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PubMed1976

Pharmacokinetics of amitriptyline infused intravenously in man.

Amitriptyline was given to four male volunteers by constant rate intravenous infusion. Blood samples were collected before, during and at various times after the infusion for estimation of the serum concentrations of amitriptyline. The level of nortriptyline never reached a detectable level. A two compartment open model was shown to be applicable to the data obtained. The meaning of the parameters obtained by a non-linear, least squares curve fitting procedure is discussed and the values are compared to those recently published for nortriptyline. The calculated biological half-life of amitriptyline was about 17 hours, a figure which differs considerably from previously calculated values for volunteers, but is in accordance with some newer results from patients.

Adult↗
PubMed1988

Acute effects of amitriptyline on human performance and interactions with diazepam.

The effects of psychomotor performance and attention of amitriptyline 75 mg administered without and with diazepam 10 mg have been investigated in 12 healthy subjects. The effects of the compounds were evaluated by objective tests (measurement of body sway, critical flicker fusion, visual reaction time, tachistoscopy, short term visual memory, tapping test, arithmetical calculation and Clement's code) and subjective measurements (visual analogue scales and side effects questionnaire). Measurements were taken before treatment and after 1, 3, 6, 8 and 24 h. Placebo did not affect either the objective or the subjective measurements. Diazepam caused a reduction in attention and performance after 1 h which had disappeared at 3 h. Amitriptyline caused a marked reduction in attention and performance, reaching a peak 3 hours after drug administration and persisting until 8 h. the deterioration in vigilance induced by amitriptyline was potentiated by concomitant diazepam.

Adult↗
PubMed1996

The effect of chronic administration of amitriptyline on the effects of subsequent electroconvulsive treatment on responsiveness of alpha 1-and beta-adrenoceptors in the rat cortical slices.

Both antidepressant drugs and repeated electroconvulsive shock (ECS) produce adaptive changes in cerebral neurotransmitter systems. As in the clinical practice ECS is used almost always after therapeutical failure of pharmacotherapy, we investigated presently how chronic administration of an antidepressant amitriptyline affects the action of subsequent multiple ECS in rats. Amitriptyline differed from ECS and from other classical antidepressant in producing no beta-downregulation and potentiating the inhibitory effect of protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (TPA), on responses of alpha 1-adrenoceptor system to noradrenaline. The action of ECS on alpha 1-adrenoceptor system remained essentially unaffected by previous amitriptyline administration. Its downregulatory effect on responses of beta-adrenoceptor system to noradrenaline, and particularly to isoproterenol, were attenuated by previous drug treatment. The present results suggest that previous chronic administration of antidepressant drugs may alter the effect of subsequent ECS.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1988

Charcoal bezoar. Small-bowel obstruction secondary to amitriptyline overdose therapy.

Nasogastric administration of activated charcoal is effective in decreasing the half-life of amitriptyline. A case is reported in which this therapy for amitriptyline overdose led to charcoal bezoar formation and small-bowel obstruction. Amitriptyline's atropinic side effects on the gut make this a possible complication in such patients.

Adult↗
PubMed1986

Non-differential inhibition of histamine and serotonin release from mast cells by amitriptyline.

A differential amine release from mast cells induced by an inhibitory effect of the antidepressant drug amitriptyline on the release of histamine but not on that of serotonin has recently been reported. In view of the potential biological importance of a differential release of mast cell amines we have studied the effect of amitriptyline on the dynamics of the secretory process using a combination of vital berberine staining (demonstrating intracellular granules that have released amines) and measurement of histamine, serotonin (5-HT), and heparin release. The results show a non-differential inhibition of the release of histamine and 5-HT by amitriptyline. The basic pattern of the secretory process, studied in terms of granule extrusion and amine release from intracellular granules, was unaffected by the drug.

Amitriptyline↗
PubMed1994

Heart rate analysis in 24 patients treated with 150 mg amitriptyline per day.

Twenty-four patients treated with 150 mg amitriptyline per day for an episode of major depression underwent a standardized heart rate analysis (HRA) before therapy and after 14 days. The battery of cardiovascular reflex tests included the determination of the coefficient of variation (CV) while resting and during deep respiration, a spectral analysis of heart rate, the heart rate response to standing, and the Valsalva manoeuvre. The results of the initial HRA did not differ from a group of 24 normal control subjects matched for age and sex. On day 14 of treatment the patients showed significantly reduced values of heart rate variability in all tests (P < 0.0001), probably due to the anticholinergic side effects of amitriptyline. Heart rate increased from 78.1 to 93.6 bpm on average (P < 0.0001). Abnormal CV at rest was registered in 96% of the patients; during deep respiration 29% showed abnormal CV results. An abnormal spectral analysis was found in 100% of the cases (low frequency peak: 42%, mid-frequency peak: 100%, high frequency peak: 79%). The heart rate response to standing was abnormal in 75% and the Valsalva test in 33% of the cases. Eighty-eight percent of the patients fulfilled the criteria of a cardiovascular autonomic neuropathy under the conditions of amitriptyline therapy. As yet, the consequences of these changes for the patients have not been sufficiently elucidated.

