Chlorpromazine Levels Research Articles

Pharmacokinetics of neuroleptic drugs and the utility of plasma level monitoring.

Variability in response to antipsychotic drug treatment may be caused by variable patient compliance, interactions with other drugs, pharmacokinetic variations and variations in concentration-response relationships at the receptor level. Pharmacokinetic variations may in some cases be compensated by individual dosage adjustments based on plasma drug level measurements. The interpatient variability in response to a certain time-course of drug concentrations at the receptor site could hitherto only be assessed by clinical judgement. New methods for in vivo assessment of receptor occupancy hold promise for possible measurement of parameters accounting for at least part of the interindividual variation in drug response at the receptor level. Monitoring of fluphenazine, perphenazine, thiothixene and sulpiride plasma levels by specific chemical assay methods seems to offer some guidance to individualization of drug doses. Definite therapeutic plasma level ranges have not been established for chlorpromazine and haloperidol. However, monitoring plasma levels of chlorpromazine or haloperidol might be of value when drug-induced toxicity is suspected, and as a means of controlling patient compliance.

Effect of trifluoperazine and other drugs on matrix vesicle formation by chicken growth plate chondrocytes in primary cell culture

Growth plate chondrocytes in primary culture release alkaline phosphatase (AP)-rich matrix vesicles (MV) into the culture medium. While these are thought to derive from the plasma membrane by a membrane fusion-dependent process, the mechanism is not fully understood. Recently, a cytosolic protein, synexin, has been shown to promote membrane fusion in a number of systems, and thus may be involved in MV formation. Since the action of synexin is selectively inhibited by trifluoperazine (TFP) and other phenothiazines, we examined the effects of these drugs, and imipramine, on cellular AP production and formation of AP-containing MV by cultured chondrocytes. In addition, we studied the effect on cell division, protein biosynthesis, and incorporation of palmitate into cellular and MV lipids. All of the drugs reduced cellular AP in a concentration-dependent manner; however, at the higher levels, chlorpromazine (CPZ) and TFP caused a transient sharp rise in MV AP activity. At IC 50 levels, the drugs were more inhibitory to cellular AP than to MV AP, appearing to enhance significantly the transfer of available cellular AP into MV. In contrast, the drugs stimulated incorporation of [ 3H]palmitate into cellular lipids, but either had no effect on, or actually inhibited, incorporation of the fatty acid into MV. At these levels, the drugs had little effect on cell division and protein biosynthesis. The inhibitory effect of IC 50 levels of CPZ on palmitate incorporation into MV appears to have resulted from impairment of vesicle formation per se, since at these levels the drug stimulated incorporation of the fatty acid into the cells. The transient stimulatory effect of higher levels of CPZ on MV AP levels, and the enhanced transfer of AP into MV by the drugs generally, may result from the effect of the drugs on membrane structure. Since TFP was not inhibitory to MV formation, it is doubtful that synexin was directly involved.

Plasma level monitoring of antipsychotic drugs. Clinical utility.

