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Antipsychotics: The Essentials Module 1 Introduction

Flavio Guzmán, 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?

Schizophrenia) .The Discovery of Chlorpromazine Chlorpromazine as antihistaminic Henri Laborit • (Anesthesia) Jean Delay and Pierre Deniker • (1952.

Chlorpromazine Ad .

A history of antipsychotic drug development. . Comprehensive psychiatry 1999.Development of antipsychotic drugs after chlorpromazine 1952 • Chlorpromazine 1967 • Haloperidol 1978 • Thioridazine 1957 • Perphenazine 1972 • Fluphenazine Shen WW.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.60 Suppl 12:22-3. The Journal of Clinical Psychiatry 1999. . A historical perspective of clozapine.

Clozapine Antipsychotics Abbot.Post. 158-159 (2010) . A Schizophrenia: The drug deadlock| Nature 468.

• A new generation of drugs were approved after the development of clozapine.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.

Antipsychotics Classification .

16:488-501 . 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.Classic and commonly used terms Neuroleptics (conventional antipsychotics. Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? Current pharmaceutical design 2010. Murthy V.

First Generation Antipsychotics • Terminology • Classification .

New York: Cambrigde University Press. 2008 . Neurolepsis Psychomotor slowing Emotional quieting Affective indifference Stahl. 3rd ed.Terminology: neuroleptics Neuroleptic: term used for first generation (typical) antipsychotics because of their ability to produce neurolepsis. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. S M.

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

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

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

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

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 2 .

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 .

Hippius H. 2009) . The “atypicality” of antipsychotics: a concept re-examined and re-defined. Carlsson A.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 (Gründer G. Nature Rev Drug Disc 8:197-202.

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 .

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

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 .