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PubMedDate not supplied

Urinary metabolites of amitriptyline in the dog.

Dogs excreted approximately 45% of an oral dose of 14C-amitriptyline (30 mg/kg) in the urine in 24 hr. Two new urinary metabolites of the drug were identified as dihydrodiol derivatives of amitriptyline and nortriptyline, respectively. The major metabolite in dog urine was 10-hydroxyamitriptyline, excreted mainly in conjugated form. Other metabolites were characterized as 10-hydroxynortriptyline, amitriptyline N-oxide, and nortriptyline. Together, these metabolites accounted for approximately 47% of the urinary radioactivity.

Amitriptyline↗
PubMed1991

Pharmacological characteristics of high-affinity serotonin uptake systems established through gene transfer.

Inactivation of a neurotransmitter, after its stimulated release, via high-affinity uptake mechanisms is an essential regulatory step of neurotransmission in both the central and peripheral nervous systems. To initiate explorations of the molecular mechanisms and the underlying biochemical architecture of high-affinity neurotransmitter uptake systems, we have used gene transfer technology to establish and identify novel cellular models that express these systems. Human genomic DNA was transfected into mouse L-M fibroblasts and two independently arising, clonal cell lines (L-S1 and L-S2) have been identified as expressing high-affinity serotonin (5-HT) uptake systems. The 5-HT uptake characteristics of L-S1 and L-S2 are essentially comparable (in terms of Na+ dependence, temperature sensitivity, imipramine antagonizability, kinetic saturability and high affinities) and those of L-S1 have been reported previously. Furthermore, competition studies utilizing catecholamine neurotransmitters and their amino acid precursors demonstrated that these systems are highly specific for 5-HT. Several known inhibitors of high-affinity 5-HT uptake systems (including amitriptyline, desipramine, fluoxetine, imipramine, nortriptyline, tryptamine, 5-methoxytryptamine and N-acetyl 5-methoxytryptamine) were assessed in terms of their respective potencies to inhibit 5-[3H]HT uptake by L-S1 and L-S2 cells. For L-S1 cells, the rank order of inhibitor potencies is imipramine greater than amitriptyline greater than fluoxetine greater than desipramine = nortriptyline greater than tryptamine greater than 5-methoxytryptamine greater than N-acetyl-5-methoxytryptamine. For L-S2, the rank order is similar to that of L-S1 except that fluoxetine is more potent than amitriptyline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Steady-state plasma levels during antidepressant therapy with amitriptyline and amitriptylinoxide.

Plasma levels of amitriptyline, amitrypylinoxide, and their metabolites were analyzed in a controlled clinical trial with two groups of depressed patients. After administration of both drugs, demethylated and hydroxylated derivatives proved to be the main metabolites, and to a great extent amitriptylinoxide was reduced to amitriptyline. Continuous oral application of 150 mg/os per day of each drug resulted in therapeutically effective concentrations in both groups; however, concentrations were two to three times higher in the group receiving amitriptyline, rather than amitriptylinoxide. Based on the steady-state plasma levels, the total clearance of amitriptyline was calculated with a magnitude of 7 ml/min per kg. A first-order kinetic model was proposed to estimate the steady-state concentrations of consecutive metabolites, employing available kinetic data. Computed levels of nortriptyline after application of amitriptyline and amitriptylinoxide were 61.1 and 20.3 ng/ml, respectively, compared to nortriptyline levels determined with HPLC, which were 70.1 and 26.5 ng/ml, respectively. The model is discussed in relation to its practical use during monitoring of drug therapy with tricylics.

Adult↗
PubMed1989

Management of depression in the elderly.

