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First-generation antipsychotics (FGA), which are also known as typical antipsychotics, first emerged in the 1950s. In terms of pharmacodynamics, they primarily act by attaching to dopamine D2 receptors in the brain and reducing dopamine activity, which is considered to be overactive in people with psychosis (Factor, 2020). FGAs have a high affinity for dopamine D2 receptors and are considered to be highly potent. Examples of FGAs include chlorpromazine, levomepromazine, clopenthixol, flupenthixol, and haloperidol.
Second-generation antipsychotics (SGA), also titled atypical antipsychotics, were generated in the 1990s and have a mechanism of action that is different from the FGAs one. SGAs have a lower connection with dopamine D2 receptors and a higher connection with other receptors, such as serotonin 5-HT2A receptors (D’Agostino et al., 2022). SGAs have a lower association with dopamine D2 receptors than FGAs and are considered to be less potent (Shakir et al., 2022). Examples of SGAs include aripiprazole, risperidone, quetiapine, olanzapine, and paliperidone.
Pharmacokinetics-wise, FGAs have a lower level of bioavailability, which means that a higher proportion of the drug is metabolized before it reaches the bloodstream and its target in the brain. Hence, a higher dose is needed to achieve the same effect as a lower dose of an SGA (Muñoz-Negro et al., 2020). Additionally, FGAs have a shorter half-life, meaning they are eliminated from the body faster, which may lead to more frequent dosing and greater fluctuations in drug levels in the bloodstream.
In summary, first- and second-generation antipsychotics differ in terms of their pharmacodynamics as they have dissimilar mechanisms of action and various paths of pharmacokinetics. FGAs bind at a higher level to dopamine D2 receptors and are considered more potent, while SGAs have a lower connection to dopamine D2 receptors and are considered less potent. Additionally, FGAs have a lower bioavailability and shorter half-life than SGAs.
References
D’Agostino, A., Aguglia, A., Barbui, C., Bartoli, F., Carrà, G., Cavallotti, S., Chirico, M., Ostinelli, E. G., Zangani, C., Martinotti, G., Ostuzzi, G., & STAR Network Depot Investigators. (2022). Off–label long acting injectable antipsychotics in real–world clinical practice: A cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study. BMC Psychiatry 22, 442. Web.
Factor, S. A. (2020). Management of tardive syndrome: Medications and surgical treatments. Neurotherapeutics, 17, 1694–1712. Web.
Muñoz-Negro, J. E., Gómez-Sierra, F. J., Peralta, V., González-Rodríguez, A., & Cervilla, J. (2020). A systematic review of studies with clinician-rated scales on the pharmacological treatment of delusional disorder. International Clinical Psychopharmacology, 35(3), 129-136. Web.
Shakir, M., Willems, A. E., van Harten, P. N., van Lutterveld, R., & Tenback, D. E. (2022). The effect on relapse rate and psychiatric symptomatology: Switching a combination of first- and second-generation antipsychotic polypharmacy to antipsychotic monotherapy in long-term inpatients with schizophrenia and related disorders. A pragmatic randomized open-label trial (SwAP trial). Schizophrenia Research, 243, 187-194. Web.
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