Theoretical depiction of plasma concentrations following either an intravenous bolus dose immediately followed by initiation of a continuous intravenous infusion or initiation of a continuous intravenous infusion only.

greater than expected increase in blood concentrations. This is illustrated in the graph of Figure 5.6, which shows that for a hypothetical patient, phenytoin blood concentrations are plotted against dose of phenytoin. The graph demonstrates that as one approaches doses that result in therapeutic concentrations of phenytoin, the rise in concentrations becomes nonlinear such that an increase in dose from 300 to 400 mg (33% increase) produces a 300% increase in phenytoin concentration. Thus, it is easy to see how toxicity may arise quickly following what was seemingly a small increase in dose; under linear circumstances such a small increase in dose would have resulted in concentrations still within the therapeutic range. This nonlinearity often occurs because the drug-metabolizing enzymes for the drug become saturated at typical blood concentrations, such that despite increases in dose, drug is still metabolized at the same rate and blood concentrations go up unexpectedly. In this case, following Michaelis-Menten enzyme kinetics, the maximum velocity (Vmax) has been reached and the rate of drug metabolism remains constant.

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