The steady-state plasma concentrations of antipsychotic drugs show large interpatient variations but remain relatively stable from day to day in each individual patient. Monitoring of antipsychotic drug concentrations in plasma might be of value provided the patients are treated with only 1 antipsychotic drug. Some studies have reported a relationship between therapeutic response and serum antipsychotic drug 'concentrations' as measured using the radioreceptor assay (RRA) method, which measures dopamine receptor-blocking activity in plasma. Most studies, however, have failed to demonstrate such a relationship, and the RRA does not seem to provide the generally useful tool for plasma concentration monitoring of antipsychotic drugs that was hoped for initially. A lack of correlation between dopamine receptor-blocking activity in plasma and therapeutic response may be due to differences in the blood-brain distribution of both antipsychotic drugs and their active metabolites. Chemical assay methods (e.g. GLC and HPLC) have been used in studies which examined the relationships between therapeutic response and antipsychotic drug concentrations in red blood cells and in plasma. It seems that for these drugs, measuring red blood cell concentrations does not offer any significant advantage over measuring plasma concentrations. Reasonably controlled studies of plasma concentration-response relationships using randomly allocated, fixed dosages of chlorpromazine, fluphenazine, haloperidol, perphenazine, sulpiride, thioridazine and thiothixene have been published but often involve relatively few patients. A correlation between therapeutic response and plasma concentrations of thioridazine and its metabolites has not been demonstrated, and plasma level monitoring of thioridazine and its metabolites therefore appears to have no clinical value. Clinical behavioural deterioration concomitant with high plasma concentrations of chlorpromazine and haloperidol have been reported. A dosage reduction might be considered after 2 to 4 weeks' treatment in non-responders who have plasma chlorpromazine concentrations above 100 to 150 micrograms/L or plasma haloperidol concentrations above 20 to 30 micrograms/L. Non-responders and good responders to chlorpromazine treatment, however, have plasma drug concentrations in the same range, and a therapeutic range of plasma chlorpromazine levels has not been defined. Therapeutic plasma haloperidol concentrations (i.e. 'window') in the range of 5 to 20 micrograms/L have been reported by some investigators, but others have found no such relationship.(ABSTRACT TRUNCATED AT 400 WORDS)

Blood levels of neuroleptics: state of the art

Difficulties in developing techniques to measure plasma levels of neuroleptic drugs have included the presence of metabolites, as well as cross-reactivity not only between these metabolites and the parent compound but between drugs (e.g., a phenothiazine and a tricyclic). Although newer techniques have minimized some of these problems, interpretation of published data must also recognize such design limitations as variable dose, small sample size, etc. The literature is reviewed on the relationship between therapeutic response and plasma levels of chlorpromazine, thioridazine, thiothixene, fluphenazine, butaperazine, and haloperidol. It is suggested that additional studies, carefully designed, on dosage and plasma levels could help in achieving the lowest possible therapeutic dosage and thus in minimizing side effects.

Interaction of chlorpromazine with the human erythrocyte membrane.

The interaction of the amphipath chlorpromazine (CPZ) with the human erythrocyte membrane was evaluated. The partition coefficient of CPZ between the membrane bilayer and the aqueous compartment, measured spectrophotometrically, ranged between 1 and 3 X 10(3). An independent estimate, 4.6 X 10(3), was obtained by a novel method which avoided the measurement of binding and determined instead the variation of the hemolytic potency of the amphipath with the ratio of buffer volume to membrane volume. The maximal uptake of CPZ exceeded 2 X 10(9) molecules/red cell, corresponding to a volume greater than that of the bilayer itself. Such heavily loaded membranes were increased in thickness more than 2-fold, suggesting the formation of a CPZ-rich zone at the center of the bilayer. Ghosts loaded with massive levels of CPZ condensed approximately 20-fold in surface area and increased proportionately in thickness, suggesting the formation of a novel CPZ-lipid solution. CPZ caused hemolysis by a colloid-osmotic mechanism. By measuring the simultaneous uptake of mannitol and sucrose, we determined that CPZ induced holes of constant size but variable number. If circular, the holes would have had a diameter of approximately 14 A. The time-averaged number of holes ranged from 0.09 per cell (signifying intermittency) to 16. Freeze-fracture electron microscopy of CPZ-treated red cells revealed multiple round patches of nearly particle-free bilayer up to 0.3 micron in diameter with crowding of the intramembrane particles into the surrounding membrane. We interpret these images to signify lateral phase separation within the CPZ-treated bilayer. Hemolysis could, therefore, result from the intermittent opening of weak seams at phase boundaries; these could then be fluctuating slits approximately 14 A in width and of variable length, rather than simple circular holes.

Subnanogram Quantitation of Chlorpromazine in Plasma by High-Performance Liquid Chromatography with Electrochemical Detection

A specific and sensitive high-performance liquid chromatographic (HPLC) method for the quantitative determination of subnanogram levels of chlorpromazine in plasma is described. Following extraction of chlorpromazine and the internal standard, prochlorperazine, HPLC analysis is carried out on a cyano column with a mobile phase consisting of 0.1 M ammonium acetate in acetonitrile (10:90 v/v). The use of oxidative thin-layer amperometric detection allowed the quantitation of 0.25ng of chlorpromazine/ml of plasma with a coefficient of variation of 5.1%. The HPLC method has adequate sensitivity to follow plasma concentration–time profiles up to 24hr following low single oral doses of chlorpromazine in healthy volunteers.

