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PubMed2006

Excess fatality from desipramine in children and adolescents.

OBJECTIVE: To compare the case fatality rate (CFR) from desipramine ingestion in children and adolescents with that of other tricyclic antidepressants. METHOD: All mentions of desipramine, amitriptyline, imipramine, nortriptyline, and doxepin in children and adolescents recorded in the American Association of Poison Control Centers Toxic Exposure Surveillance System from 1983 to 2002 were analyzed. The CFR for each drug was defined as the ratio of the number of deaths/number of mentioned exposures. RESULTS: There were 24 fatalities in children younger than 6 years old (desipramine, n=10; amitriptyline, n=7; doxepin, n=3; imipramine, n=3; nortriptyline, n=1) and 144 fatalities in older children and adolescents (desipramine, n=56; amitriptyline, n=30; doxepin, n=16; imipramine, n=31; nortriptyline, n=11). The CFR from desipramine was significantly higher compared with the other tricyclic antidepressants in children younger than 6 years old (chi=36, p<.001) and in older children and adolescents (chi=155, p<.001). The CFR from desipramine exceeded that of amitriptyline, doxepin, imipramine, and nortriptyline by 7- to 8-, 4-, 6- to 12-, and 7- to 10-fold, respectively. CONCLUSIONS: The excess CFR from desipramine in children and adolescents and the reports of sudden death in children treated with therapeutic doses call for caution in prescribing desipramine to children and adolescents.

Adolescent↗
PubMed2006

[Maintenance electroconvulsive therapy in elderly psychotic unipolar depression].

BACKGROUND AND OBJECTIVE: This study was designed to assess the safety and efficacy of continuation/maintenance electroconvulsive therapy (ECT) in elderly psychotic major depressed patients after ECT remission. PATIENTS AND METHOD: Using a longitudinal randomized single-blind design, we compared the two-year outcome of two subgroups of psychotic unipolar depressed elderly patients who were ECT remitters: one treated with a maintenance nortriptyline regimen (n = 13) and one treated with combined maintenance ECT plus nortriptyline (n = 6). RESULTS: During 2 years of maintenance treatment in elderly psychotic unipolar depressed ECT remitters, relapse/recurrence rates were significantly higher in the nortriptyline subgroup than in the combined ECT plus nortriptyline subgroup. The tolerability of both treatments was similar. CONCLUSIONS: This study supports the use of combined maintenance ECT and antidepressant treatment in elderly psychotic unipolar depressed patients who are ECT remitters.

Aged↗
PubMed2000

Treatment of cognitive impairment after poststroke depression : a double-blind treatment trial.

BACKGROUND AND PURPOSE: Patients with poststroke major depression have a greater severity of cognitive impairment than nondepressed patients even when matched for size and location of stroke lesion. Prior treatment studies have consistently failed to show an improvement in cognitive function even when poststroke mood disorders responded to antidepressant therapy. We examined the response of cognitive function to treatment with nortriptyline or placebo in a double-blind trial. METHODS: Patients with major (n=33) or minor (n=14) depression participated in a double-blind treatment study with nortriptyline or placebo. They were examined for change in depressive mood, measured by the Hamilton Rating Scale for Depression (HAM-D), and change in cognitive impairment, assessed by the Mini-Mental State Examination (MMSE), after treatment with nortriptyline or placebo. Cognitive treatment response, as measured by the MMSE, was compared between patients whose depression did and did not respond to treatment. RESULTS: Patients whose poststroke depression remitted (predominantly associated with nortriptyline treatment) had significantly greater recovery in cognitive function over the course of the treatment study than patients whose mood disorder did not remit (predominantly associated with placebo treatment). CONCLUSIONS: Our findings support the contention that poststroke major depression leads to a "dementia of depression." Prior studies failed to show an effect of treatment because the effect size was too small. Successful treatment of depression may constitute one of the major methods of promoting cognitive recovery in victims of stroke.

Affect↗
PubMed2002

Combined pharmacotherapy and psychotherapy as maintenance treatment for late-life depression: effects on social adjustment.

