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Module 1 - Introduction

This document provides an overview of antipsychotic drugs, including their history and classifications. It discusses the discovery of chlorpromazine in 1952 as a breakthrough for psychiatry. First generation antipsychotics (FGAs) are classified based on their chemical structure and potency, while second generation antipsychotics (SGAs) are defined by their year of FDA approval and chemical class. The key differences between FGAs and SGAs are that FGAs antagonize mainly D2 receptors, increasing risks of neurological side effects, while SGAs antagonize 5HT2A and D2 receptors, increasing risks of metabolic side effects instead. Clozapine is confirmed to be effective for treatment-resistant schizophrenia, but otherwise there is no

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598 views30 pages

Module 1 - Introduction

This document provides an overview of antipsychotic drugs, including their history and classifications. It discusses the discovery of chlorpromazine in 1952 as a breakthrough for psychiatry. First generation antipsychotics (FGAs) are classified based on their chemical structure and potency, while second generation antipsychotics (SGAs) are defined by their year of FDA approval and chemical class. The key differences between FGAs and SGAs are that FGAs antagonize mainly D2 receptors, increasing risks of neurological side effects, while SGAs antagonize 5HT2A and D2 receptors, increasing risks of metabolic side effects instead. Clozapine is confirmed to be effective for treatment-resistant schizophrenia, but otherwise there is no

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psychopharmacology
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© Attribution Non-Commercial (BY-NC)
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PPTX, PDF, TXT or read online on Scribd
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Antipsychotics: The Essentials Module 1 Introduction

Flavio Guzmn, MD
Mental Health Teaching Hospital Dr. Carlos Pereyra Mendoza Argentina

Outline
Antipsychotics History
The discovery of chlorpromazine Clozapine Second Generation Antipsychotics

First Generation Antipsychotics


Terminology Classification

Second Generation Antipsychotics


Terminology List of agents

Differences between FGAs and SGAs

Antipsychotics history: Why is it important?

The Discovery of Chlorpromazine


Chlorpromazine as antihistaminic

Henri Laborit
(Anesthesia)

Jean Delay and Pierre Deniker


(1952, Schizophrenia)

Chlorpromazine Ad

Development of antipsychotic drugs after chlorpromazine

1952
Chlorpromazine

1967
Haloperidol

1978
Thioridazine

1957
Perphenazine

1972
Fluphenazine

Shen WW. A history of antipsychotic drug development. Comprehensive psychiatry 1999;40:407-14.

Clozapine

Clozapine timeline
1975 1961
Clozapine synthesis Reports of agranulocytosis Withdrawal by manufacturer

1989
Reintroduction to market

1972
Clinical trials begin

Hippius H. A historical perspective of clozapine. The Journal of Clinical Psychiatry 1999;60 Suppl 12:22-3.

Post- Clozapine Antipsychotics

Abbot, A Schizophrenia: The drug deadlock| Nature 468, 158-159 (2010)

Key points
Chlorpromazine discovery in 1952 was a breakthrough for psychiatry. Serendipity in drug discovery implies the finding of one thing while looking for something else. A new generation of drugs were approved after the development of clozapine.

Antipsychotics Classification

Classic and commonly used terms


Neuroleptics (conventional antipsychotics, typical antipsychotics) Atypical antipsychotics (serotonin-dopamine antagonists) Dopamine partial agonists (Aripiprazole)

Proposed new terms (WPA)


First generation antipsychotics

Second generation antipsychotics Third generation antipsychotics

Mailman RB, Murthy V. Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? Current pharmaceutical design 2010;16:488-501

First Generation Antipsychotics


Terminology Classification

Terminology: neuroleptics
Neuroleptic: term used for first generation (typical) antipsychotics because of their ability to produce neurolepsis.
Neurolepsis
Psychomotor slowing Emotional quieting Affective indifference

Stahl, S M. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. New York: Cambrigde University Press; 2008

Chemical Classification of FGAs


Phenothiazines
Aliphatic Chlorpromazine Promazine Triflupromazine Piperidines Thioridazine Mesoridazine Piperacetazine Piperazines Trifluoperazine Fluphenazine Perphenazine Acetophenazine Prochlorperazine
Thioxanthenes Thiothixene Chlorprothixene

Dibenzoxazepines Loxapine
Butyrophenones Haloperidol Droperidol Diphenylbutylpiperidines Pimozide

Phenothiazines
Phenothiazines Aliphatic Piperidines Piperazines
Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

Aliphatic - Chlorpromazine
Phenothiazines

Aliphatic Chlorpromazine Piperidines Piperazines


Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

Piperidines - Mesoridazine
Phenothiazines

Aliphatic Piperidines Mesoridazine Piperazines


Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

Butyrophenones - Haloperidol
Butyrophenones Haloperidol Droperidol

Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

FGA Classification According to Potency


Agent Low Potency Chlorpromazine Loxapine Mid Potency Perphenazine Chlorpromazine equivalence (mg) 100 10 10

Molindone
Haloperidol High Potency Fluphenazine

10
3 2

Pimozide

Key points
First generation antipsychotics are commonly classified according to chemistry and potency. High potency agents (haloperidol) have a higher risk of extrapyramidal symptoms. Low potency drugs (chlorpromazine) are more sedating and show a higher risk of hypotension and anticholinergic effects.

Second Generation Antipsychotics

Terminology: Atypical antipsychotics


Atypical antipsychotics
Originally:

Later broadened to include:


Efficacy against cognitive and negative symptoms Lack of prolactin elevation

Lower EPS risk

Efficacy for treatmentresistant patients

Currently in debate
(Grnder G, Hippius H, Carlsson A. The atypicality of antipsychotics: a concept re-examined and re-defined. Nature Rev Drug Disc 8:197-202, 2009)

Second Generation Antipsychotics


Drug Clozapine (Clozaril) Risperidone (Risperdal) Olanzapine (Zyprexa) Quetiapine (Seroquel) Ziprasidone (Geodon) Aripiprazole (Abilify) Chemical Class Dibenzodiazepines Benzisoxazole Thienobenzodiazepines Dibenzothiazepines Benzisothiazolyls Quinolinones Year Approved (FDA) 1989 1993 1996 1997 2001 2002

Second Generation Antipsychotics


Drug Paliperidone (Invega) Iloperidone (Fanapt) Asenapine (Saphris) Lurasidone (Latuda) Chemical Class Benzisoxazole Piperidinyl-benzisoxazole Dibenzo-oxepino pyrrole Benzisothiazol Year Approved (FDA) 2006 2009 2009 2010

Key Points
The concept of atypicality is not yet completely defined. Ten second generation antipsychotics are available in the US market.

Differences Between First and Second Generation Antipsychotics

Pharmacological profile
First Generation Antipsychotics D2 Antagonism Second Generation Antipsychotics 5HT2A/D2 antagonism

Adverse effects profile


First Generation Antipsychotics Second Generation Antipsychotics

Higher risk of neurological side effects

Higher risk of metabolic side effects

Are SGAS more effective than FGAs?


No evidence of benefit of SGAs over FGAs in the treatment of negative symptoms of schizophrenia Clozapine has shown clear utility in treatment-resistant schizophrenia

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