Acetaminophen toxic metabolites

Biochemical mechanism of A-acetylcy teine As glutathione is used to conjugate the acetaminophen toxic metabolite, the antidote N-acetylcysteine helps to facilitate glutathione synthesis by increasing the concentrations of one of the reactants of the first synthetic step. 

Severe pain should be treated with an opioid such as morphine, hydromorphone, methadone, or fentanyl. Moderate pain can be treated effectively in most cases with a weak opioid such as codeine or hydrocodone, usually in combination with acetaminophen. Meperidine should be avoided owing to its relatively short analgesic effect and its toxic metabolite, normeperidine. Normeperidine may accumulate with repeated dosing and can lead to central nervous system side effects including seizures. 

Glutathione is also implicated in the removal of toxic metabolites from the analgesic paracetamol (USA acetaminophen). Oxidative metabolism of paracetamol produces an A-hydroxy derivative, and this readily loses water to generate a reactive and toxic quinone imine, which interacts with proteins to cause cell damage. 

Ethanol Multiple effects on neurotransmitter receptors, ion channels, and signaling pathways Antidote in methanol and ethylene glycol poisoning Zero-order metabolism duration depends on dose Toxicity Acutely, CNS depression and respiratory failure chronically, damage to many systems, including liver, pancreas, GI tract, and central and peripheral nervous systems Interactions Induces CYP2E1 Increased conversion of acetaminophen to toxic metabolite... 

Acetaminophen is one of the drugs commonly involved in suicide attempts and accidental poisonings, both as the sole agent and in combination with other drugs. Acute ingestion of more than 150-200 mg/kg (children) or 7 g total (adults) is considered potentially toxic. A highly toxic metabolite is produced in the liver (see Figure 4-5). 

FIGURE 37.2. Metabolism and mechanism of acetaminophen toxicity. Bioactivation of acetaminophen by P450 enzymes results in the formation of the reactive intermediate (NAPQI) which forms covalent protein adducts with glutathione which is then converted to mercapturic acid. When the amount of the reactive metabolite formed exceeds the glutathione available for binding, the excess metabolite binds to tissue molecules resulting in centrilobular hepatic necrosis. 

An example of a popular pharmaceutical with a toxic metabolite is acetaminophen (2, 3). A portion of the acetaminophen metabolized in the liver is converted to a reactive intermediate/ N-acetyl-p-benzoquinoneimine (NAPQI)/ which is an excellent substrate for nucleophilic attack by free sulfhydryl groups in proteinS/ as shown in Scheme 11.4. By substituting a high concentration of an alternative... 

Though induction of CYP is generally associated with potential treatment failure, administration of a CYP inducer may also produce toxicity by increasing the accumulation of a toxic metabolite, such as in the case of acetaminophen, as described in Chapter 16. 

Phenacetin is metabolized to acetaminophen and sulfhemaglobin-forming metabolite and other toxic metabolites. In the absence of adequate glutathione or a glutathione substitute, acetaminophen is further metabolized to cytotoxic and hepatotoxic molecules. 

CD-1 mice given a single i.p dose of 600 mg PBO per kg body weight were found to have suffered less hepatotoxicily when treated with acetaminophen (6(H) mg kg 1 body weight p.o.) at either 2 hours prior to or 1 hour following PBO administration. This reduced hepatotoxicity was measured via GSH and sorbitol dehydrogenase levels, as well as subsequent histopathology of (he liver. Since the hepatic MFO system metabolizes acetaminophen to a toxic metabolite, the decreased toxicity seen in ibis experiment is likely duo to inhibition of such oxidase enzymes by PRO (Brady el /., 195111). 

Figure 35.13 Acetaminophen toxicity. A minor metabolic product of acetaminophen is N-acetyl-p-benzoquinone imine, This metabolite is conjugated to glutathione. Large doses of acetaminophen can deplete liver glutathione stores.

In many cases of severe hepatotoxicity, renal injury is also present and may range from oliguria to acute renal failure. The etiology of the renal injury may be a direct effect of a toxic metabolite of acetaminophen, M-acetyl-p-benzoquinone-imine (discussed in the next section), generated by renal cytochrome oxidase or a consequence of hepatic injury resulting in hepatorenal syndrome. Isolated cases of myocardial injury have been reported rarely. ... 

Centrolobular necrosis is often a dose-related, predictable reaction secondary to drugs such as acetaminophen however, it also can be associated with idiosyncratic reactions, such as those caused by halothane. Also called direct or metabolite-related hepatotoxic-ity, centrolobular necrosis is usually the result of the production of a toxic metabolite (see Fig. 38-1). The damage spreads outward from the middle of a lobe of the liver. 

---