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PubMed1986

Amitriptyline pharmacokinetics and clinical response: I. Free and total plasma amitriptyline and nortriptyline.

A group of 30 patients suffering from endogenous depression was treated with 150 mg amitriptyline (AT) for 21 days. Depression ratings and determinations of total and free plasma AT and nortriptyline (NT) were performed weekly. No correlation between clinical improvement and any of the biochemical parameters was found. Thus, this study does not support the existence of a therapeutic window for AT. A highly significant correlation was calculated between free and total AT and free and total NT, and also between the free fractions of AT and NT; moreover, age correlated significantly and positively with total plasma AT, but not with NT, and negatively with the free fractions of both AT and NT. The absence of correlation between clinical improvement and pharmacokinetic parameters is discussed for its possible significance. The finding that responders are also found in patients with "low" levels of antidepressants (corroborating the pharmacokinetic and pharmacodynamic data obtained in animals submitted to a long-term treatment with antidepressants) suggests that the concept of the need for steady-state levels with low fluctuations should be re-examined. In the light of these results the clinical effectiveness of treatment with higher drug doses, administered at larger intervals, in order to produce high amplitude fluctuations of the antidepressant should be studied.

Adult↗

PubMed1987

Severe nortriptyline intoxication due to change from a generic to a trade preparation.

Drug toxicity associated with a drastic increase in blood level developed when a trade preparation was inadvertently substituted for generic nortriptyline. There is a good deal of speculation that different preparations of psychotropic medications may differ substantially in bioavailability, but the frequency of variability of clinical and toxic effects is not clear. Bioinequivalence should be considered as a possible cause of otherwise unexplained changes in response to a psychoactive drug, especially if benefits and side effects are correlated with blood levels.

Adult↗

PubMedDate not supplied

The effects of nortriptyline and mesoridazine on neurons and glia in vitro.

The ultrastructural changes produced by Mesoridazine and Nortriptyline in neurons and glia in vitro are reported. Concentrically laminated bodies (CLB) and increased numbers of dense bodies were produced by exposure to these drugs. The number and complexity of the CLB increased with increased dose and longer time in vitro and their formation appeared to be reversible.

Animals↗

PubMed1982

A sensitive gas chromatographic assay for amitriptyline and nortriptyline in plasma.

A method for the quantitative determination of the tricyclic antidepressant drug amitriptyline (AT) and its active major metabolite, nortriptyline (NT), in plasma is described. The method involves a three-step extraction procedure, no derivatization, and a rapid run on a gas--liquid chromatograph equipped with a nitrogen detector. The standard curves were linear in the range of 25-1,000 ng/ml. The lower detection limit was 2-5 ng/ml for both drugs. The method is specific for AT and NT, with a recovery of AT and NT of 68 and 71%, respectively. The precision of the method, expressed as the coefficient of variation, was 10.7% for AT and 12.9% for NT within 25--1,000 ng/ml. The method has proven to be suitable for monitoring plasma levels of AT and NT in patients, and in animals during experimental studies on pharmacokinetics after therapeutic and toxic doses of NT.

Amitriptyline↗

PubMed1987

Steady-state concentrations of amitriptyline and its metabolite nortriptyline in Saudi patients.

The serum concentrations of amitriptyline (AMI) and its metabolite nortriptyline (NT) were determined in 54 Saudi patients treated for long durations with a daily oral dose (0.111 to 4.167 mg/kg) of AMI. Ten of these patients were concomitantly treated with neuroleptic drugs. The mean (SEM) of the dose-normalized steady-state serum concentration (Css) of AMI in patients who received AMI alone (Group I) was [46.1 (6.5) ng X ml-1/mg X kg-1], with mean NT/AMI Css ratio of 0.962 (0.122). A significantly higher mean of Css of AMI [82.3 (18.8 ng X ml-1/mg X kg-1] was acquired for patients who concomitantly received AMI and neuroleptic drugs (Group II). However, the difference in the mean NT/AMI Css ratio between Group I and Group II [0.929 (0.197)] was not significant. Also, the results of this study indicate that Css of AMI and the NT/AMI Css ratio in Saudi patients treated for depression with AMI alone are not significantly different from those reported for subjects from Western populations.

Amitriptyline↗

PubMed1987

Distribution of nortriptyline in human blood: effects of temperature, pH, and drug concentration.