Primary care physicians have a vital role to play in identifying depression in their elderly patients. Diagnosis may be difficult, because symptoms are atypical and frequently include psychomotor agitation, somatic symptoms, and complaints of memory loss. Patients with medical illnesses, such as cancer, postmyocardial infarction, stroke, Parkinson's disease, and early Alzheimer's disease are particularly vulnerable to depression. Drugs that may cause depressive symptoms are digitalis at toxic levels, beta-blockers, centrally acting antihypertensives, immunosuppressants, and nonsteroidal anti-inflammatory agents. Cyclic antidepressants are the drugs of first choice. Selection depends on the patient's physical health and current medications and the side effect profile of the drug. Side effects are more pronounced in old age because of drug accumulation owing to slowed clearance. Troublesome side effects are anticholinergic effects, orthostatic hypotension, sedation, cardiotoxicity, and weight gain. The most useful antidepressants for geriatric patients are the secondary amines, desipramine and nortriptyline. The second-generation drug trazodone has the advantage of causing the least anticholinergic effects, but it is very sedating. Before treatment, the patient should have an electrocardiogram, liver function tests, tonometry, sitting and standing blood pressures, evaluation of urinary symptoms for outflow obstruction, review of current medications, and estimation of suicide risk. Cyclic antidepressants are contraindicated during recovery from myocardial infarction, in heart disease when there is severe impairment of myocardial performance, in seizure disorders, and in the presence of glaucoma or a large prostate. Drug interactions that may cause trouble can occur with epinephrine, MAO inhibitors, thyroid hormone, cimetidine, and centrally acting antihypertensives. Dosage should start low, increasing usually by 25 mg every 4 to 5 days until a therapeutic level is reached. Failure of a noradrenergic antidepressant after 4 to 5 weeks can be followed by a trial of a serotonergic drug. Drug serum level monitoring is useful for imipramine, desipramine, and nortriptyline. Monoamine oxidase inhibitors are effective in many elderly patients who are resistant to TCAs. Sympathomimetic drugs must be avoided with MAOIs. Elderly patients are at high risk of toxicity and drug interactions with lithium. Electroconvulsive therapy is useful for patients who do not respond to drug treatment, but medical complications, particularly cardiovascular, often occur in patients 75 or older. Many patients relapse after ECT. Psychotherapy together with pharmacotherapy may be the optimal treatment for elderly depressives. Older patients are more likely to become chronically depressed than younger patients. The risk of suicide in depressed elderly males is high, particularly in those with psychosocial problems, and depression rises with age.

Aged↗
PubMed1987

Initial severity and diagnosis influence the relationship of tricyclic plasma levels to response: a statistical review.

There is considerable controversy about the clinical value of monitoring tricyclic antidepressant plasma levels. To investigate this issue the authors pooled data from 17 published plasma level studies of imipramine, amitriptyline, or nortriptyline, involving over 400 patients. The findings suggest that tricyclic antidepressant plasma level monitoring is important primarily for patients who are severely depressed or who have endogenous features. Monitoring is especially important for such patients who are treated with amitriptyline or nortriptyline, since failure to respond may be associated with very low or very high plasma levels. These data have implications for tricyclic antidepressant plasma level monitoring and future research.

Antidepressive Agents, Tricyclic↗
PubMedDate not supplied

[Pharmacogenetics of antidepressant metabolism. Value of the debrisoquin test].

The drug monitoring of antidepressants in blood plasma has revealed considerable interindividual differences in steady-state levels. For some compounds recent results strongly suggest that this phenomenon finds an explanation in genetic differences in the metabolism of the drugs by monooxygenases (cytochrome P-450) in the liver. Thus, a genetic deficiency has been described in 5-10% of the European population in the metabolism of debrisoquine and sparteine. Clinical experience shows that the separation of subjects into extensive metabolizers (EM) and poor metabolizers (PM) is also valid for drugs of interest in psychiatry, such as some betablockers and antidepressants like amitriptyline, nortriptyline and desipramine. Actually, PMs of debrisoquine may develop excessively high levels of these antidepressants in blood during the treatment. On the other hand, it is probable that, at least, one oxidative pathway of maprotiline belongs to the genetic polymorphism of debrisoquine, but a deficiency in the metabolism of this test substance does not necessarily mean high levels of maprotiline. Today's clinical experience shows that, in some cases, PMs of debrisoquine do not respond to a treatment with nortriptyline. However, this has not been demonstrated for amitriptyline. It is predicted that pharmacogenetic tests will find their place in psychopharmacotherapy, especially for subjects candidates for a long-term treatment or susceptible to suffer from side effects. However, the validity of the test remains to be demonstrated for other drugs, like benzodiazepines and neuroleptics, but also in the case of patients suffering from organic diseases or under treatment with potential competitors.

