Sheila Dawling

GRADUAL WITHDRAWAL OF DIAZEPAM AFTER LONG-TERM THERAPY

41 outpatients who were long-term consumers of diazepam in therapeutic dosage were gradually withdrawn from the drug over 3 months by stepwise reduction. In a double-blind procedure half the patients began withdrawal immediately and half after 8 weeks. Of 36 patients who completed treatment, 16 (44.4%) experienced true withdrawal phenomena on reducing their drugs, but 8 other patients had pseudo-withdrawal reactions at a time when their drug treatment was unchanged. The pseudo-withdrawal reactions consisted of an increase in anxiety symptoms only, whereas true withdrawal symptoms also included perceptual changes and psychotic symptoms. Examination of pharmacological and clinical predictors of withdrawal phenomena and later relapse showed that personality factors were the most important, patients with passive-dependent traits having a significantly greater prevalence of withdrawal reactions.

High plasma nortriptyline levels in the treatment of depression. I.

Following a 3‐day single‐dose kinetic study, 21 moderate to severely depressed inpatients were treated with 100 mg of nortriptyline nightly. Eighteen patients completed the 4‐wk trial. The severity of depression was measured by weekly Hamilton Rating Scale and global rating. Blood for plasma nortriptyline estimation was taken at weekly intervals 12 hr following the nighttime dose. There was a 610ld variation in mean plasma nortriptyline levels, ranging from 120 µg/L to 681 µg/L. Patients with high plasma levels (<200 µg/L) showed significantly poorer clinical responses than those with levels below this limit. This study provides very strong support for the view that, in routine treatment, high plasma nortriptyline levels are significantly less effective than intermediate levels. Single‐dose pharmacokinetic data obtained on the same patients showed a highly significant correlation with mean steady‐state plasma levels obtained, which themselves correlated with clinical response. The value of predicting high plasma nortriptyline levels which are associated with poor response is discussed.

Nortriptyline in depressed patients with high plasma levels. II

Eighteen depressed patients were routinely treated with 100 mg nonriptyline nightly for 4 wk. Steady‐state plasma nortriptyline concentrations were measured at weekly intervals for each patient at the same time as clinical assessments were carried out. Steady‐state nonriptyline levels ranged between 120 µg/L and 681 µg/L (mean, 293 µg/L), which represents a 6‐fold interindividual variation. A single oral dose of 100 mg nonriptyline was given to 17 of the 18 patients prior to treatment. Plasma nortriptyline concentrations were obtained at regular intervals over a 3‐day period. Several kinetic parameters were calculated for each patient. The plasma nonriptyline half‐life (t½) ranged from 22 to 88 hr and the plasma clearance ranged between 8 and 55 L/hr. Highly significant correlations were obtained between steady‐state nortriptyline levels and both t½ (p < 0.01) and clearance (p < 0.0001). A high correlation (p < 0.0001) was also obtained between single‐dose 48‐hr nonriptyline levels and steady‐state nonriptyline levels. We have been able to demonstrate a strong relationship between individual patient differences in nonriptyline kinetics and steady‐state plasma concentrations and associated therapeutic effects. The pharmacokinetic data obtained in the patients appear to be different to those reponed in studies carried out in normal healthy volunteers. Reasons for this are discussed. The use of simple kinetic parameters in predicting the high nonriptyline levels is also discussed.

Nortriptyline metabolism in chronic renal failure: Metabolite elimination

Single oral dose kinetics of nortriptyline and of its two major metabolites, conjugated and unconjugated 10‐hydroxynortriptyline, were studied in eight healthy subjects and 15 patients with chronic renal failure, five of whom were being treated with hemodialysis. Nortriptyline kinetics were unaltered, but the elimination of the metabolites was reduced in both groups of patients. In chronic renal failure the excretion of nortriptyline metabolites appeared to be the rate‐limiting step in nortriptyline elimination. Three depressed hemodialysis patients were treated with nortriptyline (75 mg at night) for 6 wk. The ratios of the steady‐state plasma concentrations of unconjugated 10‐hydroxynortriptyline to nortriptyline (0.74 to 2.30) were in the same range as those in a control group of depressed patients with adequate renal function (0.53 to 4.08) who were also receiving nortriptyline. Conjugated 10‐hydroxynortriptyline in renal failure patients was slow to reach steady‐state concentrations and these were 10 to 20 times as high as those of the control depressed patients. Conjugated 10‐hydroxynortriptyline in dialysis fluid during treatment showed that a mean 43 ± 7% (SD) of the dose was removed by a 10‐hr dialysis. Dialysis clearance of conjugated 10‐hydroxynortriptyline was 58 ± 8 (SD) ml min−1, but nortriptyline and unconjugated 10‐hydroxynortriptyline were not appreciably removed by dialysis. Hemodialysis is not likely to be of value in the management of acute nortriptyline poisoning.

Dosage adjustment from simple nortriptyline spot level predictor tests in depressed patients.

