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PubMed1994

Experimental amitriptyline poisoning: treatment of severe cardiovascular toxicity with cardiopulmonary bypass.

STUDY OBJECTIVE: To compare cardiopulmonary bypass (CPB) with more conventional therapy in the treatment of severe amitriptyline poisoning. DESIGN: Prospective, randomized, controlled, laboratory investigation. INTERVENTIONS: Profound cardiovascular toxicity was induced in 20 anesthetized Yorkshire swine (72 +/- 8.3 kg) by amitriptyline infusion at 0.5 mg/kg/min. Ventilation was adjusted to keep arterial pH at 7.50 +/- 0.05 and the PCO2 at 35 mm Hg. The swine were randomized in a 1:1 ratio to one of two groups, CPB or control. Both groups received amitriptyline infusion until they experienced near-lethal toxicity, defined as a systolic blood pressure below 30 mm Hg for one minute. The control group was then given supportive treatment, including IV fluids, sodium bicarbonate, vasopressors, and standard pharmacologic (advanced cardiac life support) interventions. Control animals failing to respond to supportive measures after five minutes were given open-chest cardiac massage for 30 minutes or until the return of spontaneous circulation. The CPB group received only mechanical support by CPB for 90 to 120 minutes. No sodium bicarbonate, antiarrhythmics, or cardiotonic agents were provided to the CPB group during this resuscitation. RESULTS: All 20 animals experienced cardiac conduction delays, dysrhythmias, and progressive hypotension within 30 minutes of receiving IV amitriptyline at 0.5 mg/kg/min. The ten swine receiving CPB as treatment for cardiovascular toxicity were able to completely correct the dysrhythmias, cardiac conduction abnormalities, and hypotension produced by the amitriptyline; however, only one of ten control animals could be resuscitated (P = .0001). Nine of ten swine treated with CPB were easily weaned off bypass without any pharmacologic intervention; however, one required norepinephrine to be weaned. All 11 resuscitated swine were able to be salvaged. CONCLUSION: CPB improved survival in our swine model of severe amitriptyline poisoning.

Amitriptyline↗
PubMedDate not supplied

Topical amitriptyline in healthy volunteers.

BACKGROUND AND OBJECTIVES: The antidepressant amitriptyline is used as an adjuvant in the treatment of a variety of chronic pain conditions. This drug interacts with many receptors and ion channels, such as Na+ channels. In a randomized, double-blinded, and placebo-controlled trial, we investigated whether amitriptyline also is capable of providing cutaneous analgesia when applied topically in 14 healthy volunteers. METHODS: Amitriptyline hydrochloride was prepared as a 45% water/45% isopropanol/10% glycerin solution and titrated to pH 8.5 with sodium hydroxide. Four areas, 2 on each arm, of approximately 1 cm(2) each were marked on the ventral aspect of the upper arm. A piece of gauze, placed on each of the marked areas and affixed to the arm with an occlusive plastic dressing, was saturated via syringe with placebo and amitriptyline solutions (10 mmol/L, 50 mmol/L, and 100 mmol/L). After 1 hour, the dressings and gauze were removed. A 16-G blunt needle was used to grade the pain at the marked area once per hour (1 = complete analgesia, 10 = normal pain sensation). RESULTS: The analgesic effects of 50 mmol/L and 100 mmol/L solutions of amitriptyline were significantly higher than those of the placebo or the 10 mmol/L solution. However, no significant difference was found between the analgesia provided by the placebo solution versus the 10 mmol/L solution or between the 50 mmol/L versus the 100 mmol/L solution. The only side effect observed was a concentration-dependent redness of the skin. CONCLUSIONS: Topically applied amitriptyline is effective as an analgesic in humans. Different vehicles may improve its efficacy and decrease the skin redness observed.

Administration, Cutaneous↗
PubMed2005

Amitriptyline and nortriptyline inhibit interleukin-1 release by rat mixed glial and microglial cell cultures.

