Nortriptyline serum level

The TCAs are the only antidepressant class in which effectiveness is dependent on serum level. Attainment of the minimal therapeutic level is typically required for effectiveness. Exceeding the maximum treatment level usually provides no additional benefit and risks toxicity. Unique in this regard is nortriptyline, which is the only TCA with a therapeutic window. This means that beyond the maximum therapeutic level of 150ng/mL nortriptyline not only risks toxicity but is actually less effective at treating depression. Please refer to Table 3.9 for a summary of dosing guidelines and therapeutic levels. 

Dose adjusted according to serum levels (therapeutic window for nortriptyline)... 

The secondary amine TCAs, including desipramine and nortriptyline, lack active metabolites and have fairly linear kinetics. These TCAs have a wide therapeutic window, and serum levels are reliable in predicting response and toxicity. 

Desipramine and nortriptyline are preferred. Can monitor serum levels. 

Chronic abuse of alcohol can lead to enhanced activity of cytochrome P450 enzymes and a consequent decrease in tricyclic antidepressant (TCA) serum levels. Central receptor interactions between alcohol and TCAs can cause impaired motor abilities (evident with amitriptyline, clomipramine, doxepin, and nortriptyline). 

There are anecdotal reports of trazodone decreasing heparin serum levels by about 20%. Clomipramine, nortriptyline, and trazodone can raise warfarin serum levels up to 30%. 

Phenytoin, a liver enzyme inducer, decreases serum levels of TCAs (especially desipramine and clomipramine). An increase in serum levels of nortriptyline and trazodone has also been reported. In these cases, the net effect of enzyme induction (by phenytoin) and enzyme inhibition (by TCAs) seem to be in favor of the inhibitory effects. Carbamazepine also induces liver enzymes, with a consequent reduction in serum levels of TCAs (amitriptyline, desipramine, doxepin, and nortriptyline). These effects of carbamazepine have not been observed with clomipramine, but have been reported with selective serotonin reuptake inhibitors (SSRIs). 

Most APDs, as well as TCAs, are inhibitors of the cytochrome P450 enzymes, thus potentially increasing each other s serum levels. For haioperidoi, an increase in serum levels of TCAs (by about 2-fold) is found in up to 10% of patients treated with ciomipramine or nortriptyiine (but is not found with desipramine). Levomepromazine can significantly increase ciomipramine serum levels. Perphenazine has been found to increase serum levels of amitriptyline, desipramine, and nortriptyiine, while thioridazine has been reported to increase desipramine serum levels. Thiothixene levels are usually increased by TCAs such as doxepin, nortriptyline, and clomipramine (the latter combination increases the risk for tardive dyskinesia). 

This can increase TCA serum levels (clomipramine and nortriptyline). Desipramine levels were not found to be impaired, although an additive adverse effect profile is evident (nausea, tremor, and tachycardia). 

Fluvoxamine inhibits the cytochrome P450 liver catabolic enzymes (predominantly this is inhibition of N-demethylation), leading to an increase in tricyclic antidepressant (TCA) serum levels. Plasma levels of several antidepressant drugs (e.g. amitriptyline, clomipramine, desipramine, imipramine, maprotiline, and nortriptyline) have been reported to increase by up to 4-fold during co-administration with fluvoxamine. Fluvoxamine at a daily dose of 50-100 mg causes a 3-4-fold increase in the plasma concentration of mirtazapine. 

Carbamazepine induces hepatic catabolic enzymes, with a consequent reduction in serum levels of antidepressants (mainly described with amitriptyline, desipramine, doxepin, imipramine, mianserin, and nortriptyline). A decrease in bupropion serum levels was also reported with carbamazepine. These effects were not observed with clomipramine. Fluoxetine and fluvoxamine inhibit the metabolism of carbamazepine and valproate (up to 30% and 50% increases in serum levels, respectively). No significant interaction has yet been found between paroxetine and carbamazepine or valproate. 

