Drug Dosing Issues and Resources

This blog is intended to share thoughts and insights related to arriving at the correct therapeutic dosage and support for ePrescribing. It does not rely on a specific drug nomenclature. These comments apply equally to dosing in adults as well as dosing in pediatrics.

Various posts will address important aspects of pharmacokinetics as they apply to the appropriate use of medications, and some of the human factors necessary to supplement drug product information. In addition, there will be digressions to address emerging concepts such as pharmacogenomics and other factors invovled in dosage adjustments.

Automated screening for drug allergy has been a less than satisfactory experience for most pharmacists. Alerts tend to be very broad, identifying all possible cross-reactivity for medicine list, and the data concerning the presence of an allergy are often records of intolerances rather than true allergy. In the era of electronic prescribing, an allergy alert may prompt a change in therapy, exposing the patient to a drug which may not have been the prescribers first choice. It is important that these alerts be based on quality history, a full understanding of these adverse drug events, and other types of idiosyncratic reactions which may be relayed by patients as "allergic" reactions. The quality of the data, and the sophistication of the alerts, will continue to be limitations to the automated screening, and challenge all healthcare providers. 

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.

Pediatric dose calculations represent a particular challenge to some healthcare professionals. A drug reference book can help, but there are additional considerations which are not part of the text. Considerations such as the maturation of the child and nutritional status are not easily factored. In addition, drug interactions may play a role in the adjustment of dose. When using a pediatric dosage calculator, it is important that the medicine list be reviewed, as a calculator typically focuses on only a single medication. Augmenting the decision-making process with drug interaction software can help assess these influences on dosing. Both processes are essential in arriving at an appropriate therapeutic dosage.
 

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.

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.

The threshold at which an adjustment of dosage may be necessary depends on not only the route of elimination, but the mechanisms involved in renal elimination of the drug in question. Sometimes this can be indicated by drug classifications. An understanding of the complexity of drug elimination by the kidney is required. The kidney functions as a group of individual nephrons (units). Each unit is capable of filtration as well as active secretion and reabsorption. Renal elimination is the sum of all these processes, and drugs which are eliminated by the kidney can rely to differing extents on each process. 

Filtration is essentially passive, but secretion is an active process. It should be recognized that the ability to secrete a drug offers a “buffer” of sorts to allow the elimination of some drugs even when glomerular filtration rate (GFR) is below normal. It is not until GFR reaches approximately 30 mL/min that a sufficient number of “unit nephrons” has been eliminated to have an impact on the elimination of drugs with high secretion. 

Here is the key point: drugs excreted solely by filtration will require adjustment at higher levels of renal function (as estimated by creatinine clearance which emphasizes filtration) as compared to drugs which are secreted. It is not enough to say a drug is renally eliminated. The actual mechanism of the drug’s excretion can also be important to determine the therapeutic dosage. Fortunately most drugs have an allowable dosage range, and adjustments are provided in drug product information.

Here is an example: Aminoglycoside antibiotics and penicillin antibiotics are both eliminated by the kidney. In traditional dosing, we begin to adjust doses of aminoglycosides even when renal function is near normal (ClCr approximately 70 mL/min). That is because these drugs are ONLY eliminated by filtration, and therefore more sensitive to modest decrease in the number of functioning nephrons. Penicillins are often not adjusted unless renal function is very poor (usually around a ClCr of 30 ml/min). This is because in addition to filtering at the glomerulus, the kidney actively secretes these drugs, an efficient means of removing drug (essentially pumping them out as opposed to letting them flow out). It is only when the functional mass of nephrons becomes very small (as reflected in the creatinine clearance) that we have concerns for drug accumulation and toxicity for drugs which are actively secreted.

An additional thought: Drugs which have a component of elimination which is not dependent on the kidney can often be given safely at full doses despite significant renal impairment since the “back-up” elimination pathway prevents dramatic accumulation.