Pro-inflammatory cytokines, such as interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha have been suggested to be involved in the pathophysiology of depression and in the mechanism of action of antidepressant drugs. Until now the effect of antidepressants on cytokines has been examined only in plasma, blood mononuclear cells and spleen, which reflect the activity of peripheral cytokine network. The aim of this study was to evaluate the effect of amitriptyline and its metabolite nortriptyline on the release of IL-1beta and TNF-alpha by lipopolysaccharide (LPS)-activated rat mixed glial and microglial cell cultures. LPS stimulated the release of both cytokines. The exposure of mixed glial culture to amitriptyline and nortriptyline led to a decrease in both IL-1beta and TNF-alpha release. Moreover, amitriptyline reduced LPS-stimulated IL-1beta release by microglial cultures. Although amitriptyline reduced secretion of both cytokines, the drug did not affect IL-1beta and TNF-alpha mRNAs in mixed cell cultures. Our study has shown for the first time that amitriptyline and nortriptyline administered at concentrations which may be achieved in plasma and brain structures during treatment, inhibit the secretion of IL-1beta and TNF-alpha in rat mixed glial and microglial cell cultures. The obtained results support the previous observations that antidepressants are able to reduce peripheral release of pro-inflammatory cytokines and suggest that the cytokine network may be involved in the central mechanism of action of amitriptyline and nortriptyline.

Amitriptyline↗
PubMed2006

Adverse effects of gabapentin and lack of anti-allodynic efficacy of amitriptyline in the streptozotocin model of painful diabetic neuropathy.

Amitriptyline and gabapentin are the primary treatments for painful diabetic neuropathy (PDN), and it is clear that they produce beneficial effects, but there are questions about these treatments that have not been adequately addressed. For example, although there is a growing consensus that the therapeutic effects of amitriptyline in pain patients are independent of its effects on mood, it is not clear that amitriptyline has specific and direct effects on pain. There is also a fairly broad consensus that gabapentin is safe and well tolerated, but the side-effect profile of gabapentin has not been adequately assessed in pain populations. The rat streptozotocin (STZ) model of PDN was used (a) to assess the effects of amitriptyline on objective, quantitative measures of tactile allodynia, a common type of pain in PDN patients, and (b) to assess the side effects of gabapentin using measures of motor/ambulatory and cognitive function. Amitriptyline did not attenuate STZ-induced mechanical allodynia, even after chronic administration of high doses. Gabapentin produced robust anti-allodynic effects but also produced deficits in tests of motor/ambulatory and cognitive functions. The present experiments suggest that the beneficial effects of amitriptyline in PDN may not be a result of anti-allodynic efficacy and that gabapentin produces robust anti-allodynic effects but may also produce significant motor and cognitive deficits even at or near the lowest effective doses. These findings challenge the consensus opinions about these primary treatments for PDN and suggest that their therapeutic and adverse effects should be explored further in pain patients.

Amines↗
PubMed2000

Amitriptyline reduces myofascial tenderness in patients with chronic tension-type headache.

The tricyclic anti-depressant amitriptyline is widely used in the treatment of chronic tension-type headache. The aim of the present study was to investigate whether the analgesic effect is caused by a reduction of muscle pain or by a general reduction of pain sensitivity. Thirty-three non-depressed patients with chronic tension-type headache were treated with amitriptyline 75 mg/day and with the highly selective serotonin reuptake inhibitor citalopram 20 mg/day in a 32-week, double-blind, placebo-controlled, three-way crossover study. At the end of each treatment period, actual headache intensity and pericranial myofascial tenderness were recorded, pressure pain detection and tolerance thresholds were measured in the finger and in the temporal region and the electrical pain threshold was measured at the labial commissure. Amitriptyline reduced tenderness and headache intensity significantly more than placebo (P=0.01 and P=0.04, respectively). The reduction in tenderness could be ascribed solely to the group of patients who responded to amitriptyline treatment by at least 30% reduction in headache while tenderness was unchanged in non-responders. Amitriptyline did not affect pressure or electrical pain thresholds at any of the examined locations. Citalopram had no significant effect on any of the examined parameters. These findings indicate that amitriptyline elicits its analgesic effect in chronic myofascial pain by reducing the transmission of painful stimuli from myofascial tissues rather than by reducing overall pain sensitivity. We suggest that this effect is caused by a segmental reduction of central sensitization in combination with a peripheral anti-nociceptive action.

