Tricyclic antidepressants serum levels

TABLE 3.9. Doses and Serum Levels of Tricyclic Antidepressants... 

Drugs that can increase carbamazepine serum levels include cimetidine, danazol, diltiazem, erythromycin, felbamate, clarithromycin, fluoxetine, isoniazid, niacinamide, propoxyphene, ketaconazole, itraconazole, verapamil, valproate, troleandomycin, loratadine, nicotinamide, tricyclic antidepressants, SSRIs, nefazodone, protease inhibitors. 

Drugs that can decrease carbamazepine serum levels include charcoal, cisplatin, doxorubicin, felbamate, hydantoins, rifampin, phenobarbital, primidone, theophylline. The serum levels of oral contraceptives, haloperidol, bupropion, anticoagulants, felbamate, valproic acid, felodipine, tricyclic antidepressants, acetaminophen, ziprasidone, voriconazole, topiramate, tiagabine, olanzapine, and lamotrigine can be lowered by carbamazepine. 

Boehnert, M.T. and Lovejoy, F.H. (1985) Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after and acute overdose of tricyclic antidepressants. N Engl Med 313 474 79. 

Antacids reduce the absorption and enzyme-inducing drugs may decrease serum levels. Cimetidine and propranolol both increase serum levels. There can be competition for metabolic pathways by some tricyclic antidepressants (TCAs) and SSRIs (especially fluoxetine) which may increase serum levels. 

Yeragani VK, Pohl R, Balon R, Kulkarni A, Keshavan M. Low serum iron levels and tricyclic antidepressant-induced jitteriness. J Clin Psychopharmacol 1989 9(6) 447-8. 

Leucht S, Hackl HJ, Steimer W, Angersbach D, Zimmer R. Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients. Psychopharmacology (Berl) 2000 147(4) 378-83. 

Differences in biotransformation capacities have been identified for at least two distinct groups poor metabolizers and extensive metabolizers. Poor metabolizers demonstrate a deficiency in one or more pathways of the cytochrome P/450 enzyme system. Since the metabolism of antidepressants and neuroleptics depends on this system (see appendix A), poor metabolizers may be at risk for complications of therapy. For certain tricyclic antidepressants and neuroleptics, it has been established that these individuals will demonstrate increased serum levels and exaggerated medication response. Additionally, they wiU be more susceptible to side effects. Although data is limited on the SSRIs, similar patterns are evident. 

Tobacco smoke reduces serum levels of a wide range of drugs and dose adjustment may be necessary when smokers have given up, particularly with theophylline, beta-blockers, adrenergic agonists, nifedipine, tricyclic antidepressants, phenothiazines, benzodiazepines and insulin. 

Use with tricyclic antidepressants or sympathomimet-ics may increase the effects of these medications or of thyroid USP, possibly leading to coronary insufficiency or cardiac arrhythmias. Use with oral antidiabetic agents or insulin may affect dosage requirements of these agents. Estrogens, which increase serum thyroxine-binding globulin levels, raise thyroid USP requirements. 

Side Effects and Toxicity. Adverse effects to the tricyclic antidepressants, primarily the result of the actions of these compounds on either the autonomic, cardiovascular, or central nervous systems, are summarized in Table 3. The most serious side effects of the tricyclics concern the cardiovascular system. Arrhythmias, which are dose-dependent and rarely occur at therapeutic plasma levels, can be life-threatening. In order to prevent adverse effects, as well as to be certain that the patient has taken enough drug to be effective, the steady-state serum levels of tricyclic antidepressant drugs are monitored as a matter of good practice. A comprehensive review of structure—activity relationships among the tricyclic antidepressants is available (42). 

DISTRIBUTION AND SERUM LEVEL MONITORING Once absorbed, tricychc antide pressants are widely distributed. They are relatively lipophilic and strongly bind to plasma proteins and constituents of tissues, leading to apparent volumes of distribution as high as 10-50 L g. The tendency of tricyclic antidepressants and their ring-hydroxy metabolites to accumulate in cardiac tissue adds to their cardiotoxicity. Serum concentrations of antidepressants that correlate meaningfully with clinical effects are only established for a few tricychc antidepressants (particularly amitriptyline. 

Drugs that can increase the serum levels/effects of tricyclic antidepressants... 

Drugs whose serum levels/effects can be Increased by tricyclic antidepressants... 

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). 

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. 

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. 

Tricyclic antidepressants Alprazolam has been found to increase imipramine and desipramine serum levels by about 25%. The mechanism is unknown. ... 

In general, the concurrent use of most opioids and tricyclics is uneventful, although lethargy, sedation, and respiratory depression have been reported. Tramadol should be used with caution with tricyclic antidepressants because of the possible risk of seizures and the serotonin syndrome. Dextroproposyphene may cause moderate rises in the serum levels of amitriptyline and nortriptyUne, and methadone may moderately raise desipramine levels. The bioavailability and the degree of analgesia of oral morphine is increased by clomipramine, desipramine and possibly amitriptyline. 

The CNS depressant effects of opioids and the tricyclic antidepressants are expected to be additive. The reasons for the increased morphine levels and analgesic effects that occur with some tricyclics are not understood. The increased analgesia may be due not only to the increased serum levels of morphine, but possibly also to some alteration in the way the morphine affects its receptors. Dextropropoxyphene probably inhibits liver metabolism of some tricyclic antidepressants by inhibiting the activity of the cytochrome P450 isoenzyme CYP2D6, and as a result the serum levels of the tricyclic antidepressants rise. It is suggested that the methadone may possibly inhibit the hydroxylation of the desipramine, thereby raising its levels. ... 

In vitro experiments with human liver slices indicate that methylphenidate inhibits the metabolism of imipramine, resulting in raised blood levels. The accelerated response to tricyclic antidepressants may also be partly due to increased serum levels in the presence of methylphenidate, although the adverse effects observed were not entirely consistent with elevated levels of tricyclics. There are also reports suggesting that... 

Information is limited. Some therapeutic improvement including accelerated response is seen in some patients. This may be partially because of the very marked rise in the blood levels of the antidepressant due to methylphenidate, but may also be due to an additional effect on mood attributable to methylphenidate. Concurrent use may cause adverse effects sufficiently severe to necessitate withdrawal of methylphenidate, but it is not certain whether this can solely be attributed to increases in serum levels of tricyclic antidepressants. Information about other tricyclic antidepressants is lacking. However, it has been suggested that concurrent use in children and adolescents may be undesirable, due to case reports of adverse behavioural effects. If concurrent use is deemed necessary it would seem prudent to monitor concurrent use for adverse tricyclic effects (e.g. dry mouth, blurred vision, urinary retention) and adjust the dose as necessary. 

Stewart DE. High-fiber diet and serum tricyclic antidepressant levels. JC/m Psychopharmacol (1992) 12, 438-40. 

Cimetidine is a potent liver enzyme inhibitor, which reduces the metabolism of the tricyclic antidepressants, and may also reduce the hepatic clearance of these drugs. This results in a rise in their serum levels. Ranitidine does not interact because it is not an enzyme inhibitor. 

Troleandomycin increases the plasma levels of imipramine, and an isolated report suggests that josamydn may possibly increase amitriptyline serum levels. Erythromycin may possibly raise clomipramine levels, but was not found to interact with other tricyclic antidepressants in one study. 

Information about other tricyclic antidepressants is lacking, but the manufacturers of modafinil point out that other poor metabolisers (about 7 to 10% of the Caucasian population) may possibly also show increased serum tricyclic antidepressant levels in the presence of modafinil. Therefore monitoring concurrent use would seem to be a prudent precaution. 

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