Adult↗
PubMed1992

Amitriptyline, clovoxamine and cognitive function: a placebo-controlled comparison in depressed outpatients.

No longer prescribed only for vegetative signs of depression, tricyclic antidepressants also lessen depressive cognitive distortions. Less clear is whether they ameliorate depressed patients' other cognitive deficits in memory, information processing speed, and psychomotor performance. We tested the alternative hypothesis that amitriptyline, because of its anticholinergic and sedative properties, would exacerbate depressed patients' cognitive disturbances. Depressed outpatients received double-blind placebo (n = 15), amitriptyline (n = 10), or clovoxamine fumarate (n = 10), a serotonin reuptake inhibitor relatively lacking in anticholinergic properties. Depression, memory, and psychomotor performance were assessed at baseline and after 7 and 28 days of drug treatment. Depression was alleviated after all treatments, including placebo. Only amitriptyline impaired performance on tests of memory, producing a significant decrement, relative to placebo, after 4 weeks of treatment. None of the treatments adversely affected performance on psychomotor tasks. These findings add to the evidence that antidepressant drugs with high anticholinergic activity can impair memory, despite alleviation of depression.

Acoustic Stimulation↗
PubMed1995

Multicenter double blind study of paroxetine and amitriptyline in elderly depressed inpatients.

Paroxetine is a phenylpiperidine compound which is a selective serotonin reuptake inhibitor (SSRI). Ninety-one hospitalised patients with a major depression (DSM-III) aged 65 and over from six Austrian and one German center were entered into the study, which compared the efficacy and tolerability of paroxetine versus amitriptyline. After 6 weeks both groups showed similarly good therapeutic results. In the paroxetine group, 64.3% of the patients had a 50% or more reduction of the HAMD total score compared to 58.1% in the amitriptyline group. Side effects were distributed similarly in both groups. Patients in the paroxetine group showed a higher incidence of anxiety and agitation; anticholinergic side effects were registered more often in the amitriptyline group.

Aged↗
PubMed1988

Amitriptyline-related peripheral neuropathy. Case report.

Although amitriptyline is not usually regarded as toxic to the peripheral nervous system (PNS) and is even prescribed by some for neuropathic pain, there are sporadic reports of peripheral neuropathy following overdose or prolonged use of the drug. The scarcity of data leads us to report a case we have followed for 3 years clinically and electromyographically. A 54 year old man on oral amitriptyline 150 mg uninterruptedly for 2 years consulted us for lower limb paresthesias and was found on clinical examination to have reduced ankle jerks and mild distal global hypoesthesia. EMG yielded a pattern of sensorimotor neuropathy compatible with axonal disease in all four limbs. The history was unremarkable and the laboratory data were within normal limits. After discontinuation of amitriptyline therapy both the clinical and EMG pattern gradually normalized. We draw attention to the possible risk, infrequent though it is, of PNS neurotoxicity of a widely used drug reputedly harmless from this point of view.

Amitriptyline↗
PubMed2003

A new formulation of controlled release amitriptyline pellets and its in vivo/in vitro assessments.

Controlled-release amitriptyline pellets (ATP) were formulated and its oral bioavailability was assessed in human volunteers after oral administration under fasting conditions. Core pellets were prepared using a CF granulator by two different methods (powder layering and solvent spraying) and coated with Eudragit RS or RL 100. Physical characteristics and dissolution rates of core pellets and coated pellets were evaluated to optimize the formulation. Powder layering method resulted in a better surface morphology than solvent spraying method. However, physical properties of the products were poorer when prepared by powder layering method with respect to hardness, friability and density. The dissolution profile of amitriptyline coated with Eudragit RS 100 was comparable to that of commercially available amitriptyline enteric-coated pellets (Saroten retard). After the oral administration of both products at the dose of 50 mg, the mean maximum concentrations (Cmax) were 36.4 and 29.7 ng/mL, and the mean areas under the concentration-time curve (AUC(0-96)) were 1180.2 and 1010.7 ng.h/mL for ATP and Saroten retard, respectively. The time to reach the maximum concentrations (Tmax) was 6 h for both formulations. Statistical evaluation suggested that ATP was bioequivalent to Saroten retard.

Adult↗
PubMed2002

[External ophthalmoplegia caused by amitriptyline poisoning].