Most antipsychotic drugs as well as tricyclic antidepressants (TCAs) are inhibitors of the chytochrome P450 liver catabolic enzymes, thus potentially increasing each other s serum levels. Chlorpromazine increases imipramine serum levels. Levomepromazine can cause a significant increase in clomipramine serum levels. Perphenazine has been reported to increase the serum levels of amitriptyline, desipramine, imipramine, and nortriptyline. Thioridazine has also been shown to increase TCA serum levels (mainly desipramine). Marked extrapyramidal side-effects have been reported in a few cases with fluphenazine or perphenazine when fluoxetine was added to the regimen. The mechanism is not known. A mutual increase in serum levels of both thioridazine and paroxetine is evident when these agents are... 

An increase (about 2-fold) in serum levels of tricyclic antidepressants (TCAs) is found in up to 10% of treated patients (most established with clomipramine and nortriptyline). Such serum level abnormalities are not observed with desipramine. Marked extrapyramidal side-effects have been reported (a few cases only) with haloperidol when fluoxetine is added to the regimen. Fluoxetine and paroxetine have been shown to increase haloperidol serum levels (by about 20%), presumably via inhibition of cytochrome P450 enzymes. 

Part of the explanation for the increased C3S1S depression is that both alcohol and some of the tricyclics, particularly amitriptyline, cause drowsiness and other CNS depressant effeets, which can be additive with the effects of alcohol. The sedative effects have been reported to be greatest with amitriptyline, then doxepin and imipramine, followed by nortriptyline, and least with amoxapine, clomipramine, desipramine, and protriptyline. In addition acute alcohol intake causes marked increases (100 to 200%) in the plasma levels of amitriptyline, probably by inhibiting its first pass metabolism. Alcohol-induced liver damage could also result in impaired amitriptyline metabolism. The lower serum levels of imipramine and desipramine seen in abstinent alcoholics are attributable to induction of the cytochrome P450 isoenzymes by alcohol. ... 

Buspirone 15 mg every 8 hours given with amitriptyline 25 mg every 8 hours for 10 days had no significant effect on the steady-state serum levels of amitriptyline or its metabolite, nortriptyline, in healthy subjects. No evidence of a pharmacodynamic interaction was seen. There would seem to be no reason for avoiding concurrent use. 

The serum levels of amitriptyline, desipramine, doxepin, imipramine and nortriptyline can be reduced (halved or more) by carbamazepine but there is evidence that this is not necessarily clinically important. In contrast raised clomipramine ievels have been seen in patients taking carbamazepine. An isolated report describes carbamazepine toxicity in a patient shortly after she started to take desipramine. 

A study found that carbamazepine reduced the serum levels of nortriptyi-ine by 58% and of amitriptyline plus its metabolite, nortriptyline, by 60% in 8 psychiatric patients. In 17 other patients carbamazepine reduced serum doxepin levels by 54% and doxepin plus its metabolite, nordox-epin, by 55%. A retrospective study of very large numbers of patients confirmed that carbamazepine approximately halves the serum levels of amitriptyline and nortriptyline. An elderly woman needed her nortriptyline dosage to be inereased from 75 to 150 mg daily to achieve effective antidepressant serum levels when carbamazepine 500 to 600 mg daily was added. ... 

The reduction in the serum levels of amitriptyline, desipramine, doxepin, imipramine and nortriptyline caused by the interaction with carbamazepine appears to be established but the clinical importance is very much less certain. Evidence from one study, that achieved a beneficial response in patients taking tricyclics and carbamazepine suggests that it is possibly not necessary to increase the tricyclic dosage to accommodate this interaction. The fact that a retrospective study found that increased imipramine doses were being given to those taking carbamazepine suggests that this interaction will be naturally accounted for. If carbamazepine is added to treatment with any of these tricyclics, be aware that the dose of the tricyclic may need to be titrated up to achieve the desired therapeutic response. Remember too that the tricyclics can lower the convulsive threshold and should therefore be used with caution in patients with epilepsy. 

A patient taking amitriptyline had a marked increase in the total serum levels of amitriptyline and its metabolite, nortriptyline, after taking josamycin but no toxicity was reported. It was suggested that josamydn had inhibited amitriptyline metabolism. This is only an isolated case and its general significance is unknown. 

