NEUROLEPTICS

ANTI-PSYCHOTICS

PREPARED BY:
SABIN SHRESTHA
M-PHARM (CHEMISTRY)
[email protected]
 SYLLABUS:
Classify Phenothiazeines.
Describe the SAR of Phenothiazeines.
Discuss about the structure, MOA and properties of Promazine
hydrochloride, Chlorpromazine hydrochloride, Triflupromazine,
Prochlorperazine maleate, Trifluoperazine hydrochloride.
Chlorprothixene (Loxapine succinate, Clozapine).
Fluro buterophenones (Haloperidol, Droperidol, Risperidone).
Beta amino ketones (Molindone hydrochloride) and Benzamides
(Levosulpride).
ANTIPSYCHOTICS OR NEUROLEPTIC OR
TRANQUILLIZER:
 positive symptoms of
psychosis in schizophrenia:

The mesocorticolimbic
pathway originates through
the VTA and passes through
the amygdala, nucleus
accumbens, and
hippocampus. These
functions are relative to
memory, emotional
regulation, motivation, and
reward.
NEGATIVE AND COGNITIVE
SYMPTOMS OF SCHIZOPHRENIA:

The mesocortical pathway transmits

dopamine from the VTA to the prefrontal
cortex.
Schizophrenia is a mental disorder
characterized by continuous or relapsing
episodes of psychosis. Major symptoms
include hallucinations (typically hearing
voices), delusions, and disorganized
thinking. Other symptoms include social
withdrawal, and flat affect.
Controls motor movements
Hypo →Parkinson’s disease
Hyper → chorea, dyskinesias
and tics.

The nigrostriatal pathway

transmits dopaminergic
neurons from the zona
compacta of the substantia
nigra to the caudate nucleus
and putamen.
The tuberoinfundibular
pathway transmits dopamine
from the hypothalamus to the
pituitary gland.

This pathway controls the

secretion of certain hormones,
including prolactin, from the
pituitary gland.
 positive symptoms of negative and cognitive
psychosis in schizophrenia symptoms of schizophrenia

Controls motor movements

Hypo →Parkinson’s disease
Hyper → chorea, dyskinesias and tics
 ANTIPSYCHOTICS OR NEUROLEPTIC OR
TRANQUILLIZER:
 Antipsychotics, also known as
neuroleptics, are a class of
psychotropic medication primarily
used to manage psychosis
(hallucinations, delusions, disorder
thoughts)
 They are also the mainstay together
with mood stabilizers in the
treatment of bipolar disorder.
 INTRODUCTION
 Tranquillizers are used primarily for the treatment
of symptoms of mental diseases.
 They are used in the symptomatic treatment of
psychosis, such as schizophrenia and psychosis.

Schizophrenia can be divided into two types:

 Positive symptoms: are those that are not
normally found in healthy individuals,
including hallucinations, delusions, and thought
disorder.
 Negative symptoms: represent the loss of
qualities normally present in healthy
individuals, including impoverishment of
thought, blunted emotion, attention deficit, and
lack of motivation.
 GENERAL MODE OF ACTION

 All antipsychotics except cloazapine have

potent dopamine (D2) receptor blocking action.

 Clozapine and other atypical antipsychotics

have significant 5-HT2 and α1 blocking action
and are relatively selective for D4 receptor.
CHEMICAL CLASSIFICATION
CLASSIFICATION
CHEMICAL CLASSIFICATION
PHENOTHIAZINE DERIVATIVES:
 CHEMICAL CLASSIFICATION
BENZODIAZEPINES DERIVATIVES:

OLANZAPINE CLOZAPINE QUETIAPINE

CHEMICAL CLASSIFICATION
FLURO BUTYROPHENONES DERIVATIVES:
CHEMICAL CLASSIFICATION
RAUWOLFI A ALKALOIDS DERIVATIVES:
CHEMICAL CLASSIFICATION
THIOXANTHINES DERIVATIVES:
CHEMICAL CLASSIFICATION
MISCELLANEOUS DERIVATIVES:

ARIPIPRAZOLE
PHENOTHIAZINES
 PHENOTHIAZINES:
Promazine:
Properties and uses: It is a white or almost white crystalline
powder, slightly hygroscopic in nature. It is well soluble in
water, alcohol, and methylene chloride. It has low clinical
potency, medium extrapyramidal toxicity, high sedative effect,
and high hypotensive action. It is used as dopamine receptor
antagonist and neuroleptic.

Storage: It should be stored in well-closed airtight container

and protected from light.

