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PubMed1981

Differential effect of chronic desipramine and amitriptyline treatment on rat brain adrenergic and serotonergic receptors.

Serotonergic and adrenergic receptors were examine in rat brains by direct binding assays after chronic treatment with tricyclic antidepressants. Chronic amitriptyline (AMT) treatment (10 mg/kg/day i.p. for 21 days) decreased specific 3H-spiperone binding in the cortex and not in the caudate nuclei. Specific 3H-dihydroalprenolol (3H-DHA) binding was reduced in cerebellar but not in cerebral cortex. Chronic desipramine (DMI) treatment given in the same dose schedule, on the other hand, decreased specific 3H-DHA binding in both cerebellar and cerebral cortex. Specific 3H-spiperone binding in the cerebral cortex was also reduced but to a lesser extent than that in the AMT treated group. Scatchard analysis showed that reductions in 3H-spiperone or 3H-DHA binding in all cases were due to decreases in number of binding sites (Bmax) and not to changes in dissociation constants (KD). No change was observed in 3H-serotonin (3H-5HT), 3H-clonidine, or 3H-WB-4101 binding. The results show that there is no single common change in brain adrenergic and serotonergic receptors after chronic AMT and DMI treatment.

Amitriptyline↗
PubMed1982

Lack of effect of raphe lesions on serotonin S2 receptor changes induced by amitriptyline and desmethylimipramine.

Spiperone binding was studied in rat cortical and striatal homogenates by direct binding assay after chronic (10 mg/kg/day i.p. for 21 days) treatment with the tricyclic antidepressants amitriptyline (AMT) and desmethylimipramine (DMI). Both AMT (a potent serotonin reuptake inhibitor) and DMI (a weak serotonin reuptake inhibitor) treatment were associated with decreased specific binding of 3H-spiperone and 3H-mianserin in the cortex (markers for serotonin S2 receptors) of 31-45% of normal rats, but not the binding of 3H-spiperone in the striatum (a marker for dopamine D2 receptors). The same chronic treatment of raphe-lesioned rats with AMT or DMI produced equivalent (38-40%) decreased specific binding of these ligands in the cortex but no change in striatum. These results suggest that synaptic serotonin concentration may not be the factor responsible for the decreased number of spiperone binding sites observed after chronic antidepressant treatment.

Amitriptyline↗
PubMed1989

Chronic treatment with amitriptyline produces subsensitivity to the hypothermic effects of yohimbine.

1. Two but not one week of treatment with amitriptyline (AMI) produces subsensitivity to the hypothermic effects of the alpha 2 antagonist yohimbine. 2. Subsensitivity persisted for the three weeks during which it was measured following the discontinuation of AMI. 3. Two weeks of twice daily injections of saline did not alter the thermic response to this agent. 4. The results support other data indicating tricyclic antidepressants (TCAs) subsensitize alpha 2 mediated thermic changes and are consistent with reports that TCAs down-regulate alpha 2 receptors.

Amitriptyline↗
PubMed1990

The effect of nortriptyline-specific active immunization on amitriptyline toxicity and disposition in the rabbit.

Rabbits were actively immunized by a conjugate of nortriptyline (NT) to study the effect of specific anti-NT antibodies on toxicity and disposition of amitriptyline (AT). Control and immunized rabbits received 115 mg/kg AT intraperitoneally (i.p.). The lethality dose (LD) profile exhibited a gentle slope; LD100 and LD0 were separated by 100 mg/kg. Mortality was significantly reduced from LD67 to LD43 (P less than 0.05). Total plasma concentrations of the toxin were increased in the immunized group compared to the control group. AUC0.5-24 h value was 5-fold higher in the immunized group than in the control group. Moreover, a smaller fraction of unbound toxin in plasma was observed in the immunized group than in the control group. These observations indicate that AT was actively sequestered by antibodies. The intensity of this phenomenon was a function of both the antibody affinity constant (10(9) M-1) and the neutralizing capacity (varying from 0.005 to 0.2 mg/kg) of the circulating antibodies in each immunized rabbit. Results clearly show that anti-NT antibodies are able to effectively sequestrate AT.

