Why Is High Therapeutic Index Preferable

1. Describe how acetaminophen is metabolized. The liver metabolizes more than 90% of the acetaminophen taken to sulfate and glucuronide conjugates, which are water soluble and eliminated in the urine. In children, sulfation is the primary pathway until the age of 10-12 years, whereas glucuronidation predominates in adolescents and adults. Hepatotoxicity is the result of formation of the reactive and toxic metabolite NAPQI by the cytochrome P450 (CYP) system. Glutathione can bind NAPQI and lead to excretion of nontoxic mercapturate conjugates. As glutathione stores are diminished, NAPQI is not detoxified, and it covalently binds to the lipid bilayer of hepatocytes, causing hepatic centrilobular necrosis. Glutathione must be replaced by sulfhydryl compounds from the diet or from drugs such as the antidote NAC. See notes given by Dr. Dahms for three pathways of acetaminophen metabolism. APAP already has an OH group so it can be directly acted on by Phase II enzymes 2. Describe which organ system needs to be monitored after significant acetaminophen ingestion and how and why you would monitor it. Liver** (pancreas and kidney were also mentioned but are not considered the MOST important) This can be monitored by: Serum levels of alanine aminotransferase and bilirubin Prothrombin time (slower clotting because prothombin which is produced the liver is present in lower amounts when there is liver damage. Coagulation time increases in instances of liver damage.) 3. Identify the mechanism of action of the antidote for acetaminophen poisoning. If less than 4 hours from ingestion, activated charcoal should be given to decrease absorption of APAP in the intestine. The antidote for APAP poisoning is N -acetylcysteine (NAC). NAC is theorized to work through a number of protective mechanisms. NAC is a precursor of glutathione and increases the available glutathione to conjugate NAPQI. It may also enhance sulfate conjugation of any unmetabolized APAP. NAC also functions as an antiinflammatory and antioxidant and has positive inotropic effects. NAC increases local nitric oxide concentrations, and this vasodilatory effect on microcirculatory blood flow enhances local oxygen delivery to peripheral tissues. These microvascular effects are associated with a decrease in morbidity and mortality even in the setting of established hepatotoxicity. NAC has sulfhydryl groups which are detoxifying. NAC  GSH ** 4. Describe what is meant by a toxic/therapeutic ratio. The therapeutic index (also known as therapeutic ratio), is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects. Quantitatively, it is the ratio given by the toxic dose divided by the therapeutic dose. A commonly used measure of therapeutic index is the toxic dose of a drug for 50% of the population (TD50) divided by the minimum effective dose for 50% of the population (ED50). A high therapeutic index is preferable to a low one: this corresponds to a situation in which one would have to take a much higher amount of a drug to do harm than the amount taken to do good.

5. Given the amount Frank ingested, describe what you would do before knowing the level and if the known level of acetaminophen in his blood test is 75 micrograms/ml. 15 pills is approximately 7.5 grams (7.5 -10 g = toxic dose) Frank should be treated before knowing his level and then monitored closely. 75 micrograms/ml is the very lowest of the toxic range. 1. What daily doses (adult and pediatric) have been noted to induce hepatic dysfunction due to repeated acetaminophen ingestion? Most cases of acetaminophen poisoning occur because people take smaller doses over a long period of time. In this setting, doses of 4000 mg daily can be toxic. Acetaminophen should be used cautiously on a chronic basis because several case reports show that it may be hepatotoxic at therapeutic doses. In children, daily maximum oral dosing is not to exceed 90 mg per kilogram of body weight. ALT and AST limits are approximately 40 IU/L 2. How does chronic acetaminophen toxicity differ from the acute overdose with respect to utilization of the Nomogram? The nomogram should not be used to assess chronic or repeated ingestions. 3. Since subsequent analysis revealed undetectable serum acetaminophen levels, is any treatment warranted for this patient? Chronic acetaminophen ingestions: Patients may give a history of several doses taken over 24 hours or more, in which case the nomogram cannot accurately estimate the risk of hepatotoxicity. In such cases, we advise NAC treatment if the amount ingested was more than 150–200 mg/kg or 6–7 g within a 24-hour period, if liver enzymes are elevated, or if the patient falls within a high-risk group (see above). Treatment may be stopped 24–36 hours after the last dose of acetaminophen if liver enzymes and PT/INR are normal.