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PubMed2004

State-dependent block of voltage-gated Na+ channels by amitriptyline via the local anesthetic receptor and its implication for neuropathic pain.

Amitriptyline is a tricyclic antidepressant, which also alleviates various pain syndromes at its therapeutic plasma concentration (0.36-0.90 microM). Accumulated evidence suggests that such efficacy may be due to block of voltage-gated Na(+) channels. The Na(+) channel alpha-subunit protein consists of four homologous domains (D1-D4), each with six transmembrane segments (S1-S6). The aims of this study were to locate the amitriptyline receptor in the Na(+) channel alpha-subunit and to compare the amitriptyline affinity in open, inactivated, and resting states of the Na(+) channel. Wild-type and mutant rat skeletal muscle alpha-subunit Na(+) channels were expressed in human embryonic kidney cells and assayed under whole-cell voltage clamp conditions. Our results indicate that the amitriptyline receptor overlaps with the local anesthetic receptor to a great extent in Na(+) channels. Residues N434 (at D1-S6), L1280 (D3-S6), and F1579 (D4-S6) may jointly form parts of the amitriptyline/local anesthetic receptor, with residue L1280 being most critical for amitriptyline binding. Open-channel block by amitriptyline was assessed in inactivation-deficient Na(+) channels and compared with the resting- and inactivated-channel block in wild-type channels. The open-channel block by amitriptyline has the highest affinity, with a 50% inhibitory concentration (IC(50)) of 0.26 microM. The inactivated-channel block by amitriptyline had a weaker affinity (0.51 microM), whereas the resting-channel displayed the weakest affinity (33 microM). We hypothesize that selective block of both persistent late openings and the inactivated state of neuronal Na(+) channel isoforms by amitriptyline also occurs at its therapeutic concentration and likely contributes to its efficacy in pain syndromes.

Amitriptyline↗
PubMed2006

A proposed mechanism for amitriptyline neurotoxicity based on its detergent nature.

Although amitriptyline has gained attention as a potent local anesthetic, recent animal studies showed that it can cause irreversible neural impairment. We hypothesized that nerve membrane disruption caused by solubilization, a common detergent property, accounted for amitriptyline neurotoxicity. We used a two-phase approach to test our hypothesis. Firstly, we determined (1) the molecular aggregation concentration of amitriptyline, (2) the concentration of amitriptyline that disrupts artificial lipid membranes and (3) the concentration of amitriptyline that causes hemolysis. Secondly, we compared these levels with neurotoxic concentrations determined from assessment in a rat model of spinal anesthesia using changes in cutaneous stimulus threshold (CST). Amitriptyline concentrations that caused molecular aggregation, model membrane disruption and hemolysis were 0.46%, 0.35% and 0.3%, respectively. Animal study showed a significant increase in CST at >or=0.3% of amitriptyline, indicating neurological impairment. Since amitriptyline caused model membrane disruption and hemolysis at the molecular aggregation concentration, solubilization plays a role in the destruction of artificial membranes and erythrocytes. Furthermore, these concentrations are also in good agreement with the minimum concentration causing neurological injury. Therefore, while additional studies, including histopathology, are necessary to clarify this observation, amitriptyline neurotoxicity appears to be associated with its detergent nature.

Amitriptyline↗
PubMed1996

Chronic amitriptyline exposure reduces 5-HT3 receptor-mediated cyclic GMP formation in NG 108-15 cells.