Summary20 routine patients with endogenous depression were investigated in a kinetic and 4 week treatment study. Steady-state plasma nortriptyline concentrations above 200μg/L were associated with a highly significant poorer therapeutic outcome.The correlations between the 24, 48 and 72 hour concentrations and steady-state concentration were very good (r = 0.81, 0.97, 0.94; p < 0.0001) and better than the correlation between half-life and steady-state (r = 0.65; p < 0.01). The Spearman rank correlations (Rs) between amelioration of depression measured by the Hamilton Rating Scale (HRS) and the 24, 48 and 72 hour concentrations were highly significant (Rs = 0.74, 0.79, 0.79; p < 0.001) but for half-life (Rs = 0.33) the correlation was not significant.The single 48 hour plasma nortriptyline concentration following a single oral dose is recommended as a reliable simplified monitoring test suitable for a busy clinic. The test is useful for dosage adjustment to maximise antidepressant action and minimise toxicity. A tentative dosage adjustment schedule for individualising antidepressant treatment with nortriptyline based on the 48 hour or the 24 hour plasma concentration is proposed.

Effect of delayed administration of activated charcoal on nortriptyline absorption

SummaryActivated charcoal is known to reduce the absorption of therapeutic doses of nortriptyline in vivo when administered 30 min after drug ingestion. In a group of volunteers, one sachet (10 g) of a new activated charcoal preparation, ‘Medicoal’ was found to produce a highly significant reduction in nortriptyline absorption when given as long as four hours after nortriptyline dosing. Activated charchoal may therefore be useful in the treatment of tricyclic antide-pressant poisoning even if a delay of several hours ensues before medical help is sought.

Nortriptyline therapy in elderly patients: Dosage prediction after single dose pharmacokinetic study

SummarySixteen depressed elderly patients in hospital (mean age 81 years) received a single oral dose of nortriptyline prior to commencing treatment with this drug. Plasma nortriptyline measurements after the single dose were used to calculate the plasma drug clearance and to predict the daily dose required for each patient to achieve a steady-state concentration within the suggested therapeutic range of 50–150 µg·l−1. Using these dosage regimes, the mean observed steady-state concentration showed a significant correlation with the predicted values (r=0.71, p<0.002). All patients had steady-state concentrations within or very close to this suggested range (mean 106, range 38–157 µg·l−1). Use of the prediction test can prevent the development of toxic plasma concentrations and enhance the possibility of therapeutic success. Our findings suggest that a safe starting dose of nortriptyline for the elderly is 30 mg per day.

Rapid measurement of basic drugs in blood applied to clinical and forensic toxicology.

A gas chromatographic method is presented to measure blood, serum or plasma concentrations of more than 40 basic drugs. The sensitivity is 0·05 mg/L or less, which represents medium-high therapeutic and overdose concentrations, and in many instances the major active metabolites are also quantified. The paper describes a single step extraction from basic solution into n-butyl acetate containing maprotiline internal standard. Disposable glass tubes are used, with direct chromatography of the upper organic layer. GLC analysis is conducted for 10 min isothermally on a packed column (3% SP2250) with nitrogen-phosphorus detection. The coefficient of variation (CV) of the assay is between 2% and 5%, and data on the reproducibility of retention times are presented.

Fatal lignocaine poisoning: report of two cases and review of the literature

1 Two fatal cases of deliberate self-poisoning with lignocaine are reported, one by oral ingestion and one by intravenous injection. Post-mortem blood lignocaine concentrations were 40 and 53 mg/l, respectively. 2 Lignocaine self-poisoning is rare since no formulations for oral use other than gels are available. However, serious toxicity can follow the oral application or ingestion of such gels, especially in children and in the elderly. Fatalities due to accidental oral overdosage with 10-25 g of lignocaine in adults have also been reported. 3 The frequent incidental occurrence of lignocaine in specimens submitted for toxicological analysis should not exclude the possibility of poisoning with this compound.

Monitoring of tricyclic antidepressant therapy

During the three-year period 1978-1980, 2141 plasma samples from 1055 patients receiving therapy with amitriptyline (77%) or nortriptyline (23%) were analysed using GLC with nitrogen selective detection. Compared to the recommended therapeutic ranges, wild inter-individual differences were observed in plasma drug concentration, even when corrections for dosage were made. Concentrations ranged from below the limit of sensitivity of the assay (5 microgram.1(-1)) to greater than 1 mg.1(-1). The reporting of toxic symptoms subjective side-effects) was found not to reliably predict high drug concentrations. Serious complications, however, were associated with high plasma drug concentrations. Neither nortriptyline nor amitriptyline displayed dose-dependent pharmacokinetics over the concentration ranges studied. Treatment with either drug produced age-related increases in drug concentration, which were more pronounced in female patients. With amitriptyline therapy, there was an age-related decrease in the plasma nortriptyline:amitriptyline ratio, suggesting that demethylation may be more influenced by increasing age than hydroxylation. Plasma drug monitoring of tricyclic antidepressant therapy is the only reliable means of ensuring that all patients receive a fair opportunity to benefit from these drugs.