Adult↗
PubMedDate not supplied

Determination of amitriptyline and its major basic metabolites in human urine by high-performance liquid chromatography.

A high-performance liquid chromatographic method for the routine, simultaneous determination of amitriptyline and its basic metabolites in human urine has been developed. 10-Hydroxylated metabolites are analyzed as their 10,11-dehydro analogs, and primary and secondary amines as their N-trifluoroacetyl derivatives. The use of gradient elution enables amitryptyline, nortriptyline trifluoroacetate, desmethylnortriptyline trifluoroacetate, and the corresponding 10, 11-dehydro analogs to be separated from both each other and from the internal standard used. In this way all six compounds may be conveniently measured in a single chromatogram, with good sensitivity and accuracy. Following administration of a single oral dose (25 mg) of amitriptyline hydrochloride to two human subjects, no unchanged drug was found in any of the urine samples analyzed up to 72 hr after dosing, and only small amounts of nortriptyline and desmethylnortriptyline were observed. 10-hydroxynortriptyline was the major biotransformation product (about 40% of the dose) in urine, with 10-hydroxyamitriptyline and 10-hydroxydesmethylnortriptyline present as minor metabolites. During 72 hr after administration, approximately 60% of the dose was recovered as these five metabolites.

Adult↗
PubMed1979

Hydroxylated metabolites of tricyclic antidepressants: preclinical assessment of activity.

Studies investigating a possible relationship between the plasma concentration of tricyclic antidepressants and clinical response have measured only the tertiary and secondary amine forms of these drugs. The present study shows that the hydroxy metabolites of tricyclic antidepressants might also be active. Hydroxylated imipramine, desipramine, chlorimipramine, and nortriptyline inhibit the uptake of norepinephrine and serotonin into synaptosomes to the same extent as do their parent compounds. Hydroxylated nortriptyline and imipramine reverse or prevent reserpine-induced motor retardation and ptosis. Following chronic imipramine, significant steady-state concentrations of unconjugated hydroxylated metabolites are present in rat tissues including the cerebrospinal fluid. Accounting for steady-state concentrations of hydroxylated metabolites of tricyclic antidepressants in man may help to clarify whether there is a relationship between active drug concentration and clinical effect.

Animals↗
PubMed1979

Cardiovascular and autonomic actions of ciclazindol and tricyclic antidepressants.

The novel antidepressant ciclazindol had no significant effect on blood pressure at doses of up to 25.6 mg/kg i.v. in anaesthetised rats. Desipramine, imipramine, nortriptyline and amitriptyline evoked significant decreases at 0.8-1.6 mg/kg. Ciclazindol had no sustained haemodynamic actions in anaesthetised cats apart from a small rise in dp/dt. The ECG waveform showed only minor voltage changes. Desipramine and nortriptyline elevated haemodynamic variables at low doses but decreases occurred at higher doses. Amitripyline and imipramine decreased blood pressure. ECG changes evoked by the tricyclics included QRS complex distortion, ventricular ectopic beats, nodal rhythm, bundle branch block and ventricular tachycardia. In skin wheal tests ciclazindol was equiactive with the tricyclics as a local anaesthetic. In isolated tissues ciclazindol was not anticholinergic, showed no marked antagonism of 5-HT, potentiated responses to noradrenaline and was weakly antihistaminic. Ciclazindol appears to be pharmacologically different from the tricyclics and may not produce the unwanted side effects associated with these compounds.

Animals↗
PubMed1979

Plasma levels of tricyclic antidepressants and clinical efficacy: review of the literature -- part II.

