Plasma Chlorpromazine Research Articles

Probable Case of Neuroleptic Malignant Syndrome Following Administration of Antituberculotic Drugs in a Chlorpromazine-Treated Patient

Neuroleptic malignant syndrome (NMS), a potentially fatal adverse reaction to neuroleptics, is known to occur more often in the initial stage of antipsychotic treatment. We describe a patient with chronic schizophrenia who, in a few days after the addition of antituberculotic drugs to his antipsychotic regimen, developed probable NMS without pyrexia. We reasoned that rifampin, a strong hepatic enzyme inducer, decreased the plasma chlorpromazine concentration of the patient, with the result of cholinergic hyperactivity and finally, the symptoms of NMS. Therefore, physicians should be aware of drug interactions and the likelihood of NMS, and consider antipsychotic dose adjustment when prescribing drugs that may influence pharmacokinetic properties of antipsychotics in a patient with schizophrenia receiving long-term antipsychotic treatment.

Intérêt des antidépresseurs chez le patient schizophrène présentant un syndrome dépressif

Resume La depression est frequente chez les patients schizophrenes (7 a 75%), a l’origine d’un handicap fonctionnel. Elle est de plus associee a une augmentation des rechutes et du risque suicidaire. Une attitude courante consiste en la prescription associee d’antidepresseurs et d’antipsycho-tiques chez ces patients (11 a 43%). L’existence d’interactions metaboliques et pharmacocinetiques entre antidepresseurs et antipsychotiques merite d’etre connue. Pour l’evaluation de la symptomatologie depressive chez le patient schizophrene, les echelles non specifiques sont les plus utilisees (HDRS, BDI, MADRS), et ce malgre l’existence d’echelles specifiques permettant la distinction entre les signes negatifs et depressifs (CDS, PDS). L’effet d’un antidepresseur chez le patient schizophrene presentant une symptomatologie depressive n’a fait l’objet que de peu d’etudes controlees comprenant un groupe placebo, etudes pourtant necessaires en l’absence de traitement de reference. Une meta-analyse recente a montre que l’effet benefique des antidepresseurs (tricycliques, inhibiteurs de la recapture de la serotonine ou autres) chez le patient schizophrene presentant une symptomatologie depressive etait demontre, mais seulement avec un faible niveau de confiance. Parmi les inhibiteurs de la recapture de la serotonine, la sertraline est la seule molecule a avoir fait l’objet d’etudes comparatives controlees contre placebo.

The use of a side effect as a qualitative indicator of plasma chlorpromazine levels

Chlorpromazine (CPZ) is widely used in South African hospitals. The purpose of this study was to determine whether any physiological parameter (side-effect) could be correlated with plasma concentrations of CPZ or its metabolites. In the absence of a blood level, such a correlation could serve as a qualitative indicator of the amount of chlorpromazine in the body. Such a marker can assist the psychiatrist with therapeutic decisions regarding poor compliance and the lack of response with the drug. Fifteen schizophrenic patients were included in this study and regression analysis was used to determine any correlation between CPZ, 7-hydroxychlorpromazine, Chlorpromazine- N-oxide, Nor 1 chlorpromazine, Nor 2chlorpromazine, chlorpromazine sulfoxide, Nor 2 chlorpromazine sulfoxide and blood pressure, pulse rate, sedation and finger tremor. No correlation was seen between blood pressure or pulse rate and plasma concentrations of CPZ or the metabolites. A good correlation was seen between sedation, 7- hydroxychlorpromazine ( P=0.035) and chlorpromazine sulfoxide ( P=0.016). The results suggest that as the levels of chlorpromazine sulfoxide increase, the probability of sedation increases, while increasing levels of 7-hydroxychlorpromazine have the opposite effect. A good correlation was also seen between finger tremor and chlorpromazine levels ( P=0.035). These results suggest that there is a 50% probability that the patient would experience finger tremor when the plasma concentration of chlorpromazine is 46 ng/ml. This study demonstrated the potential for the use of sedation and finger tremor as qualitative indicators of the plasma concentration of CPZ and two metabolites. Further studies with larger patient numbers are warranted.