Pattern of Recovery from Scbizophrenic Psychosis at 2 dosage levels of Chlorpromazine

Pattern of Recovery from Scbizophrenic Psychosis at 2 dosage levels of Chlorpromazine

Regional aspects of the delay of acquisition conditioned avoidance responding by chlorpromazine

Chlorpromazine injected into the amygdala, septum, or caudate delayed the acquisition of a one-way active avoidance response. Injections into nine other brain areas were inactive. Following a standard dose of chlorpromazine at its ED 50 for delaying avoidance acquisition, tissue levels of chlorpromazine from those animals displaying reduced acquisition were significantly higher in the caudate and amygdala than from animals not demonstrating a drug effect.

Problems in therapeutic blood monitoring of chlorpromazine.

Chlorpromazine (CPZ) therapeutic drug monitoring is beset by inconclusive and controversial evidence on the positive correlation of plasma CPZ concentration and psychiatric improvement. Failure to establish meaningful correlation between plasma concentration and clinical benefit may be explained by chemical assay problems; differences in the pharmacokinetic plasma CPZ and metabolite profile due to age, acuteness or chronicity of the disease; drug interactions; and duration of neuroleptic treatment. At the other end, measurement of clinical effects in psychiatry suffers such drawbacks as less distinct and specific clinical end points, the patient's subjectiveness of symptoms and the investigator's subjectiveness on clinical scoring, and the ethical consideration of placebo use. Our data showed the following:L (1) Plasma levels of CPZ parent compound correlated better with improvement in thought disorders and paranoid delusion than with total Brief Psychiatric Rating Scale; there were no correlations with depression and withdrawal retardation. (2) Chronically treated patients achieved significantly lower plasma CPZ compared to acutely treated patients on oral CPZ dose but not those treated with an intramuscular dose. (3) Children, in comparison to adults, require higher doses to achieve similar plasma CPZ levels and have a lower response threshold, both for clinical improvement and toxicity. (4) The plasma concentration of CPZ can be diminished by concomitant use of anticholinergics. (5) A drug "holiday" increases peak plasma concentration of CPZ and may benefit the nonresponders.

Effect of intramuscular chlorpromazine on serum prolactin levels in schizophrenic patients and normal controls

Serum prolactin levels were monitored for 2 hours after injection of chlorpromazine (CPZ) 50 mg intramuscularly (i.m.) in 6 male normal controls and 14 newly admitted male chronic schizophrenics. The increase in serum prolactin levels in the male normal controls was not significantly different from that in patients. Serum prolactin levels were compared in 18 male and 22 female psychotic patients of various psychiatric diagnoses who received 50 mg of CPZ i.m., and 7 male and 6 female patients who received 25 mg CPZ i.m. No significant sex or dose differences were seen in the magnitude of the prolactin response after i.m. CPZ. These results suggest that doses of CPZ 25 or 50 mg i.m. may result in maximal prolactin secretion in most subjects and that lower doses are needed to test the hypothesis that dopamine receptors are supersensitive in schizophrenia or the affective psychoses. In six patients with mixed diagnoses, serum levels of CPZ and other active metabolites were determined by radioreceptor binding assay; peak serum drug levels were highly correlated with peak serum prolactin levels ( r=0.92) during the first 2 hours following CPZ 50 mg i.m.

Pharmacokinetics and dosage of chlorpromazine in goats.

