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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://pennhealth.com/health_info/anima
tionplayer/nerve_conduction.html
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, Parkinson’s Disease,
Alzheimer’s 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.
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 fatsoluble molecules that have crossed into the cells
Blood-Brain-Barrier
• 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 bloodcerebrospinal fluid barrier (BCB), a function of
the choroid plexus.
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 body.
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 agents?
• Mechanisms for drug targeting in the brain involve
going either "through" or "behind" the BBB.
• 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://www.clinicaloptions.com/HIV/Man
agement%20Series/NeuroAIDS/Animati
on/Blood%20Brain%20Barrier.aspx
Introduction to the CNS
• http://biosingularity.wordpress.com/2007
/05/07/neurons-and-how-they-workanimation
• http://www.healthscout.com/animation/6
8/10/main.html
Neurotransmitters found in the
CNS
HO
O
Me
Me
HO
NH2
HO
NH2
(Small Peptides)
N
H3C
O
Me
HO
HO
Acetylcholine
Endorphins
Dopamine
Noradrenaline
O
NH2
HO
HN
HO
NH2
N
H
Serotonin
(5-Hydroxytryptamine)
5-HT
N
Histamine
O
NH2
O
gamma-aminobutyric acid
(GABA)
HO
OH
NH2
Glutamate
It’s a balancing act!!
• Current models of CNS diseases often
attribute the physiological cause of the
disease to an imbalance of
neurotransmitters.
Acetylcholine
• 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 Alzheimer’s disease.
Norepinephrine
• 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ﾊ are found in
the locus coeruleusﾊ, the pons and the reticular formation
in the brain. These neurons provide projections to the
cortex, hippocampusﾊ, thalamusﾊ 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
hippocampus
Thalamus
HO
NH2
HO
Dopamine
• 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ﾕs
disease, while an increase in dopamine
concentration has a role in the development of
schizophrenia.
Biosynthesis of Epinephrine
CO2H
HO
HO
Tyrosine
NH2
hydroxylase
HO
L-Tyrosine
NH2
CO2H
HO
Dopa
Decarboxylase
OH
OH
HO
-hydroxylase
HO
Norepinephrine
(Noradrenaline)
HO
Dopamine
Levodopa
(L-DOPA)
Dopamine
NH2
NH2
HO
NHMe
N-methyl transferase
(in Adrenal medulla)
HO
Epinephrine
(Adrenaline)
HO
NH2
HO
Dopamine
•
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 schizophrenia.
Dopamine and Parkinson’s Disease
• In patients with Parkinson’s 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 nigra.
Parkinson’s 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ﾕ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 Parkinson’s disease, there is degeneration of the substantia nigra which produces the chemical dopamine deep inside the brain
Parkinson’s 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 Parkinson’s disease patients, all aspects of movement are
impaired, resulting in the characteristic features of the disease ﾐ
slowness of movement, stiffness and effort required to move a
limb and, often, tremor.
• Dopamine levels in the brain’s 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.
Parkinson’s Disease
• http://www.parkinsonshealth.com/About
PD/Section.aspx?SectionId=798d598e2a1c-4747-ac81-cd92f475744b
• http://www.medindia.net/animation/parki
nsons_disease.asp
History
• 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 Parkinson’s 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 Parkinson’s
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
NH3+
HO
Polar groups
HO
Dopamine
Mostly protonated
to the
corresponding
ammonium salt
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 corecipients 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嗾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. LDopa is still today the cornerstone of Parkinson therapy.
Biosynthesis of Epinephrine
CO2H
HO
HO
Tyrosine
NH2
hydroxylase
HO
L-Tyrosine
NH2
CO2H
HO
Dopa
Decarboxylase
OH
OH
HO
-hydroxylase
HO
Norepinephrine
(Noradrenaline)
HO
Dopamine
Levodopa
(L-DOPA)
Dopamine
NH2
NH2
HO
NHMe
N-methyl transferase
(in Adrenal medulla)
HO
Epinephrine
(Adrenaline)
Wait a minute!
• If dopamine is too polar to cross the
BBB, how can L-DOPA cross it?
NH3+
HO
HO
NH3
Polar groups
HO
Dopamine
+
Polar groups
Mostly protonated
to the corresponding
ammonium salt
HO
L-DOPA
O
O
Mostly protonated
to the corresponding
ammonium salt
H
Polar group
Answer!
• 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).
NH3+
HO
HO
O
O
Active Transport
(crosses BBB)
NH3+
HO
HO
O
H
H
L-DOPA
(In Blood)
O
Dopamine Decarboxylase
(DDC)
(In Brain)
NH3+
HO
HO
Dopamine
L-DOPA
(In Brain)
•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
doesn’t 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.
