A patient has taken a potentially lethal dose of acetaminophen. The current preferred antidotal involves administration of a drug that (AIPG 2012)
|A||Alkalinizes the urine to facilitate acetaminophen excretion|
|B||Causes metabolic acidosis to combat the toxic metabolites / metabolic alkalosis|
|C||Inhibits hepatic oxidative metabolism to inhibit formation of acetaminophen’ s toxic metabolite|
|D||Is rich in sulfhydryl (-SH groups) of acidic drugs.|
a. We give N-acetylcysteine for acetaminophen poisoning and use it because it is a sulfhydryl-rich drug that, if given soon enough and properly enough, can prevent hepatic necrosis. At safe blood levels, the major pathways of acetaminophen elimination involve glucuronidation and sulfation.
b. When these pathways are overwhelmed, as occurs with acetaminophen poisoning, a cytochrome P450—dependent pathway attempts to handle the metabolic load.
c. So long as ample hepatocyte stores of glutathione (—SH compound) are available, cytotoxicity will not occur. However, severe poisoning depletes —SH stores, and so a hepatotoxic metabolite (probably hydroxylated product or N-acetyl-benzoiminoquinone) attacks key cellular macromolecules. That leads to hepatic necrosis.
d. N-acetylcysteine react with the toxic metabolite, thereby sparing —SH groups on key hepatocyte macromolecules.
e. Alkalinization of the urine is of no benefit with acetaminophen poisoning, as it is with severe salicylate poisoning (because raising urine pH reduces tubular reabsorption of salicylate and increases its excretion). Superoxide anion radical, or hydrogen peroxide, are not directly involved in the cytotoxicity. Allalinization is useful in forceful elimination of acidic drugs.