Adult↗
PubMed1998

Double-blind, multicenter comparative study of sertraline and amitriptyline in hospitalized patients with major depression.

Sertraline is a selective serotonin reuptake inhibitor (SSRI) for which marketing approval has been obtained recently in Germany. The results of several double-blind, placebo-controlled studies have demonstrated that sertraline has a clear antidepressive effect. However these studies have been conducted in outpatient populations. In the context of this multicenter study, a total of 160 inpatients were treated with sertraline 50-150 mg or amitriptyline 75-225 mg over a period of 6 weeks in a double-blind fashion. Sixty-two patients in the sertraline and 59 patients in the amitriptyline group were evaluated for efficacy in the according-to-protocol (ATP) population; 80 sertraline and 75 amitriptyline patients were evaluated for safety in the Intention-to-treat population (ITT). No statistically significant differences were detected between the two groups in the efficacy analysis performed on the basis of the Hamilton Depression Scale (HAM-D) total score and Clinical Global Impression (CGI). Due to its sedating properties, amitriptyline was found to be significantly more effective with regard to the HAM-D factor "sleep disturbance". The safety analysis, which was based on the CGI, the global assessment at the end of study and a score for somatic adverse events (FSUCL) revealed statistically significant advantages of sertraline over amitriptyline. Amitriptyline was associated with more autonomic and circulatory side effects, while epigastric complaints occurred more often with sertraline. The incidence of nausea - a typical SSRI side effect - was the same in both groups.

Adrenergic Uptake Inhibitors↗
PubMed1997

LI 160, an extract of St. John's wort, versus amitriptyline in mildly to moderately depressed outpatients--a controlled 6-week clinical trial.

Up to now, the antidepressant efficacy of the extract of St. John's wort, LI 160, has been compared to imipramine and maprotiline, demonstrating similar antidepressant efficacy in mildly to moderately depressed patients, treated either with LI 160 or the respective synthetic comparator. In the study reported here, LI 160 (total daily dose: 900 mg) was compared with the sedating tricyclic amitriptyline (total daily dose: 75 mg) in a controlled, randomized, multicentre trial. At the end of the 6-week study, the major target variable, the Hamilton Depression Scale response rate, exhibited no statistically significant difference between the groups, although a tendency for a better response rate was seen in the amitriptyline group. The secondary efficacy parameters, decreases in the total Hamilton Depression and Montgomery-Asberg scores, showed a significant advantage for amitriptyline, but only at week 6. With regard to tolerability, LI 160 was clearly superior to amitriptyline, particularly in relation to anticholinergic and Central Nervous System adverse events. Thus, 37% of the LI 160 treated patients reported adverse events, compared to 64% in the amitriptyline group. This considerable superiority in tolerability for LI 160 in relation to amitriptyline, could confer an advantage in improving compliance for antidepressant pharmacotherapy.

Adult↗
PubMed2004

Contralateral effect of amitriptyline and bupivacaine for sciatic nerve block in an animal model of inflammation.

