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Anti-Psychotic Drugs

Dr. Nilesh Patel


M.Pharm, MBA, PhD
Assistant Professor
B. K. Mody Government Pharmacy
College, Rajkot
Antipsychotic drugs
Antipsychotic drugs (also called
neuroleptics or major tranquilizers) are
used primarily to treat schizophrenia (a
biologic illness), but they are also effective in
other psychotic states, including manic
states with psychotic symptoms such as
grandiosity, paranoia, and hallucinations,
and delusions.
Antipsychotic drugs

 Antipsychotic drugs are not curative and


do not eliminate the chronic thought
disorder, but they often decrease the
intensity of hallucinations and delusions
and permit the person with
schizophrenia to function in a
supportive environment.
Antipsychotic drugs
 Psychoses: These are severe psychiatric illness
with serious distortion of thought, behavior, capacity
to recognize reality and of perception (delusions and
hallucinations). There is inexplicable misperception
and misevaluation; the patient is unable to meet
the ordinary demands of life .
Antipsychotic drugs
 Psychoses: These are severe psychiatric illness
with serious distortion of thought, behavior, capacity
to recognize reality and of perception (delusions and
hallucinations). There is inexplicable misperception
and misevaluation; the patient is unable to meet
the ordinary demands of life .
History of Antipsychotic drugs
 Antipsychotic drugs have been used in Western
medicine for more than 50 years.
 Chlorpromazine (1952) and Reserpine were the
first drugs found to be useful in schizophrenia.
 Tricyclic and MOA inhibitor antidepressant in
1957-58.
 Major novel antipsychotics are selective serotonin
reuptake inhibitor and it has been introduced in
1980s.
 Little attention was paid to Cade's report in 1949
that Lithium could be used for excitement and
mania: its effective use started in the 1960s and
now it has a unique place in psychiatry.
Classification of antipsychotic drugs
Classification of antipsychotic drugs
Phenothiazine is an organic compound that occurs in
various antipsychotic and antihistaminic drugs.
It has the formula S(C6H4)2NH.
This yellow tricyclic compound is soluble in acetic acid,
benzene, and ether. The compound is related to the
thiazine-class of heterocyclic compounds.
Derivatives of the parent compound find wide use as drugs.
Numbering:-

6 5 4
S
7 3

8 10
2
9 N 1

History:-
•During second world war, a number of phenothiazine derivatives were
Prepared in the laboratories of the French pharmaceutical
manufacturer,‘RHONE POULENC’ in Paris
•Promazine possess strong anti-histaminic activity.
•Synthesis of chlorpromazine, a very large number of phenothiazine
derivatives.
•Possessing pharmacological actions like sedative and hypnotic
potent antihistaminic, tranqulizer, analgesic , urinary antiseptic
Modifications of the alkyl side chain:-
1) Maximum potency is retained when there is a three carbon spacing
between the basic amino group and the nitrogen of the phenothiazines
nucleus.
2) Substitution on the propylene chain of 10-(3-aminopropyl) phenothiazine
may also influence antipsychotic potency.

CH2CH2CH2 N(CH3)2
1 2 3

a) Methyl group at 1 position


a
b) Cyclopropane ring at 1 position
c) Oxygen introduced at 1-position
Modification of basic amino group:-
a) effect of 3o amino group
b) alkylation of basic amino group
c) replacement of dimethylamino group of chloropromazine
i) with pyrrolidine, morpholinyl
ii) with piperidyl, piperazine
eg:-
S

N COCH2CH3

(CH2)3 N N CH2CH2OH

Carphenazine
d) Bridged piperidine derivatives :retains nueroleptic property

N Cl

(CH2)3 N

Bridged piperidine derivative

e) Introduction of hydroxyl, methyl, groups at 4 position:-increases potency

N Cl

(CH2)3 N OH
f) Esterified with long chain fatty acids to produce slowly absobed, long
acting,
Lipophilic prodrugs
S

Ex:-
N CF3

(CH2)3 N N CH2CH2OCO(CH2)8CH3

Fluphenazine decanoate

Phenothiazine ring substitution:-


a) Substitution at 2 position is optimal for neuroleptic potency.
potency increases in the following order of position of ring
substitution:-
1<4<3<2
b) 2-substitution of the phenothiazine nucleus increases the neuroleptic
potency
in the following order:-
OH<H<CN<CH3<Cl<CF3
c) Oxidation of the 5 sulfur of antipsychotic phenothiazines decreases
activity
d) Aza-phenothiazines are more effective agents.

N N

(CH2)3 N(CH3)2
1-Azophenothiazine
Phenothiazines synthesis:-

(CH2)2N(CH3)2
O CH2N(CH3)2 O

benzodioxanes ethaniolamines

H CH3
N CH2CH2N
CH3
N CH2CH3
CH2CH2N(CH3)2 ethylenediamines
diethazine

S
S

N
N Cl
CH2CHN(CH3)2
(CH2)3N(CH3)2
CH3
Chlorpromazine
promethazine
Treatment of appropriate diphenylamine with a mixture of sulfur and iodine

S
I2
N
H N
H
DIPHENYLAMINE
PHENOTHIAZINE
Promethazine:-

Chemically, promethazine hydrochloride appears as a


white to faint yellow crystlline powder that is practically
odorless.

