Antipsychotics

"Psychosis" refers to the singular form of a severe mental

health condition characterized by a loss of contact with
reality.

On the other hand, “PSYCHOSES" is the plural form of

the word and refers to a group of related disorders that
share this characteristic feature.

SYMPTOMS
• Delusions SUBSTITUTION at POSITION 2-
• Hallucinations Substitution at the second position of the phenothiazine
• Disorganized thinking and speech nucleus with an electron-withdrawing substituent such as a
• Abnormal behavior halogen (e.g., fluorine, chlorine) or a nitro group has been
• Reduced ability to function daily in life shown to INCREASE the antipsychotic activity of
phenothiazines.
Psychoses can occur in different forms, such as:
• Schizophrenia Chlorpromazine
• Bipolar disorder
• Severe depression
The estimated prevalence of psychoses in the population is
approximately 1%.

Classification of Antipsychotic drugs

1. Phenothiazine derivatives:
 Chlorpromazine
 Prochlorperazine
 Trifluoperazine
 Trifluopromazine
 Promazine
2. Butyrophenones: SUBSTITUTION at POSITION 3-
 Haloperidol Substitution at the 3-position of the phenothiazine nucleus
can INCREASE the antipsychotic activity of the
 Droperidol.
compound compared to its unsubstituted derivatives.
3. Miscellaneos:
 Pimozide (Diphenylbutylpiperidine)
SUBSTITUTION at POSITION 1 and 4-
 Molindone (Indolone) Substitution at the 1 and 4 positions of the phenothiazine
4. Atypical antipsychotic drugs: nucleus with certain functional groups such as alkyl or
 Clozapine alkoxy, can lead to a DECREASE in antipsychotic activity.
 Loxapine Substitutions at positions 1 and 4 are not preferred for
 Asenapine antipsychotic activity.
 Paliperidone
 Quetiapine NITROGEN-CONTAINING SIDE CHAIN
 Sertindole For these compounds to have antipsychotic activity, they
must contain a nitrogen-containing side-chain substituent
 Aripiprazole
on the ring nitrogen. In addition, the ring nitrogen and the
 Risperidone nitrogen in the side-chain must be separated by a three-
 Olanzapine carbon chain.
 Ziprasidone
 Zotepine SAR OF BUTYROPHENONE

Phenothiazines BUTYROPHENONE is a type of medication used to treat

Phenothiazines are a class of drugs that are PRIMARILY
used to treat psychosis and other mental health conditions.
They work by blocking the action of DOPAMINE, a
neurotransmitter in the brain that is involved in regulating
mood, behavior, and cognition.
certain mental health conditions primarily block dopamine
receptors in the brain. Specifically, they block dopamine
D2 RECEPTORS, which are thought to be involved in the
development of certain symptoms of schizophrenia and
other mental health conditions.

Phenothiazines are effective in treating the positive

symptoms of psychosis such as hallucinations, delusions,
disorganized speech, and bizarre behavior.

INTACT CARBONYL / KETO GROUP

SAR of Phenothiazines The intact carbonyl group is crucial for their antipsychotic
activity.

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 Antipsychotics
If the carbonyl group is replaced by another functional
group the electronic and steric properties of the molecule
can be altered. This can affect the binding of the drug to
the dopamine receptors, resulting in DECREASED
antipsychotic activity.
FLUORINE ATOM IN PARA-POSITION OF ARYL
GROUP-
The presence of a fluorine atom in the para-position of the
aryl group of butyrophenones has been shown to
INCREASE their affinity for dopamine receptors.
Introducing other atoms or molecules in place of the
fluorine atom has been shown to DECREASE the
antipsychotic activity.
The main difference between a fluorine atom and other
atoms or molecules is their ability to interact with
hydrogen bond acceptors on the dopamine receptor site. In
simpler terms, the more electronegative an atom is, the
more it can form a strong hydrogen bonding.
STRONG BOND = STABLE = ENHANCED DRUG
ACTIVITY
PROPYLENE BRIDGE
The presence of a propylene bridge is necessary for
antipsychotic activity, and altering its length or branching
can DECREASE this activity.
Shortening, lengthening, or branching of the propylene
bridge has been shown to have negative effects on the
drug's effectiveness as an antipsychotic agent.
INCORPORATION OF BASIC NITROGEN INTO 6-
MEMBERED RINGS
Nitrogen atom in the 6-membered ring structure of
butyrophenones is important. Basic nitrogen can act as a
proton acceptor and form strong electrostatic interactions
with acidic groups on target receptors in the CNS,
INCREASING the drug's activity.
This basic nitrogen can also increase the drug's solubility
and enhance its ability to cross the blood-brain barrier,
further contributing to its CNS activity.
THIOTHIXENE
Describe the structure of Thiothixene
Thioxanthenes are a class of antipsychotic medications that
are structurally similar to phenothiazines. But they have a
carbon atom doubly bonded to the propylidene side chain
instead of a nitrogen-hydrogen (N-H) moiety.
Like phenothiazines, thioxanthenes are thought to
primarily work by blocking dopamine receptors in the
brain.
The subtle difference in structure can affect the way the
medication interacts with receptors in the brain and can
influence its overall effectiveness and potential side effects.
THIOXANTHENE
PHENOTHIAZENE
DIFFERENTIATE THE MECHANISM OF ACTION
AND ADVERSE EFFECTS OF 1ST GENERATION
ANTIPSYCHOTICS AND 2ND GENERATION
ANTIPSYCHOTICS.
First-generation antipsychotics (FGAs) block dopamine D2
receptors in the brain and have varying degrees of
blockade of other receptors, leading to control of positive
symptoms of psychosis. They have a high incidence of
extrapyramidal symptoms (EPS) and may cause sedation,
weight gain, anticholinergic effects, and orthostatic
hypotension.
Second-generation antipsychotics (SGAs) also block
dopamine D2 receptors but have a higher affinity for
serotonin 5-HT2A receptors, which may contribute to their
efficacy in treating negative symptoms of psychosis and
reducing EPS. They have a lower risk of EPS and tardive
dyskinesia but are associated with a higher risk of
metabolic side effects such as weight gain, diabetes, and
dyslipidemia. They may also cause sedation, orthostatic
hypotension, and anticholinergic effects, but to a lesser
extent than FGAs.
WHAT IS THE USE OF LITHIUM SALTS?
Lithium salts are used as a mood stabilizer in the treatment
of bipolar disorder. While they are not typically used as a
first-line treatment for psychosis, they may be used in
conjunction with other antipsychotic medications to help
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 Antipsychotics
manage symptoms of mania or to prevent relapse of
bipolar symptoms.

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