Download Anatomy of the Brain (seizures)

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
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”
Dopamine
Acetylcholine
Serotonin
(5-Hydroxytryptamine)
(5-HT)
Norepinephrine
GABA (-aminobutyric acid)
Neurotransmitter
Too little leads to:
Too much leads to:
Acetylcholi ne
Memory impairment
Depression
Aggress ion
Depression
Dopamine
Dementia
Depression
Psychosis
Anxiety
Confusion
Serotonin
Depression
Aggress ion
Anxiety
Norepinephrine
Depression
Dementia
Anxiety
GABA
Anxiety
Reduced Anxiety
Reduced Aggress ion
Schizophrenia
Schizophrenia
• http://www.healthscout.com/animation/68/
49/main.html
• http://www.abilify.com/abilify/channels/sch
_content.jsp?BV_UseBVCookie=Yes&cha
nnelName=Schizophrenia%2fSch_Brain_
Sch_Abilify&referrer=null
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/entrie
s/dh52dr.html
HN
N
NH2
Histamine
• 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.
HN
Inside the CNS:
N
NH2
Histamine
•
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.
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
• 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.
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.
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 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.
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 hives.
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://www.healthscout.com/animation/68/
20/main.html
• http://pennhealth.com/health_info/animatio
nplayer/allergies.html
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.
N
H3C
CH2
O
N
CH2
N
NMe2
NMe2
NMe2
Phenbenzamine
O
Mepyramine
Diphenhydramine
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 H1receptor, 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
chlorpromazine.
S
S
N
N
H3C
NMe2
Cl
Promethazine
(Phenargan)
(currently used as an anti-emetic)
NMe2
Chlorpromazine
Antihistamines to Antipsychotics?
• http://ajp.psychiatryonline.org/cgi/content/f
ull/160/10/1895?etoc
S
S
N
N
H3C
NMe2
Cl
Promethazine
(Phenargan)
(currently used as an anti-emetic)
NMe2
Chlorpromazine
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.
S
S
N
N
H3C
NMe2
Cl
Promethazine
(Phenargan)
(currently used as an anti-emetic)
NMe2
Chlorpromazine
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).
S
S
N
N
H3C
NMe2
Cl
Promethazine
(Phenargan)
(currently used as an anti-emetic)
NMe2
Chlorpromazine
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.
• 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.
Chlorpromazine
S
N
Cl
NMe2
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%.