Plasma Concentration and Toxicity

The alternative question is whether blood level monitoring might help to avoid toxicity. A variety of data support this view. The risk of delirium is substantially increased at amitriptyline plasma concentrations above 450 ng/mL and is moderately increased at concentrations above 300 ng/mL (Livingston et al. 1983; Preskorn and Simpson 1982). But amitriptyline is the most anticholinergic tricyclic and is most likely to produce delirium. The risk of first-degree atrioventricular block is also increased with plasma concentrations of imipramine greater than 350 ng/mL (Preskorn and Irwin 1982). The risk of seizures also increases at higher doses and, presumably, higher blood levels, although a clear plasma-level threshold for seizures has not been demonstrated. Following overdose, tricyclic blood levels greater than 1,000 ng/mL can be achieved, and the risks of delirium, stupor, cardiac abnormalities, and seizures are all substantially increased (Preskorn and Irwin 1982; Rudorfer and Young 1980; Spiker et al. 1975).

The value of blood level monitoring to avoid serious adverse effects has been hard to demonstrate because rates of serious toxicity are low so that large samples are required to demonstrate any increase in risk at higher blood levels. For some adverse reactions (e.g., delirium), early warning signs may prompt dose reduction. Alternatively, there may be no warning for seizures or cardiac arrhythmia, and blood level monitoring might be most useful for reducing the risk of those adverse events.

If blood level monitoring is undertaken, the clinician needs to remember that the patient needs to be at steady state, the blood sample should be drawn before the next dose (a trough level), and the sample should be sent to the laboratory promptly. For a quantitative estimate the laboratory will usually employ high-performance liquid chromatography (HPLC). In a competent laboratory, the coefficient of variation for an HPLC assay is usually less than 10%. This assay is relatively specific; however, other drugs can interfere. Because there are many modifications of the HPLC technique, the interfering drugs will vary by site. Under the best of circumstances, there will still be biological variability of the compound (discussed earlier in subsection "Steady-State Concentrations"). Add to this occasional missed doses or laboratory problems, and there will be considerable sample-to-sample variability. For these reasons, the clinician should not view the concentration reported as a precise measure. Yet, because concentrations vary across such a wide range, it may be very helpful to know if the level is low (e.g., 25-75 ng/mL), moderate (e.g., 100-300 ng/mL), or high (e.g., 300-1,000 ng/mL).

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