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First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects

Michael D Jibson, MD, PhD
Section Editor
Stephen Marder, MD
Deputy Editor
Richard Hermann, MD


Antipsychotic medications have been used for more than 60 years to treat acute psychosis from any cause and to manage chronic psychotic disorders such as schizophrenia. As a class, antipsychotics are also effective in the treatment of acute agitation, bipolar mania, and other psychiatric conditions.  

First-generation antipsychotics (FGAs), also known as neuroleptics, conventional or typical antipsychotics, have significant potential to cause extrapyramidal side effects and tardive dyskinesia. This propensity to cause movement disorders is the primary difference between FGAs and second-generation antipsychotics (SGAs). In other respects, such as other side effects and their mechanism of action, the two classes have substantial overlap and comparable efficacy.

The pharmacology, administration, and side effects of FGAs are discussed here. The pharmacology, administration, and side effects of SGAs are discussed separately. The efficacy and administration of antipsychotic drugs for specific psychotic disorders are also described separately, as are antipsychotic poisoning, tardive dyskinesia, neuroleptic malignant syndrome, and other antipsychotic drug side effects. (See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects" and "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment" and "Bipolar disorder in adults: Pharmacotherapy for acute mania and hypomania" and "Unipolar major depression with psychotic features: Epidemiology, clinical features, assessment, and diagnosis" and "Delusional disorder" and "Brief psychotic disorder" and "Treatment of postpartum psychosis" and "First generation (Typical) antipsychotic medication poisoning" and "Second generation (atypical) antipsychotic medication poisoning" and "Tardive dyskinesia: Etiology and epidemiology" and "Neuroleptic malignant syndrome" and "Pharmacotherapy for schizophrenia: Side effect management".)


The mechanism of action of all first-generation antipsychotics (FGAs) appears to be postsynaptic blockade of brain dopamine D2 receptors. Evidence supporting this mechanism includes strong antagonism of D2 receptors in both cortical and striatal areas [1], a high correlation between D2 receptor binding and clinical potency [2], and a consistent requirement of 65 percent D2 receptor occupancy for antipsychotic efficacy in functional imaging studies [3]. The nonspecific localization of FGA dopamine binding throughout the central nervous system is consistent with their risk of movement disorders and prolactinemia. Aside from their common activity as D2 antagonists, each FGA has distinct effects on neuronal 5-HT2a, alpha-1, histaminic, and muscarinic receptors, which generally correspond to their individual side effect profiles, as shown in the table (table 1).

High and low potency FGAs — The pharmacologic differences described above are the basis for the classification of FGAs as either high- or low-potency drugs. The high-potency FGAs (fluphenazine, haloperidol, loxapine, perphenazine, pimozide, thiothixene, and trifluoperazine) are dosed in the range of 1 to 10s of milligrams and have low activity at histaminic and muscarinic receptors. They are associated with little sedation, weight gain, or anticholinergic activity, but a high risk for extrapyramidal side effects. The low-potency FGAs (chlorpromazine and thioridazine) are dosed in 100s of milligrams and have high histaminic and muscarinic activity with a corresponding increased prevalence of sedation and anticholinergic effects, but lower risk of extrapyramidal side effects.

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Literature review current through: Sep 2017. | This topic last updated: Mar 06, 2017.
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