OBJECTIVE: This study examined the effects of maintenance treatment for late-life depression on social adjustment. The authors hypothesized that elderly patients recovering from depression would have better social adjustment with medication and interpersonal psychotherapy than with medication or psychotherapy alone. METHOD: Patients aged 60 and older recovering from recurrent major depression were randomly assigned to one of four treatments: nortriptyline and interpersonal psychotherapy, nortriptyline and clinic visits, placebo and psychotherapy, or placebo and clinic visits. The Social Adjustment Scale was administered every 3 months until illness recurrence. Combined treatment was compared to monotherapy on scores over 1 year among patients who remained in recovery (N=49). RESULTS: Patients receiving nortriptyline and interpersonal psychotherapy maintained social adjustment, which declined in those receiving monotherapy. CONCLUSIONS: Treatment of late-life depression with nortriptyline and psychotherapy is more likely to maintain social adjustment than treatment with either alone. Combination therapy improves not only duration but quality of wellness.

Age Factors↗
PubMed2004

P-glycoprotein reduces the ability of amitriptyline metabolites to cross the blood brain barrier in mice after a 10-day administration of amitriptyline.

P-glycoprotein (P-gp) is a 170-kDa membrane protein and the gene product of the multiple drug resistance (MDR1 or ABCB1) gene. It constitutes an important part of the blood-brain barrier and actively exports a number of molecules across the blood-brain barrier back into the vascular space, subsequently reducing central nervous system (CNS) bioavailability of these substances. The aim of the present study was to investigate the pharmacokinetics of amitriptyline and its metabolites in P-gp (also called mdr1ab or abcb1ab) knockout mice and controls after a long-term adminstration for 10 days. Knockout mice and controls received s.c. injections of amitriptyline (10 microg/g bodyweight) twice daily for 10 days. After 10 days, the animals were sacrificed and the concentrations of amitriptyline and nortriptyline and both their E-10-OH and Z-10-OH metabolites were measured with high-performance liquid chromatography in the cerebrum, plasma, spleen, kidney, testes, lung, liver, muscle and fat. Except for amitriptyline, the brain concentrations of all other examined substances were significantly higher in the P-gp knockout mice. Compared to controls, concentrations of nortriptyline were 2.6-fold higher, E-10-OH-nortriptyline 10-fold higher, Z-10-OH-nortriptyline seven-fold higher, E-10-OH-amitriptyline two-fold higher and Z-10-OH-amitriptyline five-fold higher. The present study confirms that P-gp plays an important role in the interaction between CNS drugs and the blood-brain barrier. Without P-gp at the blood-brain barrier, the brain concentrations of the substances were up to 10-fold higher, showing that P-gp plays an active role in exporting CNS drugs out of the brain. Recent clinical studies showing different side-effects in patients with P-gp polymorphisms confirm the clinical importance of these findings.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Amitriptyline dosage prediction in elderly patients from plasma concentration at 24 hours after a single 100mg dose.

Fifteen depressed elderly patients (14 female, 1 male; mean age 85 years) received a single oral dose of amitriptyline. The concentration of amitriptyline plus nortriptyline in a blood sample taken 24 hours later was used to predict by means of a nomogram the amitriptyline dosage required for each patient. Each dose was selected to produce steady-state amitriptyline plus nortriptyline concentrations close to 140 micrograms/L. The daily dosage ranged from 20 to 100mg (mean 62mg). Patients received the individually calculated dose each night, and weekly blood samples were obtained for drug analysis. At 2 weeks, mean amitriptyline plus nortriptyline concentrations were 118 +/- 21 micrograms/L. Eight of the patients were studied for a further 2 weeks and the mean amitriptyline plus nortriptyline concentration was then 111 +/- 19 micrograms/L. The dose prediction test is easy to use and ensures each patient receives an adequate but safer dose of amitriptyline than might otherwise be prescribed routinely.

Aged↗
PubMed1986

Oxidation of tricyclic antidepressant drugs, debrisoquine and 7-ethoxyresorufin, by human liver preparations.

