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Transcript
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.
Agonists and Antagonists
• http://www.uri.edu/pharmacy/animation/ani
mation.html#aa
Definitions
• Extrapyramidal side effects: Physical
symptoms, including tremor, slurred
speech, akathesia (inability to sit still),
dystonia (repetitive muscle contractions),
anxiety, distress, paranoia, bradyphrenia
(slowed thought), and drug-induced
parkinsonianism that are primarily
associated with improper dosing of or
unusual reactions to neuroleptic (antipsychotic) medications.
Treatment of Schizophrenia
• ‘Neuroleptic’ drugs are potent antagonists
at the D2 receptor
• These drugs are often associated with
extrapyrimidal neurological effects
Examples of Neuroleptic Drugs
F
S
N
O
N
Cl
NMe2
Chlorpromazine
(Thorazine)
Initially developed as an anesthetic
OH
Cl
Haloperidol
(Haldol)
Long acting drug that can be given by injection
(every 4 weeks) to non-compliant patients.
Atypical Antipsychotic Drugs
• Generally have fewer extrapyramidal
effects
• Generally regarded as more selective for
D2 receptors in the proper region of the
brain
Examples of Atypical Antipsychotic Drugs
Clozapine
(Clozaril)
Olanzapine
(Zyprexa)
Resperidone
(Risperdal)
Quetiapine
(Seroquel)
Reward pathways in the CNS
• The most important reward pathway in brain is the
mesolimbic dopamine system.
• This circuit (VTA-NAc) is a key detector of a
rewarding stimulus. Under normal conditions, the
circuit controls an individual’s responses to natural
rewards, such as food, sex, and social interactions,
and is therefore an important determinant of
motivation and incentive drive.
Ventral Tegmental Area
• The ventral tegmentum or the ventral tegmental area
(VTA) (tegmentum, Latin for covering) is part of the
midbrain, lying close to the substantia nigra.
• The ventral tegmentum is considered to be part of the
pleasure system, or reward circuit, one of the major
sources of incentive and behavioral motivation. Activities
that produce pleasure tend to activate the ventral
tegmentum, and psychostimulant drugs (such as
cocaine) directly target this area. Hence, it is widely
implicated in neurobiological theories of addiction.
• It is also shown to process various types of emotion and
security motivation, where it may also play a role in
avoidance and fear-conditioning.
Nucleus Accumbens
• The nucleus accumbens, part of the limbic
system, plays a role in sexual arousal and
the "high" derived from certain recreational
drugs.
• These responses are heavily modulated
by dopaminergic projections from the
limbic system.
• 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
Cocaine
• Cocaine is a dopamine reuptake inhibitor,
a noradrenaline reuptake inhibitor and a
serotonin reuptake inhibitor.
• Cocaine is addictive due to its effect on
the mesolimbic reward system
• Cocaine is still used as a topical
anesthetic, particularly in surgeries of the
nose and throat.
Cocaine
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
mesylate (i.e. methanesulfonate) salt is sold under
tradenames including Edronax, Norebox, Prolift, Solvex 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.
Tricyclic Antidepressants
• 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.
Tricyclic Antidepressants
• 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.
Selective Serotonin Reuptake Inhibitors (SSRI’s)
Fluoxetine (Prozac)
Paroxetine
(Seroxat, Paxil, Aropax)
Duloxetine
(Cymbalta, Yentreve)
Sertraline hydrochloride
(Zoloft, Lustral)
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. A person with narcolepsy is likely to
become drowsy or to fall asleep, often at inappropriate times and
places.
• 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.
• Additionally, SPECT scans found people with ADHD to have
reduced blood circulation, and a significantly higher
concentration of dopamine transporters in the striatum
which is in charge of planning ahead.