Amitriptyline↗
PubMed1992

Liver delta-aminolevulinate dehydratase activity in amitriptyline- or chlorpromazine-treated rats.

Amitriptyline (AMT) and chlorpromazine (CPZ) (0.5 mg per animal, i.p.) were injected into rats separately for 30 days and their effects on heme metabolism in liver were examined. Significant decreases in the delta-aminolevulinate dehydratase activity were observed following the administration of both drugs (mean value of AMT-group: 6.58 U/g tissue; and CPZ-group: 7.04 U/g tissue) in comparison to that of controls (11.71 U/g tissue); however total liver heme content was not altered. When 24-h urinary excretions of delta-aminolevulinate (ALA) and porphobilinogen (PBG) were measured on the last day of the experiment, a slight (AMT-group: 38.40 micrograms/day) to distinct (CPZ-group: 59.11 micrograms/day) increase of urinary ALA was observed, while PBG excretion tended to decline only moderately under CPZ (3.52 micrograms/day), but significantly in presence of AMT (2.16 micrograms/day). Mean values obtained from control group were 32.12 micrograms/day for ALA and 4.25 micrograms/day for PBG.

Amitriptyline↗
PubMed1986

Effect of amitriptyline on laminar differentiation of neonatal rat olfactory bulb.

Amitriptyline (AT) was injected i.p. (0.01 g/kg) into newborn rats for 12 days. Stereometric measurements of coronal sections of the olfactory bulbs showed that the area of the external plexiform layer (EPL) in the AT-treated group was significantly smaller than that of control rats. Rats treated with AT also showed a significantly lower increase in body weight compared with the saline-injected control group.

Amitriptyline↗
PubMed1992

Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, crossover trial.

Amitriptyline (AT) relieves some patients with postherpetic neuralgia (PHN). Many patients suffer side effects and better therapies are necessary. The aim of this study was to evaluate the efficacy of maprotiline (MT) (noradrenergic) compared to AT (mixed noradrenergic and serotonergic) in this disorder. Thirty-five patients entered a randomized, double-blind, crossover trial of these two agents. We found that MT relieved PHN in many patients but was not as effective as AT. Side effects were troublesome with both agents. Relief of steady pain, brief pain and pain on tactile stimulation occurred. Four groups of responses were identified. Some patients reported relief with both agents, some with neither agent and others with only one of the drugs. Most patients were not depressed and analgesia was observed to occur without change in depression ratings in most patients who responded. This result provides evidence that in some patients AT may act via a selective noradrenergic mechanism in relieving PHN and that individuals may differ in the balance and type of neurotransmitters inhibiting pain. Selective noradrenergic agents may be effective if AT fails.

Aged↗
PubMed1995

Out-patient cognitive-behavioural therapy with amitriptyline for chronic non-malignant pain: a comparative study with 6-month follow-up.

A study was carried out in a multidisciplinary pain clinic with the purpose of comparing the effectiveness of outpatient cognitive-behavioural therapy (CBT) with amitriptyline (AMI) to that of supportive therapy with AMI. The treatments were given weekly over 8 weeks. Global and continuous outcome measures were used. Analysis was by chi-square for global data and MANOVA with baseline scores as covariants for continuous variables. No significant differences could be demonstrated. The scores over a 6-month follow-up period suggested a delayed positive advantage for CBT but this only approached and did not achieve statistical significance. The findings are discussed.

Adult↗
PubMed1996

Plasma and brain pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites after one and six half-life repeated administrations to rats.

The purposes of the present study were as follows: 1. After an acute intraperitoneal (IP) administration of amitriptyline (AMI) to male Sprague-Dawley rats we found that: (i) its absorption rate is rapid; (ii) its elimination half-life is much shorter than in humans; and (iii) its levels largely exceeded those of its metabolites. The most important metabolites being 10-hydroxynortriptyline and nortriptyline in plasma and brain, respectively. 2. After six (every half-life) repeated IP administrations: (i) AMI kinetic parameters were unchanged; and (ii) amounts of metabolites were significantly increased and the levels of AMI were lowered both in plasma and brain.

Amitriptyline↗
PubMed1996

Pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites in streptozocin-induced diabetic rats.