An in vitro study of putative factors causing postvenipuncture redistribution of the tricyclic antidepressant nortriptyline (NT) in blood was carried out in blood samples from a single subject. The influence of varying temperature, pH, and drug concentration on the protein binding of NT was assessed by equilibrium dialysis. The influence of the same variables on the distribution of NT in whole blood was measured by calculating the cell/plasma (C/P) drug concentration ratios after centrifugation of blood samples. Variation in temperature did influence the distribution of NT in blood considerably. From 4 to 37 degrees C, the C/P ratio was found to increase from 1.0 +/- 0.1 to 1.7 +/- 0.2, and protein binding expressed as unbound fraction from 2.9 +/- 0.2 to 7.0 +/- 1.1% (mean +/- SD). Neither pH variations within the 7.0-7.6 range, nor variations in drug concentration, were found to alter NT distribution at 37 degrees C. The observed effect of temperature on NT distribution shows that handling of blood samples from patients taking NT should be standardized in order to avoid errors of interpretation.

Buffers↗

PubMed1993

Concurrent liquid chromatographic measurement of fluoxetine, amitriptyline, imipramine, and their active metabolites norfluoxetine, nortriptyline, and desipramine in plasma.

An expedient and specific liquid chromatographic method for a concurrent measurement of fluoxetine (FLU), norfluoxetine (NFLU), amitriptyline (AMI), nortriptyline (NTRIP), imipramine (IMI), and desipramine (DES) is described. Using a mixture of acetonitrile:methanol:0.056 M ammonium acetate:1 M ammonium hydroxide (100:10:4.5:2.6, by volume) as mobile phase, the compounds along with doxepin (DOX) (internal standard) were separated on a 10 mu, 8 mm x 10 cm C18 Resolve cartridge in conjunction with radial compression liquid chromatographic module, and were detected in the effluent spectrophotometrically at 220 nm. A hexane:isoamyl alcohol (98:2, by volume) solution was used for extraction of plasma and the drugs were removed from the organic phase with 0.03% phosphoric acid prior to injection. Under these conditions, no interference in the assay was observed, and the retention times of NFLU, DOX, FLU, AMI, IMI, NTRIP, and DES were 7.8, 11.6, 16, 17.8, 20.9, 31, and 35 min, respectively. The assay was highly linear (r > 0.994), and the within- and between-day coefficient of variance was consistently < or = 9.8%. This assay is currently being used to simultaneously measure these drugs in patients and to investigate their steady-state pharmacokinetics when used in combination.

Amitriptyline↗

PubMed1994

The use of therapeutic drug monitoring data to document kinetic drug interactions: an example with amitriptyline and nortriptyline.

Therapeutic drug monitoring data for amitriptyline (AT) and nortriptyline (NT) collected during 10 years (total of 4,278 analyses in 2,937 patients) were evaluated to study how other drugs affect the kinetics at steady state. The distribution of the ratio concentration/daily dose (C/D) in patients treated with the antidepressant only was compared with that in patients on different concomitant drugs. Patients on phenothiazines or dextropropoxyphene had a significantly higher mean C/D of NT than controls, both when AT and when NT had been given. The highest values were seen with levomepromazine and thioridazine. On the contrary, the mean C/D of both AT and NT in patients on carbamazepine was about 50% lower than in those treated with the antidepressant only. Benzodiazepines did not affect the steady-state kinetics of AT or NT. Intraindividual comparisons of the ratio C/D in subjects with analyses performed when off and on concomitant drugs corroborate previous results showing that drugs metabolized by the debrisoquine hydroxylase (CYP2D6) inhibit the metabolism of NT and that carbamazepine induces the metabolism of both AT and NT. Modeling of the dose dependency of the NT interactions with levomepromazine, perphenazine, and thioridazine revealed that the ratio C/D was most affected at low doses of the antidepressant and at high doses of the phenothiazine. The distribution of the doses given was the same in patients on monotherapy as in patients with interacting drugs, which means that many patients treated with phenothiazines had concentrations above the therapeutic range and that most patients treated with carbamazepine had subtherapeutic levels. The present study shows that therapeutic drug monitoring may serve as a valuable tool to discover and quantify drug interactions.

Adolescent↗

PubMed1996

Extreme values of the concentration/dose ratio as a risk factor of obtaining suboptimal nortriptyline serum concentrations.

Using nortriptyline as an example of a typical tricyclic antidepressant, I studied the relation between the steady-state concentration/dose ratio (C/D) and the performance of therapeutic drug monitoring (TDM), with a focus on the frequency of serum concentrations located in the therapeutic interval. A TDM database comprising 1,214 patients, of whom 619 patients had more than one sample taken, was used. The median C/D value for the patients was 4.05 [nM]/mg with 5th and 95th percentiles of 1.80 and 9.60, respectively. A total of 18.6% of the patients with C/D values below the 5th percentile had serum concentrations in the therapeutic interval at the first occasion, increasing to 49% for the average of the succeeding samples. These values were lower than those for the total group, 60.4 and 68.9%, respectively. For those with C/D values exceeding the 95th percentile, 36.2% had initial serum concentrations in the therapeutic interval, increasing to 66.3% for the average of succeeding samples. Only 11 patients (0.9%) had very high initial serum concentrations (> 1,200 nM). Thus patients with low C/D values are at risk of being underdosed, even after successive samples, whereas adequate dose correction is more likely to be implemented for those with average or high C/D values. Saturation kinetics for those with low C/D values was not a problem of clinical significance. Neither was lack of steady-state at the first occasion a problem for those with high C/D values (suspected poor metabolizers).

