Nortriptyline dosage

A diabetic patient taking glipizide and aspirin started taking nortriptyline, and, at the same time, his treatment with nifedipine was replaced by diltiazem 180 mg daily initially, raised to 240 mg daily after a week. Several changes in the nortriptyline dosage were made over a 4-week period because its plasma levels became unexpectedly high (the ratio of plasma nortriptyline to its dosage were approximately doubled). ... 

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. ... 

A 69-year-old man with bipolar disorder, who had been taking venlafaxine up to 337.5 mg daily, thioridazine 25 mg at night, and sodium valproate 1.2 g daily for several months with no adverse motor symptoms, experienced extrapyramidal effects 3 to 4 days after the venlafaxine had been gradually replaced by nortriptyline 50 mg daily. Symptoms persisted despite withdrawal of thioridazine, but improved on reduction of the nortriptyline dosage to 20 mg daily. The cause of the reaction was not known, but it was suggested that there may have been an interaction between venlafaxine and nortriptyline possibly modulated by thioridazine or sodium valproate. 

Determination of nortriptyline plasma concentrations is not routinely recommended but may be useful in identifying toxicity, drug interactions, or noncompliance (adjustments in dosage should be made according to clinical response, not plasma concentrations) therapeutic range is 50-150 ng/ml... 

Routine monitoring of plasma concentrations of antidepressants, while technically feasible for most drugs, is of uncertain value (except for nortriptyline). However, studies suggest that at least 20% of patients become noncompliant at some time or other. Thus, a "poor response" in a patient for whom an adequate dosage of drug has been prescribed may be shown by measurement of the plasma drug concentration to be due merely to failure to take the drug. 

There are no accurate data on the worldwide use of the many tricyclic compounds listed in Table 1, and the availability of particular drugs varies from country to country. The dosage range for all these compounds is 50-300 mg/ day, with the exception of nortriptyline, which has an upper limit of 200 mg, and protriptyline, which is more potent (range 10-60 mg/day). Well-controlled comparisons are few, but it is clear that these drugs resemble each other more than they differ. Their adverse effects will be discussed for the class as a whole, with distinguishing features of specific compounds mentioned when appropriate. 

Colored ion-pair complexes were found useful for extractive spectrophotometric assays of a number of analytes oseltamivir [20], nortriptyline hydrochloride in pharmaceutical formulations [21], zolmitriptan in tablets [22], finasteride in tablets [23], and dosage forms of amoxycillin and flucloxacillin [24]. In all cases, the chromoge-nic reagent and analyte formed ion-pairs that obeyed Beer s law and were suitable for quantitative determinations. 

Large genetic differences in rate of metabolism concentrations of drug and metabolite (nortriptyline) cannot be predicted from dosage. Evidence for correlation between plasma concentrations and therapeutic response is mainly negative. 

A comparative study of 99 patients taking amitriptyline or nortriptyline alone, and 60 other patients also taking perphenazine 10 mg daily, found that although the tricyclic antidepressant dosages were the same, the plasma tricyclic antidepressant levels of the perphenazine group were up to 70% higher. ... 

The interaction between clonidine and the trieyelics is established and clinically important. The incidence is uncertain but it is not seen in all patients. Avoid concurrent use unless the effects can be monitored. Increasing the dosage of clonidine may possibly be effective. The clonidine dosage was apparently successfully titrated in 10 out of 11 hypertensive patients already on amitriptyline or imipramine. Only clomipramine, desipramine and imipramine have been implieated so far, but other tricyclics would be expected to behave similarly (amitriptyline, nortriptyline and protriptyline have been shown to interact in animals ). The tetracyclic antidepressants maprotiline and mianserin do not generally appear to interact with clonidine. The isolated case of hypotension with trazodone is of unknown general importance. 

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. 

The interactions with cimetidine are well established, well documented and of clinical importance. The incidence is uncertain hut most patients could be affected. Those taking amitriptyline, desipramine, doxepin, imi-pramine or nortriptyline who are given cimetidine should be warned that adverse effects such as mouth dryness, urine retention, blurred vision, constipation, tachycardia, postural hypotension may be more likely to occur. Other tricyclic antidepressants would be expected to be similarly affected. If symptoms are troublesome reduce the dosage of the antidepressant (33 to 50% has been suggested) or replace the cimetidine with ranitidine, which does not appear to interact. Other H2-ieceptor antagonists that do not cause enzyme inhibition (e.g. famotidine and nizatidine) would also not be expected to interact. 

A number of other reports and studies clearly confirm that marked increases occur in the levels of amitriptyline, " clomipramine, desipramine, " imipramine " and nortriptyline, " accompanied by toxicity, if fluoxetine is added without reducing the dosage of the tricyclic antidepressant. Delirium and seizures have also been described, and a death has been attributed to chronic amitriptyline toxicity caused by fluoxetine. The pharmacokinetics of fluoxetine appear not to be affected by amitriptyline. ... 

In 9 healthy subjects, sertraline 50 mg daily increased the maximum plasma levels of desipramine 50 mg daily by 31% at steady-state, and increased the AUC by 23%. A later related study in 17 healthy subjects by the same group of workers found that, using the same drug dosages, sertraline increased the desipramine maximum plasma levels by 44%, the minimum levels by 19% and the AUC by 37%. The maximum plasma levels and AUC of the sertraline were increased about twofold. Other studies have found that sertraline increases desipramine, " imipramine, and nortriptyline levels, but it has also t n suggested that sertraline has no effect on imipramine levels. - ... 

Information seems to be limited to these reports. It would seem prudent to monitor for trieyolie adverse effeets (sueh as dry mouth, blurred vision and urinary retention) in patients given valproate and amitriptyline, clomipramine, or nortriptyline and to reduee the dosage of the tricyclic if necessary. Where possible eonsider monitoring tricyclic levels. Information about other trieyelie antidepressants seems to be lacking. The occurrence of status epileptieus in another patient reinforces the fact that the tricyclics can lower the eonvulsive threshold and should therefore be used with caution in patients with epilepsy. 

Po and Irwin (1979) used TLC to separate numerous tricyclic neuroleptic tranquilizers. Samples were dissolved in ethyl acetate, and the mobile phase consisted of mixtures of different n-alcohols with water. Circular development in a Camag U chamber was used, and spots were detected by fluorescence quenching. The /Jp values of some of the better known drugs developed in methanol-water (90 10) were amitriptyline, 0.17 clopenthixol, 0.40 doxepin, 0.42 nortriptyline, 0.37 and promazine, 0.14. Shirke et al. (1994) determined amitriptyline and chlordiazepoxide in combined dosage forms using ethyl acetate-methanol-dieth-ylamine (9.5 0.5 0.05) mobile phase and scanning at 245 nm. 

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