Psychosis is a severe mental disorder characterized by a loss of contact with reality through disturbed perceptions, thoughts, emotions and behavior. Common symptoms include delusions, hallucinations, incoherent speech and inappropriate behavior. The document discusses various types of psychosis and drugs used to treat psychotic illnesses. Antipsychotics like chlorpromazine, haloperidol and sulpiride work by blocking dopamine receptors in the brain to reduce psychotic symptoms. The mechanisms of action and uses of different classes of antipsychotics including phenothiazines, butyrophenones, and benzamides are described.

1. PREPARED BY:
MS. JYOTI RANI
DRUGS ACTING ON CNS-
ANTI-PSYCHOTICS
MS. JYOTI RANI
ASSISTANT PROFESSOR
BUEST,SPES

2. What is Psychosis?
 The word Psychosis is derived from two Greek words
psyche meaning mind/soul and osis means
“abnormal condition or derangement”.
 Psychosis is a severe mental disorder in which
thought and emotions are so impaired that contact is
lost with external reality.
lost with external reality.
 Symptoms may include delusions and hallucinations.
 Other symptoms may include incoherent speech and
behavior that is inappropriate for the situation.
 There may also be sleep problems, social withdrawal,
lack of motivation, and difficulties carrying out daily
activities.

3. Types of Psychosis
 (a) Acute and chronic organic brain syndromes (cognitive disorders) Such as delirium and
dementia with psychotic features; such as confusion, disorientation, defective memory disorganized
thought and behaviour.
 (b) Functional disorders No underlying cause can be defined; memory and orientation are mostly
retained but emotion, thought, reasoning and behaviour are seriously altered.
 (i) Schizophrenia (split mind), i.e. splitting of perception and interpretation from reality—
 (i) Schizophrenia (split mind), i.e. splitting of perception and interpretation from reality—
hallucinations, inability to think coherently.
 (ii) Paranoid states with marked persecutory or other kinds of fixed delusions (false beliefs) and loss
of insight into the abnormality.
 (iii) Mood (affective) disorders The primary symptom is change in mood state; may manifest as:
Mania—elation or irritable mood, reduced sleep, hyperactivity, uncontrollable thought and speech,
may be associated with reckless or violent behaviour.
Depression—sadness, loss of interest and pleasure, worthlessness, guilt, physical and mental
slowing, melancholia, self-destructive ideation. A common form of mood disorder is bipolar disorder
with cyclically alternating manic and depressive phases. The relapsing mood disorder may also be
unipolar (mania or depression) with waxing and waning course.

4. Drugs used in Psychotic illness
 Antipsychotics drugs are used in the treatment of psychiatric disorders i.e.
abnormalities of mental function. The psychoactive drugs render the patient
calm and peaceful by reducing agitation and anxiety.
 Psychoactive drugs does not cure mental disorders but the available drugs do
control most symptomatic manifestations and behavioral deviances, facilitate
the patient’s tendency toward remission and improve the capacity of patient for
the patient’s tendency toward remission and improve the capacity of patient for
social, occupational, and familial adjustment.
 Synonyms:, Neuroleptics, Psychoactive or psychotropic drugs.

5. Classification
• Phenothiazeines Promazine hydrochloride,
Chlorpromazine hydrochloride*,
Thioridazine hydrochloride,
Piperacetazine hydrochloride,
Prochlorperazine maleate,
Trifluoperazine hydrochloride.
• Ring Analogues of Chlorprothixene
• Ring Analogues of
Phenothiazeines
Chlorprothixene
Thiothixene,
Loxapine succinate,
Clozapine.
• Butyrophenones Haloperidol,
Droperidol,
Risperidone
• Beta amino ketones Molindone hydrochloride
• Benzamides Sulpieride