Quinidine can reduce the clearance of desipramine, imipramine, nortriptyline and trimipramine, and quinine can reduce the clearance of desipramine, thereby increasing their serum levels. 

Escitalopram 20 mg daily for 21 days increased the maximum serum levels and AUC of a single 50-mg dose of desipramine by 40% and 100%, respectively. The UK manufacturers predict that clomipramine and nortriptyline will be similarly affected. ... 

Terbinafme markedly increased the AUC of desipramine in a pharmacokinetic study. Case reports describe increases in the serum levels of amitriptyline, desipramine, imipramine and nortriptyline, with associated toxicity, in patients additionally given oral terbinafme. 

A 37-year-old woman who had been taking amitriptyline 75 mg daily, valproate and olanzapine for 3 years, developed extreme dryness of the mouth, nausea and dizziness shortly after starting to take terbinafine 250 mg daily. Serum levels of amitriptyline and its metabolite nortriptyline rose from just under 400 nanomol/L to over 1800 nanomol/L. Terbinafine was stopped, and the amitriptyline dose reduced to 25 mg daily, but the amitriptyline and nortriptyline levels did not return to baseline for several months. The patient had normal CYP2D6 metaboliser status. ... 

Amitriptyline and nortriptyline plasma levels can be increased by sodium valproate and valpromide, but in contrast, an isolated report attributes a paradoxical rise in serum desipramine levels to the withdrawal of valproic acid. Valproate pharmacokinetics may be moderately affected by amitriptyline. Status epilepticus has been attributed to elevated clomipramine levels in a patient taking valproic acid. 

Reduced serum levels of amitriptyline and its metabolite, nortriptyline, were observed in depressed patients taking amitriptyline along with 900 mg St. John s wort daily for 12 to 14 days (Johne et al. 2002). 

A 73-year-old man developed anticholinergic delirium on a combination of VPA and amitriptyline. The adverse effects included muscular rigidity, ataxia, dysarthria, somnolence, agitation, and disorientation. This prompted a retrospective review in which it was discovered that patients taking tricyclic antidepressant medications (amitriptyline or nortriptyline) in conjunction with VPA had higher mean serum levels of amitriptyline or nortriptyline compared to those taking tricyclic antidepressants without VPA [194 ]. 

Wisner KL, Perel JM. Serum nortriptyline levels in nursing... 

Wisner KL, Perel JM. Serum nortriptyline levels in nursing mothers and their infants. Am J Psychiatry 1991 148(9) 1234-6. 

Evidence from two patients suggests that imipramine can raise serum phenytoin levels but nortriptyline and amitriptyiine appear not to do so. Phen i oin possibiy reduces serum desipramine iev-els. Note that the tricyciics aiso iower the convuisive threshoid. 

Other studies have shown that nortriptyline 75 mg daily had an insignificant effect on the serum phenytoin levels of 5 patients, and that amitriptyline had no effect on the elimination of phenytoin in 3 subjects. ... 

A falsely elevated imipramine level was recorded when HPLC was used to determine serum imipramine levels in a patient taking imipramine, quetiapine, fluvoxamine, lithium and docusate. The abnormal readings were found to have been caused by a metabolite of quetiapine, and normal readings were obtained by altering the wavelength for detection of imipramine. Nortriptyline levels have been found to be falsely elevated in a patient also taking quetiapine when blood was analysed using fluorescence polarisation immunoassay, but were normal when an HPLC... 

Markedly increased serum amitriptyline levels developed in five patients and increased serum nortriptyline levels in another patient when they took fluconazole. Mental changes, syncope, and prolonged QTc interval occurred in some of these patients and there is also a report of prolonged QT interval and torsades de pointes associated with the concurrent use of amitriptyline and fluconazole in a further patient. 

An elderly woman taking nortriptyline 75 mg daily and other drugs (eielosporin, morphine, metoelopramide, bumetanide as well as an unnamed antibaeterial) was given flueonazole (loading dose of 200 mg, followed by 100 mg daily). After eoneurrent use for 13 days her trough serum nortriptyline levels had risen by 70% (from 149 to 252 nanograms/mL). ... 

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