Chlorpromazine pharmacokinetics

Phenothiazines (acepromazine, propio-promazine, promazine, trimepra-zine, methotrimeprazine, thioridazine, chlorpromazine) 7.5-64,000 2.2-66.5 1.0-3.7 Acepromazine was determined in horse plasma with good results the method is suitable for pharmacokinetic studies 43... 

Clinicians should be aware of a few drug interactions with Zolpidem. Flumazenil acts as an antagonist to the hypnotic effects of zolpidem. There is decreased alertness when zolpidem is combined with cimetidine. There is an increase in anterograde amnesia in volunteers treated with a combination of imipramine and zolpidem. Haloperidol, ranitidine, chlorpromazine, warfarin, and digoxin, along with cimetidine and flumazenil, do not alter the pharmacokinetics of zolpidem (Salva and Costa, 1995). 

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. 

Peet M, Middlemiss DN, Yates RA. Pharmacokinetic interaction between propranolol and chlorpromazine in schizophrenic patients. Lancet 1980 2(8201) 978. 

Older The elderly are at increased risk of adverse drug reactions in general due to altered pharmacokinetics and polypharmacy. For example, reactions to halothane, chlorpromazine, flucloxacillin and co-amoxiclav are more common in elderly patients... 

Where it is possible to predict likely metabolites and a full interpretation of the parent drug spectrum has been made, the mass spectrometer can be used as a specific detection system in selected ion monitoring (SIM) mode (see Selected ion monitoring, p. 25). The early impetus provided by the development of mass fragmentography in the identification of chlorpromazine metabolites [64] has led to many further applications [65,66,68]. The extension of SIM to quantitative drug measurement with the incorporation of internal standards e.g. [88] has again opened up new possibilities in pharmacokinetic studies in clinical pharmacology, a topic discussed separately below. 

Pharmacokinetic. Agents metabolised in the liver provide higher plasma concentrations when another drug that inhibits hepatic metabolism, e.g. cimetidine, is added. Enzyme inducers enhance the metabolism of this class of P-blockers. P-adrenoceptor blockers themselves reduce hepatic blood flow (fall in cardiac output) and reduce the metabolism of p-blockers and other drugs whose metabolic elimination is dependent on the rate of delivery to the liver, e.g. lignocaine (lidocaine), chlorpromazine. 

Hatanaka T, Sato S, Endoh M, Katayama K, Kakemi M, and Koizumi T (1988) Effect of chlorpromazine on the pharmacokinetics and pharmacodynamics of pentobarbital in rats. Journal of Pharmacobiodynamics 11(1) 18-30. 

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). 

PK Yeung, et al. Radioimmunoassay for the N-oxide metabolite of chlorpromazine in human plasma and its application to a pharmacokinetic study in healthy humans. J Pharm Sci 76 803, 1987. 

Johnson, K.E. Pieper, J.A. An HPLC method for the determination of diltiazem and three of its metabolites in serum. J.Liq.Chromatogr., 1990, 13, 951-960 [extracted metabolites serum doxepin (IS) LOD 3 ng/mL non-interfering carbamazepine, chlorpromazine, gedlopamil, imipramine, lidocaine, prochlorperazine, quinidine, thioridazine, trimeprazine pharmacokinetics]... 

GI absorption of chlorpromazine is modified unpredictably by food and probably is decreased by antacids. Antipsychotic agents bind significantly to membranes and to plasma proteins. Elimination kinetics can be multiphasic and variable with dose, and termination of action may rely on clearance of both active metabolites and the parent compound. Approximate elimination half-lives of clinically employed antipsychotic agents are provided in Table 18-2 see also Appendix II, Pharmacokinetic Data in the 11th edition of the parent text. 

C. Pharmacokinetics. These dmgs have large volumes of distribution (Vd = 10-30 L/kg), and most have long elimination half-lives (eg, chlorpromazine = 18-30 hours). Elimination is largely by hepatic metabolism. See Table 11-59, p 381. 

Ishizaki T, Chiba K, Saito M, Kobayashi K, lizuka R The effects of neuroleptics Qialoperidol and chlorpromazine) on the pharmacokinetics of valproic acid in schizophrenic patients. JC/m Psyehopharmacol ( 9S4) 4, 254-61. 

