Anti Psychotics

Anti-Psychotics
Introduction
• Psychotic disorders are one of the most disabling groups of severe
mental disorders worldwide.
• They are associated not only with personal disability and suffering but
also:
• Immense family burden
• Increased risk for suicide
• Physical morbidity, and premature death
• Antipsychotics are the mainstay in the treatment of psychosis, and
they alleviate the positive symptoms & improve negative symptoms
• Historically been referred to as:
• Major tranquilizers (emotional quieting & sedation)
• Ataractics (produce calmness or serenity)
• Neuroleptics (Greek term for clasping)
• Classified as:
• Traditional, Typical or FGAs
• Atypical, conventional or SGAs
• Atypical or Third generation (TGAs)
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Pathophysiology of Schizophrenia-
Neurotransmitters
• Multi-neurotransmitter involvement is likely.
• Dopamine (DA) hypothesis- most recognized neurotransmitter-based
theory regarding psychosis.
• DA hyperactivity in limbic system leading to positive symptoms:
• Increased presynaptic dopaminergic turnover has been noted in schizophrenia
• DA hypofunction in prefrontal cortex thought to be associated with negative
symptoms.
Serotonin
• Increase in serotonin (5-HT) transmission and 5-HT transporter
density in subcortical regions, no changes in cortical regions.
• Use of serotonin type 2a (5-HT2A) antagonists leads to increased DA release
in prefrontal cortex.
Glutamate
• Glutamate is associated with numerous processes involved in
cognition memory & perception.
• Recent evidence suggests that glutamatergic receptor dysfunction may
be related to the etiology of schizophrenia
• Glutamate plays an important role in neurodevelopment, synapse organization,
and sensorimotor gating
• The glutamatergic corticostriatal pathway inhibits DA function in the ventral
striatum.
• Deficiencies in glutamate produce symptoms similar to DA hyperactivity.
• Decreased glutamate release also leads to decreased gamma-aminobutyric
(GABA)-ergic tone, leading to neurotoxicity and psychotic symptoms.
• N-methyl-D-aspartate (NMDA) receptor dysfunction may play a role.
• Use of NMDA antagonists leads to positive symptoms by increasing DA release in
limbic areas and reducing DA release from the ventral tegmental area leading to negative
symptoms.
• Metabotropic glutamate receptor 5 (mGluR5) has been shown in mice and
human genetic studies to be related to pathology of schizophrenia.
• However, postmortem data have not shown this.
• mGluR5 activation may augment NMDA receptor function through direct
modulation and may be a target for future antipsychotic trials
GABA
• Involved in neural circuitry of the prefrontal cortex. Alterations in
neural circuitry thought to be involved in higher-order cognitive
deficits in schizophrenia.
• Reductions in the number of parvalbumin cells and under expression
of glutamic acid decarboxylase are thought to contribute to functional
deficit in GABA in the prefrontal cortex.
• Parvalbumin cells play a role in cell-cycle regulation, second messenger
production, and muscle contraction.
• Chandelier and wide arbor cells are thought to coordinate the fine
control of the synchrony and spatial extent of pyramidal cell activity in
the prefrontal cortex.
• The disruption of these functions is thought to lead to the loss of temporal and
spatial organization necessary for higher-order cognitive processes.
Acetylcholine
• Nicotinic involvement in schizophrenia:
• Administering nicotinic acetylcholine receptor (nAChR) antagonists in healthy
subjects can induce schizophrenia-type symptoms.
• Patients with schizophrenia administered nicotine acutely demonstrate
transient improvement in sensory information processing
• Expression level of the alpha 7 nAChR is decreased in persons with
schizophrenia.
• nAChR antagonist block synaptic transmission at autonomic ganglia,
skeletal neuromuscular junctions & CNS nicotinic synapses
• Muscarinic involvement- Post-mortem studies found decreased
expression of muscarinic acetylcholine receptor (mAChR) expression
in various brain regions.
First Generation AP
• Mechanism of Action
• Antipsychotic effect is thought to be mediated by a decrease in central
dopaminergic transmission.
• Likely related to blockade of postsynaptic D 2 receptors in the
mesolimbic area and possibly the mesocortical area of the brain.
• Blockade of D2 receptors in other areas leads to a variety of adverse
effects.
• In addition to their effects on DA, FGAs antagonize other receptors:
• Alpha –adrenergic
• Serotonergic
• Histaminergic
• Muscarinic to varying degrees.
• Low potency agents have greater effects.
Mechanism of Action of FGAs
Predominat D2 receptor Blockers; clinical effectiveness occurs 60-70% blockade.
RECEPTOR EFFECTS
D2 Mesolimbic tract: Antipsychotic effect
Nigrostraiatal tract:EPSEs
Tuberoinfundibular tract: Prolactin level elevation
Mesocortical tract: Secondary negative symptoms-caused by AP (worsens)
5-HT2A Improves negative symptoms, decreased EPSEs
M1 Anticholinergic effects: dry mouth & Blurred vision (ensure not hallucinations/Illusions),
Decreased sweating,constipation,slowed bladder activity
H1 Sedation, weight gain (increased appetite),orthostasis
Alpha -1 Orthostasis,dizziness,sedation
Alpha-2 Sexual dysfunction
GABA Lowers seizure threshold (avoid in known epilepsy & withdrawal),produce anxiety
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