BACKGROUND: Using a carrageenan inflammation rat model, we evaluated two experimental approaches to prolong sciatic nerve block on contralateral hyperalgesia. Method. We performed ipsilateral sciatic nerve block on the inflamed hind paw with bupivacaine-loaded microspheres suspended in dexamethasone (bupivacaine 12.5 mg) and with amitriptyline (6.25 and 12.5 mg) as ultralong-acting local anaesthetics. Bupivacaine (1.25 mg) was used as long-acting local anaesthetic and saline was used as a control. The sixth group received amitriptyline 6.25 mg intraperitoneally (n=10 for each group). RESULTS: The duration of ipsilateral nerve block was 2 h for bupivacaine, 7 h for amitriptyline 6.25 mg, 11 h for amitriptyline 12.5 mg and 21 h for bupivacaine-loaded microspheres in suspension with dexamethasone. Whereas contralateral hyperalgesia was not observed during block produced by bupivacaine-loaded microspheres, contralateral hyperalgesia was observed with sciatic nerve block using amitriptyline. CONCLUSIONS: Because of the differential effect observed on the contralateral side, the mechanism underlying the prolongation of ipsilateral block with amitriptyline may not result only from a prolonged Na(+) channel blockade but might be explained by a local toxic effect or lack of systemic actions.

Amitriptyline↗
PubMed2001

A comparison of tramadol, amitriptyline, and meperidine for postepidural anesthetic shivering in parturients.

UNLABELLED: Tramadol is effective for treating shivering during epidural anesthesia in parturients. In addition to its low affinity to opioid receptors, tramadol exerts a modulatory effect on central monoaminergic pathways. In this respect, there are parallels between the mechanisms of the action of tramadol and antidepressants such as amitriptyline. Meperidine is often recommended for the treatment of postanesthetic shivering. This prospective, double-blinded, and randomized clinical study was performed to compare the antishivering effects and accompanying side effects among tramadol, meperidine, and amitriptyline for the treatment of postepidural anesthetic shivering. Forty-five parturients who shivered during cesarean delivery under epidural anesthesia and requested antishivering treatment were randomly allocated to one of three groups for IV treatment: Group T (n = 15) received tramadol 0.5 mg/kg, Group M (n = 15) received meperidine 0.5 mg/kg, and Group A (n = 15) received amitriptyline 15 or 20 mg. The response rate (shivering ceased after treatment in 15 min) was 87% and 93% for Groups T and M, respectively, compared with 13% in Group A (P < 0.01). The time that elapsed from treatment to the time shivering ceased was 5.1 +/- 3.6 min (mean +/- SD) for Group T and 4.2 +/- 2.3 min for Group M. There was a significantly more frequent incidence (33%) of somnolence in Group M when compared with Groups T (7%) and A (0%) (P < 0.01). However, no significant differences were shown for pruritus, nausea, vomiting, or Apgar scores of newborns. We concluded that both tramadol and meperidine show a significantly faster response rate in the treatment of postepidural anesthetic shivering when compared with amitriptyline in the dosage used; tramadol had a decreased incidence of somnolence when compared with meperidine. IMPLICATIONS: This study was performed to compare the antishivering and side effects among tramadol, amitriptyline, and meperidine for the treatment of postepidural anesthetic shivering in parturients. Both tramadol and meperidine show a significantly faster response rate in the treatment of shivering when compared with amitriptyline. Tramadol had a less frequent incidence of somnolence than meperidine.

Adolescent↗
PubMed2002

Peripheral amitriptyline suppresses formalin-induced Fos expression in the rat spinal cord.

UNLABELLED: We examined the effects of systemically, spinally, and peripherally administered amitriptyline on formalin-induced Fos immunoreactivity in the lumbar spinal cord. Formalin (2.5%), injected subcutaneously into the rat hindpaw, increased Fos immunoreactivity in laminae I-II, III-IV, and V-VI of the dorsal L5 spinal cord. Amitriptyline, administered both systemically and spinally before formalin, increased flinching and concurrently decreased biting/licking behaviors, but neither route of administration produced any statistically significant change in Fos immunoreactivity. Amitriptyline coadministered with the formalin reduced both flinching and biting/licking behaviors, and significantly reduced Fos immunoreactivity, particularly in laminae I-II. These immunohistochemical changes reflect the net behavioral effects observed after the different routes of drug administration. The profile of amitriptyline action after peripheral administration may be of clinical importance because of the potential use of antidepressants as topical analgesics. IMPLICATIONS: In the formalin test, amitriptyline produces different effects on pain behaviors after systemic, spinal administration and peripheral administration. Fos protein, an indicator of neuronal activity after noxious stimulation, is upregulated after formalin injection. We examined the effects of amitriptyline on such expression and observed a reduction in expression with peripheral administration.

