/dh52d
  r.html

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• 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. New evidence also indicates
  that histamine plays a role in chemotaxis of
  white blood cells.

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Inside the CNS

• 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.

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Histamine Receptor Subtypes
Receptor Type Tissue Locations Biological Effects

H1 Smooth muscle, endothelium, CNS tissue Acute allergic responses, also motion sickness
H2 Parietal cells Secretion of gastric acid
H3 CNS Modulates neurotransmission
H4 Basophils in the bone marrow Regulating immune responses
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• 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.

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Inside the CNS

• 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.

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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.

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• 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.

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• 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
  blood.
• 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.

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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.

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• 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.

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• 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 hives.

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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.

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• 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.

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Allergic reaction Histamine and Antihistamines

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• http//pennhealth.com/health_info/animationplayer/
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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.

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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.

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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 chlorpromazine.

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Antihistamines to Antipsychotics?

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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.

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Antihistamines to Antipsychotics?

• The drug had been developed by Laboratoires
  Rhone-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. 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).

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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
  1952 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.

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• The first published clinical trial was that of
  Jean Delay and Pierre Deniker at Ste. Anne
  Hospital in Paris in 1952, in which they treated
  38 psychotic patients with daily injections of
  chlorpromazine.
• Drug treatment with chlorpromazine went beyond
  simple sedation with patients showing
  improvements in thinking and emotional behavior.
  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.

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Chlorpromazine

• 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.