In the present study, we investigated the effects of chronic in vitro administration of amitriptyline, a tricyclic antidepressant, on cyclic GMP formation stimulated by 5-hydroxytryptamine (5-HT) in the neuroblastoma x glioma hybrid cell line, NG 108-15, 5-HT (0.01-100 microM)-stimulated cyclic GMP formation was concentration-dependent and was sensitive to ICS 205-930, a 5-HT3 receptor antagonist. Exposure of NG 108-15 cells to 5 microM amitriptyline for 3 days significantly reduced 5-HT-stimulated cyclic GMP formation. Acute treatment with amitriptyline had no effect on 5-HT-stimulated cyclic GMP formation. The reduction by chronic amitriptyline exposure of 10 microM 5-HT-stimulated cyclic GMP formation was concentration-dependent over the concentration range examined (0.5 to 10 microM). The IC50 of amitriptyline was 1.9 microM. In contrast, amitriptyline exposure, even at a concentration of 8 microM, failed to modify cyclic GMP formation stimulated by bradykinin, sodium nitroprusside, or atrial natriuretic peptide. Increases in intracellular Ca2+ concentration ([Ca2+]i) evoked by 10 microM 5-HT were attenuated in amitriptyline-exposed cells, while 100 nM bradykinin-induced [Ca2+]i increases were not affected. In addition, chronic exposure to 5 microM amitriptyline caused a decrease in affinity (Kd) of [3H]zacopride specific binding to 5-HT3 recognition sites. The Bmax for the labelled ligand remained unchanged. These results suggest that chronic amitriptyline exposure reduces 5-HT-stimulated cyclic GMP formation and [Ca2+]i increases, and this may reflect the functional changes of 5-HT3 receptors.

Amitriptyline↗
PubMed1996

Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics.

BACKGROUND: Divalproex sodium has been found to be efficacious in the prophylaxis of migraine headaches and the management of the manic phase of bipolar syndrome. Because amitriptyline is also prescribed in these patient populations, data are needed on their potential for interaction. METHODS: The effect of concomitant administration of divalproex sodium on the pharmacokinetics of amitriptyline and its active metabolite, nortriptyline, was investigated in an open-label, sequential, two-period phase I study. Ten healthy male and five healthy female subjects received 50 mg amitriptyline hydrochloride on two occasions: (1) alone (period 1) and (2) 2 hours after receiving the ninth dose of 500 mg divalproex sodium (Depakote) administered once every 12 hours (period 2). RESULTS: Amitriptyline area under the curve was increased 31% from the combined effect of decreased first-pass metabolism and inhibition of systemic metabolism. The elevated nortriptyline plasma levels reflected primarily the increase in amitriptyline concentrations but also appeared to involve modest inhibition of nortriptyline elimination. For the sum of amitriptyline and nortriptyline concentrations, the peak plasma concentration mean was 19% higher with concomitant divalproex dosing. The mean area under the curve for the sum of amitriptyline and nortriptyline concentrations was 42% higher with concomitant divalproex dosing than it was for dosing with amitriptyline alone. CONCLUSION: These results suggested that a lower dose of amitriptyline might be considered when divalproex is administered concomitantly.

Adult↗
PubMed2003

Peripheral interactions between dextromethorphan, ketamine and amitriptyline on formalin-evoked behaviors and paw edema in rats.

The local, peripheral administration of antidepressants and excitatory amino acid receptor antagonists can cause analgesia in a number of conditions. The present study examined the effects of combinations of dextromethorphan and ketamine, two clinically used N-methyl-D-aspartate (NMDA) receptor antagonists, with amitriptyline on formalin-evoked behaviors and paw edema. Pretreatment with amitriptyline or dextromethorphan (10-300 nmol) resulted in suppression of flinching behaviors induced by 2.5% formalin, but ketamine had no intrinsic effect. Combination of an inactive dose of dextromethorphan with amitriptyline, and vice versa, resulted in an increase of analgesia so that previously inactive doses now caused significant analgesia. Combinations of multiple doses of ketamine with amitriptyline did not modify the response to amitriptyline. Both dextromethorphan and ketamine increased the paw edema induced by formalin, and this was blocked by low doses of amitriptyline. In the absence of formalin, amitriptyline (1-100 nmol) caused a dose-related suppression of the paw edema produced by dextromethorphan and ketamine. Amitriptyline also blocked paw edema produced by 5-hydroxytryptamine and compound 48/80. Each of the drugs used in this study exerts multiple pharmacological effects. Increased analgesia by drug combinations (amitriptyline/dextromethorphan) could show the involvement of a number of these mechanisms (e.g. NMDA receptor blockade, blockage of sodium channels, blockage of biogenic amine receptors), while a lack of intensification (amitriptyline/ketamine) could reflect occluded actions due to expression of similar actions by the other drug. Paw edema induced by dextromethorphan and ketamine involves inhibition of biogenic amine reuptake, and the ability of amitriptyline to block biogenic amine receptors likely accounts for its inhibiton of these actions. Combinations of these particular agents could represent a method for augmented analgesia and minimization of local adverse reactions.