The authors have critically reviewed the literature regarding the relationship between plasma levels of tricyclic antidepressant and their clinical efficacy. When available, drug-drug interactions, pharmacokinetics, and other factors influencing plasma levels of tricyclic antidepressants are discussed. Although many studies are confounded by significant methodological and statistical problems, it appears to these reviews that the available evidence suggests a curvilinear relationship between nortriptyline plasma levels and antidepressant efficacy in tricyclic responsive endogenously depressed inpatients, with maximal therapeutic efficacy achieved with notriptyline plasma levels between 50-175 ng/ml. The evidence for imipramine supports a linear relationship between plasma levels of imipramine plus desmethylimipramine and clinical response in nondelusional endogenously depressed tricyclic responsive inpatients. For amitriptyline, the picture is less clear. However, with the exception of one well-controlled study, the available evidence suppprts some significant relationship between amitriptyline plus nortriptyline plasma levels and antidepressant efficacy in tricyclic respoonsive endogenously depressed patients, but it is not clear as to whether this is a linear relationship or a curvilinear one. For the other antidepressants: protriptyline, desmethylimipramine, doxepin, clomipramine, maprotiline, and butriptyline, a significant relationship (if any) awaits further elucidation. It is important to point out that these plasma level relationships probably do no generalize to other types of depressions (e.g. neurotic, characterological, delusional, acute situationa, etc.) and clearly do not apply to every endogenous tricyclic responsive patient. /owever, it appears that, in general, a clinician will obtain therapeutic efficacy for endogenously depressed patients if these guidelines are followed. The actual therapeutic levels will depend on the assay's sensitivity and specificity and may vary from center to center, illustrates the importance of each center defining its own therapeutic limits, or conversely all centers adoptina a universal reproducible assay methodology for each compound measured. Despite these limitations, these reviewers feel that routine monitoring of plasma levels of the tricyclic antidepressants is a useful method to maximize therapeutic efficacy and prvent undue side effects, as well as to insure good medication compliance.

Antidepressive Agents, Tricyclic↗
PubMedDate not supplied

Interaction between antidepressants and alpha-adrenergic receptor blocking agents.

Yohimbine and phentolamine administered in doses regarded as blocking presynaptic alpha-adrenoreceptors counteracted locomotor sedation elicited in rats by antidepressant drugs (imipramine, nortriptyline and amitriptyline). The reduction of noradrenaline (NA) utilization in the brain evoked by a single dose of antidepressants and the increase of NA utilization induced by chronic treatment with imipramine or nortriptyline were prevented by yohimbine. The results indicate the role of presynaptic alpha-adrenoceptors in the influence of tricyclic antidepressants on NA neurons in the brain.

Adrenergic alpha-Antagonists↗
PubMed1982

Liquid-chromatographic determination of amitryptyline and its metabolites in serum, with adsorption onto glass minimized.

To study correlations between the concentrations, in serum, of amitriptyline and its most important metabolites with clinical response in patients, we developed a "high-performance" liquid-chromatographic method for routine determination of amitriptyline, nortriptyline, total 10-hydroxy-amitriptyline, desmethylnortriptyline, and E(trans)- and Z(cis)-10-hydroxynortriptyline. These compounds are extracted from 1 mL of alkalinized serum into hexane/isoamyl alcohol (99/1 by vol). Perazine is the internal standard. To minimize irreversible adsorption of the drugs onto the glassware, 5 micrograms of maprotiline is added to the organic phase just before evaporation. After a 10-min resolution on a silica column eluted with acetonitrile/methanol/NH4OH (1 mol/L), absorbance is measured at 240 nm. Only chlorimipramine, doxepin, procainamide, and N-acetylprocainamide may interfere with assay of the compounds that probably are therapeutically relevant: amitriptyline, nortriptyline, and E-10-hydroxynortriptyline. Uremia, lipemia, and icterus also do not affect the analysis.

Adsorption↗
PubMed1997

Psychotropic medications and cytochrome P450 2D6: pharmacokinetic considerations in the elderly.

