Clinical Pharmacokinetics of Atypical Antipsychotics

Abstract

In the past, the information about the dose-clinical effectiveness of typical antipsychotics was not complete and this led to the risk of extrapyramidal adverse effects. This, together with the intention of improving patients' quality of life and therapeutic compliance, resulted in the development of atypical or second-generation antipsychotics (SGAs). This review will concentrate on the pharmacokinetics and metabolism of clozapine, risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole and sertindole, and will discuss the main aspects of their pharmacodynamics. In psychopharmacology, therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding adverse effects by keeping long-term exposure to the minimal effective blood concentration. The rationale for using therapeutic drug monitoring in relation to SGAs is still a matter of debate, but there is growing evidence that it can improve efficacy, especially when patients do not respond to therapeutic doses or when they develop adverse effects. Here, we review the literature concerning the relationships between plasma concentrations of SGAs and clinical responses by dividing the studies on the basis of the length of their observation periods. Studies with clozapine evidenced a positive relationship between plasma concentrations and clinical response, with a threshold of 350-420 ng/mL associated with good clinical response. The usefulness of therapeutic drug monitoring is well established because high plasma concentrations of clozapine can increase the risk of epileptic seizures. Plasma clozapine concentrations seem to be influenced by many factors such as altered cytochrome P450 1A4 activity, age, sex and smoking. The pharmacological effects of risperidone depend on the sum of the plasma concentrations of risperidone and its 9-hydroxyrisperidone metabolite, so monitoring the plasma concentrations of the parent compound alone can lead to erroneous interpretations. Despite a large variability in plasma drug concentrations, the lack of studies using fixed dosages, and discrepancies in the results, it seems that monitoring the plasma concentrations of the active moiety may be useful. However, no therapeutic plasma concentration range for risperidone has yet been clearly established. A plasma threshold concentration for parkinsonian side effects has been found to be 74 ng/mL. Moreover, therapeutic drug monitoring may be particularly useful in the switch between the oral and the long-acting injectable form. The reviewed studies on olanzapine strongly indicate a relationship between clinical outcomes and plasma concentrations. Olanzapine therapeutic drug monitoring can be considered very useful in assessing therapeutic efficacy and controlling adverse events. A therapeutic range of 20-50 ng/mL has been found. There is little evidence in favour of the existence of a relationship between plasma quetiapine concentrations and clinical responses, and an optimal therapeutic range has not been identified. Positron emiss...

Avaliação da microextração líquido-líquido dispersiva para determinação do levetiracetam e da risperidona por técnicas cromatográficas acopladas a espectrometria de massas

“…A RSP compõe a classe dos antipsicóticos atípicos, e diferentemente dos típicos, ou de primeira geração, seu mecanismo de ação age antagonizando seletivamente os receptores dopaminérgicos tipo D2, D3 e D4 e os receptores serotoninérgicos do tipo 5-HT2a e 5-HT7 (FONSECA et al, 2013;MAURI et al, 2007).…”

“…A metabolização ocorre principalmente no fígado pelas enzimas do citocromo P450 (CYP), isoforma CYP2D6 e, em menor extensão pela CYP3A4 (MAURI et al, 2007). Estas isoformas são responsáveis pela hidroxilação da RSP, formando os metabólitos 9-hidroxi-risperidona (9-OH-RSP) (Figura 2.1b) e 7-hidroxi-risperidona (7-OH-RSP) (MANDRIOLI et al, 2011).…”

“…Entretanto, influências genéticas envolvendo a isoforma CYP2D6 exercem um papel importante na variabilidade dos parâmetros farmacocinéticos (MAURI et al, 2007), sendo que, o tempo de meia-vida da RSP aumenta de 3 horas para 22 horas em indivíduos que apresentem danos neste sistema de metabolização, enquanto que a 9-OH-RSP apresenta tempo de meia-vida em torno de 22 horas, independentemente de haver ou não prejuízos hepáticos (MAURI et al, 2007). A eliminação da RSP e 9-OH-RSP é predominantemente pela via renal (CABOVSKA; COX; VINKS, 2007;MAURI et al, 2007 (ARAVAGIRI et al, 2003).…”

“…A eliminação da RSP e 9-OH-RSP é predominantemente pela via renal (CABOVSKA; COX; VINKS, 2007;MAURI et al, 2007 (ARAVAGIRI et al, 2003). Assim, a monitorização terapêutica dos antipsicóticos é considerada de extrema importância, para a otimização da terapia, individualização da dose, redução do número de hospitalizações e de efeitos adversos ao paciente (MANDRIOLI et al, 2011).…”

“…Assim, a monitorização terapêutica dos antipsicóticos é considerada de extrema importância, para a otimização da terapia, individualização da dose, redução do número de hospitalizações e de efeitos adversos ao paciente (MANDRIOLI et al, 2011). Além disso, uma vez que o metabólito 9-OH-RSP é capaz de contribuir na ação farmacológica juntamente com a RSP, mensurar apenas a concentração desta pode levar a interpretações errôneas nos estudos de monitoramento plasmático (MAURI et al, 2007).…”