CNS_Total drugs and their actions on body.ppt

CNS_Total drugs and their actions on body.ppt

1. 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.

2. 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.”

3. 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.
•Oxygen, glucose, and white blood cells are molecules that are able
to pass through this barrier. Red blood cells cannot.

4. 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, a function of
the choroid plexus.

5. 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. 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 [3].

6. What is the purpose of the BBB?
•The blood-brain barrier protects the brain from the many chemicals flowing
around the body. 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 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.

7. 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. Other strategies to go through the BBB may entail the use of
endogenous transport systems, including carrier-mediated transporters
such as glucose and amino acid carriers; receptor-mediated transcytosis for
insulin or transferrin; and blocking of active efflux transporters such as p-
glycoprotein. Strategies for drug delivery behind the BBB include
intracerebral implantation and convection-enhanced distribution.
Nanotechnology could also help in the transfer of drugs across the BBB.
Recently researchers have been trying to build nanoparticles loaded with
liposomes to gain access through the BBB. More research is needed to
determine which strategies are most effective and how they can be
improved for patients with brain tumors.

8. The Blood Brain Barrier
•http://www.clinicaloptions.com/HIV/
Management%20Series/NeuroAIDS/
Animation/Blood%20Brain%20Barrier.aspx

9. Neurotransmitters found in the
CNS
H
3C O
N
O
Me
Me
Me
Acetylcholine
HO
HO
HO
NH
2
Noradrenaline
HO
HO
NH
2
Dopamine
Endorphins
(Small Peptides)
Serotonin
(5-Hydroxytryptamine)
5-HT
N
H
HO
NH
2
NH
2
HO
O
gamma-aminobutyric acid
(GABA)
HO
O
NH
2
OH
O
Glutamate
HN
N NH
2
Histamine

10. It’s a balancing act!!
•Current models of CNS diseases often
attribute the physiological cause of the
disease to an imbalance of
neurotransmitters.

11. Acetylcholine
•All ACh receptors in the CNS are nicotinergic. The
stimulating effect of nicotine is due to the influence of
these receptors.
•Acetylcholine ﾔacts
ﾕ
or ﾔis transmitted
ﾕ
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ﾕs disease.

12. 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.

13. 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".

14. Locus ceruleus

15. hippocampus

16. Thalamus

17. •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.
HO
HO
NH
2
Dopamine

18. Biosynthesis of Epinephrine
HO
NH
2
CO
2H
L-Tyrosine
Tyrosine
hydroxylase
HO
NH
2
CO
2H
Levodopa
(L-DOPA)
HO
HO
NH
2
Dopamine
HO
Dopa
Decarboxylase
Dopamine
-hydroxylase
HO
HO
NH
2
OH
Norepinephrine
(Noradrenaline)
HO
HO
NHMe
OH
Epinephrine
(Adrenaline)
N-methyl transferase
(in Adrenal medulla)

19. •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.
HO
HO
NH
2
Dopamine

20. 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.

21. 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.

22. In Parkinson’s disease, there is degeneration of the substantia nigra which produces the chemical dopamine deep inside the brain

23. 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.

24. 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.

25. 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.

26. 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
HO
HO
NH
3
+
Dopamine
Polar groups
Mostly protonated
to the
corresponding
ammonium salt

27. 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. L-Dopa is still today the
cornerstone of Parkinson therapy.

28. Biosynthesis of Epinephrine
HO
NH
2
CO
2H
L-Tyrosine
Tyrosine
hydroxylase
HO
NH
2
CO
2H
Levodopa
(L-DOPA)
HO
HO
NH
2
Dopamine
HO
Dopa
Decarboxylase
Dopamine
-hydroxylase
HO
HO
NH
2
OH
Norepinephrine
(Noradrenaline)
HO
HO
NHMe
OH
Epinephrine
(Adrenaline)
N-methyl transferase
(in Adrenal medulla)

29. Wait a minute!
•If dopamine is too polar to cross the
BBB, how can L-DOPA cross it?
HO
HO
NH
3
+
Dopamine
Polar groups
Mostly protonated
to the corresponding
ammonium salt
HO
HO
NH
3
+
L-DOPA
Polar groups
Mostly protonated
to the corresponding
ammonium salt
O O
H
Polar group

30. 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.
•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.

31. •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.
HO
HO
H
N
CO
2H
NH
2
H
3C
HO
HO
NH
3
+
O O
H
L-DOPA Carbidopa

32. 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/neuro/mod6/carb.html

33. 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.

34. Serotonin
•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 theMidbrain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.
N
H
HO
NH
2
5-Hydroxytryptamine, or 5-HT

40. What is serotonin?
N
H
HO
NH
2
5-Hydroxytryptamine, or 5-HT
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
serotonin—serotonergic neurons—are abnormal, there is a risk of sudden infant death
syndrome (SIDS) in an infant.[1]

41. 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.

