Many drugs are metabolized to active metabolites. This is usually carried out by the liver in the form of reductions, oxidations, and the addition of methyl, acetyl, and other groups. While metabolites are usually a fraction as potent as the parent compound, in some situations they may be more potent and may accumulate to significant concentrations under the right conditions. Often the metabolites of lipophilic drugs are made more water soluble to facilitate renal excretion. However, intensive care unit (ICU) patients often have renal and/or hepatic impairment altering the clearance of the drugs and their metabolites. Thus, while a particular drug may be hepatically metabolized, renal insufficiency may impair its excretion and lead to buildup of an active metabolite. Other metabolites may not be active in terms of the original effect of the drug but are actually more toxic than the parent compound. Both of these situations may have dire consequences.

Meperidine is a prime example of this problem. This is a commonly used narcotic in anesthesiology and other settings including the ICU and its half-life is approximately 3 hours. It is hepatically metabolized to normeperidine (half-life of 15 to 20 hours), which can build up in the face of renal impairment and promote seizure activity when it reaches high enough concentrations. These seizures are not reversed by naloxone, which is usually used to reverse the deleterious effects of most narcotics.

Morphine is another very commonly used narcotic in the ICU that is metabolized to two active metabolites, 3- and 6-glucuronides. The half-life of morphine is usually 2 to 3 hours. The 3-glucuronide is not active as an analgesic but does cause sedation and can precipitate seizures. The 6-glucuronide is active as an analgesic, in fact, more so than morphine itself. Both of these metabolites are dependent on renal excretion and may build up in critically ill patients with renal insufficiency, leading to prolonged sedation and/or respiratory depression or possibly seizures like normeperidine.