6. PHENOTHIAZINES
 Phenothiazines are chemically constituted by a lipophilic, linearly fused
tricyclic system having a hydrophilic basic amino alkyl chain. The following is
the general structure of antipsychotic drugs.
4
5
6
 Phenothiazines are the derivatives of phenothiazine tricyclic heterocyclic
moiety. The central ring possesses nitrogen and sulphur heteroatom
N
H
S
1
2
3
6
7
8
9
10

7. SAR of Phenothiazeines
1. Substitution at the second position of phenothiazine nucleus by electron withdrawing substituent
increases antipsychotic activity. Ex: Chlorpromazine (chlorine)
2. Substitution at the 3-position of phenothiazine nucleus increases antipsychotic activity than
unsubstituted derivatives but not by substitution at 2-position.
3. Substitution at 1 and 4 positions of phenothiazine nucleus reduces the antipsychotic activity.
4. Phenothiazines must have a nitrogen-containing side-chain substituent on the ring nitrogen for
4. Phenothiazines must have a nitrogen-containing side-chain substituent on the ring nitrogen for
antipsychotic activity. The ring and side-chain nitrogen must be separated by a three carbon chain.
5. The side chains are either aliphatic, piperazine, or piperidine derivatives. Piperazine side chains
confer the greatest potency and the highest pharmacological selectivity.
6. Fluphenazine and long chain alcohols form stable, highly lipophilic esters, which possess markedly
prolonged activity.
7. Substitution on the side chain with a large or polar groups such as phenyl, dimethylamino or
hydroxyl results in loss of tranquilizing activity.
8. The phenothiazines produce a lesser degree of central depression than the barbiturates or
benzodiazepines.

8. CHLORPROMAZINE
Chlorpromazine is classified as a low-potency typical antipsychotic
MOA. Its mechanism of action is not entirely clear but believed to
be related to its ability as a dopamine antagonist. It also has anti-
serotonergic and
Anti-histaminergic properties.
Synthesis. It is synthesized by the cyclization of
3- chlorodiphenylamine with sulphur in presence of small amount of
iodine as catalyst and then with 3-chloro-N,N-dimethylpropan-1-amine in
the presence of base sodium amide.
Uses. 1. Chlorpromazine is used in the management of psychotic conditions. It also controls
excitement, aggression and agitation.
2. It has antiemetic, antipruritic, anti-histaminic and sedative properties.

9. PROMAZINE
Promazine
N
N
S
N,N-dimethyl-3-(10H-phenothiazin-
10-yl)propan-1-amine
It is a medication that belongs to the phenothiazine class of
antipsychotics. An older medication used to treat
schizophrenia but seldom used now.
Uses
1. Promazine has antipsychotic properties
2. It is also used to control nausea and vomiting
THIORIDAZINE
Thioridazine
S
N S
N
10[2-(Methyl-2-piperidyl)
ethyl]-2-(methylthio)-
phenothiazine
 It is a first generation antipsychotic drug belonging to
the phenothiazine drug group and was previously widely
used in the treatment of schizophrenia and psychosis.
 The branded product was withdrawn worldwide in 2005
because it caused severe cardiac arrhythmias .
 Its actions and uses are very much identical to those of
chlorpromazine

10. PROCHLORPERAZINE
N
N
N
S
Cl
Chemistry. Prochlorperazine is a phenothiazine derivative
associated with piperazine.
MOA. Prochlorperazine is analogous to chlorpromazine; both of these
agents antagonize dopaminergic D2 receptors in various pathways of
the central nervous system. This D2 blockade results in
antipsychotic, antiemetic and other effects.
Uses
Prochlorperazine
2-chloro-10-(3-(4-methyl
piperazin-1-yl)propyl)-
10H-phenothiazine
Uses
1. Prochlorperazine is an antipsychotic and tranquilizing agent. It is
used to treat various
psychiatric disorders such as schizophrenia, mania, involution
psychoses, senile and tonic psychoses.
2.It also has antiemetic properties

11. TRIFLUOPERAZINE
Chemistry. Trifluoperazine is a fluorinated phenothiazine
derivative. It also possesses a piperazine nucleus.
MOA. Trifluoperazine has central antiadrenergic,
antidopaminergic, and minimal anticholinergic effects.
It is believed to work by blockading dopamine D1 and D2
receptors, relieving or minimizing such symptoms of
schizophrenia as hallucinations, delusions, and disorganized
schizophrenia as hallucinations, delusions, and disorganized
thought and speech.
Uses. Trifluoperazine has been used to control psychotic
disorders.
It is effective to control excessive anxiety, tension,
aggressiveness and agitation.