Data obtained from human studies in vivo show that the dispositions of the tricyclic antidepressant drugs desmethylimipramine (DMI) and nortriptyline are related to the debrisoquine hydroxylation phenotype. To obtain insight into the enzymic mechanisms behind this, the metabolism of debrisoquine and antidepressant drugs by human liver preparations have been studied. The 2-hydroxylation of DMI in vitro correlates with the 4-hydroxylation of debrisoquine among various livers (rs = 0.90). Debrisoquine inhibits DMI hydroxylation competitively, and DMI inhibits debrisoquine hydroxylation, suggesting that DMI hydroxylation is catalysed by the debrisoquine hydroxylase in human liver. By monitoring the hydroxylation of DMI in various fractions during separation and purification of cytochrome P-450 from human liver microsomes we have purified a cytochrome P-450 which efficiently hydroxylates this drug. The apparently electrophoretically homogeneous enzyme had a molecular weight of 51,500 and hydroxylated DMI and debrisoquine at rates of up to 0.95 and 0.45 nmol/min . nmol P-450, respectively. This is probably the major debrisoquine hydroxylating cytochrome P-450 in man. Nortriptyline 10-hydroxylation correlates strongly (r = 0.96) with debrisoquine hydroxylation in human liver microsomes. Nortriptyline inhibits DMI-hydroxylation competitively, and the drug also inhibits the 4-hydroxylation of debrisoquine. Thus it is probable that nortriptyline is hydroxylated by debrisoquine hydroxylase. Imipramine N-demethylation did not correlate significantly (P greater than 0.1) with debrisoquine hydroxylation among microsomes from nine livers. However, if a liver from a subject, which was a poor metabolizer of debrisoquine in vivo, was included, a correlation was obtained (r = 0.79, P less than 0.01, N = 10). Imipramine demethylation also correlated with DMI-hydroxylation only if the 'poor metabolizer' liver was included (r = 0.75, P less than 0.05, N = 10). Debrisoquine inhibited imipramine demethylation competitively. The data indicate that imipramine can interact with debrisoquine- and DMI-hydroxylase, but it is uncertain if this enzyme plays an important quantitative role in its demethylation. Ethoxyresorufin O-deethylation correlated with DMI hydroxylation (r = 0.80) in human liver preparations, and DMI inhibited the former reaction in what is probably a mixed competitive-non-competitive inhibition. Liver preparations from a subject who was a poor oxidizer of debrisoquine both in vivo and in vitro had unusually low capacity to metabolize ethoxyresorufin. Thus ethoxyresorufin, at least partly, seems to interact with an enzyme that can metabolize DMI in human liver.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMedDate not supplied

The effect of some microsomal enzyme inducers on amitriptyline distribution in rats.

The influence of different types of enzyme inducers: phenobarbital, Aroclor 1254 and benzo(a)pyrene, on distribution of amitriptyline and its metabolite nortriptyline in rats was investigated. The level of amitriptyline and nortriptyline in serum, brain, heart and liver was determined by gas chromatography. The maximum concentration values of amitriptyline and nortriptyline as well as areas under concentration-time curves (AUC0-6) in serum and organs were statistically compared using Student t test and AUCCOMP computer program. The results suggest that studied xenobiotics significantly influence the distribution of amitriptyline and nortriptyline in rats. The changes of these drugs concentration in target organs may be very important from the toxicological point of view.

Amitriptyline↗
PubMed1991

[Plasma and urine kinetics of amitriptyline oxide and its metabolites. Comparison of intravenous infusion and oral administration in volunteers].

