Medicinal Chemistry II: Antipsychotics and Schizophrenia

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Questions and Answers

What is the primary category of mental illness that includes schizophrenia?

Mood disorders

Psychoses (correct)

Personality disorders

Neuroses

What is the minimum number of symptoms required for a diagnosis of schizophrenia?

One

Three

Four

Two (correct)

What is the name of the hypothesis that suggests that schizophrenia results from increased dopaminergic neurotransmission?

Psychosis theory

Dopamine hypothesis (correct)

Schizophrenia hypothesis

Neurotransmission theory

What is the duration of time that symptoms must persist for a diagnosis of schizophrenia?

6 months Signup and view all the answers

What is the term for the ability to comprehend reality, which is retained in anxiety disorders?

Reality testing Signup and view all the answers

What is the category of mental illness that includes anxiety disorders?

Neuroses Signup and view all the answers

What is the term for the symptoms of delusions and sensory hallucinations?

Psychosis Signup and view all the answers

Before a diagnosis of schizophrenia can be made, what must be ruled out?

Affective disorders Signup and view all the answers

Serotonergic modulation is associated with a beneficial increase in which neurotransmitter release?

Dopamine release Signup and view all the answers

What type of receptors can be located postsynaptically as well as presynaptically on dopamine neurons?

D2-type receptors Signup and view all the answers

What are dopamine receptors located presynaptically on dopamine cell bodies and nerve terminals called?

Autoreceptors Signup and view all the answers

What is the effect of autoreceptors on neuronal firing and dopamine synthesis and release?

They negatively modulate neuronal firing and dopamine synthesis and release Signup and view all the answers

What is the cause of the parkinsonian-like movement side effects of neuroleptics?

Antagonism of dopamine D2 receptors Signup and view all the answers

What percentage of patients experience extrapyramidal side effects from neuroleptics?

30-50% Signup and view all the answers

What is a common metabolic side effect of neuroleptics?

Weight gain Signup and view all the answers

What type of antipsychotics act as D2 receptor partial agonists?

Atypical antipsychotics Signup and view all the answers

What is the beneficial effect of neuroleptics?

Antiemetic effects Signup and view all the answers

What is the prototype of the phenothiazine-thioxanthene group of antipsychotic agents?

Chlorpromazine Signup and view all the answers

What is the structural difference between phenothiazines and thioxanthenes?

Thioxanthenes have a carbon at position 10 Signup and view all the answers

What increases the antipsychotic efficacy of phenothiazines?

Substitution of an electron-withdrawing group at position 2 Signup and view all the answers

What is the effect of N-dealkylation of the side chain of phenothiazines?

Decreases antipsychotic activity Signup and view all the answers

How can phenothiazines and thioxanthenes be divided based on substitution at position N10?

Into 3 groups: aliphatic, piperidine, and piperazine Signup and view all the answers

What is the characteristic of phenothiazines with an aliphatic side chain?

They have a low potency Signup and view all the answers

What is the characteristic of phenothiazines with a piperidine ring in the side chain?

They have a low incidence of extrapyramidal effects Signup and view all the answers

What is the effect of haloperidol on hypotension?

It causes mild hypotension Signup and view all the answers

What is the effect of replacing the keto moiety with other groups in butyrophenones?

It decreases neuroleptic potency Signup and view all the answers

What is the characteristic of the most potent butyrophenone compounds?

They have a fluorine substituent in the para position Signup and view all the answers

What is the use of haloperidol decanoate in noncompliant people?

It is used for its long duration of action Signup and view all the answers

What is the effect of lengthening or shortening the three-carbon propyl chain in butyrophenones?

It decreases neuroleptic potency Signup and view all the answers

What is the characteristic of the tertiary amino group in butyrophenones?

It is essential for neuroleptic activity Signup and view all the answers

What is the use of droperidol in anesthesia?

It is used for its sedative and antiemetic effects Signup and view all the answers

What is the result of replacing the keto function in butyrophenones with 4-flurophenylmethane?