Dosage forms: Promazine injection B.P., Promazine oral

suspension B.P., Promazine tablets B.P.
 PHENOTHIAZINES:
Chlorpromazine:

Properties and uses: It is a white or almost white crystalline

powder, freely soluble in ethanol and well soluble in water.
It is used as dopamine receptor antagonist and neuroleptic.

Storage: It decomposes on exposure to air and light, hence, it

should be stored in well-closed airtight containers and protected
from light.

Dose: The usual dose is 75–80 mg daily in divided doses for

psychiatric patients. As an antiemetic, it is 25–50 mg.

Dosage forms: Chlorpromazine HCl injection I.P. B.P.,

Chlorpromazine tablets I.P., B.P., Chlorpromazine oral solution
B.P.
 PHENOTHIAZINES:
Triflupromazine:
Properties and uses: It is a white to pale yellow, crystalline
powder, hygroscopic in nature, soluble in alcohol and freely
soluble in water. It has lower sedative and hypotensive
effects than chlorpromazine, and greater milligram potency
as an antipsychotic, used as dopamine receptor antagonist
and
neuroleptic.

Storage: It should be stored in well-closed airtight container

and protected from light.

Dosage forms: Trifluoperazine HCl injection I.P.,

Trifluoperazine HCl tablets I.P., Trifluoperazine tablets B.P.
PHENOTHIAZINES: Prochlorperazine
PHENOTHIAZINES: Chlorprothixene
PHENOTHIAZINES:
Prochlorperazine:
Properties and uses: It is a white or pale yellow crystalline powder,
well soluble in water and alcohol. It is more potent on a milligram basis
than its alkylamino counterpart, chlorpromazine because of the high
prevalence of extra-pyramidal symptom (EPS). It is mainly used for
anti-emetic effect, not for its anti-psychotic effect, used as dopamine
receptor antagonist and neuroleptic.
Storage: It should be stored in well-closed airtight container and
protected from light.
Dose: For nausea and vomiting: Adult: As mesylate: 12.5 mg by deep
IM. If required, may give further doses via oral route. For psychosis:
Adult: As mesylate: 12.5–25 mg by deep IM injection twice/day or
thrice/day.
Dosage forms: Prochlorperazine maleate tablets I.P., Prochlorperazine
mesylate injection I.P., Prochlorperazine tablets B.P., Prochlorperazine
buccal tablets B.P.
 SAR OF PHENOTHIAZINES
Activity of phenothiazines is determined by the following:

 1. Nature of alkyl side chain at C-10.

 2. Amino group of side chain.
 3. Substituents on aromatic ring.
 SAR OF PHENOTHIAZINES:
Nature of alkyl side chain at C-10:
 Potency is maximum when there is three carbon between two ‘N’
atom for example promazine.

 Introduction of methyl group at C-1 decreases antipsychotic

activity.

 Addition of –CH3 at C-2 or C-3 has very little effect on activity.

SAR OF PHENOTHIAZINES:
Amino group of side chain:
 3° nitrogen shows maximum potency and 2° or 1° nitrogen shows
reduced or abolished activity for example triflupromazine.
 N-alkylation with more than one carbon decreases activity.
 Activity is decreased when dimethylamino group is replaced by
pyrolidinyl, morpholinyl, or thiomorpholinyl groups. For example
Prochlorperazine.

Substituents on aromatic ring:

 Substitution at C-2 position is optimal for neuroleptic activity. In
general, potency at different positions increases in the following order
1 < 4 < 3 < 2. Potency of the various groups increase in the following
order OH < H< CN < CH3 < Cl < CF3.
 Oxidation of the Sulphur at 5th position of antipsychotic
phenothiazine decreases activity.
 Thioxanthines: Chlorprothixene:
 Properties and uses: It is a white
or almost white crystalline
powder, slightly soluble in
methylene chloride, and soluble in
water and alcohol. It is used in the
treatment of acute and chronic
schizophrenia, psychotic and other
conditions in which anxiety,
agitation, and tension
predominate.

 Storage: It should be stored in

well-closed airtight container and
protected from light.
 Dibenzoxazepinones: Loxapine succinate:
Properties and uses:

 Exist as white to off-white crystalline powder,

slightly soluble in water or alcohol.

 It may give rise to possible anticholinergic and

antiadrenergic activity.

 It is used for symptomatic control of

schizophrenia.

Dose: The usual dose is 20–250 mg/day.

