Alteration of dose should be approached with an appreciation for several key factors. Other factors should be considered related to dosage administration. A drug reference book is only a starting point. One should not be so cautious about drug dosing that the therapeutic benefit of the drug is lost. Inadequate dosing may lead to treatment failure. Accumulation related to impaired elimination requires repeated dosing. In evaluating possible risks of accumulation, it is also important to balance the timing of drug accumulation, and the relationship of elevated concentrations to specific adverse effects. Drugs which are dosed for a very limited period of time, or drugs which have wide therapeutic “windows”, may not warrant much in the way of dosage adjustment.
The initial dose of a regimen is often not adjusted, serving as a “loading” dose to achieve therapeutic response. Subsequent dosage may be adjusted by lengthening the interval or reducing the size of an individual dose. Different drug classifications may require different dosing adjustment strategies. It is important to employ a strategy which does not compromise the efficacy of the drug – so drugs which need high “peaks” for efficacy should generally be adjusted by interval, while drugs which need a continuous presence in the serum should be adjusted by the size of the individual dose.
Selection of an alternative which is hepatically metabolized may be an option, but one must consider metabolites as a part of evaluation. For example, Morphine and meperidine are hepatically metabolized, but each has a metabolite which accumulates in renal impairment. In the case of morphine, additional sedation/respiratory depression may result. Meperidine’s metabolite results in neuroexcitation, potentially leading to seizures with repeated dosing. However, a single dose of either agent is not likely to result in harm. Other metabolites which may be of concern include NAPA, and desmethyldiaepam.