Amitriptyline↗
PubMed1999

Acute amitriptyline in a rat model of neuropathic pain: differential symptom and route effects.

The present study was designed to determine whether amitriptyline, a prototypical tricyclic antidepressant, could produce pain relieving properties in a rat model of neuropathic pain. Nerve injury was produced by tight ligation of the lumbar 5th and 6th dorsal roots and this resulted in persistent stimulus evoked neuropathic pain symptoms (tactile allodynia and thermal hyperalgesia). Thermal hyperalgesia was measured using a focused light beam directed at the ventral surface of the paw while tactile allodynia was determined using Semmes-Weinstein monofilaments applied to the ventral surface of the paw. Amitriptyline was administered systemically (intraperitoneal), spinally (intrathecal cannula), and locally (subcutaneously) via direct injection into the dorsal surface of the paw. Following systemic administration, amitriptyline completely reversed thermal hyperalgesia (10 mg/kg) in the injured paw. Spinal administration of amitriptyline (60 microg) also produced an antihyperalgesic effect. Interestingly, local administration of amitriptyline (100 nmol) had an immediate antihyperalgesic effect that persisted for 120 min following administration. Amitriptyline had no alleviating effect against mechanical allodynia regardless of the route of administration, but curiously, produced hyperaesthesia in the contralateral paw. These results indicate that in the rat model of spinal nerve ligation, amitriptyline is effective in alleviating thermal hyperalgesia (systemically, spinally and locally) but is ineffective against mechanical allodynia. The peripheral efficacy of amitriptyline suggests the possibility of the development of cream formulations that may be able to increase the local concentration of amitriptyline without increasing the systemic dose and the subsequent occurrence of side effects.

Amitriptyline↗
PubMed2006

Binding of naproxen and amitriptyline to bovine serum albumin: biophysical aspects.

Binding of the drugs naproxen (which is an anti-inflammatory) and amitriptyline (which is an anti-depressant) to bovine serum albumin (BSA) has been studied using isothermal titration calorimetry (ITC), in combination with fluorescence and circular dichroism spectroscopies. Naproxen is observed to bind more strongly to BSA than amitriptyline. The temperature-dependent ITC results indicate the interaction of one molecule of naproxen with more than one protein molecule. On the other hand, amitriptyline binds to BSA with a reaction stoichiometry that varies from 1:1.2 to 1:2.9. The van't Hoff enthalpy, which is calculated from the temperature dependence of the binding constant, agrees well with the calorimetric enthalpy in the case of naproxen binding to BSA, indicating adherence to a two-state binding process. However, their disagreement in the case of amitriptyline indicates conformational changes in the protein upon ligand binding, as well as with the rise in temperature. The spectroscopic results did not suggest appreciable conformational changes as a result of binding; hence, the discrepancy could be attributed to the temperature-induced conformational changes. With increases in the ionic strength, a reduction in the binding affinity of naproxen to BSA is observed. This suggests the prevailing electrostatic interactions in the complexation process. The preponderance of the hydrophobic interactions in the binding of amitriptyline to BSA is indicated by the absence of any dependence of the ionic strength. A predominance of electrostatic interactions in the case of naproxen binding to BSA and that of hydrophobic interactions in the case of amitriptyline binding to BSA is further strengthened by the results of the binding experiments performed in the presence of ionic and nonionic surfactants. The binding parameters indicate that Triton X-100 blocks the hydrophobic binding sites on BSA, thereby altering the binding affinity of amitriptyline toward BSA. A partial overlap of the binding sites for these drugs is indicated by the binding parameters obtained in the titration of naproxen to the amitriptyline-BSA complex and vice versa. Thus, the results provide a quantitative understanding of the binding of naproxen and amitriptyline to BSA, which is important in understanding their effect as therapeutic agents individually and in combination therapy.