The study objective was to obtain detailed information on the plasma and urine kinetics of amitriptylinoxide (CAS 4317-14-0) and its metabolites. For this reason, 60 mg of amitriptylinoxide was administered to 12 subjects, both by intravenous infusion and by oral dosage, in a study performed according to a randomized two-way cross-over design. In plasma, we succeeded in analyzing the metabolites amitriptyline and nortriptyline in addition to the parent substance amitriptyloxide. The tests for the parent substance amitriptylinoxide revealed maximum plasma levels of 721 and 686 ng/ml at 1.96 h (i.v. infusion) and 0.82 h (oral formulation), respectively. Mean values of 2331 (infusion) and 1714 h.ng/ml (oral formulation) were determined for the area under the curve from time 0 to infinity AUC (0-infinity). We also produced a comprehensive evaluation of amitriptyline, however, this was not possible for the metabolite nortriptyline. In urine, we succeeded in a reliable quantification of 4 metabolites, namely cis-OH-amitriptylinoxide, trans-OH-amitriptylinoxide, amitriptyline and OH-nortriptyline, in addition to the parent substance amitriptylinoxide. In individual samples, nortriptyline, cis-OH-amitriptyline and trans-OH-amitriptyline were additionally identified. In the course of the study, there were no reports or observations of any adverse reactions in addition to the side effects known for amitriptylinoxide from literature. There were no clinically relevant differences in tolerability observed between these two preparations.

Administration, Oral↗
PubMed1995

Breastfeeding and sertraline: a 24-hour analysis.

BACKGROUND: Few reports exist on the levels of antidepressants in breast milk or on observed behavioral effects, if any, of neonates who are breast-fed. Thus, a dilemma exists for women who would like to breast-feed but require psychotropic medications. METHOD: Analysis of sertraline levels was performed on eight samples of breast milk obtained over a 24-hour period, after 3 weeks of breastfeeding, from a lactating patient taking sertraline and nortriptyline. During this same 24-hour period, two serum samples each were taken from mother and child for analysis of sertraline and nortriptyline levels. After 7 weeks of exclusive breastfeeding, an additional serum sample was obtained from mother and child for analysis of sertraline levels. Drug metabolites were not measured. RESULTS: Breast milk levels of sertraline were lowest 1 hour before the ingestion of sertraline and highest 5 to 9 hours after ingestion of the drug. The infant's serum sertraline and nortriptyline levels were nondetectable. CONCLUSION: These data indicate that sertraline levels in breast milk vary substantially over 24 hours and appear to be lowest within the 2 hours before and 1 hour after ingestion of the medication, with the peak probably occurring between Hours 1 and 9 postingestion. However, the absence of detectable serum sertraline and nortriptyline levels in the infant suggests that if either medication is present in infant serum, its concentration would be extremely low. No abnormal occurrences have been noted in the development of the infant. It would be important in future studies to measure metabolites in addition to medication levels since the former have been associated with untoward events in an infant.

1-Naphthylamine↗
PubMed1994

Tricyclic antidepressant concentrations in plasma: an estimate of their sensitivity and specificity as a predictor of response.

An analysis of the literature on tricyclic antidepressant level in blood using receiver operating characteristics curves as the primary statistical tool was performed. For nortriptyline, a significant curvilinear relationship between therapeutic response and nortriptyline was observed that ranged from 58 to 148 ng/ml. The sensitivity and specificity for the nortriptyline therapeutic window were 78 and 61%, respectively. The response rate within the therapeutic range was 66% versus 26% outside the therapeutic range. For desipramine, a significant linear relationship between therapeutic response and desipramine concentration in plasma was observed. The threshold concentration in plasma for therapeutic response was 116 ng/ml. The sensitivity and specificity for the desipramine threshold level in blood were 81 and 59%, respectively. The response rate above the threshold level was 51% versus 15% below the therapeutic threshold concentration. For imipramine, a significant curvilinear relationship between therapeutic response and total imipramine (imipramine+desipramine) concentration in plasma was observed between 175 and 350 ng/ml. The sensitivity and specificity for the total imipramine concentrations in plasma were 52 and 74%, respectively. The response rate within the therapeutic range was 67% versus 39% outside the therapeutic range. For amitriptyline, a significant curvilinear relationship between therapeutic response and total amitriptyline (amitriptyline+nortriptyline) concentration in plasma was observed between 93 and 140 ng/ml. The sensitivity and specificity for the total imipramine concentrations in plasma were 37 and 80%, respectively. The response rate within the therapeutic range was 50% versus 30% outside the therapeutic range.