BACKGROUND: The genetically polymorphic cytochrome P450 2D6 isozyme (CYP2D6) is responsible for the metabolism of numerous psychotropic medications pertinent to the practice of geriatric psychiatry. Optimal use of psychotropics in the elderly requires a thorough understanding of the determinants of marked variability in plasma concentrations. This review article will focus on basic pharmacokinetic considerations for elderly patients when psychotropics metabolized by CYP2D6, such as nortriptyline and desipramine, are prescribed. METHOD: A MEDLINE search was conducted using the subject headings "cytochrome P450," "pharmacokinetics," and "psychotropics." Relevant articles from bibliographies were also collected. RESULTS: CYP2D6 activity does not change with age. Approximately 5% to 10% of whites are poor metabolizers for CYP2D6 and are at risk for drug toxicity. Among Asians, although the prevalence of poor metabolizers in only 1%, the distribution of CYP2D6 activity in extensive metabolizers is shifted toward lower values relative to whites. CYP2D6 activity may be impaired by inhibitors such as paroxetine and fluoxetine. Inhibition of CYP2D6 activity may result in nonlinear plasma drug concentration kinetics, as well as kinetic drug interactions when other drugs metabolized by CYP2D6 are coadministered. Among extensive metabolizers, there is considerable interindividual variation in CYP2D6 activity. Significant correlations have been reported between individual CYP2D6 activity and plasma concentrations of nortriptyline and desipramine. CONCLUSION: Clinical measurement of CYP2D6 activity may potentially assist in prediction of doses required to achieve therapeutic plasma concentrations of psychotropics metabolized by CYP2D6 in individual patients. Although CYP2D6 activity does not change with age, the pharmacokinetics of psychotropics metabolized by CYP2D6 may change because of age-associated changes in hepatic blood flow, volume of distribution, and renal elimination of metabolites.

Age Factors↗
PubMed1999

Postmortem drug redistribution--human cases related to results in experimental animals.

Femoral blood is widely accepted as the most reliable postmortem specimen for drug analysis in forensic toxicology. There is considerable evidence that the drug concentrations in peripheral blood samples are closer to the antemortem level than the concentration in cardiac blood. In the present study drug concentrations measured in postmortem femoral and/or heart blood samples from eight cases were compared with the concentration found in serum samples from the same subject collected antemortem or perimortem. The drugs involved were amitriptyline, nortriptyline, imipramine, verapamil and chloroquine. Two additional cases with very early postmortem blood samples, as well as femoral blood samples from later autopsy, involved amphetamine and tetrahydrocannabinol. The results from the human cases were compared with results from rat experiments on similar drugs. The samples were analyzed by high performance liquid or gas chromatography. The cases with tricyclic antidepressants had a median postmortern femoral blood to antemortem serum drug concentration ratio of 3.3, the 95% reference range being from 1.1 to 6.0 (pooled data). Large variations of the ratios were seen. The extremes noted were a postmortem femoral blood to antemortem serum drug concentration ratio of 0.9 in a case with nortriptyline and 49 in the case with chloroquine. The low ratio in the former case could be due to attempted resuscitation, while the high ratio in the latter case is probably due to the extremely high apparent volume of distribution and a high blood to plasma concentration ratio for chloroquine. Accordingly, it is dubious whether the drug concentration found in femoral blood at autopsy can be accepted as being representative for the antemortem level. The results obtained from the human cases in the present study were generally in reasonable agreement with previous rat experiments, confirming that the animal studies when interpreted carefully, are indicative of the changes observed in man as well as a previous study in pigs. Studies on drug concentrations in pigs are not necessarily more representative for the findings in humans than experiments with a smaller animal like the rat. The postmortem concentration changes observed for tetrahydrocannabinol in man were found to be unpredictable, while in the accompanying experimental rat study there was a significant postmortem decrease in the tetrahydrocannabinol blood concentration measured in blood from the inferior vena cava. In special cases where the diagnosis of overdose is to be used as judicial evidence, a single sample of blood may prove insufficient. In such cases, analyses of several samples of blood and tissue will increase the possibility of reaching a correct conclusion, but reference values on drug concentrations in tissues are often missing.

Adolescent↗
PubMed1995

Applicability of clinical pharmacotherapy guidelines for major depression in primary care settings.

