What are the Main Concentration-time Relationships? - Drugs Moving from First- to Zero-order Kinetics
In clinical practice, when the dose of a drug with capacity-limited metabolism is increased to the point at which saturation occurs, there is no immediate indication for the prescriber that this has occurred. The first sign that the critical dose has been exceeded is the appearance of adverse effects, except for some drugs where serial monitoring of the plasma concentration may provide an earlier indication.
When adverse effects become evident, all that prescribers can do is to interrupt dosing and wait for the amount of drug remaining in the body to fall. This will happen at a constant rate until there will come a point at which the enzyme is no longer saturated and is again capable of functioning according to first-order principles with a constant half-life (Fig 15). The fact that the rate of metabolism is unable to respond to the higher plasma concentrations has a particularly marked impact on the area under the curve (AUC), a marker of the overall exposure to the drug dose. The figure shows the response to a single dose but it is apparent that repeated doses would result rapidly in dangerous accumulation of the drug.
Serial measurement of plasma concentration after interruption of dosage can help to identify the time when treatment can be reintroduced. However, in the case of phenytoin (and other drugs where treatment withdrawal could have serious results), once the toxic effects have disappeared it is usually better to reintroduce treatment at a lower dosage, to reduce the risk of convulsions if concentration were to fall too far.
It will be apparent that, for drugs whose elimination is characterised by zero-order kinetics, the concept of half-life is meaningless.