Drug-induced ocular motor disorders occurring during coma may be difficult to distinguish from structural cerebral lesions. We recently encountered a case of reversible amitriptyline-induced external ophthalmoplegia, which was first described by Mladinich and Carlow in 1977. We suggest that the mechanism for gaze paresis and loss of vestibulo-ocular reflex due to amitriptyline overdose involves the modulation of neurons of the pontine paramedian reticular formation, the rostral fasciculus longitudinalis medialis, and the vestibulo-ocular reflex. Clinical features that might be useful when distinguishing amitriptyline-induced ophthalmoplegia from structural brain lesions--such as basilar thrombosis--include the preservation of corneal response, purposeful withdrawal from noxious stimuli, rapid recovery within 24 hours, and the reversal of symptoms by physostigmine.

Adult↗
PubMed2002

Differential effects of amitriptyline, nefazodone and paroxetine on performance and brain indices of visual selective attention and working memory.

RATIONALE: Antidepressants may vary widely in their potential to impair cognitive and psychomotor functions. Little is known about their effects on event-related brain potentials (ERPs).OBJECTIVES. To compare the effects of three pharmacologically different antidepressants on performance and ERPs in tasks of selective attention and working memory. METHODS: Subjects were treated for 8 days with amitriptyline (sedative/anticholinergic TCA), nefazodone (5-HT(2) receptor antagonist), paroxetine (SSRI) and placebo, in a double-blind, crossover design. Measurements were carried out on day 1 and 8 of each treatment period. A task was used in which memory load (two and four items) and attention (focused, divided) were orthogonally varied. RESULTS: On day 1 amitriptyline increased reaction times (focused attention) and the percentage of misses (load 4>load 2) and false alarms. Sensitivity (A') was reduced as a function of memory load. Effects were greatly diminished on day 8. The ERP analysis yielded a reduced early frontal positive difference wave related to memory load (day 1). Attention-related search negativity was slightly prolonged. P3 latency (stimulus evaluation time) was prolonged. P3 amplitude was reduced (mainly on day 8) suggesting diminished attention capacity. Nefazodone increased reaction times and miss rates and reduced sensitivity (A') on day 8 only. Paroxetine speeded responses on day 1 and slightly increased miss rates on day 8. Performance effects of nefazodone and paroxetine did not interact with the task factors. Search negativity and P3 measures were not affected. CONCLUSIONS: The results suggest that the pharmacologically selective serotonergic antidepressants lack the specific memory and attention deficits seen with amitriptyline. Both performance and ERP data suggest that paroxetine and nefazodone may influence response-related processes, while for nefazodone an effect on other processes cannot be excluded.

Adult↗
PubMed2004

Hemoperfusion in a child with amitriptyline intoxication.

Tricyclic antidepressant overdose is one of the most common causes of serious drug poisoning in children and adults. We report a 17-month-old girl with severe amitriptyline intoxication. She was admitted to hospital because of lethargy and seizures. It was estimated that she took approximately 75 mg/kg of amitriptyline 2 h before admission. On examination she was comatose, had ventricular tachycardia and multifocal clonic seizures. Intravenous fluid, per oral activated charcoal, diazepam, lidocaine, and sodium bicarbonate infusion were given. However, there was no response to this therapy, and the patient remained in a deep coma with cardiac arrhythmias and seizures. Hemoperfusion (HP) was performed for 2 h. During this procedure, cardioversion was used six times due to ventricular fibrillation. She had a very good clinical response to HP and no complication was observed. We suggest that HP may be an effective treatment in children with severe amitriptyline intoxication.

Amitriptyline↗
PubMed1990

Formation of cytotoxic metabolites from phenytoin, imipramine, desipramine, amitriptyline and mianserin by mouse and human hepatic microsomes.

The effects of enzyme induction on the generation of cytotoxic metabolites from phenytoin, mianserin, imipramine, desipramine and amitriptyline by mouse liver microsomes has been investigated and then compared with the bioactivation mediated by human hepatic microsomes. Cytotoxicity was assessed by co-incubation of drug and microsomes with human mononuclear leucocytes which served as target cells. Enzyme induction was assessed by measurement of hepatic cytochrome P-450 content, and determination of alkoxycoumarin O-dealkylase activity. None of the compounds investigated were metabolized to cytotoxic metabolites in the presence of control mouse microsomes. However, significant bioactivation could be observed for each drug when incubated with microsomes prepared from mice pretreated with either phenobarbitone (60 mg/kg) or beta-naphthoflavone (75 mg/kg). The rank order for metabolism-dependent cytotoxicity with phenobarbitone-induced mouse microsomes (expressed as % cell death) was phenytoin (14.6%) greater than desipramine (10.5%) greater than imipramine (7.5%) greater than mianserin (3.4%) greater than amitriptyline (3.1%). Expression of cytotoxicity with phenytoin required pre-exposure of the target cells to trichloropropane oxide, an opoxide hydrolase inhibitor. Only mianserin and desipramine were activated to cytotoxic metabolites by human liver microsomes. Analysis of stable metabolites revealed that mianserin underwent extensive (greater than 80%) metabolism by both control and induced mouse microsomes and that the principal metabolites, 8-hydroxymianserin, desmethylmianserin and mianserin N-oxide, were the same as those produced by human liver microsomes. These data suggest that mianserin is activated to a cytotoxic metabolite selectively by a constitutive form of human cytochrome P-450, whereas phenytoin, amitriptyline and imipramine are selectively activated by forms of mouse cytochrome P-450 which are induced by either phenobarbitone or beta-naphthoflavone.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1980

