Dose Administration

The medication generic name is only one way to specify a therapeutic dosage. If a compound is available in multiple dosage forms a particular generic name may have a number of specific dosage ranges. For example, an extended release product which is dosed once daily may have a very different dosage range than its immediate-release counterpart. At the very least the acceptable frequency of administration is very different. Differences in bioavailability between products as well as salt forms may need to be addressed through separate dosage ranges. The drug brand name unfortunately is also not a simple relationship to the generic drug. For example, a brand name can be applied to an ophthalmic product and a systemic tablet. Additional differentiators (such as route) would need to be included in any review prior to dose administration.

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As with renal impairment, all pharmacokinetic processes may be affected by hepatic disease and must be considered in dosage administration. Unfortunately there is not a dosing calculator which can encompass these elements, and individualized assessment is needed. The primary process affected by hepatic impairment is the metabolism of drugs. This can affect bioavailability (increases) and systemic clearance/removal of drug (decreases) from the circulation. Both of these effects lead to increased concentrations in the body. As with renal impairment, the potential accumulation of drugs and an increase in adverse effects/toxicity which may occur is the primary concern. Specific dosage precautions must be considered.

It is important to evaluate the degree of liver impairment. Just like in renal impairment, liver impairment is not an “all-or-none” phenomenon, and must be evaluated in relative terms. Unlike renal impairment, there is no quick way to estimate hepatic function. Sometimes that is better, since it requires a more thoughtful and complete analysis. Liver function CAN be evaluated by looking at what the liver does from a physiologic standpoint.

Elevation of hepatic transaminases (AST and ALT) is not a very reliable indicator of function. These enzymes are released from hepatic cells and serve as an indication of acute injury. But the liver has a large redundancy and damage which occurs over long period of time can lead to serious impairment even in the absence of transaminase elevations.

The liver is responsible for synthesis of proteins, including albumin and clotting factors. Elevated prothrombin/INR and/or low serum albumin concentrations indicate that the synthetic capacity of the liver is diminished. The liver is also responsible for excretory functions through the conjugation of bilirubin. Elevations in bilirubin may indicate impairment of this function. There are also other indicators of hepatic function, such as serum ammonia. There is a classification scheme (the Pugh-Child scale) which takes several of these factors into account and may be used to classify the degree of liver impairment into mild, moderate, and severe levels. Specific dosage adjustment and/or contraindications have been published using these criteria for some drugs.

 
It is important to note that medicine interactions are not obvious in evaluating hepatic impairment. Interactions which block a metabolic pathway may be considered as a type of transient, functional hepatic impairment.

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.

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