It results in diphenylbutylpiperidine neuroleptics Signup and view all the answers

What is the main mechanism by which atypical neuroleptics improve on the efficacy of antipsychotics?

By complementing or replacing D2 dopaminergic antagonism with an action on serotonergic transmission Signup and view all the answers

Which of the following is a benzazepine derivative?

Clozapine Signup and view all the answers

What is a serious drawback to the use of clozapine?

Agranulocytosis Signup and view all the answers

Which enzyme is mainly involved in the metabolism of clozapine?

CYP3A4 Signup and view all the answers

What is risperidone's activity compared to clozapine?

More potent antidopaminergic and less potent antimuscarinic activity Signup and view all the answers

What is the main difference between risperidone and clozapine in terms of extrapyramidal effects?

Risperidone can induce extrapyramidal symptoms at low daily doses Signup and view all the answers

How is risperidone metabolized?

CYP2D6-catalyzed 9-hydroxylation Signup and view all the answers

What is a characteristic of atypical neuroleptics such as clozapine and risperidone?

Limited adverse extrapyramidal effects at low daily doses Signup and view all the answers

Study Notes

Schizophrenia and its Treatment

Serotonergic modulation enhances striatal dopamine release beneficially.
Atypical antipsychotics act as D2 receptor partial agonists (e.g., aripiprazole).
D2-type receptors exist both postsynaptically and presynaptically on dopamine neurons; autoreceptors modulate firing and dopamine synthesis negatively.
Side effects from antipsychotics arise from antagonism at various receptors: H1, α1/α2 adrenergic, M1 muscarinic, serotonin, and D2 dopamine receptors.
Increased D2 potency correlates with more severe side effects, including sedation, hypotension, and sexual dysfunction.
Extrapyramidal side effects affect 30-50% of patients, manifesting as acute dystonias, akathisia, and parkinsonian symptoms.
Neuroleptics can cause metabolic and endocrine side effects, such as weight gain and hyperprolactinemia.

Historical and Diagnostic Aspects

Schizophrenia defined historically ~100 years ago, requiring two or more core symptoms (delusions, hallucinations, disorganized speech/behavior).
Social functioning must markedly decline and symptoms should persist continuously for at least six months.
Affective disorders and substance abuse must be ruled out before diagnosis.

Etiological Considerations

The "dopamine hypothesis" suggests schizophrenia results from increased dopaminergic neurotransmission.

Typical Neuroleptics

Typical neuroleptics include phenothiazines and thioxanthene derivatives.
Chlorpromazine is the prototype agent in the phenothiazine class; phenothiazines feature a tricyclic structure.
Substituents influence potency; electron-withdrawing groups enhance efficacy.
Phenothiazines and thioxanthenes can be classified based on the side-chain structure: aliphatic, piperidine, and piperazine.

Side Effects of Typical Neuroleptics

Aliphatic compounds (e.g., chlorpromazine) are lower in potency.
Piperidine derivatives (e.g., thioridazine) exhibit fewer extrapyramidal effects but can have cardiac depressant actions.

Butyrophenones

Neuroleptic potency is affected by structural modifications in the butyrophenone skeleton.
Haloperidol is a notable butyrophenone used effectively in treatment; its extended-release form is suitable for noncompliant patients.

Atypical Neuroleptics

Atypical antipsychotics aim to enhance D2 antagonism and engage serotonergic transmission.
Include benzazepine derivatives (e.g., clozapine, olanzapine) with a reduced risk of extrapyramidal side effects.
Clozapine is known for its effectiveness in treatment-resistant cases but poses risk of agranulocytosis, warranting regular blood monitoring.

Benzisoxazole and Benzisothiazole Derivatives

Risperidone antagonizes serotonin and dopamine receptors, demonstrating significant antidopaminergic effects while limiting antimuscarinic activity.
Although effective, risperidone can cause extrapyramidal symptoms and hyperprolactinemia compared to clozapine.

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Description

This quiz covers the medicinal chemistry of antipsychotics, including typical and atypical neuroleptics, and their use in treating schizophrenia. It also touches on the portrayal of schizophrenia in the movie A Beautiful Mind.