42. 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.[6]

43. Anatomy of the Brain
(seizures)
•http://www.epilepsy.com/web/animation.
php?swf=what_is

44. 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

46. 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”

47. Schizophrenia
•http://www.healthscout
.com/animation/68/49/main.html
•http://www.abilify.
com/abilify/channels/sch_content.jsp?
BV_UseBVCookie=Yes&
channelName=Schizophrenia
%2fSch_Brain_Sch_Abilify&referrer=null

48. Historical: Drugs to treat
schizophrenia
•http://www.pbs
.org/wgbh/aso/databank/entries/dh52dr.
html

49. •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.
HN
N NH
2
Histamine

50. Disorders involving histamine:
Histapenia (deficiency of histamine) and histadelia
(abundance of histamine) can cause both neurological
and physical disorders.

Histapenia may be caused by
excess copper levels, as this decreases blood
histamine.
•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.

51. 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.

52. 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.

53. 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.

54. 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.

55. Allergic reaction: Histamine
and Antihistamines
•http://www.healthscout
.com/animation/68/20/main.html
•http://pennhealth.
com/health_info/animationplayer/allergi
es
.html

56. 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.
CH
2N
NMe
2
Phenbenzamine
O
NMe
2
Diphenhydramine
CH
2N
N
NMe
2
Mepyramine
O
H
3C

57. Antihistamines to Antipsychotics?
•In common use, the term antihistamine refers
only to H
1
-receptor antagonists, also known
as H
1-antihistamines. It has been
discovered that these H
1-antihistamines are
actually inverse agonists at the histamine H
1-
receptor, rather than antagonists per se.

58. 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.
N
Promethazine
(Phenargan)
(currently used as an anti-emetic)
S
H
3C NMe
2
N
Chlorpromazine
S
Cl NMe
2

59. Antihistamines to Antipsychotics?
•http://ajp.psychiatryonline
.org/cgi/content/full/160/10/1895?etoc
N
Promethazine
(Phenargan)
(currently used as an anti-emetic)
S
H
3C NMe
2
N
Chlorpromazine
S
Cl NMe
2

60. 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.
N
Promethazine
(Phenargan)
(currently used as an anti-emetic)
S
H
3C NMe
2
N
Chlorpromazine
S
Cl NMe
2

61. 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).
N
Promethazine
(Phenargan)
(currently used as an anti-emetic)
S
H
3C NMe
2
N
Chlorpromazine
S
Cl NMe
2

62. 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%.

63. 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.

64. 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.

65. 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/
paths_b02.htm

66. 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.

67. Depression
•http://www.healthcentral
.com/depression/introduction-5003-109.html
•http://www.healthcentral
.com/depression/introduction-5003-109.html
•http://www.healthscout.com/animation/68/10/main.html
•http://www.insidecymbalta.
com/patient_resources/neuro_animation.jsp

68. 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
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.
O
N
H
Atomoxetine
(Strattera, Eli Lilly & Co.)
CH
3
H
3C
NHCH
3
OH
Epinephrine
HO
HO

69. Atomoxetine
•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
N
H
Atomoxetine
(Strattera, Eli Lilly & Co.)
CH
3
H
3C
NHCH
3
OH
Epinephrine
HO
HO

70. •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.
HO
HO
NHMe
OH
Epinephrine
(Adrenaline)
O
Reboxetine
N
H
O
O

71. •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.
HO
HO
NHMe
OH
Epinephrine
(Adrenaline)
O
Viloxazine
O
O
H
N

72. Further ‘tinkering’ with the structure of
the antipsychotic drugs led to a drug
which was useful in treating depression
N
Chlorpromazine
(anti-psychotic)
S
Cl NMe
2
N
Imipramine
(anti-depressant)
NMe
2

73. 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.
N
Chlorpromazine
(anti-psychotic)
S
Cl NMe
2
N
Imipramine
(anti-depressant)
NMe
2

74. “Tricyclic” Antidepressants
•The ‘tricyclic’ antidepressants share the
common structural feature of fused 6-7-6
membered rings, as shown below.
A
Nitrogen or carbonSingle or double bond

75. Tricyclic Antidepressants
A
Nitrogen or carbon
N
Me
MeAmitriptyline
(Elavil, etc.)
N
N
Me
Me
Cl
Clomipramine
(Novartis)
N
N
Me
HDesipramine
N
N
Me
MeImipramine
N
Me
MeNortryptyline
Single or double bond

76. 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
poisoning.[1]

77. 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.

78. 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.