Nortriptyline metabolism

Inhibition of nortriptyline metabolism by dextropropoxyphene has been reported (20). 

Barbiturates and heavy smoking induce nortriptyline metabolism and decrease therapeutic efficacy phenothiazines and haloperidol decrease its metabolism, decreasing therapeutic efficacy methylphenidate, cimetidine, oral contraceptives, propoxyphene, and beta-blockers may inhibit nortriptyline metabolism, increasing plasma levels and toxicity (see Tables 5 through 7). 

Steiner E, Koike Y, Lind M, von Bahr C. Increased nortriptyline metabolism after treatment with pentobarbital in man. Acta Pharmacol Toxicol (Cope ) (1986) 59(Suppl 4), 91. 

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

Interaction with drug metabolism liquorices, which are the most commonly used herbs in TCM can increase metabolites (e.g., nortriptyline, desipramine, and norclomipramine) of tricyclic antidepressants (TCAs) and may produce more side effects (such as dry mouth, constipation, palpitation, etc.) (Xu, 2004 Zhu Huang, 2004). 

The metabolism and elimination of TCAs takes several days to occur, the elimination half-life ranging from 20 hours for amitriptyline to 80 hours for protriptyline. The half-life values for the desmethylated metabolites such as desmethylimipramine and nortriptyline are approximately twice those of the parent compounds imipramine and amitriptyline. It is also well established that the half-life values of the TCAs are considerably greater in the elderly, which predisposes such patients to a greater possibility of severe side effects. 

This chapter describes the structure and neurochemical function of TCAs, metabolism and significant interactions with other medications, side effects, and specific recommendations for monitoring of side effects in children and adolescents. Because of the recent concern regarding the sudden deaths of children stabilized on TCAs, particular attention will be paid to the potential cardiovascular effects of these medications. The chapter will focus on the five TCA medications that have been most widely used in children amitriptyline (AMI), nortriptyline (NT), imipramine (IMI), desipratnine (DMI), and clomipramine (CMI). 

The adverse effects of TCAs are also similar to those reported in adults (see Chapter 7). The secondary amine TCAs (e.g., desipramine, nortriptyline) are generally as well tolerated as newer antidepressants. Increased blood pressure may be more likely to occur in children than in adults but hypertension per se is rare ( 135). The most common cardiovascular effect is mild tachycardia. Despite their generally favorable adverse effect profile, secondary amine TCAs can cause serious toxicity in children and adolescents just as in adults when a taken in an overdose or when a high TCA plasma level occurs as a result of slow metabolism ( 136). For that reason, most clinicians reserve TCAs for the child or adolescent who has at least a moderate depressive disorder unresponsive to a trial of one or more newer antidepressants. In such instances, TDM should be done at least once to ensure plasma concentrations greater than 450 ng/mL do not develop ( 137). Such levels are associated with an increased risk of the following ... 

As a result, these subjects require twofold to threefold higher daily doses of nortriptyline (a 2D6 substrate) to achieve therapeutic plasma levels. Conversely, in these ultrarapid-metabolizing populations, the prodrug codeine (another 2D6 substrate) is metabolized much faster to morphine, often resulting in undesirable adverse effects of morphine, such as abdominal pain. 

Cyt 2D6 metabolizes haloperidol, risperidone, thioridazine, sertindole, olanzapine and clozapine common substrates - fluoxetine, paroxetine, sertraline, venlafaxine, amitriptyline, clomipramine, desipramine, imipramine, nortriptyline, propranolol, metoprolol, timolol, codeine, encainide, flecanide. Common inhibitors - paroxetine, sertraline, fluoxetine. 

Nortriptyline was one of the first clinically important drugs to be shown to be metabolized by CYP2D6 (46,47). These early studies (prior to the era of genotyping) were performed in phenotyped panels of healthy subjects and the results have been confirmed in vivo in patients as well as... 

St John s wort can cause drug interactions by inducing hepatic microsomal drug-metabolizing enzymes or the drug transporter P-glycoprotein, which causes a net efflux of substrates, such as amitriptyline, from intestinal epithelial cells into the gut lumen (SEDA-24,12). In 12 patients (9 women, 3 men) the addition of St John s wort 900 mg/ day to amitriptyline 150 mg/day led to a 20% reduction in plasma amitriptyline concentrations, while nortriptyline concentrations were almost halved (210). 

Metabolism by CYP2D6 is of major importance for the hydroxylation of nortriptyline, making it susceptible to... 

Various neuroleptic drugs inhibit the metabolism of imi-pramine, nortriptyline, and amitriptyline (SED-11, 114) (672,673). 

If, following absorption, medications were undisturbed by the body, we would need to take only one dose for an eternal effect. Of course, this is not the case. As soon as drugs enter the bloodstream, the process of metabolism ensues. The body recognizes the drug as a foreign substance and eliminates it outright (say, via the kidneys, as in the case of lithium) or transforms it chemically, using a complex enzyme mechanism located in the liver. This chemical transformation enables the medication to be eliminated from the body. In some cases, the chemical transformation produces a new compound that may also have therapeutic effects (or, in some rare instances, a toxic effect). For example, fluoxetine (trade name Prozac) is transformed into norfluoxetine, which is also an antidepressant. A similar situation occurs with the old tricyclic antidepressants (amitriptyline—trade name Elavil—to nortriptyline the latter, in fact, is... 

AMOXAPINE, CLOMIPRAMINE, DOXEPIN, IMIPRAMINE, NORTRIPTYLINE, TRIMIPRAMINE PROTEASE INHIBITORS Possibly t adverse effects of amoxapine with atazanavir and ritonavir Inhibition of CYP3A4-mediated metabolism of amoxapine, clomipramine and doxepin inhibition of CYP3A4-, CYP2D6-and CYP2C9-mediated metabolism of imipramine inhibition of CYP2D6-mediated metabolism of nortriptyline and trimipramine Monitor closely... 

TERBINAFINE ANTIDEPRESSANTS- IMIPRAMINE, NORTRIPTYLINE Possible T plasma concentrations ofTCAs Terbinafine strongly inhibits CYP2D6-mediated metabolism of nortriptyline Warn patients to report t side-effects of TCAs such as dry mouth, blurred vision and constipation, which may be an early sign of t TCA levels. In this case, consider i dose of TCA... 

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