Interpretation of Drug Levels in Acute and Chronic Disease States

Abstract

Serum drug concentration monitoring can be an invaluable aid to patient management, particularly in certain pathological conditions when individualisation of dosage is particularly critical. To be clinically useful, however, drug levels must be interpreted in the context of all factors that could influence the correlation between the concentration of the drug in plasma and the intensity of action. Several such factors may be operating in acute and chronic disease states. For example, a number of pathological conditions are associated with marked changes in the fraction of free, pharmacologically active drug in plasma and this will result in disruption of the normal relationship between total serum drug level and effect, as seen for phenytoin in uraemia. An altered response to a given serum drug level in disease states may also be caused by changes in tissue distribution, by abnormal accumulation of pharmacologically active metabolites in plasma or by changes in end-organ responsiveness. The latter are best illustrated by the altered sensitivity to digoxin in patients with various conditions, including hypokalaemia and thyroid disease. In addition to the factors listed above, consideration should also be given to potential interactions with concomitantly used drugs and to the possibility of analytical errors, especially in view of the evidence that the performance of otherwise reliable drug assays may be grossly impaired in certain diseases (e.g. uraemia), due to abnormal plasma composition and/or accumulation of interfering metabolites. In view of these complexities, a correct interpretation of serum drug levels requires a good knowledge of clinical pharmacology and a close collaboration between physician and laboratory. In any case, serum drug concentrations, like other laboratory tests, are not a substitute for careful patient observation, and any decision about drug treatment should be primarily based upon evaluation of the clinical state and, whenever possible, direct measurement of drug effects.

Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies

“…Serum protein binding changes shortly after dialysis or renal transplantation, but clearance may not change markedly (Kang & Leppik, 1984), and failure to monitor unbound concentrations can lead to errors in dosing. Although other highly bound AEDs such as valproic acid have not been as extensively studied, it would be prudent to measure free concentrations of all highly bound AEDs during renal failure or other states in which endogenous binding sites may be altered, such as hypoalbuminemia, or in patients receiving drugs competing for protein binding sites such as aspirin, naproxen, tolbutamide, phenylbutazone, and other highly protein‐bound agents (Perucca et al, 1985).…”

“…TDM can also help in guiding the magnitude of replacement dosages for patients receiving AEDs, which are efficiently removed during dialysis. For highly bound drugs, the unbound fraction increases markedly in patients with renal disease, and therefore monitoring total serum concentrations can be misleading in this situation (Perucca et al, 1985).…”

Alfentanil Infusions in Patients Requiring Intensive Care

“…The reduced volume of distribution may be due to a reduction in the free fraction of alfentanil due to an increase in plasma ai-acid glycoprotein concentrations (Perucca et al 1985). No significant relationship between alfentanil clearance and serum creatinine was demonstrated.…”

“…The clinical effects of changes in ai-acid glycoprotein are variable and the resultant alteration in free drug fraction difficult to predict (Perucca et al 1985). If clinical effects are to be seen it will be in the neonate and other patients with low plasma concentrations of a)-acid glycoprotein.…”

Interlaboratory Variability in the Quantification of New Generation Antiepileptic Drugs Based on External Quality Assessment Data

“…In the early 1970s, the realization that pharmacokinetic variability was a major factor affecting clinical response to antiepileptic drugs (AEDs) led to major improvements in the management of patients with epilepsy (1). In particular, awareness that steady‐state concentrations of AEDs can be influenced markedly by interpatient differences in genetic background (2), age (3), associated disease (4), and comedication (5) resulted in greater attention being given to tailoring drug dosage to meet individual requirements. Evidence also was obtained, at least for some drugs, that clinical response correlated better with serum drug concentration than with the prescribed daily dose, an observation that was crucial in establishing the value of therapeutic drug monitoring (TDM) as an aid to dosage adjustments (6,7).…”