Plasma and brain levels of amitriptyline (AMI), its demethylated and hydroxylated metabolites were determined after acute IP administration of AMI (20 mg/kg) in streptozocin-induced diabetic Sprague-Dawley rats. Results showed 1. in plasma: rapid AMI absorption, but slow elimination; the proportion of AMI similar to those of the rest of compounds; the proportion of its demethylated metabolite, nortriptyline, 1.8-fold higher than that of 10-hydroxy-nortriptyline. 2. in brain: the proportions of AMI and nortriptyline were 9.5- and 2.6-fold higher respectively, than those of whole hydroxylated metabolites, which represented 7.4% of the total amount.

Amitriptyline↗
PubMed1995

Effects of amitriptyline on GABA-stimulated 36CI- uptake in relation to a behavioral model of depression.

The dominant-submissive relationship established between two rats competing for food is a model of depression and is used here to divide animals into two behaviorally distinct groups. Basal and GABA-stimulated 36CI- uptake was investigated for both dominant and submissive rats as well as the in vitro effect of the antidepressant amitriptyline (AMI). Because the antidepressant action of AMI only appears after chronic treatment, the effect of chronic injections of AMI on these behavioral and biochemical measures was also studied. Basal 36CI- uptake is significantly higher for dominant rats than for submissive rats. Increasing concentrations of AMI added to membrane vesicles enhanced 30 microM GABA-stimulated chloride uptake for dominant rats and inhibited it for submissive rats. Chronic treatment of dominant and submissive rats with AMI reversed these in vitro effects. The biochemical data correspond to the changes of the rats behavior in the dominance test after chronic treatment with AMI. However, this correlation is more clear for dominant than for submissive rats. Specific chloride influx was used as a measure of the sensitivity of GABAA receptor to GABA. This revealed different sensitivity states for GABAA receptors in tissues obtained from dominant and submissive rats. It is possible that the distinct conformational states of GABAA receptor are responsible for differences in rats behavior and in vitro effects of AMI before and after in vivo treatment of rats with this anti-depressant.

Amitriptyline↗
PubMed1987

Cytogenetic effects of amitriptyline hydrochloride in somatic and germ cells of mice.

Amitriptyline hydrochloride, an antidepressant drug, was tested in mice for mutagenic effects in the somatic cells by the micronucleus test and in the germ cells by the air drying technique of Evans et al. Mice were treated orally with the drug at a dose of 70, 140 and 210 mg/kg body weight. The results indicate that the drug is capable of inducing mutations both in the mitotic and meiotic cells of mice.

Amitriptyline↗
PubMed1985

Determination of citalopram, amitriptyline and clomipramine in plasma by reversed-phase high-performance liquid chromatography.

The determination of citalopram, amitriptyline, clomipramine and their desmethyl metabolites after alkaline diethyl either extraction from plasma is achieved by high-performance liquid chromatography using two internal standards and mu Bondapak C18 as stationary phase. Elution is carried out isocratically at 0.5 or 1 ml/min with a mixture of acetonitrile-potassium dihydrogen phosphate-distilled water (45:50:5). Detection is monitored by absorption at 254 nm. The detection limit is less than 5 ng/ml for each compound. The coefficients of variation are between 1.3% and 9.4% for 8-360 ng/ml. Interference from 22 possible co-medications is discussed. The technique can be used for therapeutic monitoring of these antidepressants as well as in analytical toxicology.

Amitriptyline↗
PubMed1985

Bicarbonate therapy for the cardiovascular toxicity of amitriptyline in an animal model.

The beneficial hemodynamic effects of sodium bicarbonate as treatment for tricyclic antidepressant poisoning were investigated in an animal model. Seven adult dogs (17.5 to 20 kg) were poisoned by an intravenous infusion of amitriptyline. Toxicity was defined as a doubling of the initial QRS width. A continuous infusion was used to maintain toxicity for 30 minutes after which 44.5 mEq of sodium bicarbonate was administered intravenously. Five of the animals survived to completion of the experiment. Three of the surviving animals developed dysrhythmias. All dysrhythmias ceased within one minute of administration of sodium bicarbonate. An increase in mean blood pressure (P less than .05) and serum pH (P less than .05) and a decrease in mean QRS width (P less than .05) occurred following administration of sodium bicarbonate. The maintenance of toxicity for 30 minutes suggests that this model can be used for future studies of tricyclic antidepressant poisoning.

