Antipsychotics 1

ANTIPSYCHOTICS I
PHAM 4159 - Dr. F. Ndubi

Introduction:
 Most widely used class of drugs in treating psychosis is
the neuroleptics/1st generation antipsychotics.
Neurolepsis translates to “take hold” (lepsis) of CNS.
 Typical neuroleptics act mainly by biochemical and clinical

antagonism of dopamine D2 receptors, resulting often in
debilitating extrapyramidal side effects.
 Atypical antipsychotics usually act via other mechanisms

instead of/in addition to dopamine D2 receptor blockade,
causing less marked EP s/e.
Introduction..
 Generally, 1st generation antipsychotics benefit patients
with schizophrenia or other psychotic illness marked by
agitation, aggressive/impulsive behavior and impaired
reasoning.
 Provide calming, mood-stabilizing and anti-hallucinatory

effect.
 Beneficial psychiatric impact is unquestioned, in spite of

sometimes severe EP side effects.
Classification:
 Classified both chemically and by predominant MoA.
 1st generation neuroleptics – Phenothiazines,

Butyrophenones and Thioxanthenes.
 2nd generation antipsychotics – Dibenzodiazepines

(Benzazepines), Benzisothiazoles and Benzisoxazoles.
Lower potential for EP s/e.
 Others – Indoles, Indolones and miscellaneous

antipsychotics.
Phenothiazines
Chemistry and properties of the phenothiazines.

Introduction:
 Classical antipsychotic agents, chlorpromazine is the
prototype.
 Achieve antipsychotic activity by direct and complex

interaction with dopamine D2 receptors in the
mesolimbic and mesocortical systems.
 Phenothiazine nucleus first synthesized in 1883, no

antipsychotic activity. Development led to synthesis of
chlorpromazine in the 1950s, and further derivatives.
Closely related to Promethazine, antihistamine.
Chemistry:
Phenothiazines:
Side effects:
 Sedation, hypotension and sexual dysfunction due to
Histamine H1 receptor blockade.
 Antimuscarinic s/e – Cardiac, ophthalmic, GI and

genitourinary effects.
 Extrapyramidal s/e – Acute dystonias (facial grimacing,

torticollis, etc.), akathisia (motor restlessness) and
bradykinesia, rigidity, tremor, masked face and shuffling
gait.
SAR:
 Replacement of phenothiazine N with olefinic C retains
antipsychotic activity (Thioxanthenes).
 Chlorine atom at the C2 position in chlorpromazine is
essential for antipsychotic activity. Removal of chlorine
abolishes activity.
 Replacement of chlorine with other electron-withdrawing
groups retains antipsychotic activity.
 The amine side chain with three carbon atoms separating
the Nitrogen atoms is essential for antipsychotic activity.
 Phenothiazines containing amine side chains with 2 Cs
separating the Nitrogen atoms are predominantly
antihistaminic in nature, e.g. Promethazine.
Pharmacokinetics:
 Readily absorbed from GIT, volume of distribution 20l/kg.
>90% bound to plasma proteins, majorly albumin.
 Metabolized in the liver and kidney by CYP450-mediated

aromatic hydroxylation (position 3 and 7) followed by
glucuronide conjugation (up to 80%). Demethylation and
sulfoxide formation also feasible.
 Excretion – Renal.
 Long half life of up to 30 hours.

Metabolism:
Long-acting neuroleptics:
 Prepared by esterification of terminal –OH group of neuroleptic agents with long chain
fatty acids.
 Resulting esters given as IM depot injections with extended DoA e.g. Fluphenazine
decanoate injxn and Perphenazine enanthate.
Thioxanthenes:
 Prototype is Thiothixene.
 Structurally related to the phenothiazines, and exhibit cis-trans isomerism.
 Activity varies between the two isomeric forms.
 Saturation of the olefinic double bond in Thiothixene leads to reduction of
antipsychotic activity.
Butyrophenones
Chemistry and properties of the butyrophenones.