Amitriptyline↗
PubMed2003

Amitriptyline eliminates calculi through urinary tract smooth muscle relaxation.

BACKGROUND: We investigated the effects of amitriptyline in the urinary tract smooth muscle and urolithiasis. METHODS: Cats presenting with obstructive acute renal failure (ARF) received amitriptyline, and renal function and survival rates were analyzed. Isometric contractions and membrane potentials of rat, pig, or human isolated urinary tract smooth muscle were recorded in the presence or absence of amitriptyline. RESULTS: Twenty cats with obstructive ARF caused by urethral plugs received amitriptyline. In all cases, plugs were completely eliminated, and renal function returned to normal, with a 100% survival rate in the follow-up. Amitriptyline produced potent relaxations in rat urethral strips, accompanied by significant reductions in urethral ring membrane potential. This effect was prevented by pretreatment of urethral rings with 4-aminopyridine (4-AP), a voltage-dependent potassium channel blocker. Amitriptyline abolished in a reversible manner acetylcholine-, bradykinin-, and KCl-induced contractions in rat isolated bladder, and this effect was also prevented by 4-AP. Of interest, spontaneous and KCl-induced contractions of pig and human isolated ureter were also blocked by amitriptyline. CONCLUSION: Our results indicate that amitriptyline is an effective and potent relaxant of urinary tract smooth muscle and this effect is mediated by opening of voltage dependent-potassium channels. We suggest that amitriptyline administration may help to promote elimination of urinary calculi.

Acute Kidney Injury↗
PubMed2003

Efficacy and safety of venlafaxine ER vs. amitriptyline ER in patients with major depression of moderate severity.

INTRODUCTION: A double-blind, randomized phase-III study was conducted with the aim to compare the efficacy and safety of venlafaxine ER (extended release) with that of amitriptyline ER in moderately depressed outpatients. METHODS: Patients with major depression of moderate severity, HAM-D (Hamilton Depression scale, 21 items) score 20-26, were given a six-week double-blind treatment with venlafaxine ER and amitriptyline ER in a dosis of 75 mg each, which could be increased to 150 mg, if necessary. Efficacy was assessed using HAM-D and CGI (clinical global impression) scores. Safety analysis was carried out using the HAM-D item 3 to assess suicidality, the d2 test to evaluate attention and drug screening for benzodiazepines. Adverse events were recorded at each visit. RESULTS: 160 patients were randomized. There were 151 patients available for analysis in the intent-to-treat (ITT) population. The according-to-protocol (ATP) population consisted of 117 patients, with 60 patients in the venlafaxine ER group and 57 in the amitriptyline ER (extended release) group. The non-inferiority of venlafaxine ER compared to amitriptyline ER with reference to the primary efficacy parameter, the change of HAM-D total score, could be proven in both the ITT population and the ATP population. There were no significant differences between groups in the HAM-D response rates and the CGI scores of items 1 (severity) and 2 (improvement). Venlafaxine ER showed a more favorable safety profile than amitriptyline ER: adverse drug reactions were less frequent under venlafaxine ER than under amitriptyline ER. Most of the discontinuations in the amitriptyline ER group were due to dry mouth. The d2 test showed greater improvement of performance under venlafaxine ER. DISCUSSION: In this study with patients treated for major depression of moderate severity, the non-inferiority of venlafaxine ER compared to amitriptyline ER with respect to the chosen efficacy parameter could be demonstrated. Venlafaxine ER showed a more favorable safety profile than amitriptyline ER.

