Dosage Precautions

As with renal impairment, the threshold at which an adjustment of dosage may be necessary depends not only on the route of elimination, but the mechanisms involved. These dosage precautions are essential. Drug classifications rarely point out differences between members regarding the pathways of metabolism. Hepatic metabolism is complex, but it can generally be broadly grouped into two broad types of reactions/pathways: Phase I and Phase II reactions.

Phase I reactions include reactions which greatly modify the chemical structure of the drug. In a way, these are more difficult reactions to perform. The ability of the liver to carry out these functions can be significantly decreased at moderate levels of functional impairment. Phase II reactions are in many ways “simpler” from a chemical standpoint, and the ability to perform them can be preserved even in significant hepatic damage. For this reason, it is important to know not only whether a drug is metabolized, but also the type of metabolism. In this way a therapeutic dosage may be determined.

One of the concepts we have been trying to shed some more light on is the importance of having drug data and clinical decision support data that can be easily customized to the needs of the end user location.  In last year's Agency for Healthcare Research and Quality (AHRQ) Annual Meeting there were Guidelines Into Decision support that were presented.  These are also know as the acronym GLIDES.  These guidelines are actually a pretty interesting take on the advancement of Clinical Decision Support.

In order to account for users in various types of settings and locations, as well as different dosage precautions, this report specifically calls out the need for better customization.  This may seem a lofty goal but is, nonetheless, worthwhile.  The need to customize clinical decision support to the end user makes complete sense in the fact that being able to deliver appropriate alerts through an EMR geared toward a certain specialty is critical. For example, pediatric dosage calculations and alerts would really be most appropriate within a pediatric practice and, for this reason, these end users may want to see something different.  In an EMR for an oncology practice it would make sense that an alert specific to a chemo regimen appear.  Just something else to think about when building your drug data.

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.

• Provides reference information for ordering / prescribing medications
• Allows users to access and review medication information, including drug monographs and patient education material
• Provides information on dosing adjustments for renal impairment 
• Identifies age-based warning / Beers criteria medications

• Each drug name and drug product are distinguished by unique identifiers / drug nomenclature which are mapped to other standard drug vocabularies in RxNorm
• Allows searching for medications by generic name, brand name, or therapeutic class

• Provides content for screening medication orders for allergy and drug interactions
• Facilitates drug interaction checking 
• May be used to create medication dosing alerts including dosage range checking and dosage precautions

• Supports ePrescribing by providing data to define dosage form, route, frequency and strength
• Provides a "starter set" of common orders to facilitate Eprescribing