How Does Drug Concentration Decline Over Time? - Zero-order Kinetics
Fig 5 Graph to show decline of drug concentration with time when elimination is a zero-order process. A constant amount of drug is eliminated in a given time (rather than a constant fraction). The concept of 'half-life' is no longer relevant because the time period required for the plasma drug concentration to halve depends on the plasma concentration.
Fig 6 Graph to show how the rate of elimination fails to increase with increasing drug dose in a zero-order process. Although a dose of 2D results in twice and 3D three times the initial plasma concentrations of D at any time point, elimination of higher doses takes a greater length of time. The effect of dose increases is only predictable initially. At any subsequent time point the relationship between changes in dose and plasma concentration is difficult to predict. Similarly the time taken for the plasma concentration to halve becomes dose- and time-dependent.
Although the elimination of most drugs given in therapeutic doses is a first-order process, in which there is no limit to the capacity of the processes of metabolism and excretion, at toxic doses the availability of the metabolising enzymes may be exceeded. An important clinical example is overdosage of paracetamol where the capacity of glucuronide and sulphate conjugation is exceeded and the drug can be eliminated only by oxidation (producing a metabolite with devastating effects on liver cells). For a few drugs in common use (e.g. phenytoin, alcohol) metabolising capacity is exceeded (saturated) within the therapeutic range of dosage.
Once saturation occurs, the rate of elimination is constant and is no longer related to the amount of drug remaining in the body:
Rate of elimination = �dA/dt = �k
where k is a rate constant with units of reciprocal time (/h). This results in
zero-order kinetics where the amount of drug eliminated in a given time is a
constant amount of the drug remaining in the body (rather than a constant fraction). Given that once drug distribution has occurred, the amount of drug remaining in the body is proportional to the plasma concentration of the drug, the following equation also applies:
Rate of elimination = �dC/dt = �k
There is no longer an exponential decline in concentration but a reduction by fixed decrements within fixed time periods (Fig 5). Neither the time taken to eliminate a dose nor the concentration at specific time points is predictable as the dose increases (Fig 6).