Adult↗

PubMed1996

Nortriptyline-induced hepatic failure.

We report a case of hepatic injury after treatment with nortriptyline in a therapeutic dose. There were symptoms of hepatitis and increased prothrombin time, serum alanine aminotransferase and alkaline phosphatases. The patient recovered after discontinuation of the drug.

Alanine Transaminase↗

PubMed2003

Toxicokinetics of nortriptyline and amitriptyline: two case reports.

Two cases are presented of intentional intoxications with the tricyclic antidepressants (TCAs) nortriptyline (NT) and amitriptyline (AT). The peak plasma concentrations were 2290 microg/L and 2900 microg/L, respectively. The active metabolites E-10-hydroxynortriptyline (EHNT) and Z-10-hydroxynortriptyline (ZHNT) profiles were quite different as monitored for 5 to 10 days after presumed drug intake. In conclusion, these cases illustrate that (1) metabolite formation and elimination after intake of an overdose dose of NT and AT are stereoselective, and (2) NT and EHNT toxicokinetics and toxicodynamics are quite different. It also shows that a patient with a severe TCA overdose can still survive if he or she receives appropriate and quick supportive care, even if the prognostic markers QRS time, coma grade, and serum TCA levels predict poor outcome.

Adult↗

PubMed2006

Postpartum depression: a randomized trial of sertraline versus nortriptyline.

Symptom reduction and improvement in functioning in women with postpartum major depression treated with a tricyclic antidepressant versus a serotonin reuptake inhibitor were compared. The design was a double-blind, 8-week comparative trial of nortriptyline (NTP) versus sertraline (SERT) with a 16-week continuation phase. Women aged 18 to 45 years with postpartum major depression and a 17-item Hamilton Rating Scale for Depression score of 18 or more were eligible. Subjects were randomized to NTP or SERT and treated with a fixed-dosing strategy. Of 420 women interviewed, 109 eligible women received medication, and 95 provided follow-up data. The proportion of women who responded and remitted did not differ between drugs at 4, 8, or 24 weeks. Times to response and remission also did not differ. Psychosocial functioning improved similarly in both drug-treated groups of mothers. The total side effect burden of each drug was similar, although side effect profiles differed between agents. No clinical or demographic variables differentiated responders by drug. Women who were responders and remitters at week 8 could be identified earlier if they were treated with SERT than with NTP. Breast-fed infant serum levels were near or below the level of quantifiability for both agents.

Adaptation, Psychological↗

PubMed1991

Structure of nortriptyline hydrochloride.

C19H22N+.Cl-, Mr = 299.84, monoclinic, P2(1)/c, a = 5.070 (2), b = 34.088 (5), c = 9.976 (1) A, beta = 90.74 (2) degrees, V = 1724.0 A3, Z = 4, Dx = 1.16 g cm-3, lambda (Mo K alpha 1) = 0.70930 A, mu = 2.2 cm-1, F(000) = 640, T = 295 K, final R = 0.046 for 1381 observed reflections. The nortriptyline molecule crystallized with a 'butterfly' fold angle of 124.3 (2) degrees and an extended propylamino side chain. The amino nitrogen is involved in hydrogen bonds to two different chloride ions.

Molecular Conformation↗

PubMed1975

Pharmacokinetics of N-demethyldiazepam in patients suffering from insomnia and treated with nortriptyline.

1 Hospitalized patients suffering from insomnia were treated with N-demethyldiazepam (30 mg p.o.) for 10 days, while continuing treatment with nortriptyline (75 or 100 mg daily). 2 Clinical evaluation performed by objective rating scales showed a positive therapeutic effect. No correlation was found however between drug plasma levels and clinical efficacy. A high inter-individual variability was observed. 3 In three cases the N-demethyldiazepam disappearance curve showed a biexponential decay, with a slow first component followed by a faster one. 4 Compared with diazepam the tested drug has a longer plasma apparent half-life and a lower relative clearance.

Adult↗

PubMed1978

A comparison of some physiological and psychological effects of Motival (fluphenazine and nortriptyline) and diazepam in normal subjects.

