Dosing schedules

Whatever their type, dosing schedules are simply schemes aimed at achieving a desired effect whilst avoiding toxicity. In the discussion that follows it is assumed that drug effect relates closely to plasma concentration, which in turn relates closely to the amount of drug in the body. The objectives of a dosing regimen where continuing effect is required are:

To specify an initial dose that attains the desired effect rapidly without causing toxicity. Often the dose that is capable of initiating drug effect is the same as that which maintains it. On repeated dosing however, it takes 5 x t]/2 periods to reach steady-state concentration in the plasma and this lapse of time may be undesirable. The effect may be achieved earlier by giving an inital dose that is larger than the maintenance dose; the initial dose is then called the priming or loading dose, i.e. the priming dose is that dose which will acheive a therapeutic effect in an individual whose body does not already contain the drug.

To specify a maintenance dose: amount and frequency. Intuitively, the maintenance dose might be half the initial/priming dose at intervals equal to its plasma \}/2, for this is the time by which the plasma concentration that achieves the desired effect declines by half. Whether or not this approach is satisfactory or practicable, however, depends very much on the t^ itself, as is illustrated by the following cases:

1. Half-life 6-12 h. In this instance, replacing half the initial dose at intervals equal to the t/2 can indeed be a satisfactory solution because dosing every 6-12 h is acceptable.

2. Half-life greater than 24 h. With once-daily dosing (which is desirable for compliance) giving half the priming dose every day means that more drug is entering the body than is leaving it each day, and the drug will accumulate indefinitely. The solution is to replace only that amount of drug that leaves the body in 24 h. This quantity can be calculated once the inital dose and dose interval have been decided and the t/2 is known.

3. Half-life less than 3 h. Dosing at intervals equal to the \Y2 would be so frequent as to be unacceptable, and the answer is to use continuous intravenous infusion if the tY2 is very short, e.g. dopamine t/2,2 min; steady-state plasma concentration will be reached in

5 x \}f = 10 min) or, if the t/2 is longer, e.g. lignocaine (t /2,90 min) to use a priming dose as an intravenous bolus followed by a constant intravenous infusion. Intermittent adminstration of a drug with short tl/2 is nevertheless reasonable provided large fluctuations in plasma concentration are acceptable, i.e. that the drug has a large therapeutic index. Benzylpenicillin has a t% of 30 min but is effective in a 6-hourly regimen because the drug is so nontoxic that it is possible safetly to give a dose that acheives a plasma concentration many times in excess of the minimum inhibitory concentration for sensitive organisms.

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