Adult↗
PubMed2002

Amitriptyline for prolonged cutaneous analgesia in the rat.

BACKGROUND: Amitriptyline has been reported to be a more potent local anesthetic than bupivacaine. In keeping with the objective of identifying drugs for prolonged cutaneous analgesia, the authors compared the cutaneous analgesic effectiveness of amitriptyline and bupivacaine in rats. METHODS: Rats were subcutaneously injected on shaved dorsal skin. The skin wheal raised after injection of 0.6 ml of various concentrations of either amitriptyline or bupivacaine with and without epinephrine (1:200,000) was marked. Inhibition of the cutaneous trunci muscle reflex was evaluated quantitatively by the fraction of times a total of six pinpricks applied to the marked area failed to elicit a nocifensive motor response compared with control responses. No responses out of six pinpricks was defined as 100% maximum possible effect. RESULTS: Complete recovery from the cutaneous analgesia elicited by 0.05% and 0.5 amitriptyline versus 0.05 and 0.5% bupivacaine occurred in 9.9 +/- 0.2 and 19.3 +/- 0.4 h versus 2.2 +/- 0.1 and 16.1 +/- 0.2 h, respectively (mean +/- SE). Addition of epinephrine increased this duration to 14.1 +/- 0.1 and 21.4 +/- 0.2 h versus 3.2 +/- 0.1 and 17.0 +/- 0.3 h, respectively. Complete nociceptive blockade after coinjection of 0.25% amitriptyline, 0.25% bupivacaine, and epinephrine lasted 24 +/- 0.5 h, and complete recovery from this block took 33 +/- 0.5 h. Areas under the percent maximum possible effect versus time curve were 1,770 +/- 24 and 1,471 +/- 50% h for 0.5% amitriptyline and bupivacaine with epinephrine, respectively, whereas this value was 2,836 +/- 62% h for the coinjected 0.25% amitriptyline, 0.25% bupivacaine, and epinephrine admixture. CONCLUSION: Amitriptyline is a longer-acting local anesthetic compared with bupivacaine for cutaneous infiltration. Its analgesic effectiveness is significantly enhanced by epinephrine. Coinjection of amitriptyline and bupivacaine with epinephrine enhances the analgesic duration of both drugs.

Amitriptyline↗
PubMed1994

A double-blind, placebo-controlled study comparing mianserin and amitriptyline in moderately depressed outpatients.

We report on the results of a study comparing mianserin with amitriptyline and placebo, in outpatients with major depression (DSM-III 296.2 or 296.3). One hundred and forty-nine patients were randomized to mianserin (n = 50), amitriptyline (n = 50) or placebo (n = 49). Medication was taken in a nightly (qhs) dose. During Week 1, the maximum dose was 60 mg mianserin, 120 mg amitriptyline or two placebo capsules. Beginning at Day 7 (through Day 42) maximum dosages were 150 mg mianserin, 300 mg amitriptyline or five placebo capsules. At multiple weeks and endpoint, statistically significant reductions in the Hamilton Depression Scale (HAM-D) 17- and 21-item scores were recorded for both active drugs compared with placebo. Positive results with the HAM-D were corroborated by other measures of efficacy. There were no statistically significant differences between mianserin and amitriptyline in terms of efficacy; however, the results do suggest a more rapid therapeutic response for mianserin compared with amitriptyline, in terms of percentage of patients showing > or = 50% improvement at Weeks 2 (30% vs 23%) and 4 (61% vs 44%). The most common adverse experiences were somnolence (amitriptyline and mianserin 60%, placebo 31%) and dry mouth (amitriptyline 76%, mianserin 30% and placebo 20%). Our results indicate that mianserin is clearly superior to placebo, compares favorably with amitriptyline, and is a safe, well-tolerated, effective medication in the treatment of depressed outpatients.

Adult↗
PubMed1993

Distribution of amitriptyline and nortriptyline in blood: role of alpha-1-glycoprotein.