Amitriptyline↗
PubMedDate not supplied

Charcoal stercolith with intestinal perforation in a patient treated for amitriptyline ingestion.

A case of a patient who developed an intestinal perforation secondary to a charcoal stercolith is reviewed. The case involves a young female on methadone maintenance who received multiple-dose charcoal therapy for an amitriptyline ingestion. Peritoneal signs developed several days after admission, and an exploratory laparotomy was done. A perforation measuring 4 cm in diameter was found in the posterior wall of the sigmoid colon. A 120-gm obstructing charcoal mass was found at the site of the perforation. Previous reports of intestinal obstruction secondary to charcoal inspissation are noted, and case similarities are discussed. All reported cases of charcoal obstruction involve the administration of multiple-dose-activated charcoal in the treatment of ingestions of medications known to have antiperistaltic activity. With a rare potential of mechanical obstruction, the decision to use repetitive-dose charcoal therapy should be made judiciously when the ingested toxin or coincident therapeutic medications have antiperistaltic activity.

Adult↗
PubMed2004

Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study.

In patients with migraine with or without aura the prophylactic effect of amitriptyline (AMT) and venlafaxine (VLF) was compared in a randomized double-blind crossover study. Intolerable side effects resulted in drop out of five patients on AMT (due to hypersomnia, difficulty in concentration and orthostatic hypotension) and one patient on VLF (because of nausea and vomiting). Following the run-in period the patients (n = 52) were randomly treated with one of the study medications for 12 weeks. After a wash-out period lasting 4 weeks the patients were treated with the other drug for further 12 weeks. Both drugs had significant beneficial effect on pain parameters. Total number of side effects of VLF was low when compared with the side effect profile of AMT. In conclusion, it is suggested that VLF may be considered for the prophylaxis of migraine because of its low and/or tolerable side effect properties.

Adolescent↗
PubMed2005

CYP2D6 and CYP2C19 genotypes and amitriptyline metabolite ratios in a series of medicolegal autopsies.

In a series of 202 postmortem toxicology cases, the CYP2D6 and CYP2C19 genes were genotyped, and the concentrations of amitriptyline (AT) and six metabolites were analyzed. The polymorphic CYP2D6 and CYP2C19 genes encode enzymes participating in the metabolism of several potentially toxic drugs, and mutations in these genes may lead to adverse drug reactions, possibly even intoxications. AT was chosen as the substrate of interest because it is mainly metabolized by these enzymes, is considered relatively toxic, and ranks among the major causes of fatal drug poisoning in Finland. Our objective was to evaluate genetically determined interindividual variation in conjunction with metabolite ratios of drugs found in toxicological analysis in a series of medicolegal autopsies. Positive correlations were found between the proportion of trans-hydroxylated metabolites and the number of functional copies of CYP2D6 and between the proportion of demethylated metabolites and the number of functional copies of CYP2C19. None of the accidental or undetermined AT poisonings coincided with the CYP2D6 or CYP2C19 genotype which predicts a poor metabolizer phenotype. However, an unusually high femoral blood concentration of AT, 60mg/l, was found in one suicide case with no functional CYP2D6 genes. Our study shows a concordance of AT metabolite patterns with CYP2D6 and CYP2C19 genotypes in the presence of confounding factors typical for postmortem material. This result demonstrates the feasibility of postmortem pharmacogenetic analysis and supports the dominant role of genes in drug metabolism.

Amitriptyline↗
PubMedDate not supplied

A case study: inappropriate use of amitriptyline in the elderly.

In 1999, nearly 7 million elderly persons were prescribed potentially inappropriate medications as identified by Beer's Criteria. Amitriptyline is among the most frequently inappropriately prescribed drugs according to Beer's Criteria. Interventions to educate prescribers on Beer's Criteria are indicated to improve appropriate prescribing to the elderly population. Nurses also need to be aware of the potential adverse effects of these drugs when providing care to geriatric patients.

Aged↗