Pharmacokinetics anxiolytics

Medications that have been used as treatment for anxiety and depression in the postwithdrawal state include antidepressants, benzodia2epines and other anxiolytics, antipsychotics, and lithium. In general, the indications for use of these medications in alcoholic patients are similar to those for use in nonalcoholic patients with psychiatric illness. However, following careful differential diagnosis, the choice of medications should take into account the increased potential for adverse effects when the medications are prescribed to alcoholic patients. For example, adverse effects can result from pharmacodynamic interactions with medical disorders commonly present in alcoholic patients, as well as from pharmacokinetic interactions with medications prescribed to treat these disorders (Sullivan and O Connor 2004). 

Compared to antipsychotics, there are even fewer studies on the prescribing patterns of antidepressants done in Asian countries. Pi etal. (1985) conducted a survey of psychotropic prescribing practices reported by psychiatrists in 29 medical schools in 9 Asian countries. Daily dose range of tricyclic antidepressants (TCAs) such as amitriptyline, imipramine, and nortriptyline in Asian countries was comparable to the practice in USA. This is despite differences found between Asian and non-Asian populations in the pharmacokinetics of TCAs (Pi et al, 1993). A questionnaire on the practical prescribing approaches in mood disorders administered to 298 Japanese psychiatrists was reported by Oshima et al. (1999). As first-line treatment, the majority of respondents chose newer TCAs or non-TCAs for moderate depression and older TCAs for severe depression. Combination of antidepressants and anxiolytics was preferred in moderate depression, while an antidepressant and antipsychotic combination was common in severe psychotic depression. Surprisingly, sulpiride was the most favored drug for dysthymia. In a naturalistic, prospective follow-up of 95 patients with major depression in Japan, the proportion of patients receiving 125 mg/day or less of imipramine was 69% at one month and 67% at six months (Furukawa et al., 2000). 

B.4.2.2 Nonbenzodlazeptnes GG-NPD was used by Kivisto et al. (1999) to quantitate the nonbenzodiazepine anxiolytic buspirone and its major metabolite, l-(2-pyrimidinyl)-piperazine, using separate extraction methods and separate assays. The hmit of quantification in plasma for both compounds was 0.2 ng/mL, which makes this assay useful for pharmacokinetic studies of this compound (Kivisto et al., 1999). A rapid, simple method for analysis of buspirone in rat brain requiring a single extraction step followed by GC-NPD has also been described (Lai. et al., 1997). 

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... 

Imipramine, a TCA, was the first pharmacological agent noted to treat panic disorder (Klein 1964). Other TCAs, notably clomipramine, have also been found to have significant anxiolytic properties (den Boer et al. 1990 Modigh 1992). Studies of ethnic differences in the pharmacokinetics of the TCAs in... 

The speciflc clinical use of the numerous available benzodiazepines depends on their individual pharmacokinetic and pharmacodynamic properties. Drugs with a high affinity for the GABAa receptor (alprazolam, clonazepam, lorazepam) have high anxiolytic efficacy drugs with a short duration of action (temazepam) are used as hypnotics to minimise daytime sedative effects. Diazepam has a long half-life and duration of action and may be favoured for long-term use or when there is a history of withdrawal problems oxazepam has a slow onset of action and may be less susceptible to abuse. 

Mechanism of Action Apiperazine derivative that competes with histamine for receptor sites in the GI tract, blood vessels, and respiratory tract. May exert CNS depressant activity in subcortical areas. Diminishes vestibular stimulation and depresses labyrinthine function. Therapeutic Effect Produces anxiolytic, anticholinergic, antihista-minic, and analgesic effects relaxes skeletal muscle controls nausea and vomiting. Pharmacokinetics ... 

Mahmood, I. and Sahajwalla, C. (1999) Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug. Clin Pharmacokinet 36 277-2 7. 

Even in people with the same diagnosis and the same inclusion and exclusion criteria, there are different treatment responses based on individual variability. The most important individual variables are probably sex and age. It is unfortunate that even though affective disorders and some anxiety disorders are more prevalent in women than in men, until recently results of clinical trials did not take into consideration sex differences and variables unique to women [e.g., reproductive status and menstrual cycle]. As is demonstrated by Yonkers et al. [see Chapter 5, in this volume], there are substantial sex differences in the pharmacokinetics and pharmacodynamics of most antidepressants and anxiolytics, which influence treatment response. Attention to these variables will indeed improve the efficacy of treatment. 

Evaluations of gender differences in the pharmacokinetics, pharmacodynamics, and response to treatment for anxiolytics and antidepressants are... 

In principle, all drugs with damping action on the central nervous system could be used as anxiolytics or hypnotics, but the pharmacological and/or pharmacokinetic properties of most compounds are not appropriate for their therapeutic use ... 

In partially responsive or nonresponsive patients, the first issue is to determine whether an individual is truly treatment-resistant, because many receive nontherapeutic doses and the potential for improvement may not be adequately tested. Thus, in some situations, more aggressive treatment (dose increase, augmentation) may be appropriate, if not precluded by adverse effects. In selected cases, it may also be helpful to monitor plasma levels to ensure that they are in a reasonable range (see Pharmacokinetics/Plasma Levels earlier in this chapter). If a patient continues to demonstrate significant symptoms after a sufficient trial (2 to 3 weeks), alternatives to switching to another antipsychotic may include the addition of lithium, an anticonvulsant, or a second antipsychotic agent. An antidepressant or anxiolytic may also be helpful, especially if affective or anxiety symptoms are prominent. 

A BZD s pharmacokinetics may play a role in the occurrence, in part accounting for the increase in its incidence after the advent of short-acting BZD anxiolytics and hypnotics (e.g., lorazepam, alprazolam, and triazolam). 

Of all psychiatric medications, the psychostimulants have been the best studied in terms of their pharmacokinetics in children and adolescents (Table 14-4). Next have been studies of antidepressants, while few studies have been done on the pharmacokinetics of antipsychotics and anxiolytics in this age range. 

Table 10.1 Pharmacokinetic properties of some anxiolytic and hypnotic drugs...

The individual benzodiazepines show small differences in their relative anxiolytic, anticonvulsant, and sedative properties. However, the duration of action varies widely among this group, and pharmacokinetic considerations are often important in choice of drug. 

The effects of rifampicin on the pharmacokinetics and pharmacodynamics of buspirone were investigated in 10 young healthy volunteers. There was a significant reduction in the effects of buspirone in three of the six psychomotor tests used after rifampicin pretreatment. The interaction between rifampicin and buspirone is probably mostly due to increased CYP3A4 activity. Buspirone will most likely have a greatly reduced anxiolytic effect when it is used together with rifampicin or other potent inducers of CYP3A4, such as phenytoin and carbamazepine... 

The choice of drug as hypnotic and anxiolytic is determined by pharmacokinetic properties (see before, and Table 19.8). 

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