Therapeutic Drug Monitoring of TCAs

Studies have shown that specific changes in ECG such as prolonged QRS interval > 100 ms and a terminal 40 ms right axis deviation >120° are reliable predictors of serious cardiovascular and neurological toxicity of TCAs (8). It should be noted that studies have also shown that TCA plasma levels may not correlate very well with clinical outcome and toxicity, particularly in overdose situations. On the basis of these findings, some clinicians question the value of therapeutic drug monitoring for TCAs. Despite these arguments, the measurement of TCA levels is considered unequivocally useful for the following reasons:

When taken orally, TCAs are well absorbed but may undergo considerable first-pass metabolism and thus have considerable variability in bioavailability. Their bioavailability and absorption is also variable as these drugs, because of their anticholinergic properties, slow down gastrointestinal activity and gastric emptying. Owing to high lipophilicity, these drugs bind to plasma proteins and tissues, resulting in a high volume of distribution. A number of tertiary TCAs are demethylated by the cytochrome P-450 enzyme system into their respective secondary amine active metabolites. For example, tertiary amine TCAs such as amitriptyline, imipramine, and doxepin are metabolized to their respective active secondary amines nortriptyline, desipramine, and nordoxepin. Tertiary and secondary amine TCAs have approximately similar activity. Some TCAs are hydroxylated into active metabolites, although these metabolites are not generally measured in clinical laboratories. Some pharmacokinetic properties of TCAs are summarized in Table 1.

Metabolism of TCAs varies significantly with age. Preskorn et al. (9) examined steady state concentrations of imipramine and its metabolite desipramine in hospitalized children. The concentrations of imipramine and desipramine varied 12- and 72-fold, respectively. Race also plays an important role in the metabolism of TCAs. African Americans and Japanese usually demonstrate higher concentrations of TCAs compared with Caucasians. Asians and Hispanics respond to lower doses of TCAs because of hypersensitivity receptors (10).

Alcoholics have significantly higher clearance of TCAs compared with subjects who do not abuse alcohol. Half-lives for imipramine and desipramine in alcoholics were 10.9 and 16.5 hours compared with 19.6 and 22.5 h in healthy controls, respectively. Unbound fractions of drug in plasma were decreased in the alcoholic group for both imipramine and desipramine. Taken together, these findings suggest that an alcoholic person who has recently undergone a detoxification program may require higher doses and frequent levels of TCAs (11).

Tamayo investigated the incidence of potentially toxic serum levels (>400 ng/mL) in 196 patients on a standard dosage regimen (75-225 mg/day) of several TCAs: imipramine, amitriptyline, nortriptyline, maprotiline, and clomipramine (12). The serum concentrations of drugs in these patients ranged from 403 to 1776 ng/mL. Despite the detection of higher than therapeutic and even toxic concentrations of TCAs, only 23% of the patients showed clinical symptoms of toxicity. The factors that appeared to contribute to higher levels included interactions of TCAs with neuroleptic agents, age, and administration of doses above 2.5 mg/kg/day. In 64% of the patients, the clinical criteria suggested the need for a reduction in the dose. Although there was a lack of very good correlation between therapeutic and toxic levels and clinical efficacy as well as toxicity, the study points out the need to avoid such high concentrations in light of adequate antidepressant response. This is feasible through therapeutic drug monitoring.

Muller et al. (13) compared doses of TCAs given to patients based on clinical judgment and serum levels. In their study, although serum levels of TCAs were analyzed in both groups, the feedback and dose recommendations were only provided for the later group. The outcome was measured weekly using the Hamilton Depression Rating Scale and the Clinical Global Impressions Scale. The study concluded that treating depression with TCAs could be optimized by early therapeutic drug monitoring, which is superior to the clinical judgment.

TCAs are metabolized by the cytochrome P450 enzyme system particularly CYP2D6 which is highly polymorphic. Owing to significant variability in CYP2D6, among various populations, the need for therapeutic drug monitoring of TCAs is even stronger. It is estimated that 5-10% of Caucasians have CYP2D6 gene deletion and 3-8% have gene duplication. The rates of gene duplication are higher in other ethnic groups: 20% in Saudi Arabians (14) and 29% in Ethiopians (15). Dose recommendations and therapeutic drug monitoring of antidepressants based on genotypes are thus proposed. In addition to genetics factors, there are a number of acquired factors including co-medications, diet, smoking habit, impaired organ functions such as renal and liver, and compliance which influence blood levels of TCAs, thus justify the need for therapeutic drug monitoring. Cytochrome CYP2D6-inducing drugs such as carba-mazepine, phenobarbital, phenytoin, and rifampin increase clearance of TCAs. In contrast, the drugs that inhibit CYP2D6 decrease clearance of TCAs. These drugs include amiodarone, bupropion, celecoxib, chlorpromazine, cimetidine, citalopram, doxorubicin, haloperidol, quinidine, ranitidine, ritonavir, terbinafine, ticlopidine, and histamine H1 receptor antagonists (16,17).

In addition, when a patient fails to respond to TCA therapy, it is important to document that a specific level of the drug in serum is achieved. Similarly, measurement of blood concentrations makes the basis of overdose and toxicity management. Also, therapeutic drug monitoring provides a basis for optimal dosage and to attain a particular level on which the patient responds clinically in case there are changes in the patient's metabolism due an illness or drug-drug interactions. The other factors that justify TDM for TCAs include compliance, variation in bioavailability between different brands, patient's age, race, and change in lifestyle such as weight loss/gain, smoking, and exercise.

Laboratory practice guidelines for TDM for antidepressants including TCAs are provided by the National Academy of Clinical Biochemistry (16). TDM of the TCAs should be initiated once steady state is achieved, which takes about average of 5 days. For routine monitoring, samples should be collected during the terminal elimination phase, 1-14 h after the last dose for once-daily dosing and 4-6 h after the last dose for divided daily dosing. When patients are treated with the tertiary amines, because of their substantial contribution to pharmacological activity, the secondary amine metabolites should also be measured. The secondary amines are further metabolized to hydroxy metabolites, which should be monitored only in specific cases of renal impairment where these metabolites may accumulate and thus contribute significantly in drug toxicity.

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