Chapter 19 Therapeutic drug monitoring and chemical aspects of toxicology
Introduction
• to provide information relevant to the diagnosis and management of patients suspected to have taken drug overdoses
• to provide such information in patients taking drugs therapeutically
This chapter covers these topics and discusses the metabolic sequelae of some common poisonings.
Monitoring of specific drugs
Phenytoin
The therapeutic effectiveness of this frequently prescribed anticonvulsant drug is difficult to assess without monitoring. It has a low therapeutic ratio and the signs of toxicity may mimic the neurological diseases that can be associated with epilepsy. Furthermore, phenytoin has unusual pharmacokinetic properties: the enzyme responsible for the elimination of the drug (hepatic CYP2C9) becomes saturated within the therapeutic range of plasma concentrations, giving rise to zero-order kinetics. This phenomenon has several important implications. In particular, the relationship between plasma concentration and dose is non-linear (Fig. 19.3); thus small increments in dose may lead to disproportionate increases in steady-state plasma concentrations. On the other hand, even if the dose is unchanged, a small decrease in drug-metabolizing enzyme activity, or the presence of other drugs that inhibit phenytoin metabolism, could transform a therapeutic plasma concentration to a toxic concentration. Figure 19.3 also indicates the wide variation of doses required to achieve therapeutic plasma concentrations in different individuals.
Digoxin
This phenomenon is partly a result of the existence of various factors that alter either the therapeutic response to a given plasma concentration of digoxin or the plasma concentration achieved on a particular dose (Fig. 19.5). Hypokalaemia is a particular problem because many patients treated with digoxin are also receiving diuretics, which may cause this (see Case history 21.2). In addition, renal impairment may be a consequence of congestive cardiac failure; this is important because digoxin is mostly eliminated via the kidneys. It is thus very important to consider the clinical setting when assessing the significance of plasma digoxin concentrations. It is good practice always to measure the plasma potassium concentration when digoxin is measured.
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