Effects of Trihexyphenidyl on Plasma Chlorpromazine in Young Schizophrenics*

This study investigated the effects of trihexyphenidyl on chlorpromazine (CPZ) plasma levels and clinical state in 20 relatively young schizophrenic patients diagnosed using the DSM-III. Spontaneous changes in CPZ plasma levels over time were also examined. Trihexyphenidyl significantly increased CPZ plasma levels (average 41%) but did not produce clinical change. The trihexphenidyl-induced increase in CPZ plasma levels was independent of CPZ oral dosage and of CPZ plasma levels. Chlorpromazine plasma levels decreased non significantly (about 13%) over the four weeks following steady state, but there was marked inter-subject variability, and CPZ levels rose in some subjects. Although identical CPZ doses produced widely variable plasma levels, CPZ plasma levels correlated significantly with oral dose. The views that antiparkinsonian drugs interfere with neuroleptic efficacy, and do so by lowering neuroleptic plasma levels, are questioned.

Plasma Nor1-Chlorpromazine Concentrations

Plasma nor1-chlorpromazine (nor1-CPZ) and chlorpromazine concentrations were measured by gas chromatography--mass fragmentometry in 15 inpatients receiving stable doses of chlorpromazine. Nor1-CPZ concentrations averaged 20% of chlorpromazine concentrations and were highly correlated with them. Relative concentrations of nor1-CPZ increased with age. Nor1-CPZ concentrations per milligram dose were higher in black than in white patients.

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)

Changes in plasma and erythrocyte chlorpromazine concentrations during sample storage

Changes in plasma and erythrocyte chlorpromazine concentrations during sample storage

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.

Does a plasma level of chlorpromazine help?

Forty-eight newly admitted schizophrenic patients were treated with a fixed, conservative (6.6 mg/kg) dose of chlorpromazine (CPZ) for 28 days. CPZ plasma levels were measured by a gas chromatography mass spectrometry method (GCMS) using 2H6-chlorpromazine as an internal standard. At the end of the fixed-dose period, "responders" had the same plasma levels as "non-responders", suggesting that lack of response is primarily a matter of the illness' sensitivity to CPZ, not to a plasma level below some therapeutic window. After the fixed-dose period, the dosage of CPZ was increased in the "non-responders" by physician's choice. Improvement occurred over a wide range of 10-225 picomoles (3-72 ng)/ml. Above 300 picomoles (95 ng/ml) 4 inaccessible patients eventually became much worse, suggesting psychotoxicity. It is in the inaccessible patient whose illness is only minimally, or not at all, sensitive to CPZ that a plasma level might be especially useful. Interpretation of plasma levels is complicated by the speed of response: some initial non-responders improved by the 56th day of treatment on very conservative plasma levels.

High-performance Liquid Chromatographic Assay for Nanogram Determination of Chlorpromazine and its Comparison with a Radioimmunoassay

A specific and sensitive high-performance liquid chromatographic (HPLC) method for the quantitative determination of plasma chlorpromazine concentrations is described. The procedure is capable of determining 1 ng of chlorpromazine/ml and is adequate for following plasma concentration-time profiles after 7-mg single intravenous doses. After a simple organic extraction of the drug and an internal standard (mesoridazine) from plasma, the organic layer was transferred to a vial and evaporated to dryness at 55d̀ under nitrogen. The residue was dissolved in 200 μl of HPLC grade acetonitrile. Aliquots (70-100 μl) were chromatographed, and the drug was quantitated in the range of 1-15 ng/ml of plasma using a fixed-wavelength UV detector. Plasma concentrations determined by the method were compared with those obtained by a previously reported radioimmunoassay specific for chlorpromazine and N-desmethylchlorpromazine. The two methods agreed favorably with a correlation coefficient of 0.993 and a slope of 0.994.

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.

Interaction of Chlorpromazine and Nortriptyline in Patients with Schizophrenia

Seven male inpatients suffering from acute schizophrenia were treated with chlorpromazine elixir 100mg 8-hourly for 9 weeks. Nortriptyline 50mg 8-hourly was added during weeks 4, 5 and 6. Plasma chlorpromazine concentrations, antipyrine plasma half-life, blood pressure, pulse rate, pupil size, salivation, handwriting and clinical state were measured at weekly intervals. Plasma chlorpromazine concentrations rose when nortriptyline was added, and the antipyrine plasma half-life was prolonged. Blood pressure dropped on institution of chlorpromazine and dropped further with the addition of nortriptyline. The pulse rate rose in a parallel fashion. Pupil size, salivation and handwriting were diminished by chlorpromazine, but hardly affected further by nortriptyline. The addition of nortriptyline dramatically reversed the therapeutic actions of chlorpromazine, mainly through pharmacodynamic interaction. It is concluded that this combination is potentially deleterious, and must be used with care.

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.

