First Generation Typical Antipsychotic Drugs

The serendipitous finding in 1951 that the major tranquilizer, chlorpromazine 1, was effective in treating delusions and hallucinations associated with schizophrenia and other psychotic disorders marks the beginning of modern therapy for schizophrenia.3 Unfortunately, treatment with chlorpromazine was accompanied by the development of EPS, some appearing even after the first dose (e.g., dystonias, akathisia). Other adverse effects were delayed for days or weeks such as parkinsonism, and the sometimes fatal neuroleptic malignant syndrome. Tardive dyskinesia, characterized by abnormal involuntary movements of the tongue, facial muscles, or limb muscles, develops in about 20% of patients and may be irreversible. Chlorpromazine also increased prolactin secretion leading to gynecomastia, galactorrhea, menstrual irregularities, sexual dysfunction, and possibly bone loss over the long term. Sedation, hypotension, and weight gain were also common with chlorpromazine. Despite these concerns, the discovery that the mechanism of action of chlorpromazine involved blockade of DA receptors led to an explosion of drugs with a similar mechanism. These included other phenothiazines (fluphenazine 27, mesoridazine 28, methotrimeprazine 29, pericyazine 30, perphenazine 31, prochlorperazine 32, thioproperazine 33, thioridazine 34, and trifluoperazine 35); the thioxanthenes (e.g., chlorprothixene 36, flupenthixol 37, and thiothixene 38); the butyrophenones (e.g., phenylbutylpiperadines including haloperidol 26, melperone 39, bromperidol 40, and pimozide 41); the substituted benzamides (e.g., sulpiride 42, amisulpride 43); and others (the dihydroindolone, molindone 44, and the dibenzoxazepine, loxapine 45). However, while all of these agents are effective in controlling the positive symptoms of schizophrenia, these drugs probably do not treat or may worsen the negative symptoms and cognitive dysfunction associated with this disease. Equally important, at therapeutic doses, these agents are associated with a similar set of side effects such as those seen after chlorpromazine.

Fluphenazine 27

Mesoridazine 28

Methotrimeprazine 29

Fluphenazine 27

Mesoridazine 28

Methotrimeprazine 29

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