Pharmacokinetic parameters which describe the distribution and elimination of chlorpromazine in goats were determined. Following the intravenous administration of a single dose (2.5 mg/kg), disposition of the drug was described in terms of the biexponential expression Cp = Ae-alpha t + Be-beta t. Based on total (free and bound) chlorpromazine levels in plasma, pseudo-distribution equilibrium was rapidly attained, and the elimination half-life was 1.51 +/- 0.48 h (mean +/- SD, n = 8). Total body clearance, which is the sum of all clearance processes, was 80 +/- 25 ml/min/kg. The curves of an animal representative of the group, based on individual rate constants associated with the two-compartment open model, showed that at 5 h after drug administration 8% and 6% of the dose were present in the peripheral and central compartments, respectively. The kinetic parameters of chlorpromazine determined at a dosage level of 10 mg/kg body weight in six goats showed that the drug followed first-order kinetics and kinetic parameters were similar after both dose levels. Based on these findings and therapeutic plasma levels, a satisfactory intravenous regimen should be 2.0-3.5 mg/kg and the drug action will persist for 5-6 h.

Thin-layer differential pulse voltammetric determination of chlorpromazine in biological fluids

The combination of a thin-layer electrochemical cell with differential pulse voltammetry can be used to determine chlorpromazine in plasma and urine. The thin-layer cell (23 μl capacity) has a wax-impregnated graphite electrode. Direct determination of chlorpromazine in urine gave a linear calibration curve for the range 4.8 × 10 -3–2.4 × 10 -4 M with 97% recovery. No interference from glutethimide, dextropropoxyphene, meprobamate, diazepam, and methaqualone-HCl was detected. Direct measurement of chlorpromazine in plasma gave a linear calibration curve for the range 2.4 × 10 -5–4.8 × 10 -4 M with 89% recovery. The procedure for plasma and urine requires only 2 min per determination. Detection levels are below that required for monitoring therapeutic levels of chlorpromazine in urine.

Effect of a drug holiday on plasma chlorpromazine levels in chronic schizophrenic patients.

Low chloropromazine (CPZ) levels have been measured in chronically treated schizophrenics. We tested six such patients to determine whether a 2-week CPZ-free period (drug holiday) would improve plasma CPZ levels. We also monitored psychiatric symptoms, autonomic function, and extrapyramidal signs. We found these patients to have low predose CPZ levels that did not change appreciably after the drug holiday. Peak levels following the holiday averaged 28 +/- 7 ng/ml higher than those measured prior to the holiday. Drug holidays are safe and should be examined more thoroughly as a means of improving plasma neuroleptic levels in chronically treated schizophrenics.

Chlorpromazine levels and the outcome of treatment in schizophrenic patients.

Plasma and saliva levels of chlorpromazine hydrochloride were measured by gas chromatography-mass spectrometry, after a standard dosage had been administered to 48 newly admitted schizophrenic patients over 28 days. Other treatments were rigorously controlled. Saliva chlorpromazine concentrations were higher than plasma concentrations generally by about four to 50 times. Saliva and plasma chlorpromazine levels were significantly related. There was great variability in individuals between plasma and saliva peaks and values over time, in plasma/saliva ratios, and in change in plasma/saliva ratio over time. Chlorpromazine plasma and saliva levels at the end of fixed, sustained dosage treatment did not correlate with the amount of improvement as measured by ten criteria from the Brief Psychiatric Rating Scale and the Mobility, Affects Cooperation, and Communication Scale. Yet levels obtained in the 24 hours after the first dose did seen related to outcome, more strongly for saliva chlorpromazine than for plasma chlorpromazine levels. A reexamination is in order of our concepts of the relationships between levels of antipsychotic drugs in the body and treatment effect.

Importance of akinesia: plasma chlorpromazine and prolactin levels

Akinesia, a common side effect of antipsychotic drugs, often goes unrecognized by physician and patient. Akinetic apathy and lack of spontaneity can be mistaken for the negative symptoms of schizophrenia and add to the well-known social and emotional disability of schizophrenic patients on maintenance therapy. The authors attempted to identify a measure that might distinguish between akinesia and the negative symptoms of schizophrenia but found no relationship between plasma and saliva chlorpromazine levels or prolactin levels and akinesia. The fact that all of the akinetic but only 31% of the nonakinetic patients rated themselves as drowsy 12 hours after their bedtime dose indicates that drowsiness is a fairly accurate correlate of akinesia.