Induction of microsomal enzyme activity by flupenthixol [proceedings

British Journal of Clinical PharmacologyVolume 9, Issue 3 p. 313P-313P Free Access Induction of microsomal enzyme activity by flupenthixol [proceedings] SA Salem, SA SalemSearch for more papers by this authorDJ King, DJ KingSearch for more papers by this authorDG McDevitt, DG McDevittSearch for more papers by this author SA Salem, SA SalemSearch for more papers by this authorDJ King, DJ KingSearch for more papers by this authorDG McDevitt, DG McDevittSearch for more papers by this author First published: March 1980 https://doi.org/10.1111/j.1365-2125.1980.tb04868.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References Breckenridge, A. (1975). Clinical implications of enzyme induction, in Enzyme Induction, edited by D. V. Parke, Basic Life Sciences 6, Plenum Press, London and New York, p. 273– 301. Latham, A.N., Padgham, C. & Hennyk-Gutt, R. (1974). The effect of fluphenazine decanoate (Moderate) on hepatic microsomal enzyme activity in man. Br. J. clin. Pharmac., 1, 277– 278. Loga, S., Curry, S. & Lader, M. (1975). Interaction of orphenadrine and phenobarbitone with chlorpromazine plasma concentration and effect in man. Br. J. clin. Pharmac., 2, 197– 208. Richens, A. (1974). The clinical consequences of chronic hepatic enzyme induction by anticonvulsant drugs. Br. J. clin. Pharmac., 1, 185– 187. Stevenson, I.H. (1977). Factors influencing antipyrine elimination. Br. J. clin. Pharmac., 4, 261– 265. Volume9, Issue3March 1980Pages 313P-313P ReferencesRelatedInformation

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.

Disappearance of chlorpromazine from plasma following drug withdrawal

Plasma chlorpromazine measured by a gas chromatographic procedure was found to disappear rapidly during the first week after withdrawal of chlorpromazine treatment in a group of 17 chronically hospitalized patients. The drug or its metabolites were no longer measurable in plasma after 8 days.

Correlation between plasma chlorpromazine and its metabolites and clinical ratings in patients with acute relapse of schizophrenic and paranoid psychosis.

Nine patients diagnosed as having acute schizophrenic psychosis were treated with chlorpromazine. Their clinical response to drug treatment was measured by the use of a clinical rating scale developed from the Present State Examination, and a nurses rating scale. Plasma levels of chlorpromazine (CPZ), 7-hydroxychlorpromazine (7OHCPZ), monodesmethylchlorpromazine (NOR1CPZ) and chlorpromazine sulphoxide (SOCPZ), were monitored during the period of hospital treatment. Correlations were made between the increase in plasma levels of drug or metabolites and improvement in the different PSE scores. These showed that the most significant correlations occurred when symptoms with high diagnostic significance for schizophrenia (Group 1) and symptoms rating perceptual disorders (P) were correlated with plasma 7OHCPZ levels in plasma samples taken before the first morning dose of CPZ. The ration of 7OHCPZ to CPZ in these samples increased significantly as clinical ratings improved, this correlation being most highly significant against the Group 1 and P scores. The ratio of 7OHPCZ to SOCPZ increased significantly only in the case of Group 1 and P scores. This indicates a preferential shift of CPZ metabolism towards the formation of the active 7OHCPZ during the period of clinical improvement.

Clinical significance of plasma chlorpromazine levels. I. Plasma levels of the drug, some of its metabolites and prolactin during acute treatment.

Seventeen acute psychotic patients were studied in the course of chlorpromazine (CPZ) treatment. Blood samples were taken weekly both before and two hours after the morning CPZ dose. Plasma levels of CPZ, CPZ sulphoxide (CPZ SO) monodesmethylated CPZ (NOR1CPZ) and 7-hydroxy CPZ (7OH CPZ) were estimated by gas chromatography. Plasma prolactin, luteinizing hormone, testosterone and oestrogens were measured by radioimmunoassay. Six of the seven patients who showed no clinical improvement had plasma CPZ levels equal to or higher than those of patients who improved. 'Non-responders' has a greater proportion of CPZ SO in pre-dosage samples. The occurrence of parkinsonian side effects was associated with a mean plasma CPZ of greater than 50 ng/ml and a mean plasma prolactin of greater than 30 ng/ml two hours after dosage. The elevation of prolactin preceded the onset of parkinsonian symptoms by 1-2 weeks. There was a significant positive correlation between mean plasma prolactin and mean plasma CPZ levels. The prolactin response may prove a useful index of the central antidopaminergic effect of neuroleptic drugs.