Pharmacokinetics neuroleptics

Besides the poor specificity of many of the assays used to determine plasma drug concentrations, another problem which has arisen from these studies has been the length of the "wash-out" period necessary before the patient is given the neuroleptic under investigation. As a result of the prolonged duration of blockade of dopamine receptors in the brain by conventional neuroleptics and their metabolites, it is necessary to allow a wash-out period of several weeks before the patients are subject to a pharmacokinetic study. This raises serious ethical questions. Perhaps with the advent of new imaging techniques it may be possible in the near future actually to determine the rate of disappearance of neuroleptics from the brain of the patient. This may enable the relationship between plasma concentration and clinical response to be accurately determined. 

In SUMMARY, it would appear that a detailed knowledge of the pharmacokinetics of the main groups of psychotropic drugs is only of very limited clinical use. This is due to limitations in the methods for the detection of some drugs (e.g. the neuroleptics), the presence of active metabolites which make an important contribution to the therapeutic effect, particularly after chronic administration (e.g. many antidepressants, neuroleptics and anxiolytics), and the lack of a direct correlation between the plasma concentration of the drug and its therapeutic effect. Perhaps the only real advances will be made in this area with the development of brain imaging techniques whereby the concentrations of the active drug in the... 

Extrapyramidal side effects (EPS) associated with SSRI medications used as single agents were reported as early as 1979 (Meltzer et ah, 1979). Since then, several case reports have been published on use of fluoxetine (Elamilton and Opler, 1992), paroxetine (Nicholson, 1992), and sertraline (Opler 1994). The SSRI medications in combination with neuroleptics can cause severe EPS (Tate, 1989 Ketai, 1993) above and beyond what may be associated with increased levels of antipsychotic medications (Goff et ah, 1991), and are perhaps related to pharmacokinetic drug interactions. 

When antipsychotics are used in conjunction with a variety of anticonvulsants, their plasma levels may be significantly altered due to pharmacokinetic interactions. For example, when CBZ and haloperidol are coadministered, their interaction may cause a significant decrease in the neuroleptic s serum levels, sometimes resulting in clinical decompensation (516). Conversely, the cessation of CBZ may lead to increased antipsychotic plasma levels. 

Knudsen P. Chemotherapy with neuroleptics. Clinical and pharmacokinetic aspects with a particular view to depot preparations. Acta Psychiatr Scand Supp11985 322(72) 51-75. 

Csernansky JG, Lombrozo L, Gulevich GD, et al. Treatment of negative schizophrenic symptoms with alprazolam a preliminary open-label study. J Clin Psychopharmacol 1984 4 349-352. Douyon R, Angrist B, Peselow E, et al. Neuroleptic augmentation with alprazolam clinical effects and pharmacokinetic correlates. Am J Psychiatry 1989 146 231-234. 

Various factors may account for the variability in response to neuroleptics. These include differences in the diagnostic criteria, concurrent administration of drugs which may affect the absorption and metabolism of the neuroleptics (e.g. tricyclic antidepressants), different times of blood sampling, and variations due to the different type of assay method used. In some cases, the failure to obtain consistent relationships between the plasma neuroleptic concentration and the clinical response may be explained by the contribution of active metabolites to the therapeutic effects. Thus chlorpromazine, thioridazine, levomepromazine (methotrime-prazine) and loxapine have active metabolites which reach peak plasma concentrations within the same range as those of the parent compounds. As these metabolites often have pharmacodynamic and pharmacokinetic activities which differ from those of the parent compound, it is essential to determine the plasma concentrations of both the parent compound and its metabolites in order to establish whether or not a relationship exists between the plasma concentration and the therapeutic outcome. 

There were no changes in lithium pharmacokinetics when risperidone was substituted open-label for another neuroleptic drug in 13 patients (634). On the other hand, an 81-year-old man had an acute dystonic reaction 4 days after lithium was added to a regimen of risperidone, valproic acid, and benzatropine (635). 

In a brief review, emphasis has been placed on pharmacokinetic interactions between neuroleptic drugs and benzodiazepines, as much information on their metabolic pathways is emerging (629). Thus, CYP3A4, which plays a dominant role in the metabolism of benzodiazepines, also contributes to the metabolism of clozapine, haloper-idol, and quetiapine, and plasma neuroleptic drug concentrations can rise. 

Yoshida K, Smith B, Craggs M, Kumar R. Neuroleptic drugs in breast-milk a study of pharmacokinetics and of possible adverse effects in breast-fed infants. Psychol Med 1998 28(1) 81-91. 

Because of the frequency of co-administration of benzodiazepines with neuroleptic drugs, it is important to consider possible adverse effects that can result from such combinations. In a brief review, emphasis has been placed on pharmacokinetic interactions between neuroleptic drugs and benzodiazepines, as much information on their metabolic pathways is emerging (166). Thus, the enzyme CYP3A4, which plays a dominant role in the metabolism of benzodiazepines, also contributes to the metabolism of clozapine, haloperidol, and quetiapine, and neuroleptic drug plasma concentrations can rise. Intramuscular levomepromazine in combination with an intravenous benzodiazepine has been said to increase the risk of airways obstruction, on the basis of five cases of respiratory impairment the doses of levomepromazine were higher in the five cases that had accompanying airways obstruction than in another 95 patients who did not (167). 

Ward A, Chaffman MO, Sorkin EM. Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic mahgnant syndrome and an update of its use in muscle spasticity. Drugs 1986 32(2) 130-68. 

Although metoclopramide has lost some ground to newer congeners, it has been the most widely used of the neuroleptic-type antiemetic drugs and is therefore the one for which the clearest picture of adverse effect, typically neuroleptic and endocrine effects, has emerged. Reactions are generally short-lived provided treatment is withdrawn the duration of reactions does not always seem to be explained by simple pharmacokinetic considerations. 

In the fifth and final chapter, Drs. Roy V. Varner and Pedro Ruiz and David R. Small, M.B.A., address the need for investigational studies focusing on pharmacokinetic, pharmacodynamic, and pharmacogenetic factors in the public psychiatric sector. After all, it is in the public sector that most of the ethnic or cultural minority groups in the United States receive their psychiatric care. Also reviewed are the results of several studies of responses to antidepressants and neuroleptics by multiethnic populations treated in the public sector. 

The pharmacology and pharmacokinetics of pimozide (86), the most important member of this class of neuroleptics, have been reviewed (520). Pimozide is well absorbed after oral administration and is widely distributed into the tissues. It has an elimination half-life of around 55 h, despite extensive hepatic metab-... 

The different chemical solutions to solubilizing problems discussed in this chapter reveal that in many cases the chemical transformation used also improves the activity profile of the parent molecule. This can be due to purely pharmacokinetic factors such as a better resorption from the organism and faster transport and diffusion. These factors explain also why solubilized drugs are generally faster eliminated and therefore show fewer symptoms of toxicity. But the pharmacological profile also can be affected. Chlorpromazine, for example (Figure 38.26), has neuroleptic properties, whereas the parent phenothi-azine possesses anthelminthic properties. In this example, the attachment of the basic moiety has totally modified the pharmacological profile. However, the replacement of the basic moiety by its carboxylic counterpart yielded a compound totally inactive as neuroleptic (C. G. Wermuth, unpublished result). 

Ereshefsky L, Saklad SR, Jann MW, et al. Future of depot neuroleptic therapy Pharmacokinetics and pharmacodynamic approaches. J Clin Psychiatry 1984 45(5 pt 2) 50-59. 

---