We end our 4-part pharmacokinetics series discussing the all important final "E" of ADME: Elimination or Excretion.

Thus far we have traversed absorption, distribution, and metabolism. But how does the drug exit the body? It can be eliminated unchanged or undergo transformation often via the liver to then be excreted. Excretion occurs via two primary routes: Renal elimination via the urine and biliary excretion into the GI tract through stool. In general, hydrophilic drugs are excreted renally while more lipophilic agents undergo hepatic metabolism and then subsequent biliary excretion.

How does this matter clinically? Most often it involves patients who've had alterations to their kidney or liver function. There are a few important principles here:

1. Patients with chronic kidney disease or acute kidney injury will many times require dose/frequency adjustment to prevent accumulation of drugs whose primary route of elimination is renal. Accumulation of drug could result in unwanted side effects such as bleeding (several anticoagulants like rivaroxaban) or seizures (antibiotics like meropenem or cefepime) for example.
2. In patients with acute kidney injury, close monitoring should occur on a daily basis as often the injury will resolve quickly with fluid administration. Therefore reduced doses/frequencies should be adjusted back to normal to avoid losing effectiveness of the drug in question.
3. How do you know when to adjust these agents? Typically you perform a calculation to estimate renal function such as Cockcroft-Gault or MDRD equations. Most of these equations are freely available on apps and often are used in electronic health records. Caution...these estimations are frequently overestimated in patients with low serum creatinine, so use good clinical judgment when you do these calculations.
4. Most drugs are adjusted based on these estimations, but some drugs have commercial serum drug level availability. You can get patient specific levels in drugs such as tobramycin, vancomycin, voriconazole, phenytoin, and others which often have a narrow therapeutic index (small window in which drug works but doesn't cause toxicity). This many times can best give a "real-time" assessment.
5. Some patients have augmented renal clearance (ARC), meaning they clear more drug than a normal patient. This happens most often in patients who are young and critically ill often via trauma. Patients who exhibit these characteristics may require increased doses or more frequent doses.
6. Hepatobiliary cleared drugs are much more difficult to dose adjust when patients have hepatic insufficiency, especially in moderate-severe cases such as cirrhosis. And things get even more complicated when they have both hepatic and renal insufficiency!

Ultimately, dose adjustments in these situations involve a careful assessment of risk/benefit for each individual patient and each individual medication to determine the best course of action. Trends are also extremely helpful, as the serum creatinine is often a lagging indicator when it comes to resolving renal function as urine output improves much quicker than will be reflected in the Chem-7. While the calculated estimation may indicate a dose adjustment is still needed, the clinician may elect to transition to a full dose knowing that the patient's renal function is actually much improved.

If you have enjoyed this series, check us out at teachmepharm.com as we apply these principles within individual drugs and drug classes so that you can best care for patients.

Look forward to our next post!

Chris Bland

TeachMePharm Co-founder and Content Developer