ANTIPSYCHOTICS

OR
NEUROLEPTICS
WHAT IS PSYCHOSIS
from the Greek "psyche", for mind/soul,
and "-osis", for abnormal condition or
derangement)
Psychotic illnesses are characterized by
disordered thought processes
 The psychoses are among the most
severe psychiatric disorders
Serious inability to think
Symptoms of false beliefs (delusions)
Abnormal sensations (hallucinations)
Representative syndromes in this
category include schizophrenia brief
psychoses, and delusional disorders.
Pathophysiology

Psychosis results from an overactivity of

dopamine function in the brain,
particularly in the mesolimbic pathway
Substance induced
 The purpose of the brain is to collect
information from the body (pain, hunger,
etc.), and from the outside world, interpret it
to a coherent world view, and produce a
meaningful response. The information from
the senses enter the brain in the primary
sensory areas. They process the information
and send it to the secondary areas where
the information is interpreted. Spontaneous
activity in the primary sensory areas may
produce hallucinations which are
misinterpreted by the secondary areas as
information from the real world.
 Tertiary brain cortex collects the
interpretations from the secondary
cortexes and creates a coherent world
view of it. A study investigating structural
changes in the brains of people with
psychosis showed there was significant
grey matter reduction in the right medial
temporal, lateral temporal, and inferior
frontal gyrus, and in the cingulate cortex
bilaterally of people before and after
they became psychotic
 sensory deprivation have shown that the
brain is dependent on signals from the
outer world to function properly. If the
spontaneous activity in the brain is not
counterbalanced with information from
the senses, loss from reality and psychosis
may occur after some hours
CLASSIFICATION

CLASSIFICATION OF ANTIPSYCHOTIC
DRUGS
PHARMACOLOGICALLY, THEY ARE
CHARACTERISED AS
dopamine receptor antagonists
5-hydroxytryptamine (5-HT) receptors
antagonists
ANTISCHIZOPHRENIC:

Antischizophrenic drugs or major

tranquillisers-conventionally refers to
those used to treat schizophrenia, one of
the most common and debilitating forms
of mental illness.
 Classification of antipsychotic drugs main
categories are:
First-generation ('typical') antipsychotics (e.G.
Chlorpromazine, haloperidol , fluphenazine,
flupenthixol, clopenthixol)
Second-generation ('atypical') antipsychotics
(e.G. Clozapine , risperidone , sertindole,
quetiapine, amisulpride, aripiprazole ,
zotepine).
 Distinction between typical and atypical
groups is not clearly defined but rests on:
Receptor profile
Incidence of extrapyramidal side effects (less
in atypical group)
Efficacy (specifically of clozapine ) in
'treatment-resistant' group of patients
Efficacy against negative symptoms.
SYMPTOMS :
Delusions
Hallucinations- Auditory, Visual, Olfactory,
and Tactile
Losing Sense of Reality
Disorganization of Thought
Thought Blocking
DISORDERS WITH PSYCHOSIS:
Bipolar Disorder
Shizophrenic disorders
Depression
Personality Disorders
BIPOLAR DISORDER
Two main different types:
Bipolar I
Manic around 1 week
Depressive around 2 weeks
Bipolar II
Depressive
Hypomanic

Treatments:
Mood Stabilizers:
- Lithium
Antipsychotics
Symptoms:
Delusions
Hallucinations
Disorganized speech and behavior
Negative Symptoms
Blunted affect (lack of emotional reactivity)
Alogia (poverty of speech)
Avolition ( lack of drive, or motivation to
pursue meaningful goals)
 Treatment:
Mood Stabilizers
Antipsychotics
TRICYCLIC ANTIPSYCHOTIC
AGENTS
Phenothiazine antipsychotic drugs
PHARMACOLOGICAL PROPERTIES
Prominent sedative effect
Adverse autonomic and neurologic
effects, severe anxiety and restlessness
(akathisia)
The risk of developing advers
extrapyramidal effects, including tardive
dyskinesia
1-EFFECTS ON COGNITIVE FUNCTION

Auditory processing and attention, spatial

organization, verbal learning, verbal
memory, and executive functions, are
impaired in schizophrenia patients. Potent
d2-antagonist neuroleptics have very limited
beneficial effects on such functions. Some
atypical antipsychotic agents with mixed
D2/5-HT2A activity (including clozapine,
quetiapine, olanzapine, and risperidone), as
well as the D2 partial agonist aripiprazole,
seem to improve cognitive functioning in
psychotic patients.
2-EFFECTS ON SLEEP

Antipsychotic drugs have inconsistent

effects on sleep patterns but tend to
normalize sleep disturbances
characteristic of many psychoses and
mania.
3-EFFECTS ON SPECIFIC AREAS OF
THE NERVOUS SYSTEM

Actions of antipsychotic agents are

based on their ability to antagonize the
actions of DA as a neurotransmitter in the
basal ganglia and limbic portions of the
forebrain.
4-CEREBRAL CORTEX