Amitriptyline↗
PubMed1986

The dexamethasone suppression test (DST) in predicting response to desipramine and amitriptyline in depressed outpatients.

The predictive value of the dexamethasone suppression test (DST) was evaluated in two consecutive clinical trials involving 99 individuals treated with amitriptyline or desipramine. Following one week observation, and following one week on low-dose desipramine or amitriptyline (50 mg), all patients who remained depressed (Hamilton score 16 or greater) were given a full clinical trial of either desipramine or amitriptyline (150-300 mg/day) over a minimum 3-5 week period. In all, 68 patients required this trial, 31 receiving amitriptyline and 37 receiving desipramine. For these patients there was no relationship between DST suppression/non-suppression vs clinical response to either desipramine or amitriptyline. There was a non-significant trend for suppressors (negative DST) to respond either spontaneously or to low-dose desipramine or amitriptyline as opposed to non-suppressors (positive DST).

Amitriptyline↗
PubMed1994

Verbal learning by major depressive disorder patients during treatment with fluoxetine or amitriptyline.

After 1 week of a single-blind placebo period, and prior to being randomly assigned to receive treatment with either fluoxetine or amitriptyline, patients meeting strict criteria for a diagnosis of major depressive disorder were given an auditory verbal learning test of working memory, and a blood sample was drawn. After 3 weeks of drug treatment with either amitriptyline or fluoxetine, the patients' symptoms were evaluated, the verbal learning test was repeated, and a second blood sample was taken. The clinical evaluation, the verbal learning test and the blood drawing were repeated a third time 3 weeks after the second assessment. The amount of anticholinergic activity in the blood samples was measured by a competitive radioligand binding assay and expressed in atropine equivalents. Analyses of variance indicated that there were no significant differences at the predrug Assessment 1 between patients subsequently assigned to the fluoxetine group compared with those assigned to the amitriptyline group. At Assessments 2 and 3, the fluoxetine and the amitriptyline groups showed equal clinical improvement but patients receiving amitriptyline did not perform as well on the verbal learning task. Serum anticholinergic activity at Assessments 2 and 3 was considerably higher in the amitriptyline group. This supports the hypothesis that blockade of muscarinic receptors impairs working memory formation. Equally effective antidepressant drugs with little or no anticholinergic action, such as fluoxetine, may be preferable in patients with pre-existing mild cognitive impairment or in patients where a slight reduction in cognitive performance is not acceptable.

Adolescent↗
PubMed1992

Dextromethorphan and mephenytoin phenotyping of patients treated with thioridazine or amitriptyline.

The metabolism of most tricyclic antidepressants and some phenothiazine neuroleptics is under the genetic control of hepatic cytochrome P-450IID6, which also regulates the metabolism of dextromethorphan. This study investigated the effect of treatment with amitriptyline or thioridazine on testing for genetically regulated efficiency of the metabolism of dextromethorphan and mephenytoin. One group of 33 patients was treated with 150 mg amitriptyline a day (the AMI group); 25 other patients received a daily dose of thioridazine, either 200 mg (200-THD group; n = 7) or 400 mg (400-THD group; n = 18). Before and after 10 days of this treatment, all patients were tested with 25 mg dextromethorphan and 100 mg mephenytoin to determine their pharmacogenetic status with respect to their hepatic drug oxidizing systems (cytochrome P-450IID6 and P-450 MP). Two patients were poor metabolizers (PMs) of dextromethorphan and three of mephenytoin. Treatment with either psychotropic drug was without significant effect on the metabolism of mephenytoin, but both amitriptyline and thioridazine increased significantly the metabolic ratio of dextromethorphan/dextrorphan. Thioridazine had the effect of changing the pharmacogenetic status of 15 efficient metabolizers of dextromethorphan to poor metabolizers; amitriptyline did not have such an effect. There was no significant correlation between day-11 plasma levels of thioridazine, mesoridazine, or sulforidazine and the metabolism of dextromethorphan, but there was a correlation between the metabolism of dextromethorphan and plasma levels of amitriptyline and nortriptyline. Amitriptyline (p less than 0.05), but not thioridazine, decreases the ratio of conjugated/total dextrorphan in urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2005

