Metabolites – Primary and Secondary

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. The liver plays an important role in the drug metabolism.

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.

Benzodiazepines are very commonly used in the ICU for sedation, to assist with mechanical ventilation, and to provide anxiolysis during painful procedures and critical illness. Many of the drugs in this class are hydroxylated to active metabolites, including midazolam and diazepam. Midazolam is normally a short-acting drug (duration of action is approximately 1 hour), but this is dependent on normal excretion of the hydroxylated metabolite. While this metabolite has only about 10% of the activity of the parent drug, renal impairment may lengthen the effect of the drug. Thus a short-acting drug may become a longer-acting drug especially when used in large doses. A long-acting benzodiazepine such as diazepam (duration of action is 3 to 5 hours) can become very long acting when its active metabolite is not cleared. Diazepam has several active metabolites, some of which are prepared and marketed as separate drugs, including temazepam and oxazepam. Thiese are commonly formed during the drug metabolism.

It should be noted that the accumulation of active metabolites secondary to hepatic and/or renal insufficiency is often compounded by the act of repetitive dosing and continuous infusions of the parent drugs. As a result a patient may not awaken from sedation for prolonged periods of time, leading to more time spent on a ventilator and an unnecessary battery of tests being performed to assess the patient’s decreased mental status. These problems are additionally compounded by the fact that many of these drugs are not used in isolation. Many patients are on several drugs at the same time, especially the benzodiazepines and narcotics. If careful attention to dosage is maintained in the face of potentially impaired clearance, these problems may be minimized. Better yet, drugs that have no active metabolites may be the preferred choice assuming all other characteristics (side effects, etc.) are equal. Instead of using diazepam or midazolam, one may choose lorazepam, which has no active or toxic metabolites. While this drug has a long duration of action (6 hours), paradoxically its effect may be shorter in ICU patients compared with the ones with active primary metabolites. Similarly, Fentanyl may be used as the preferred narcotic since its secondary metabolites are not toxic or active.

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