Amitriptyline: long-term treatment elevates alpha-adrenergic and muscarinic receptor binding in mouse brain.

The effects of long-term treatment of the tricyclic antidepressant drug, amitriptyline, on alpha-adrenergic, muscarinic and dopaminergic receptor binding were studied in mouse brain. No changes could be observed after 7 or 14 days of amitriptyline administration, but after 21 days a two-fold increase in alpha-adrenergic binding was detected in the medulla pons and in the hippocampus using [3H]WB-4101 as the binding ligand. In the same two regions, a moderate increase in muscarinic receptor binding (25%) as measured by [3H]4NMPB was seen, while no change was detected in dopaminergic receptor binding measured by [3H]spiperone. Scatchard analysis reveals that the increases in receptor densities are not a result of changes in the dissociation constants of the tritiated drugs for their receptors. It is suggested that the increase in alpha-adrenergic as well as in muscarinic binding is a consequence of a chronic blockade of these two types of receptors by amitriptyline in vivo.

Adrenergic alpha-Antagonists↗
PubMed1977

Individual variations in response of human REM sleep to amitriptyline and haloperidol.

The effect of amitriptyline and haloperidol on REM sleep was investigated in healthy human adults, with special attention to individual variations in these drugs' effects. In addition, an investigation was made of the rebound elevation of REM sleep occurring on the following night of partial differential REM deprivation (PDRD), again with emphasis being placed on individual variations in that effect. The administration of amitriptyline in a single oral dose of 25 mg was followed by an inhibition of REM sleep in all subjects. The per cent decrease in REM sleep was found to have a significant negative correlation with the per cent increase in REM sleep following PDRD in individual subjects. The amount of REM sleep during the recovery night following the night of amitriptyline medication tended to correlate with the per cent increase in REM sleep following PDRD in individual subjects. Haloperidol in a single oral dose of 1.5 mg caused REM sleep to augment in some subjects but inhibit in others. A significant correlation was noted to exist between drug-induced change in REM sleep and the per cent increase in REM sleep following PDRD.

Adult↗
PubMed1982

Withdrawal from chronic treatment with metergoline, dl-propranolol and amitriptyline enhances serotonin receptor mediated behaviour in the rat.

Acute treatment of rats with metergoline (2 mg/kg), a serotonin antagonist, prevented the behavioural syndrome produced by the serotonin agonist 5-methoxy-N',N'-dimethyltryptamine (2.5 mg/kg, 5MEODMT). dl-Propranolol (15 mg/kg) and amitriptyline (15 mg/kg) also inhibited the behavioural syndrome. The 5MEODMT behavioural syndrome was attenuated when metergoline or amitriptyline were administered daily for 14 days and 5MEODMT administered 30 min after the injection on day 14. This attenuation was not seen with chronic dl-propranolol treatment. When 5MEODMT was administered 72 h after the last injection of metergoline, amitriptyline or dl-propranolol on day 14, the behavioural syndrome was enhanced. The results suggest that withdrawal from chronic treatment with serotonin antagonists results in functional supersensitivity of serotoninergic neurones.

Amitriptyline↗
PubMed1985

Why is amitriptyline much weaker than desipramine at decreasing beta-adrenoceptor numbers?

Desipramine is consistently more effective than amitriptyline at causing beta-adrenoceptor down-regulation. Atropine, mepyramine, ketanserin, cyproheptadine and citalopram did not modify this action of desipramine in rats. Therefore inhibition of either muscarinic, histamine-H1, and 5-HT receptors or 5-HT uptake produced by amitriptyline is unlikely to account for its weaker effect on beta-adrenoceptors. A more likely explanation implicates noradrenaline uptake inhibition in vivo since amitriptyline was much weaker than desipramine and only effective after repeated dosing.

Amitriptyline↗