To interpret blood levels of tricyclic antidepressants, we studied the distributions of amitriptyline and nortriptyline in human blood and explored their control by plasma factors. Each compound (300 ng/ml) was added to whole adult blood and to cord blood with decreased alpha-1-glycoprotein (AGP). Drugs (250 ng/ml) were also added to washed erythrocytes (RBCs) resuspended in autologous plasma or saline (hematocrit = 0.4) with or without AGP, albumin, or tris(2-butoxyethyl) phosphate (TBEP), used to displace AGP-bound drugs. Plasma AGP was determined in all adult blood donors (n = 17). With adult blood, plasma amitriptyline was 393 +/- 52 ng/ml, RBC amitriptyline was 184 +/- 33 ng/ml. Plasma and RBC nortriptyline were 199 +/- 28 and 288 +/- 39 ng/ml, respectively. With saline, cellular amitriptyline and nortriptyline were 81 +/- 10 and 88 +/- 6%, respectively. With plasma, cellular amitriptyline and nortriptyline were 25 +/- 8 and 49 +/- 10%, respectively. The corresponding cord blood values were 52 +/- 12 and 62 +/- 6%. Graded increments of AGP in saline reproduced the distribution pattern seen with increasing concentrations of plasma. Albumin did not influence drug distribution. TBEP markedly increased erythrocyte amitriptyline in adult but not in cord blood. Plasma AGP correlated positively (p = 0.031) with the RBC/plasma ratio of amitriptyline. Amitriptyline is predominantly distributed in plasma, nortriptyline in RBCs. This differential distribution is dose dependent and reflects the higher binding of amitriptyline to AGP when compared with nortriptyline. Interpretation of tricyclic antidepressant blood levels is clarified by obtaining assays from RBCs and plasma.

Aging↗
PubMed1997

A double-blind, placebo-controlled study comparing the effects of sertraline versus amitriptyline in the treatment of major depression.

BACKGROUND: This study was designed to compare the efficacy, safety, tolerability profiles, and effects on quality of life of the serotonin selective reuptake inhibitor antidepressant sertraline versus the nonselective tricyclic antidepressant amitriptyline and placebo in patients with major depression. METHOD: Outpatients with DSM-III-R major depression were randomly assigned to double-blind treatment for 8 weeks with sertraline (50-200 mg daily), amitriptyline (50-150 mg daily), or matching placebo. Assessments included the Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions-Severity of Illness scale, Clinical Global Impressions-Improvement scale, Global Assessment Scale, Profile of Mood States, Beck Depression Inventory, Quality of Life Enjoyment and Satisfaction Questionnaire, and Health-Related Quality of Life battery. RESULTS: All treatment groups demonstrated statistically significant improvement from baseline in depression ratings by Week 1 and thereafter. The antidepressant effects of amitriptyline and sertraline were significantly (p < .05) greater than placebo and did not differ significantly from each other. Sertraline was associated with significantly (p < .05) greater subjective (i.e., patient-rated) improvement in mood than amitriptyline or placebo. Both active drugs were associated with greater improvements than placebo on most quality of life measurements. On several items, sertraline, but not amitriptyline, was superior to placebo. There was a discernible effect of sertraline earlier than amitriptyline on most quality of life scales. Amitriptyline therapy was associated with significantly more treatment-related adverse events, and discontinuations due to treatment-related adverse events, in comparison to both sertraline and placebo therapy. CONCLUSION: Sertraline and amitriptyline each were effective treatments for major depression as assessed by both physician- and patient-rated scales. These results show that sertraline therapy is better tolerated than amitriptyline therapy. Quality of life was also improved by effective antidepressant treatment, with sertraline showing a tendency to produce greater improvements on quality of life measures.

1-Naphthylamine↗
PubMed2000

Block of human heart hH1 sodium channels by amitriptyline.

