Nonlinear kinetics of nortriptyline in every day practice.
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Biomedical subjects
Publications and source records attributed to S Vandel.
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Nineteen major depressed inpatients were treated over three weeks with desipramine. Cardiac beta-adrenergic receptor sensitivity was evaluated by an isoproterenol test before and after the three-week treatment. Desipramine induced a beta-adrenergic sensitivity decrease in most of the patients: I 20 (isoproterenol dose necessary to increase by 20 beats/min. the basal heart rate) before treatment: 89 +/- 37 ng/kg (mean +/- SD); after treatment: 170 +/- 135 ng/kg; p(t) less than 0.03. Despite a linear relationship between pretreatment beta-adrenergic sensitivity and post-treatment clinical state, there was no relation between post-treatment cardiac beta-adrenergic sensitivity and therapeutic response or even desipramine plasma levels.
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The debrisoquine/sparteine phenotype was determined in 51 patients with depression, who were subdivided into 3 groups in terms of their drug treatment. Log (MR) for each group was compared. Patients treated with benzodiazepines had the same distribution of log (MR) as the healthy population, but the distribution was shifted towards higher values in patients treated with neuroleptics and antidepressants. It appears that the phenotypic expression of debrisoquine oxidation may be modified by drugs whose metabolism follows the same route as debrisoquine. The debrisoquine test must be carefully interpreted in patients receiving several drugs in the same time.
The linearity of the (AMT) kinetics of amitriptyline has been tested in 135 depressed dosed twice daily by measuring plasma. Their (AMT) and nortriptyline (NT) levels under steady-state conditions. The AMT concentration/dose ratios at low and high dosages were not significantly different and there was a linear relationship between the dose ratios and the concentration ratios. No change in the metabolic ratio (AMT/NT) was observed between the two dosages. Although the results are consistent with linear AMT kinetics, there may have been nonlinear kinetics in some patients as the ratio between the concentration/dose ratios in them at low and high dosages was greater than one. Those patients were characterized by a low concentration/dose ratio at low dosage. No clinical adverse effect appeared in the study.
The authors present a prospective study of a rapid desipramine dose adjustment on the basis of a 24-hour plasma concentration after a single 150 mg dose. For this, they use a prediction table constructed from data in the literature showing strong correlation between steady-state plasma levels and 24-hour single-dose levels. Despite the fact that desipramine action is not always linear, the method appears to be feasible and valid. In an attempt to reach a 150 ng/ml level, the authors obtained steady-state levels ranging from 85 to 317 ng/ml, with 14 of the 19 patients in the range between 125 and 250 ng/ml. Moreover, 11 of the 19 patients received a daily dose of 250 mg or more desipramine from the third day of treatment onward; in ten of these cases, this dose had been adapted.
The authors studied the responsiveness of cardiac beta-receptors to isoproterenol, a noradrenergic agonist, in 29 depressed patients and 13 control subjects. They showed a significantly lower sensitivity in depressed patients as compared with the control subjects. Focussing on the group of depressed patients without antidepressant treatment in the month preceding the study (n = 15) in order to avoid a bias, the following significant results were obtained: cardiac beta-adrenergic receptor sensitivity was lower in patients suffering from endogenous depression than in those suffering from reactive depression (as classified by Newcastle Scale). There was a negative linear relation between cardiac beta-adrenergic sensitivity and the posttreatment clinical state (as expressed by the MADRS score) for the 9 patients who ended a 3-week desipramine treatment period.
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The effects of valpromide on amitriptyline (AMT) and nortriptyline (NT) plasma levels were examined in 20 depressed inpatients. They all were treated with AMT, 125 mg once daily, and 10 patients also received 600 mg of valpromide daily after 10 days on AMT. In the 10 patients receiving valpromide in addition to AMT, the mean AMT level increased from 70.5 +/- 35 to 105.5 +/- 49 ng/ml (p less than 0.0003) and the mean NT level from 61.0 +/- 34 to 100.5 +/- 65 ng/ml (p less than 0.01). This increase was not related to valpromide metabolite plasma levels, nor to the age of the patients. The addition of valpromide to a stable AMT regimen may result in an increase of antidepressant plasma level with clinical implications.