A case-control, retrospective review of patients taking thioridazine 100 to 200 mg daily with either phenytoin, phenobarbital or both drugs found a reduction in both phenobarbital (approximately 25%) and thioridazine levels when taken together. Inconsistent effects were seen on the pharmacokinetics of phenytoin, with a possible trend towards a reduction in phenytoin levels. These results, together with the seizure threshold-lowering effect of phenothiazines, highlights the need to carefully monitor antiepileptic drug levels if phenothiazines are added to, or removed from therapy. See Phenothiazines + Barbiturates , p.759, for the interaction of phenobarbital with chlorpromazine. 

Single-dose studies found that the pharmacokinetics of 20-mg doses of zolpidem were unaffected by 50 mg of chlorpromazine or 2 mg of ha-loperidol. The pharmacokinetics of both of these antipsychotics were unaffected by zolpidem, except that in one study the elimination half-life of chlorpromaziue was increased irom about 5 to 8 hours. Chlorpro-mazine increased the sedative effects of zolpidem (as indicated by impaired performances of manual dexterity and Stroop s tests). It seems likely that additive sedation will be seen with other sedative dmgs. 

No pharmacokinetic interaction was found when 12 healthy subjects were given a single 7.5-mg oral dose of zopidone with chlorpromazine 50 mg. However, the overall performance in a number of psychomotor tests... 

Pharmacokinetic evidence and animal studies suggest that propranolol and chlorpromazine mutually inhibit the liver metabolism of the other drug so that both accumulate within the body. The mechanism of the interaction between propranolol and thioridazine is prohahly similar. Both beta blockers and phenothiazines can cause hypotension, and these effects could be additive. 

The interaction between propranolol and chlorpromazine appears to he established although information is limited. Concurrent use should be well monitored and the dosages reduced if necessary. The same precautions apply with propranolol and thioridazine. There seems to be no information about any interaction between other beta blockers and phenothiazines, but if the mechanism of interaction suggested above is true, it seems possible that other beta blockers that are mainly cleared from the body by liver metabolism might interact similarly with chlorpromazine, whereas those mainly cleared unchanged in the urine are less likely to have a pharmacokinetic interaction, although additive hypotensive effects would still be expected. See Table 22.1 , (p.833), for information on the metabolism of the commonly used systemic beta blockers. 

A study in 17 lithium-maintained patients found that tremor increased significantly when amitriptyline 75 to 150 mg daily was added. The greatest increments occurred within approximately 3 weeks of starting the combined treatment, but tremor activity was still significantly greater than baseline after 6 weeks. No patient discontinued treatment because of the increase in tremor. Seizures occurred in a patient on amitriptyline 300 mg daily, 13 days after lithium carbonate 300 mg three times daily was started. After recovery, combined therapy was resumed, but further seizures occurred 10 days later. Her lithium levels were 0.9 mmol/L three days before this second episode. She later took amitriptyline 500 mg daily without adverse effect. Another patient developed neuroleptie malignant syndrome after one week of treatment with lithium carbonate 300 mg and amitriptyline 25 mg, both three times daily. The patient had also received chlorpromazine for one week, just before the lithium-antidepressant therapy was started. No pharmacokinetic interaction was found in 10 therapy-resistant patients with major depression who were given amitriptyline and lithium for 4 weeks. ... 

Whatever the mechanism, a pharmaceutical incompatibility between sodium heparin and chlorpromazine hydrochloride solutions is confirmed. The clinical significance of an interaction between the two drugs after administration has not been demonstrated. The type of electrode reaction demonstrated in the model in vitro system may occur in vivo, because a biological membrane has been shown to be capable of acting as an electrode and it known that heparin is taken up by cell membranes. Binding of chlorpromazine to other mucopolysaccharides may be of significance in the pharmacokinetic disposition of the drug. 

Koytchev, R. Aiken, R.-G. Kirkov, V. Neshev, G. Vagaday, M. Kunter, U. Absolute Bioverfiigbarkeit von Chlorpromazin, Promazin und Promethazin [Absolute bioavailability of chlorpromazine, promazine and promethazine]. Arzneimittelforschung, 1994, 44, 121-125 [column temp 40 LOD 1-2 ng/mL serum pharmacokinetics]... 

ABSTRACT. From the gross and histological examinations, B-cyclodextrin (B-CyD) was found to reduce the muscular tissue damage produced by chlorpromazine hydrochloride (CPZ) on M. vastus lateralis in rabbits. The protective effect of B-CyD may be attributable to the decrease in affinity of CPZ to the tissue membrane through inclusion complexation. There was no appreciable difference in the pharmacokinetic and pharmacodynamic behaviors between CPZ and its B-CyD complex in rabbits. These results suggest that 3-CyD is useful to reduce the local tissue toxicity of CPZ without altering the pharmacological efficacy. 

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