1 The effects in normal subjects of a single oral dose of Motival (one tablet, containing fluphenazine 0.5 mg and nortriptyline 10 mg) on the contingent negative variation (CNV), reaction time, heart rate, blood pressure and self-rating scales for alertness, anxiety, tension, detachment and depression were compared with those of diazepam (5 mg and 7.5 mg) and placebo or propranolol (60 mg). 2 After diazepam (5 mg: twelve subjects and 7.5 mg: seven subjects) there was a significant decrease in CNV magnitude while after Motival (twelve subjects) there was no significant alteration in CNV magnitude compared to placebo. 3 After diazepam (7.5 mg: seven subjects) there was also a fall in subjective ratings for alertness and tension; this fall was significantly greater than the changes after Motival which did not reduce subjective ratings for alterness or tension below "average" levels. Anxiety ratings did not differ significantly between the two drugs. Changes after propranolol were intermediate in all scales. 4 It is concluded that under these conditions diazepam caused central nervous system depression while Motival did not.

Blood Pressure↗

PubMed1985

CSF and plasma levels of nortriptyline and its 10-hydroxy metabolite.

After 3 weeks' nortriptyline (NT) treatment the mean plasma concentration of its 10-hydroxy metabolite (10-OH-NT) (599 +/- 207 nmol l-1) was higher than that of the parent drug (433 +/- 199 nmol l-1) in 25 depressed patients. Also in the cerebrospinal fluid (CSF) the mean level of 10-OH-NT (67 +/- 20 nmol l-1) was higher than that of NT (39 +/- 23 nmol l-1). There was a strong correlation (P less than 0.001) between the CSF and plasma concentration of both NT (r = 0.92) and 10-OH-NT (r = 0.77). The interindividual variation in the CSF/plasma ratio of both compounds was small, compared to the variation in plasma levels. These results show that 10-OH-NT passes the blood-brain barrier as it is present in concentrations higher than those of NT in the CSF. 10-OH-NT has previously been shown to be a potent blocker of noradrenaline uptake and to have much less affinity for muscarinic receptors than NT itself. This active metabolite might therefore be a potential antidepressant with less disturbing anticholinergic side-effects.

Aged↗

PubMed1998

Food intake and the presystemic metabolism of single doses of amitriptyline and nortriptyline.

The influence of food on presystemic metabolism of single doses of amitriptyline (AMI) and nortriptyline (NT) was examined. In randomised order 25 mg tablets of each drug was given to 9 healthy, female volunteers both in the fasting state and together with a standardised breakfast. Concentrations of the drugs and of their dealkylated, hydroxylated and conjugated metabolites were measured by gas chromatography--mass spectrometry (AMI experiment) or high-pressure liquid chromatography (NT experiment). Standard pharmacokinetic parameters were calculated. Food intake did not consistently or significantly influence the bioavailability of either AMI or NT, nor the demethylation of AMI, nor the hydroxylation or the primary or secondary conjugation of NT. There were large interindividual changes in AUC of AMI after food (+94% to -44%). A significant negative correlation between AUC of AMI but not of NT during fasting conditions and per cent change in AUC after food was found (r = -0.72, P = 0.029). The implication of this (negative) correlation for an individual patient might be to keep the intake of the drug in standardised relation to food to avoid undue heavy changes in drug concentration, which might just occur with a change in time relation between intake of drug and food. From a mechanistic view the results argue against a direct and selective influence of food on the presystemic oxidation and conjugation of weakly basic drugs but does not exclude that food may reduce the presystemic metabolism of some such drugs indirectly, by enhancing their rate of hepatic delivery. Presentation of data from food interaction studies should not be restricted to general descriptions. It seems equally important to present the variability of individual data to allow inspection of the extent and direction of effects. This should be of interest for patient, prescriber as well as the regulatory agency.

Adult↗

PubMed1977

Correlations between serum ami- and nortriptyline concentrations and psychomotor performance.

Correlations of serum nortriptyline (NT) and amitriptyline (AT) levels with psychomotor performance choice reaction performance, eye-hand coordination, and divided attention was studied in two experiments each with 20 healthy subjects. In the first experiment serum NT level was measured with an isotope derivative method after treatment for 14 days with NT. In the second trial plasma AT and NT concentrations were measured with gas-chromatography after treatment for 14 days with AT. No linear correlations between the levels of the antidepressants and performance variables were found. Low levels of NT (less than 50 ng/ml) tended to shorten reaction time, and intermediate levels (50--80 ng/ml) to prolong it, when compared with the reaction times during placebo. The correlation between serum NT levels and the increase of the tyramine dose in the tyramine pressor test was not significant. A new assay method for AT and NT is presented.

Adult↗