Drug Dosing Issues and Resources

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.