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The biotransformation modification of amitriptyline by phenothiazines has been studied in 65 depressive inpatients. Thirty-four of them were treated with oral amitriptyline and 31 with a combination of amitriptyline and phenothiazine. Urinary and plasmatic results showed a decrease in hydroxylated metabolites of amitriptyline (OHAMTc and OHAMT) in patients with added phenothiazine.
A number of treatment failures occurring during antidepressant treatment may be related to the pharmacokinetics of the drug used. In fact, numerous factors are able to modify the fate of the antidepressant in the body. These factors may involve the absorption, distribution, biotransformation or elimination of the drug. The reality of these problems is illustrated by a number of clinical case reports. Such modifications lead to a variation in the quantity of drug available to exert its antidepressant action at the sites responsible for the pharmacodynamic effects. This raises the possible value of defining, and then using in practice, the therapeutic zone of the plasma concentrations of the antidepressant used, below and above which a poor therapeutic response is likely. Modern analytical techniques actually allow the routine analysis of plasma concentrations of a number of antidepressants, resulting in a more rational approach to drug therapy and a decrease in the number of depressions resistant to antidepressant treatments.
Urinary elimination of HVA, MHPG and 5-HIAA was studied in 22 depressed inpatients before and after 28 days of antidepressant treatment. Mean values did not change significantly during treatment, and were not related significantly to recovery in patients. Some marked changes in urinary metabolite levels were, however, observed in individual patients, and could be related to changes in their depression. The direction of change in urinary monoamine metabolites during treatment was associated with pretreatment levels, in that high pretreatment values tended to decrease whereas low pretreatment levels tended to increase.
Results of a study in nine alcoholic patients designed to investigate the effects on wakefulness of tiapride combined with alcohol are presented. Each patient was given successively alcohol, tiapride, and both. Changes in certain psychomotor performances during each of these three periods are described. In the study patients, the tiapride-alcohol combination produced no detrimental effect on wakefulness; on the contrary, results of one of the tests were improved.
The metabolism of amitriptyline (AMT) has been studied in two groups of depressed in-patients on long term AMT therapy: 11 patients with no other major disease and 8 patients with chronic renal failure, who were being dialysed. The patients with renal insufficiency had decreased concentrations of AMT, nortriptyline (NT) and their unconjugated hydroxymetabolites compared to patients with normal kidney function. The plasma levels of conjugated products were extremely high in the uraemics. The latter metabolites are probably inert. The reduced concentration of unconjugated hydroxymetabolites , which are active compounds, may decrease the clinical effectiveness of the drug.
The biotransformation of amitriptyline (AMT) during steady state conditions was studied in plasma and urine from 11 nonalcoholic and 10 alcoholic depressive inpatients treated with oral AMT. The 2 groups of patients had a different pattern of biotransformation. The Demethylation of AMT was lower in alcoholic than in nonalcoholic depressive patients, and conjugation and hydroxylation of AMT were also more marked in the former group. The results may be of clinical relevance since the conjugates of AMT are inactive.
The clinical importance of pharmacokinetic studies of psychotropic drugs is described. First, definitions of the main pharmacokinetic parameters which allow accurate evaluation of the fate of a drug in the organism are given. Secondly, two important points are considered: the variability of drug plasma concentrations from one patient to another with identical doses makes "standard dosages" worthless; current data evidences correlations between the therapeutic effect of a drug and it's plasma concentrations. Clinical implications of the above points are as follows: adjustment and prediction of dosages; definition of rational precepts of prescription; definition of principles for monitoring treatment. These implications are exemplified by clinical cases reported in the medical literature or seen in the department of psychiatry at the university hospital in Besançon.
The urinary excretion of amitriptyline (AMT) and seven of its metabolites was studied by mass spectrometry in 10 depressive in-patients treated to steady-state condition with oral amitriptyline. An average of 68.3% of the dose was recovered in the urine, of which 68.6% was present as conjugates. Hydroxynortriptyline and its conjugate represented 54% of the total recovery. There was marked variation in metabolite pattern between patients. The variations were not due to concomitant medication with benzodiazepines. There was no correlation between the plasma and urine concentrations of AMT and its metabolites, except for amitriptyline conjugates. Two groups of patients could be distinguished - low and high excretors, who displayed alternative routes of metabolism. The disappearance rate of AMT from plasma was determined by the metabolic clearance of AMT to its metabolites. It varied considerably between patients.