Prolonged pharmacokinetic drug interaction between terbinafine and amitriptyline.

Drugs with long terminal half-lives, such as terbinafine, have a potential for involvement in both long-lasting drug-drug interactions and interactions appearing weeks after discontinuation. We present a case report on a 37-year-old white woman with normal CYP2D6 metabolic capacity who was treated with amitriptyline, valproate, and olanzapine when terbinafine was introduced. Shortly thereafter she experienced extreme dryness of the mouth, nausea, and dizziness accompanied by a large increase in the serum concentrations of amitriptyline and nortriptyline. Terbinafine therapy was discontinued, and the amitriptyline dose was reduced. Surprisingly, the serum concentrations of amitriptyline and nortriptyline did not return to baseline until approximately 6 months later. Studies have shown that terbinafine is a highly potent competitive inhibitor of CYP2D6. CYP2D6 is an important intermediate enzyme in metabolism of amitriptyline to nortriptyline. Nortriptyline is further metabolized to 10-hydroxy metabolites, mainly by CYP2D6. It is, therefore, likely that the concomitant use of terbinafine was the major cause of the increased serum concentrations of amitriptyline and nortriptyline. Very different terbinafine elimination half-lives (17-400 hours) are stated in the physicians' reference guides. If the shortest estimates are used when adjusting the dose of interacting drugs, the risk of underestimating the duration of the interaction is large. Based on our data there is a risk of clinically significant drug-drug interactions for at least 3 months after stopping terbinafine intake.

Adult↗
PubMed1987

A double-blind comparison of citalopram (Lu 10-171) and amitriptyline in depressed patients.

In a controlled, clinical, multicentre trial comprising a total of 43 patients (17 men and 26 women) citalopram was compared double-blindly with amitriptyline. Nineteen patients of each group were classified as endogeneously depressed, whereas four patients of the citalopram group and one of the amitriptyline group were classified as non-endogenously depressed. The patients were seriously ill with a high frequency of previous depressive episodes and of mental disorders among their closest relatives. Thirteen of the patients in either group had received antidepressants without satisfactory effect before entry into the trial. Each patient was treated for a period of at least 3 weeks with daily citalopram doses of 30-60 mg or daily amitriptyline doses of 75-225 mg. A statistically significant reduction of MADRS scores (total scores as well as each of the 10 individual items) was recorded in both groups. The only difference between the groups was a trend towards a better effect on sleep disturbances in the amitriptyline group. Side-effects were recorded more frequently in the amitriptyline group than in the citalopram group, global assessment of side effects being significantly different in favour of citalopram. It is concluded that citalopram is an effective and safe drug in the treatment of endogenous depression - probably as efficacious as amitriptyline, but with fewer side effects.

Adult↗
PubMed1980

Neuropharmacological properties of amitriptyline, nortriptyline and their metabolites.