Adolescent↗
PubMed2004

Antidepressants for smoking cessation.

BACKGROUND: There are at least two theoretical reasons to believe antidepressants might help in smoking cessation. Nicotine withdrawal may produce depressive symptoms or precipitate a major depressive episode and antidepressants may relieve these. Nicotine may have antidepressant effects that maintain smoking, and antidepressants may substitute for this effect. Alternatively, some antidepressants may have a specific effect on neural pathways underlying nicotine addiction, independent of their antidepressant effects. OBJECTIVES: The aim of this review is to assess the effect of antidepressant medications in aiding long-term smoking cessation. The medications include bupropion; doxepin; fluoxetine; imipramine; moclobemide; nortriptyline; paroxetine; sertraline, tryptophan and venlafaxine. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register which includes trials indexed in MEDLINE, EMBASE, SciSearch and PsycINFO, and other reviews and meeting abstracts, in March 2004. SELECTION CRITERIA: We considered randomized trials comparing antidepressant medications to placebo or an alternative therapy for smoking cessation. We also included trials comparing different doses, using pharmacotherapy to prevent relapse or re-initiate smoking cessation and using pharmacotherapy to help smokers reduce cigarette consumption. We excluded trials with less than six months follow up. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of study population, the nature of the pharmacotherapy, the outcome measures, method of randomization, and completeness of follow up. The main outcome measure was abstinence from smoking after at least six months follow up in patients smoking at baseline, expressed as an odds ratio (OR). We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed effect model. MAIN RESULTS: There was one trial of the monoamine oxidase inhibitor moclobemide, and one of the atypical antidepressant venlafaxine. Neither of these detected a significant long-term benefit. There were five trials of selective serotonin reuptake inhibitors; three of fluoxetine, one of sertraline and one of paroxetine. None of these detected significant effects, and there was no evidence of a significant benefit when results were pooled. There were 24 trials of bupropion and six trials of nortriptyline. When used as the sole pharmacotherapy, bupropion (19 trials, OR 2.06, 95% confidence intervals [CI] 1.77 to 2.40) and nortriptyline (four trials, OR 2.79, 95% CI 1.70 to 4.59) both doubled the odds of cessation. In one trial the combination of bupropion and nicotine patch produced slightly higher quit rates than patch alone, but this was not replicated in a second study. Two trials of extended therapy with bupropion to prevent relapse after initial cessation did not show a significant long-term benefit. There is a risk of about 1 in 1000 of seizures associated with bupropion use. Concerns that bupropion may increase suicide risk are currently unproven. REVIEWERS' CONCLUSIONS: The antidepressants bupropion and nortriptyline aid long term smoking cessation but selective serotonin reuptake inhibitors (e.g. fluoxetine) do not. The fact that only some forms of antidepressants aid cessation and that they do so regardless of depressive symptoms strongly suggests that their mode of action is independent of their antidepressant effect.

Anti-Anxiety Agents↗
PubMed2002

Antidepressant prescribing in nursing homes: is there a place for tricyclics?