Antipsychotic drugs interact with

dopaminergic projections to the
prefrontal and deep-temporal (limbic)
regions of the cerebral cortex, with
relative sparing of these areas from
adaptive changes in DA metabolism
5-SEIZURE THRESHOLD
Many neuroleptic drugs can lower the
seizure threshold and induce discharges in
the electroencephalogram (EEG) that are
associated with epileptic seizure disorders.
Clozapine, olanzapine, and aliphatic
phenothiazines with low potency (e.g.,
chlorpromazine) seem particularly able to do
this.
while the more potent piperazine
phenothiazines and thioxanthenes
fluphenazine and thiothixene), risperidone,
and quetiapine are much less likely to have
this effect.
 Antagonism of DA-mediated synaptic
neurotransmission is an important action of
many antipsychotics,this prompted the
proposal that many adverse extrapyramidal
neurological and neuroendocrinological
effects of the neuroleptics are mediated by
antidopaminergic effects in the basal
ganglia and hypothalamic systems, whereas
the antipsychotic effects of neuroleptics are
mediated by modification of dopaminergic
neurotransmission in the limbic and
mesocortical systems
 Many antipsychotic drugs also block the
effects of agonists on DA-sensitive adenylyl
cyclase associated with D1/D5-receptors in
forebrain tissue
Atypical antipsychotic drugs such as
clozapine and quetiapine are characterized
by low affinity or weak actions in such tests.
Initially, the standard antipsychotics increase
firing and metabolic activity in dopaminergic
neurons. These responses eventually are
replaced by diminished presynaptic activity
(depolarization inactivation) with reduced
firing and production of DA, particularly in
the extrapyramidal basal ganglia.
 Initially in antipsychotic treatment, DA
neurons activate and release more DA,
but following repeated treatment, they
enter a state of physiological
depolarization inactivation, with
diminished production and release of DA,
in addition to continued receptor
blockade. ER, endoplasmic reticulum.
6-CHEMORECEPTOR TRIGGER
ZONE

Most antipsychotics protect against the

nausea- and emesis-inducing effects of
apomorphine and certain ergot alkaloids,
all of which can interact with central
dopaminergic receptors in the
chemoreceptor trigger zone (CTZ) of the
medulla
7-AUTONOMIC NERVOUS SYSTEM
Chlorpromazine, clozapine, and
thioridazine have particularly significant
a-adrenergic antagonistic activity. The
potent piperazine tricyclic neuroleptics
(e.g., fluphenazine, trifluoperazine,
haloperidol, and risperidone) have
antipsychotic effects even when used in
low doses and show little antiadrenergic
activity.
8-KIDNEY AND ELECTROLYTE
BALANCE

Chlorpromazine may have weak diuretic

effects because of a depressant action
on the secretion of vasopressin
9-CARDIOVASCULAR SYSTEM

Chlorpromazine and less potent antipsychotic

agents, as well as reserpine, risperidone, and
olanzapine, can cause orthostatic hypotension,
usually with rapid development of tolerance.
Thioridazine, mesoridazine, and other
phenothiazines with low potency, as well as
ziprasidone, droperidol, and perhaps high doses
of haloperidol, have a potentially clinically
significant direct negative inotropic action and a
quinidine-like effect on the heart (prolongation
of the QTc and PR intervals, blunting of T waves,
and depression of the ST segment)
10-MISCELLANEOUS
PHARMACOLOGICAL EFFECTS

Many antipsychotics enhance the

turnover of acetylcholine Chlorpromazine
and low-potency antipsychotic agents,
including clozapine and quetiapine, have
antagonistic actions at histamine
receptors that probably contribute to
their sedative effects.
TOXIC REACTIONS AND ADVERSE
EFFECTS
The most important are those on the
cardiovascular,
central and autonomic nervous systems,
and endocrine system. Other dangerous
effects are seizures, agranulocytosis,
cardiac toxicity, and pigmentary
degeneration of the retina, all
of which are rare
1-ADVERSE CARDIOVASCULAR
AND CEREBROVASCULAR EFFECTS
Orthostatic hypotension, which may result
in syncope, falls, and injuries. Hypotension
is most likely to occur with administration
of the phenothiazine depress cardiac
repolarization, as reflected in the QT
interval corrected for heart rate (QTc)
Clozapine has rarely been associated
with myocarditis and cardiomyopathy.
risk of stroke among elderly patients
treated with risperidone and olanzapine
2-ADVERSE NEUROLOGICAL
EFFECTS

Extrapyramidal motor system, occur by

high-potency D2-receptor antagonists
(tricyclic piperazines and
butyrophenones)
 3-WEIGHT GAIN AND METABOLIC
EFFECTS
Clozapine and olanzapine; somewhat less
with quetiapine; even less with fluphenazine,
haloperidol, and risperidone
4-BLOOD DYSCRASIAS4-

Mild leukocytosis, leukopenia, and

eosinophilia occurs with clozapine and
less often with phenothiazines
5-SKIN REACTIONS

Phenothiazines, including urticaria or

dermatitis.
 6-GI AND HEPATIC EFFECTS

Jaundice, typically occurs with

chlorpromazine
7-INTERACTIONS WITH OTHER
DRUGS
Chlorpromazine increases the miotic and
sedative effects of morphine and may
increase its analgesic actions.
The antimuscarinic action of clozapine
and thioridazine can cause tachycardia
and enhance the peripheral and central
effects (confusion, delirium) of other
anticholinergic agents, such as the
tricyclic antidepressants and
antiparkinson agents.
 Potentiate the effect of medically
prescribed sedatives and analgesics,
alcohol, nonprescription sedatives and
hypnotics, antihistamines, and cold
remedies.
REFERENCES :

Goodman and Gillmans manual of

Pharmacology and Therapeutics