Amitriptyline, nortriptyline and their metabolites, desmethylnortriptyline, cis and trans 10-hydroxyamitriptyline, cis and trans 10-hydroxynortriptyline and amitriptyline-N-oxide, have been tested for inhibitory effect on the uptake of serotonin (rabbit thrombocytes in vitro) and noradrenaline (mouse atria in vitro and mouse heart in vivo), for anticholinergic activity (guinea-pig ileum in vitro) and for antagonism against tetrabenazine induced inactivity as well as apomorphine and 5-hydroxytryptophan potentiating effect in mice. Amitriptyline inhibits serotonin and noradrenaline uptake equally, whereas nortriptyline is a more potent inhibitor of noradrenaline than of serotonin uptake. The metabolites resemble nortriptyline in this respect. The 10-hydroxylated metabolites are equipotent with amitriptyline as regards noradrenaline uptake inhibition. All the metabolites are less anticholinergic than amitriptyline and nortriptyline. The in vitro results are reflected in the in vivo behavioural tests, although some discrepancies are found, probably due to differences in absorption, distribution, metabolism and excretion. The importance of knowledge concerning pharmacological properties of the metabolites in comparison with amitriptyline and nortriptyline for correlating plasma levels of these and their metabolites to clinical outcome is discussed.

Amitriptyline↗
PubMed1980

Myocardial pharmacokinetics of amitriptyline and clomipramine in the isolated, perfused rabbit heart.

The myocardial pharmacokinetics of amitriptyline and clomipramine were investigated in isolated rabbit hearts, which were perfused with a modified Krebs-Henseleit solution containing the equimolar concentrations 0.25 or 0.28 micrograms ml-1 of the compounds, respectively. The rate of myocardial uptake of the drugs as a function of time was indirectly followed by determinations of the concentrations of the compounds in fractional samples of the coronary output of perfusate. The time course of disposition of amitriptyline from the myocardium was similarly followed after changing from amitriptyline perfusion to perfusion with drug-free liquid. The amitriptyline accumulation and disposition processes were found to fit bi-exponential functions indicating myocardial two-compartment characteristics of the compound. Clomipramine did only exhibit one-compartment myocardial characteristics. The biological half-life of amitriptyline in the myocardium was about 37.7 min. and a pronounced cardiac accumulation of about 340 micrograms of the compound at steady state was evidenced. The myocardial half-life of clomipramine was about 106 min. and the accumulated amount at steady state was calculated to be 1055 micrograms. After amitriptyline perfusion an increase in the pharmacokinetic rate constants k10 and k12 and a decrease in the apparent central volume of distribution was observed.

Amitriptyline↗
PubMed1985

Anticholinergic activity in the serum of patients receiving maintenance amitriptyline or doxepin therapy.

The anticholinergic activity in serum of depressive patients receiving amitriptyline (50-300 mg/day) or doxepin (50-225 mg/day) was measured using a radioreceptor assay. In this method the membrane suspension prepared from rat brain was able to bind the potent muscarinic antagonist, quinuclidinyl benzilate. Using atropine as a standard, the antimuscarinic activity of several compounds can be measured in the serum of patients receiving drugs with anticholinergic effects or side-effects. The steady state serum levels of amitriptyline and doxepin and their desmethylated metabolites, nortriptyline and desmethyldoxepin were measured by radioimmunoassay in the same serum samples. The antimuscarinic activity in serum measured as atropine equivalents was 2.7 +/- 0.4 (S.E.M.) ng/ml in amitriptyline patients and 1.1 +/- 0.2 ng/ml in doxepin patients. There was a highly significant correlation (P less than 0.001) between amitriptyline (r = 0.92) and nortriptyline (r = 0.79) concentrations and serum antimuscarinic activity. The correlation was less clear, although statistically significant for doxepin (r = 0.42, P less than 0.05) and desmethyldoxepin (r = 0.58, P less than 0.01). The better correlation between serum drug levels and antimuscarinic activity in amitriptyline than in doxepin patients is probably due to the higher affinity of amitriptyline and its desmethylated metabolite to muscarinic receptors with the doses used in the present study. The method may have clinical applications e.g. in evaluation of excessive anticholinergic activity in patients.

Adult↗