OBJECTIVE: To deduce a model describing physicians' choice of antidepressants for treating elderly nursing home patients. METHODS: Subjects were geriatric residents of 137 skilled nursing facilities who regularly received an antidepressant medication for at least one month (n = 3,440, 28% of all residents). Reasons for prescribing antidepressants and physicians' diagnoses of depression and dementia were identified by medical record audit. Residents were grouped by dementia and antidepressant target symptoms (depression, or one or more non-psychiatric symptoms, i.e. insomnia, pain, incontinence, itching). RESULTS: Selective serotonin reuptake inhibitors (SSRIs) were prescribed preferentially over tricyclic antidepressants (TCAs) for treating depression in both demented and non-demented residents, but TCAs were nine times more likely to be prescribed for treating non-psychiatric target symptoms alone. When non-psychiatric target symptoms were present without depression or dementia, both amitriptyline and nortriptyline prescribing was increased, but amitriptyline appeared to be the antidepressant of choice. In all subgroups examined, its use was two to five times more prevalent when such symptoms were present. In patients with dementia, amitriptyline prescribing declined whether or not non-psychiatric target symptoms were present, but nortriptyline prescribing did not; nortriptyline was three times more likely than amitriptyline to be prescribed in the presence of dementia. CONCLUSIONS: Physicians prescribe anticholinergic TCAs principally to treat common non-depressive symptoms in nursing home residents, preferring SSRIs for uncomplicated depression and depression with dementia. They tend to avoid prescribing anticholinergic TCAs other than nortriptyline when they recognize a patient as demented. The data suggest that physicians employ a decision model for antidepressant prescribing that simultaneously recognizes the utility of TCAs in treating non-psychiatric symptoms and the anticholinergic vulnerability of older, especially demented, patients. Whether or not this model leads to optimal patient management requires further study.

Aged↗
PubMed1980

Presynaptic alpha-adrenoceptors and the action of tricyclic antidepressant drugs in behavioural despair in rats.

The influence of the alpha-adrenolytics, yohimbine and phentolamine, given in low doses thought to block presynaptic alpha-adrenoceptors, on the action of the tricyclic antidepressants imipramine, nortriptyline and amitriptyline in the behavioural despair test was investigated in Wistar rats. Antidepressant drugs given in a single dose or for 2 weeks reduced immobility in rats. Yohimbine potentiated the effect of nortriptyline or amitriptyline administered in a single dose and the effect of imipramine and amitriptyline given for 2 weeks. The potentiating effect of phentolamine was observed only in rats receiving a single dose of nortriptyline. Yohimbine given chronically for 3 weeks together with antidepressants counteracted the effect of imipramine and nortriptyline on behavioural despair. Similarly clonidine abolished the reduction of immobility induced by antidepressants given in a single dose. It is concluded that the despair test is a behavioural model which is sensitive to the noradrenergic component of the drugs and that the blockade of presynaptic alpha-adrenoceptors facilitates the action of tricyclic antidepressants in this test.

Adrenergic alpha-Antagonists↗
PubMed1987

A comparative study of the affinities of some tricyclic antidepressants for the muscarinic cholinergic receptor in human and guinea-pig bladder, ileum and brain in relation to differential drug potency.

Following a report that nortriptyline was found useful in the control of enuresis in adults, presumably as an anticholinergic, its likely mechanism of action and apparent bladder specificity have now been investigated in vitro. The ratios of anticholinergic potencies (reciprocal of dissociation contents, Ki) for four different tricyclic antidepressants, derived from competitive binding assays with (-)[3H]QNB in tissue homogenates, in the order (human) detrusor muscle/ileal longitudinal muscle/caudate, are as follows: Nortriptyline, 5/4/7; desipramine, 2/1/5/; clomipramine, 4/3/27; amitriptyline, 25/14/56. The apparent selective effect of nortriptyline on the bladder cannot be ascribed to its higher affinity to bladder receptors. Still, this drug is the least discriminatory of the four. Hence, at a given concentration, it is expected to affect tissue embodying a low density receptor pool sooner than tissue having a large receptor reserve. The ratios of the densities of (-)[3H]QNB binding sites in the order detrusor muscle/ileal muscle/cortex is 1/3/5, supporting the present contention. In the guinea-pig, the ratios of the anticholinergic potency in the order bladder/proximal ileum/distal ileum/cortex are as follows: Nortriptyline, 25/5/6/33; desipramine, 8/2/2/14; amitriptyline, 100/14/20/100; clomipramine, 17/3/5/33. Also, the ratios of the densities of binding sites are 1/6/5/2. Hence, data derived from assays in the guinea-pig are not representative of those derived from human tissue.

Animals↗
PubMed1996

Effects of long-term treatment with dicyclic, tricyclic, tetracyclic, and noncyclic antidepressant drugs on monoamine oxidase activity in mouse brain.