Promethazine as the hydrochloride salt is freely soluble


in water and somewhat soluble in alcohol. Promethazine
is a chiral compound, occurring as a mixture of
enantiomers
Chlorpromazine:-
First synthesized on December 11, 1950, chlorpromazine was the first
drug developed with specific antipsychotic action, and would serve as
the prototype for the phenothiazine class of drugs, which later grew to
comprise several other agents.
S
S/I2

N Cl
N Cl

H H
3-chlorodiphenylamine 2-chlorophenathiazine
1.NaNH2
2.Cl(CH2)3N(CH3)2

N Cl

(CH2)3N(CH3)2

Chloropromazine
Piperazine derivatives:-
Synthesis of prochlorperazine and trifluperazine:-

S
Properties:-
S
1.NaH Pale yellow crystalline powder,
2.Br(CH2)3Cl with slightly bitter taste
N X
H N X m.p:198-2030c
X=Cl,CF3,CO(CH2)2CH3
(CH2)3Cl It is more potent than
1.NaH
2.Cl(CH2)3N NCH3
chlorpromazine
HN NCH3
It has high prvelance of extra
pyramidal effects and therfore
S S mainly used as antiemitic.

N CO(CH2)2CH3 N X

(CH)3Cl (CH2)3

N N

N N

CH3 CH3
X=Cl;prochlorperazine
Butaperazine =CF3:Trifluperazine
Hydroxyethyl piperazine derivatives:-
O
O
O H2C CH2
C N N CH2CH2OH
C N NH
C2H5O
C2H5O

H2O
HN N CH2CH2OH

S
S
HN N CH2CH2OH

N X
N X
(CH2)3N N CH2CH2OH
(CH2)3Cl

X=Cl,CF3,CH3CO,C2H5CO
Fluphenazine hydrochloride:-
Properties:-
•It is a white crystalline powder.
•It is soluble in water and alcohol and practically insoluble in ether.
•The drug is more potent, exhibits a more prolonged duration of action,
is less sedative.
Thioridazine:- Synthesis:-
1.LiPh CH3I
2.HCHO
N CH3 N CH2CH2OH N CH2CH2OH
PICOLINE
CH3

Cat/H2 SOCl2

N CH2CH2Cl
N CH2CH2OH
CH3
CH3
2-(--Methyl-1-piperidyl)
ethyl chloride
S
S
CH3SNa

N Cl
N SCH3
H
H
S

N CH2CH2Cl
CH3 N SCH3

CH2CH2

Thioridazine N

H3C
Properties:-

It is a slight yellow powder with a bitter taste.


It is freely soluble in water, chloroform and alcohol and insoluble in ether.

Uses:-
it is effevtive for relif of symptoms of neurotic depressive reactions

Metabolism :-
It is metabolised to active drug mesoridazine
generic name R2 R1
H
(A)Propyl (CH2)3N(CH3)2.HCl
dialkylaminosidechain:
i)Promazine .HCl
II)Chlorpromazine Cl (CH2)3N(CH3)2.
iii)Triflupromazine CF3 (CH2)3N(CH3)2.
(B)Alkyl piperidyl side H3C

chain: N

i)Thioridazine SCH3
(CH2)2
6 5 4
S
7 3
H3C

N 8 10
2
ii)Mesoridazine O SCH3 (CH2)2
9 N 1 R2

R1

©Propyl piperizine side


chain (CH2)3N NCH3
i)Prochlorperazine Cl

ii)fluphenazine CF3 (CH2)3N N CH2CH2OH


Phenothiazines
Pharmacologic effects and mechanism:
(1) CNS:
a. neuroleptic effect--- D1, D5---D1-like receprtors
D2-4------D2-like receptors
Antipsychotic drugs probably owe their therapeutic effects
mainly to blockade of D2-receptors (lies in midbrain-cortex
and midbrain-limbic system ).

b. antiemetic effect--- inhibit chemoreceptor trigger zone or


directly depress the medullary vomiting center.
c. temperature-regulating effect--- produce hypothermia
(2) Autonomic nervous system:
Block α-adrenergic and M-Cholinergic receptors and result in hypotension, dry
mouth, constipation and blurred vision.
(3) Endocrine system:
Increase the release of prolactin and decrease corticotropin release and secretion
of pituitary growth hormone.
Therapeutic uses
• (1) treatment of psychotic disorders:
schizophrenia, mania, paranoid states, alcoholic
hallucinosis.

• (2) treatment of nausea and vomiting of certain


causes.

• (3) anesthesia in hypothermia and artificial


hibernation (used with pethidine and
promethazine).
Adverse Effects:
• Extrapyramidal motor disturbances:
(1)Parkinson-like symptoms;
(2) akathisia;
(3) acute dystonias.
Treatment: anticholinergic

• Other side-effects:
• (dry mouth, constipation, blurred vision,
hypotension, etc.) are due to block of other
receptors, particularly α–adrenoceptors and
muscarinic ACh receptors.

Contact dermatitis, blood dyscrasias, obstructive


jaundice sometimes occurs with phenothiazines.
Adverse Effects

Tardive dyskinesia :
Comprises mainly involuntary movements of face and tongue, but
also of trunk and limbs, appearing after months or years of
antipsychotic treatment. It may be associated with proliferation
of dopamine receptors (possibly presynaptic) in corpus striatum.
Treatment is generally unsuccessful.

Cardiac toxicity and endocrine effects.

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