OBJECTIVE: To determine whether guidelines established for pharmacologic treatment of major depression are feasible in primary care. DESIGN: Prospective cohort study. SETTING: Ambulatory family health centers and internal medicine clinics. PATIENTS: Ninety-one primary care patients meeting criteria within the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition for a current major depression randomized to receive antidepressant medication after being judged by a psychiatrist as clinically eligible for pharmacotherapy in an ambulatory setting. INTERVENTION: Nortriptyline hydrochloride prescribed by primary care physicians trained in clinical guidelines specifying dosage schedules, durations, and procedures resembling those recommended by the AHCPR (Agency for Health Care Policy and Research) Depression Guideline Panel. MAIN OUTCOME MEASURES: Patient participation and continuation in medication treatment. RESULTS: Fifty-five percent of patients completed the acute phase of treatment after a mean of 6.9 visits extending over a mean of 8.1 weeks. Of those patients entering the continuation phase, 60% completed the follow-up visits for 6 months. Taken together, only 33% of patients assigned to receive antidepressant medication completed the full regimen recommended by the AHCPR guidelines. CONCLUSIONS: The treatment of depressed primary care patients within AHCPR guidelines for antidepressant medication is feasible but complex. Although primary care physicians ably adhere to these guidelines, keeping patients in treatment is difficult and possibly requires greater flexibility in treatment regimens.

Adult↗
PubMed1980

Screening of antiserotoninergic drugs with the genetically dystrophic chicken.

Line 413 early-onset, genetically homozygous dystrophic chickens were given twice-daily intraperitoneal injections of the antiserotoninergic drugs p-chlorophenylalanine hydrochloride, fluoxetine hydrochloride, ergonovine maleate, nortriptyline hydrochloride, methiothepin maleate, and methysergide bimaleate in combination with penicillamine. Except in one case, treatment with drugs significantly prolonged the righting ability of the treated dystrophic chickens, as measured by a periodic standardized flip-test procedure. Abnormally high levels of plasma creatine phosphokinase, lactate dehydrogenase, and SGOT were found in the untreated dystrophic chickens. However, of the drug-treated dystrophic chickens, in some cases the plasma enzyme activities were reduced whereas in others they were enhanced. In agreement with previous findings, the blood serotonin levels of the dystrophic chickens were found at all age groups to be significantly higher than those in the corresponding normal chickens. This phenomenon may in part account for the improvement in righting ability demonstrated in the dystrophic chickens receiving treatment with antiserotoninergic drugs.

Animals↗
PubMed1981

Serotonin uptake in blood platelets of psychiatric patients.

Platelet serotonin (5-HT) uptake was determined in 72 newly admitted, unmedicated psychiatric patients. Decreased maximum velocity (Vmax) of 5-HT uptake was present in unipolar and bipolar depressed patients as well as schizoaffective depressed patients. The apparent Michaelis constant (km) of 5-HT uptake was normal in these groups, as was Vmax and Km in manic-depressive and chronic schizophrenic patients. Treatment of depressed patients with notriptyline hydrochloride or imipramine hydrochloride increased Km significantly. There was a trend for the increase in Km in the nortriptyline-treated patients to correlate with clinical improvement. Decreased 5-HT uptake in platelets provides additional evidence for the role of 5-HT in the pathophysiologic process of some forms of depression.

Adult↗
PubMed1987

Tricyclic antidepressants in depressed patients with cardiac conduction disease.

The observation that fatalities from tricyclic antidepressant (TCA) overdose are associated with heart block and/or arrhythmias has led to concern about the cardiovascular effects of TCAs. Contrary to expectations, studies have shown TCAs to be relatively safe in patients without heart disease. However, it is unclear whether these drugs are also safe in patients with heart disease. This prospective study compared the risk of cardiovascular complication at therapeutic plasma concentrations of TCAs in 196 depressed patients, 155 with normal electrocardiograms and 41 with either prolonged PR interval and/or bundle-branch block. The prevalence of second-degree atrioventricular block was significantly greater in patients with preexisting bundle-branch block (9%) than in patients with normal electrocardiograms (0.7%). Orthostatic hypotension occurred significantly more frequently with imipramine than with nortriptyline, and in patients with heart disease.

Antidepressive Agents, Tricyclic↗