12. RING ANALOGUES OF PHENOTHIAZEINES
CLOZAPINE
It is a dibenzodiazepine derivative.
MOA. the ‘drug’ specifically blocks
dopamine D-2 and D-1 receptors essentially
in the mesolimbic* and mesocortical brain
regions, which may also involve covertly
and overtly cholinergic, seretonergic and
LOXAPINE
The drug is a member of the dibenzoxazepine
class and structurally related to clozapine. Its
antipsychotic actions are similar to those of
chlopromazine.
MOA. it has significant potency at the
5HT2A receptor and D-2 receptor.
and overtly cholinergic, seretonergic and
noradrenergic systems.

13. BUTYROPHENONES -[SAR]
1. The antipsychotic properties of butyrophenones is due to the presence of the following
general structure :
2. Intact carbonyl group of butyrophenones is necessary for antipsychotic activity.
Replacement of carbonyl group by functional groups such as CH(OH), —CH (X), —O—,
—S — , —SO2— etc., decreases activity.
3. All butyrophenones must have a fluorine atom in para-position of aryl group. The
antipsychotic activity is markedly decreased by introducing H, Cl, CH3, OCH3 or Ar
instead of fluorine at para position in aryl group.
4. Propylene bridge is required for antipsychotic properties. Shortening or lengthening
or branching of propylene bridge decreases antipsychotic activity.
5. Incorporation of basic nitrogen into 6-membered rings is important for CNS depressant
activity. Ex: Haloperidol, Droperidol.

14. HALOPERIDOL
Chemistry. Haloperidol is a butyrophenone
derivative with antipsychotic properties that
has also been found as effective in lowering
levels of hyperactivity, agitation, and mania.
MOA. The mechanism of action of haloperidol has not been entirely elucidated, but has
been attributed to the inhibition of the transport mechanism of cerebral monoamines,
particularly by blocking the impulse transmission in dopaminergic neurons. Peak plasma
levels of haloperidol reaches within 2 to 6 hours of oral administration.
levels of haloperidol reaches within 2 to 6 hours of oral administration.
Uses.
1. Haloperidol is effective in the management of hyperactivity, agitation, and mania.
2. Haloperidol is an effective neuroleptic and also possesses antiemetic properties ; It has
a marked tendency to provoke extrapyramidal effects and has relatively weak alpha-
adrenolytic properties.
3. It may also exhibit hypothermic and anorexiant effects and potentiates the action of
barbiturates, general anesthetics, and other CNS depressant drugs.

15. BETA AMINO KETONES
N
H
O
N
O
MOLINDONE
Molindone, It is sometimes described as a typical
antipsychotic, and sometimes described as
an atypical antipsychotic.
3-Ethyl-2-methyl-5-(morpholin-4-yl
methyl)-1,5,6,7-tetrahydro-4H-
indol-4-one
H
Molindone
MOA. It works by blocking the effects
of dopamine in the brain, leading to diminished
symptoms of psychosis. It is rapidly absorbed when
taken orally.
Use. in the treatment of schizophrenia.

16. BENZAMIDES
SULPIRIDE
Chemistry. It is an atypical antipsychotic
medication of the benzamide class.
MOA. Sulpiride is a selective dopamine D2 and D3
receptor antagonist.
receptor antagonist.
Uses. is used mainly in the treatment of psychosis
associated with schizophrenia and major depressive
disorder, and
sometimes used in low dosage to treat anxiety and
mild depression.

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