Introduction:
 Developed in the late 1950s by synthesis of
butyrophenone analogs of Meperidine.
 Butyrophenone analog displayed chlorpromazine-like

neuroleptic activity as well as elimination of analgesic
properties.
 Resulting SAR showed possibility to enhance neuroleptic

activity with complete elimination of analgesic properties.
Butyrophenones..
Propiophenone analog of Meperidine
displayed higher analgesic potency, but
only Butyrophenone analog displayed
neuroleptic properties.
General structure of all butyrophenones

displaying high neuroleptic activity.
Butyrophenones:
Chemistry..?
Haloperidol synthesis:
SAR:
 Attachment of tertiary amino group to C4 of the
butyrophenone skeleton is essential for neuroleptic
activity.
 Lengthening, shortening or branching of the three-carbon

propyl chain reduces neuroleptic potency.
 Replacement of the keto moiety with thioketo, olefinic or

phenoxy groups decreases neuroleptic potency.
 Reduction of keto group reduces potency.

SAR..
 Most potent butyrophenones are those bearing a fluoro
substituent at the para position of the benzene ring.
 Variations are possible at the tertiary amino group with

retention of neuroleptic activity e.g. incorporation into a
substituted piperidine, piperazine or tetrahydropyridine
ring.
 Substitution at the para position of six-membered cyclic

amine ring is essential for activity.
Pharmacokinetics:
 Haloperidol is readily absorbed from GI tract, peak
plasma levels 2-6hr after administration.
 Concentrated in the liver and CNS.
 Metabolized by keto reduction and oxidative deamination.
 Mainly excreted via kidneys, small portion secreted in

bile.
Metabolism of Haloperidol:
Metabolic steps?
Side effects:
 Haloperidol produces more pronounced extrapyramidal
side effects than chlorpromazine due to higher affinity for
D2 receptors.
 Less prominent sedative and autonomic side effects.
 Lower intensity to induce weight gain than

chlorpromazine and second-generation antipsychotics.
Assay methods:
 Chlorpromazine – IR, TLC. Assay by LC or volumetric
titration using PCA.
 Haloperidol – LC. Assay by LC.
 Flupenthixol – UV Spec (230, 264 nm). Assay by LC.
 Fluphenazine – TLC. Assay by NAT with PCA (crystal
violet indicator).
 Trifluoperazine – IR. Assay by UV Spec (256 nm).

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ANTIPSYCHOTICS I

PHAM 4159 - Dr. F. Ndubi

 Typical neuroleptics act mainly by biochemical and clinical

 Atypical antipsychotics usually act via other mechanisms

 Provide calming, mood-stabilizing and anti-hallucinatory

 Beneficial psychiatric impact is unquestioned, in spite of

 1st generation neuroleptics – Phenothiazines,

 2nd generation antipsychotics – Dibenzodiazepines

 Others – Indoles, Indolones and miscellaneous

Chemistry and properties of the phenothiazines.

 Achieve antipsychotic activity by direct and complex

 Phenothiazine nucleus first synthesized in 1883, no

 Antimuscarinic s/e – Cardiac, ophthalmic, GI and

 Extrapyramidal s/e – Acute dystonias (facial grimacing,

 Metabolized in the liver and kidney by CYP450-mediated

 Long half life of up to 30 hours.

Chemistry and properties of the butyrophenones.

 Butyrophenone analog displayed chlorpromazine-like

 Resulting SAR showed possibility to enhance neuroleptic

General structure of all butyrophenones

 Lengthening, shortening or branching of the three-carbon

 Replacement of the keto moiety with thioketo, olefinic or

 Reduction of keto group reduces potency.

 Variations are possible at the tertiary amino group with

 Substitution at the para position of six-membered cyclic

 Concentrated in the liver and CNS.

 Metabolized by keto reduction and oxidative deamination.

 Mainly excreted via kidneys, small portion secreted in

 Less prominent sedative and autonomic side effects.

 Lower intensity to induce weight gain than

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