NH3+
HO
H
N
HO
NH2
HO
O
O
HO
H3C
CO2H
H
L-DOPA
Carbidopa
SINEMET
(CARBIDOPA-LEVODOPA)
DESCRIPTION
SINEMET* (Carbidopa-Levodopa) is a combination of
carbidopa and levodopa for the treatment of
Parkinson's disease and syndrome.
• http://www.learningcommons.umn.edu/n
euro/mod6/carb.html
Endorphin
• 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 endorphins.
Serotonin
NH2
HO
5-Hydroxytryptamine, or 5-HT
N
H
• 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ﾊ, ponsﾊ and medulla. These serotonergic
pathways spread extensively throughout the brainstemﾊ, the cerebral
cortexﾊ and the spinal cordﾊ. 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.
What is serotonin?
NH2
HO
5-Hydroxytryptamine, or 5-HT
N
H
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, obsessivecompulsive disorder (OCD), migraine, irritable bowel syndrome, tinnitus, fibromyalgia, bipolar
disorder, and anxiety disorders.[citation needed] If neurons of the brainstem that make
serotonin—serotonergic neurons—are 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://www.epilepsy.com/web/animation.
php?swf=what_is
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
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”
Schizophrenia
• http://www.healthscout.com/animation/6
8/49/main.html
• http://www.abilify.com/abilify/channels/s
ch_content.jsp?BV_UseBVCookie=Yes
&channelName=Schizophrenia%2fSch_
Brain_Sch_Abilify&referrer=null
Historical: Drugs to treat
schizophrenia
• http://www.pbs.org/wgbh/aso/databank/
entries/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 (Marieb,
2001, p.414). New evidence also indicates
that histamine plays a role in chemotaxis of
white blood cells.
HN
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.
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 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/6
8/20/main.html
• http://pennhealth.com/health_info/anima
tionplayer/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
chiorpromazine.
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/conten
t/full/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ｨ and Thorazineｨ, 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 Rh冢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).
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
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冱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%.
Definitions
• 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.
Definitions
• 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ﾕ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://www3.utsouthwestern.edu/molpsych/pa
ths_b02.htm
Norepinephrine Reuptake
Inhibitors as Antidepressants
• 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.
Depression
• http://www.healthcentral.com/depression/intro
duction-5003-109.html
• http://www.healthcentral.com/depression/intro
duction-5003-109.html
• http://www.healthscout.com/animation/68/10/
main.html
• http://www.insidecymbalta.com/patient_resou
rces/neuro_animation.jsp
Norepinephrin Reuptake Inhibitors for Depression
H3C
OH
O
CH3
HO
NHCH3
N
H
HO
Atomoxetine
(Strattera, Eli Lilly & Co.)
Epinephrine
•
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ｨ 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.
Atomoxetine
H3C
OH
O
CH3
HO
NHCH3
N
H
HO
Atomoxetine
(Strattera, Eli Lilly & Co.)
Epinephrine
• 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.
O
OH
HO
NHMe
O
O
HO
Epinephrine
(Adrenaline)
N
H
Reboxetine
• 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ｨ, Noreboxｨ, Proliftｨ,
Solvexｨ or Vestraｨ.
• 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.
OH
HO
NHMe
H
N
O
O
O
HO
Epinephrine
(Adrenaline)
Viloxazine
• Viloxazine (Emovit, Vivalan, Vivarint, Vicilan) is a bicyclic
antidepressant morpholine derivative that inhibits the
reuptake of norepinephrine.
• 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
S
N
N
Cl
NMe2
Chlorpromazine
(anti-psychotic)
NMe2
Imipramine
(anti-depressant)
Historical
• 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 treatment.
S
N
N
Cl
NMe2
Chlorpromazine
(anti-psychotic)
NMe2
Imipramine
(anti-depressant)
“Tricyclic” Antidepressants
• The ‘tricyclic’ antidepressants share the
common structural feature of fused 6-7-6
membered rings, as shown below.
A
Single or double bond
Nitrogen or carbon
Tricyclic Antidepressants
A
Single or double bond
Nitrogen or carbon
N
N
Cl
Amitriptyline
(Elavil, etc.)
Me
N
Clomipramine
(Novartis)
Me
Desipramine
N
Me
Me
Me
N
Imipramine
Me
N
Me
H
N
Nortryptyline
Me
N
Me
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 reuptake 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 poisoning.[1]
Definitions
• 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
distractibility.
• 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.