 Dibenzodiazepines: Clozapine:

Properties and uses:

 It is a yellow crystalline powder, dissolves in dilute acetic acid, insoluble in water, freely
soluble in methylene chloride, and soluble in alcohol.
 It has more affinity for D1 and less for D2 dopamine receptors.
 It may have its unique profile due to the blockade of D1 receptors and M1 muscarinic activity.
 Other adverse side effects include drowsiness, dizziness, and dose related seizures.
 It is effective in individuals suffering from disorganization. For example, loose associations,
inappropriate affect, incoherence, and reduction in rational thought processes.
Dose: For Schizophrenia: Adult: 12.5 mg 1–2 times on day 1 followed by 25 mg 1–2 times on day
2 increased gradually in increments of 25–50 mg up to a daily dose of 300 mg with 14–21 days.
 FLUORO-BUTYROPHENONES DERIVATIVES:
HALOPERIDOL:
 HALOPERIDOL:
Properties and uses:
 It is useful in the management of psychotic reactions, hostility, and hyperactivity.
 Haloperidol is an effective neuroleptic and also possesses antiemetic properties.

Storage:
 It decomposes on exposure to air and light, hence, it should be stored in well-closed
airtight containers and protected from light.

Dose:
 For restlessness and confusion: Adult 1–3 mg every 8 h.
 For psychoses: Adult: 0.5–5 mg twice or thrice/ day, may increase up to 100 mg daily in
severe or resistant cases.
 FLUORO-BUTYROPHENONES DERIVATIVES:
Droperidol:
 DROPERIDOL:
Properties and uses:
 It is a white or almost white powder insoluble in water, sparingly soluble in alcohol,
freely soluble in dimethylformamide and in methylene chloride.
 The drug exhibits relatively low therapeutic potency, medium extrapyramidal toxicity,
high sedative effect, and above all high hypotensive action.
 It is frequently used in combination with the narcotic agents pre-anesthetically.
 It is a neuroleptic used as an adjunct to anaesthesia to produce sedation and reduce
incidence of nausea and vomiting. Also used as β1-adrenoceptor agonist α-adrenoceptor
agonist.

Storage: It should be stored in well-closed airtight container and protected from light.

Dosage forms: Droperidol injection B.P., Droperidol tablets B.P.

 SAR OF BUTYROPHENONES:

 Antipsychotic activity is seen when Ar group is an aromatic system in which fluoro-

substituents at para-position enhances the activity.
 When X = carbonyl ( C = O) optimal activity is seen.
 When n = 3 activity is optimal, longer, or shorter chains decrease the activity.
 3 degree nitrogen is required for highest activity.
 Ar1 group should be an aromatic and is needed; it should be attached directly to the fourth
position.
 Presence of Electron donating group at para position increase the neuroleptic activity.
Risperidone:
 Risperidone:
Properties and uses:
 It is a white or almost white powder, dissolves in dilute acid solutions, insoluble in water, freely
soluble in methylene chloride, sparingly soluble in ethanol.
 It is a typical antipsychotic and neuroleptic.
 Its adverse effects include nasal congestion, orthostatic hypotension, insomnia, and possible EPS.
Causes more EPS than other atypical agents. May cause weight gain and an increased tendency for
glucose intolerance.
 Risperidone has structural features of hybrid molecules between butyrophenone and trazodone. It is a
typical antipsychotic, effective against the negative symptoms of schizophrenia.

Storage: It should be stored in well-closed airtight containers and protected from light.

Dose: For Schizophrenia: Adult: Initially, 2 mg daily, may increase to 4 mg daily on the second day,
adjusted further in increments or decrements of 1–2 mg daily at weekly intervals. Doses may be given in
1–2 divided doses. Maintenance: 4–6 mg daily. Maximum: 16 mg/day. For elderly: Initially, 0.5 mg two
times a day gradually increased in increments of 0.5 mg twice a day. Maintenance: 1–2 mg twice a day.
Beta amino ketones (Molindone hydrochloride)
 Beta amino ketones (Molindone hydrochloride):
Properties and uses:

 Exists as white crystals, freely soluble in water or alcohol, it is a potent antipsychotic as

trifluoperazine and all the side effects resemble those of the phenothiazines.

 It is used in the treatment of schizophrenia and other psychosis.

Dose: The usual dose is 15–25 mg/day.

Benzamides (Levosulpride):
 Benzamides (Levosulpride):
 Levosulpiride is a sulpiride isomer that exerts its prokinetic action through a dual mechanism: 1)
as a D(2) dopamine receptor antagonist and 2) as a serotonin 5HT(4) receptor agonist, conferring
this drug with a cholinergic effect.

 Levosulpiride is a substituted benzamide derivative and a selective dopamine D2 antagonist with

antipsychotic and antidepressant activity.

 Levosulpiride is an antipsychotic. It is used to treat depression, digestion problems, GERD,

psychological disorders, IBS, anxiety disorder, vertigo, hallucinations, schizophrenia, and regular
heartburn.
THANK YOU