1. The individual long-term effects of the antidepressant drugs zimeldine, viloxazine, imipramine, amitriptyline, nortriptyline, maprotiline, or nomifensine, on brain mitochondrial monoamine oxidase (MAO) activity, were studied in mice that were given daily intraperitoneal injections (30 mg/kg) of these reagents for 4 weeks. 2. Both the A-form (MAO-A) and B-form (MAO-B) of MAO were inhibited after long-term administration of all the drugs except nortriptyline (MAO-A was not affected) and maprotiline (neither MAO-A nor MAO-B were affected). 3. Kinetic analysis showed a significant decrease in Vmax values, and an increase in K(m) values for MAO-B during treatment. 4. All seven drugs are competitive inhibitors of MAO-A, noncompetitive inhibitors of MAO-B, and were more potent in vitro for MAO-B. 5. MAO-A was inhibited by the following drugs (in ascending order of potency) : nortriptyline, amitriptyline, imipramine, maprotiline, zimeldine, nomifensine, and viloxazine. 6. MAO-B was inhibited by the following drugs (in ascending order of potency): nortriptyline, imipramine, maprotiline, amitriptyline, zimeldine, nomifensine, and viloxazine.

Animals↗
PubMed1976

Estimation of amitriptyline and its metabolites in serum and urine by GLC using nitrogen-specific detector.

1. A gas-chromatographic procedure for the estimation of amitriptyline and its metabolites in serum and urine using a nitrogen-specific detector is described. Specially cleaned glassware and purified solvents are used for the extraction of serum to further minimize extraneous peaks. Trimethylamine is added to serum before extraction to improve the recovery of drugs. Urine is refluxed at pH approximately 1 to hydrolyze the conjugates and to convert hydroxymetabolites to corresponding dehydro compounds. Serum is not hydrolyzed. 2. Two internal standards, one a tertiary amine similar in structure to amitriptyline and the other a secondary amine similar in structure to nortriptyline, are added to the specimen prior to extraction to obviate the need for accurate measurements of volumes during extraction and analysis. Urine and serum are washed with organic solvents at acidic pH to remove neutral and acidic impurities. Secondary bases are converted to their acetyl derivatives. 3. In the serum of a patient who is on amitriptyline therapy or who has ingested an overdose of amitriptyline, nortriptyline, a pharmacologically active metabolite is also measured. However, detection or estimation of hydroxymetabolites in serum is not clinically relevant. Hydroxylation index of an individual patient is determined by measuring the ratio of nortriptyline to its hydroxymetabolite in urine. 4. Amitriptyline and nortriptyline can be estimated in serum at a lower level of 10 and 20 ng/ml respectively. The procedure is linear over a wide range of amitriptyline and its metabolites. The use of an electronic integrator allows the estimation of different compounds with 100 fold difference in their concentration from the same chromatogram.

Amitriptyline↗
PubMedDate not supplied

Interpretation of blood and tissue concentrations in fatal self-ingested overdose involving amitriptyline: an update (1978-1979).

Thirty-two cases of fatal self-ingested overdose involving amitriptyline were studied over the two-year period 1978 to 1979. The average decedent was a 44-year-old woman who ingested amitriptyline and at least one other drug (usually ethanol, diazepam, propoxyphene, or codeine). The mean concentrations of amitriptyline and nortriptyline were significantly higher in liver than in myocardium, and they were significantly higher in myocardium than in blood. In addition, concentrations in these tissues showed significant correlation with each other. The mean tissue concentrations of amitriptyline and nortriptyline in this series of overdoses were significantly greater than those in fourteen other decedents whose deaths were not due to drug overdose but involved amitriptyline as an incidental finding. The mean ratio of amitriptyline to nortriptyline in each tissue was also significantly higher in overdose than those in the corresponding tissues of the non-overdose group, suggesting that the former ingestions were more acute. The estimated survival times showed no significant correlation with tissue concentrations of either amitriptyline or nortriptyline.

Adult↗