Plasma and saliva levels of chlorpromazine and subjective response.

Newly admitted schizophrenic patients (N=48) were given a test does of 2.2 mg/kg of chlorpromazine hydrochloride by mouth. Chlorpromazine was measured in plasma and saliva at 1, 2, 3 (saliva only), 4, 6, 8, 12 (saliva only), and 24 hours by gas chromatography-mass spectography. Subjective response at 4 and 24 hours after test dose was not significantly related to either plasma or saliva level even for dysphoric responders. Dyschoric responses to chlorpromazine appear to be idiosyncratic--rooted perhaps in altered recepter sensitivity or in a patient's very personal interpretation of drug effect.

Clinical significance of plasma drug and prolactin levels during acute chlorpromazine treatment: a replication study.

Nineteen patients with acute psychoses, the majority schizophrenics, were studied in the course of chlorpromazine (CPZ) treatment. Plasma levels of the drug, plasma prolactin (PRL), extrapyramidal side-effects (EPS) and changes in mental state were monitored weekly, as in our earlier study. The results confirm some of our previous findings: (a) plasma CPZ levels vary widely among patients and correlate poorly with daily doses of CPZ; (b) increased plasma PRL is associated with higher plasma CPZ levels and is more common among the patients who develop EPS; and (c) none of these three variables differ between groups of patients with good and poor treatment outcome. However we did not confirm our previous finding of a significant association between EPS and higher plasma CPZ, nor did we find that the ratio of CPZ-sulphoxide to CPZ differed between the improved patients and the rest.

Plasma chlorpromazine concentrations in children with behavioral disorders and mental illness

Plasma chlorpromazine (CPZ) levels were studied in children 8 to 15 yr of age who were receiving CPZ for mental disorders. The results showed that children need larger doses of CPZ than adults to attain comparable plasma concentrations. The apparent therapeutic plasma concentration in children (40 to 80 ng/ml) is lower than that reported for adults (50 to 300 ng/ml). In the children studied, the plasma concentrations declined despite maintained dosage, possibly because of autoinduction of CPZ metabolism. Doses of 6 to all mg/kg body weight, and even as much as 850 mg/day, were tolerated without significant side effects when administered in divided doses 3 or 4 times a day, while doses of less than 6 mg/kg/day frequently failed to produce the desired plasma CPZ levels.

Plasma levels of chlorpromazine in schizophrenia; a critical review of the literature.

Measurment of chloropromazine and metabolite levels in the blood has not yet developed such that it can help the clinician. Apart from their chemistry, the clinical aspects of the experimentql design of most studies leave much to be desired, so that it is not possible to draw any overall conclusions about the relationship between chlorpromazine blood levels and clinical outcome from the data currently available. Measurement of response to a single test dose may prove potentially more fruitful in predicting outcome and in establishing drug and dosage choice for a given patient than simple attempts to correlate sustained dosage levels with clinical response. For chlorpromazine, indeed for any drug, it would seem wise in the first instance to focus clinically well-designed studies on the parent substance, rather than launching into more costly, but clinically unsophisticated, studies of its metabolites.

Test dose response in schizophrenia: chlorpromazine blood and saliva levels.

A gas chromatographic/mass spectrometric method for measuring chlorpromazine using 2H6--labeled chlorpromazine as an internal standard has the potential for considerable precision and specificity. Results are reported of chlorpromazine levels in plasma and saliva after administration of a single test dose to 13 schizophrenic patients in a tightly designed experiment. There was a clear and substantive relationship between blood and saliva levels of chlorpromazine, both following a typical decay curve. Saliva and plasma levels were strongly associated for a particular patient, and there was even a strong consistency in saliva-plasma ratios between patients, with an overall statistically significant correlation between plasma and saliva levels for all measurement on all 13 patients. In general, it seems that saliva sampling has great potential as a simple noninvasive technique for investigation of chlorpromazine and other antipsychotic drugs in psychotic patients. Nevertheless, for the moment, it should be regarded as strictly experimental and not suitable for immediate clinical application.