Amitriptyline is a tricyclic antidepressant used to treat major depression and various neuropathic pain syndromes. This drug also causes cardiac toxicity in patients with overdose. We characterized the tonic and use-dependent amitriptyline block of human cardiac (hH1) Na(+) channels expressed in human embryonic kidney cells under voltage-clamp conditions. Our results show that, near the therapeutic plasma concentration of 1 microM, amitriptyline is an effective use-dependent blocker of hH1 Na(+) channels during repetitive pulses (approximately 55% block at 5 Hz). The tonic block for resting and for inactivated hH1 channels by amitriptyline (0.1-100 microM) yielded IC(50) values (50% inhibitory concentration) of 24.8 +/- 2.0 (n = 9) and 0.58 +/- 0.03 microM (n = 7), respectively. Substitution of phenylalanine with lysine at the hH1-F1760 position, a putative binding site for local anesthetics, eliminates the use-dependent block by amitriptyline at 1 microM. The time constants of recovery from the inactivated-state amitriptyline block in hH1 wild-type and hH1-F1760K mutant channels are 8.0 +/- 0. 5 (n = 6) and 0.45 +/- 0.07 s (n = 6), respectively. A substitution at either hH1-F1760K or hH1-Y1767K significantly increases the IC(50) values for resting and inactivated states of amitriptyline, but the increase is much more pronounced with the hH1-F1760K mutation. Because these two residues were proposed to form a part of the local anesthetic binding site, we conclude that amitriptyline and local anesthetics interact with a common binding site. Furthermore, at therapeutic concentrations, the ability of amitriptyline to act as a potent use-dependent blocker of Na(+) channels may, in part, explain its analgesic actions.

Amitriptyline↗
PubMed1986

Pharmacokinetics of amitriptyline influenced by oral charcoal and urine pH.

The effects of orally given activated charcoal, sodium bicarbonate and ammonium chloride on the pharmacokinetics of amitriptyline were studied in 6 volunteers in a randomized, cross-over study. The serum and urine concentrations of amitriptyline and nortriptyline were determined by HPLC for up to 72 h. Activated charcoal (50 g), given within 5 min of the amitriptyline hydrochloride dose (75 mg), reduced its absorption by 99%. When given in repeated doses from 6 h on, 50 g followed by 12.5 g at 6-h intervals, charcoal shortened the serum half-life of amitriptyline by 20% and that of nortriptyline by 35% (p less than 0.05). The renal excretions of amitriptyline and nortriptyline increased 1000-fold by the acidification of urine pH to 4. However, the cumulative excretion of amitriptyline and nortriptyline even into acidic urine only accounted for up to 5% of the dose during 72 h. Since urinary pH has a great influence on the ratio of urinary versus serum amitriptyline and nortriptyline concentrations, pH should be taken into consideration, when the clinical significance of their concentrations in urine is evaluated. Activated charcoal in adequate doses very effectively prevents the absorption of that fraction of amitriptyline which is in the stomach at the time of charcoal administration. Furthermore, given in repeated oral doses, charcoal increases, to some extent, the rate of elimination of amitriptyline and nortriptyline, probably by interrupting their enterohepatic or enteroenteric circulation.

Administration, Oral↗
PubMed1993

[Relationship between amitriptyline metabolism and polymorphic debrisoquine hydroxylation in native Chinese volunteers].

The demethylation and hydroxylation of amitriptyline were calculated from the ratios between the area under concentration--time curve (AUC) of amitriptyline and its three metabolites in eight healthy Chinese volunteers after a single oral dose of 100 mg amitriptyline. Great interindividual differences in AUCs of amitriptyline and its metabolites were observed. HPLC method was used to determine the debrisoquine hydroxylation phenotype in seven out of the eight volunteers. Six subjects were found to be rapid and one slow debrisoquine hydroxylators. The ratio between debrisoquine and 4-hydroxydebrisoquine in urine correlated significantly with the rate of amitriptyline hydroxylation and the AUCs of amitriptyline and 10-hydroxyamitriptyline, but not with that of amitriptyline demethylation. There also was a weak correlation between total plasma clearance and the hydroxylation of debrisoquine. These data suggest that the hydroxylation of amitriptyline and debrisoquine may be regulated by similar enzymatic processes and the demethylation and hydroxylation processes in amitriptyline metabolism appear to undergo two separate pathways.

