Definitions

1
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.

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Agonists and Antagonists

• http//www.uri.edu/pharmacy/animation/animation.ht
  mlaa

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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 (anti-psychotic)
  medications.

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Treatment of Schizophrenia

• Neuroleptic drugs are potent antagonists at the
  D2 receptor
• These drugs are often associated with
  extrapyrimidal neurological effects

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Examples of Neuroleptic Drugs
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Atypical Antipsychotic Drugs

• Generally have fewer extrapyramidal effects
• Generally regarded as more selective for D2
  receptors in the proper region of the brain

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Examples of Atypical Antipsychotic Drugs
Resperidone (Risperdal)
Clozapine (Clozaril)
Quetiapine (Seroquel)
Olanzapine (Zyprexa)
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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 individuals responses to
  natural rewards, such as food, sex, and social
  interactions, and is therefore an important
  determinant of motivation and incentive drive.

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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.

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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.

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• 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

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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.

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Cocaine
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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.

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Depression

• http//www.healthcentral.com/depression/introducti
  on-5003-109.html
• http//www.healthcentral.com/depression/introducti
  on-5003-109.html
• http//www.healthscout.com/animation/68/10/main.ht
  ml
• http//www.insidecymbalta.com/patient_resources/ne
  uro_animation.jsp

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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? 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.

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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.

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• 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?.
• 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.

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• 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.

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Further tinkering with the structure of the
antipsychotic drugs led to a drug which was
useful in treating depression
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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.

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Tricyclic Antidepressants

• The tricyclic antidepressants share the common
  structural feature of fused 6-7-6 membered rings,
  as shown below.

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Tricyclic Antidepressants
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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.

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Tricyclic Antidepressants

• 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.

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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.

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Selective Serotonin Reuptake Inhibitors (SSRIs)
Fluoxetine (Prozac)
Paroxetine (Seroxat, Paxil, Aropax)
Duloxetine (Cymbalta, Yentreve)
Sertraline hydrochloride (Zoloft, Lustral)
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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.

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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.