Adult↗
PubMed1999

Fluoxetine and amitriptyline inhibit nitric oxide, prostaglandin E2, and hyaluronic acid production in human synovial cells and synovial tissue cultures.

OBJECTIVE: To evaluate the effects of fluoxetine and amitriptyline on nitric oxide (NO), prostaglandin E2 (PGE2), and hyaluronic acid (HA) production in human synovial cells and synovial tissue cultures. METHODS: Human synovial cells, synovial tissue, and cartilage were cultured in the presence or absence of cytokines, lipopolysaccharides (LPS), fluoxetine, or amitriptyline. Production of NO, PGE2, and HA was determined in culture media. Sulfated glycosaminoglycan (S-GAG) synthesis was evaluated in cartilage by 35S incorporation. RESULTS: Fluoxetine (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) inhibited NO release by 56%, 62%, and 71%, respectively, in the media of synovial cells stimulated by interleukin-1alpha (IL-1alpha; 1 ng/ml) plus tumor necrosis factor alpha (TNFalpha; 30 ng/ml). Amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) caused a 16%, 27.3%, and 51.4% inhibition of NO release. Fluoxetine and amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) significantly (P<0.05) inhibited PGE2 release in the media of human synovial cells in the presence of IL-1alpha plus TNFalpha, in a dose-dependent manner (up to 88% inhibition). Fluoxetine (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) and amitriptyline (1 microg/ml and 3 microg/ml) significantly (P<0.05) inhibited PGE2 release in the media of human synovial tissue in the presence of LPS. Fluoxetine and amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) also significantly (P<0.05) inhibited HA production by human synovial cells in the presence of IL-1beta plus TNFalpha. Fluoxetine and amitriptyline (1 microg/ml) partially reversed IL-1beta-induced inhibition of 35S-GAG synthesis by human cartilage cultures (P<0.05). Neither fluoxetine nor amitriptyline had a toxic effect on cells in the concentrations used. CONCLUSION: Inhibition of NO and PGE2 production by connective tissue cells is a mechanism by which some antidepressant medications may affect pain, articular inflammation, and joint damage.

Aged↗
PubMed1994

Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia. A randomized, double-blind clinical trial.

OBJECTIVE: To compare the relative efficacy and tolerability of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia, and to identify predictors of response to amitriptyline and cyclobenzaprine. METHODS: Two hundred eight patients who fulfilled the American College of Rheumatology criteria for the classification of fibromyalgia were entered into a 6-month prospective, double-blind, multicenter trial and were randomized to 1 of 3 treatment groups: amitriptyline, cyclobenzaprine, or placebo. RESULTS: After 1 month, 21%, 12%, and 0% of the amitriptyline, cyclobenzaprine, and placebo patients, respectively, had significant clinical improvement (amitriptyline versus placebo P = 0.002, cyclobenzaprine versus placebo P = 0.02, amitriptyline versus cyclobenzaprine P not significant). These percentages increased to 36%, 33%, and 19%, respectively, at the 6-month assessment (P not significant). The nature and frequency of side effects reported by patients treated with amitriptyline and those reported by patients treated with cyclobenzaprine were similar. A normal Minnesota Multiphasic Personality Inventory (MMPI) profile at baseline was predictive of clinical improvement at the 1-month evaluation (odds ratio 3.3, 95% confidence interval 1.2-9.0). However, neither the MMPI profile nor any of the demographic, clinical, or functional parameters evaluated at baseline predicted long-term response. CONCLUSION: Our data confirm the short-term efficacy of amitriptyline and cyclobenzaprine in a small percentage of patients with fibromyalgia. Long-term efficacy could not be demonstrated because of a higher-than-expected placebo response. Predictors of response to these drugs could not be determined.

Amitriptyline↗