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A3: Antidotes in Depth

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A3: Antidotes in Depth A3: Antidotes in Depth Robert G. Hendrickson; Mary Ann Howland INTRODUCTION N-acetylcysteine (NAC) is the cornerstone of therapy for patients with potentially lethal acetaminophen (APAP) overdoses. If administered early, NAC can then prevent APAP induced hepatotoxicity. If administered after the onset of hepatotoxicity, NAC improves outcomes and decreases mortality. NAC may also limit hepatotoxicity from other xenobiotics that result in glutathione depletion and free radical formation, such as cyclopeptide- containing mushrooms, carbon tetrachloride, chloroform, pennyroyal oil, clove oil, and possibly liver failure from chronic valproic acid use.31 Finally, NAC may be useful in the management of adults with fulminant hepatic failure caused by nontoxicologic etiologies.20,75,81,84,149 HISTORY Shortly after the first case of APAP hepatotoxicity was reported, Mitchell described the protective effect of glutathione.97,127 Prescott113 first suggested NAC for APAP poisoning in 1974. Early experiments demonstrated that NAC could prevent APAP-induced hepatotoxicity in mice and that the oral (PO) and intravenous (IV) routes were equally efficacious when treatment was initiated early after ingestion.106 Several groups96,112,113,126 performed human research with oral and IV NAC in the 1970s. The US Food and Drug Administration (FDA) approved NAC for oral use in 1985 and for IV use in 2004. PHARMACOLOGY Chemistry NAC is a thiol containing (R-SH) compound that is deacetylated to cysteine, an amino acid used intracellularly. The amino acids cysteine glycine and glutamate are used to synthesize glutathione.123 Related Xenobiotics Cysteamine, methionine, and NAC, which are all glutathione precursors or substitutes, have been used successfully to prevent hepatotoxicity, but cysteamine and methionine both produce more adverse effects than NAC, and methionine is less effective than NAC. Therefore, NAC has emerged as the preferred treatment.110,137,160,162 Mechanism of Action NAC has several distinct roles in the treatment of APAP poisoning. Early after ingestion when APAP is being metabolized to N-acetyl benzoquinoneimine (NAPQI), NAC prevents toxicity by rapidly detoxifying NAPQI. After hepatotoxicity is evident, NAC decreases toxicity through several nonspecific mechanisms, including free radical scavenging, increasing oxygen delivery, increased mitochondrial adenosine triphosphate (ATP) production, antioxidant effects, and alteration of microvascular tone. NAC effectively prevents APAP induced hepatotoxicity if it is administered before glutathione stores are depleted to 30% of normal. This level of depletion occurs approximately 6 to 8 hours following toxic APAP ingestion.112,120 In this preventive role, NAC acts primarily as a precursor for the synthesis of glutathione.77 The availability ofcysteine is the rate-limiting step in the synthesis of glutathione, and NAC is effective in replenishing diminished supplies of both cysteine and glutathione. Additional minor mechanisms of NAC in preventing hepatotoxicity include acting as a substrate for sulfation,139 as an intracellular glutathione substitute by directly binding to NAPQI,29 and by enhancing the reduction of NAPQI to APAP.78,135 After NAPQI covalently binds to hepatocytes and other tissues,120 NAC modulates the subsequent cascade of inflammatory events in a variety of ways.55 NAC may act directly as an antioxidant or as a precursor to glutathione. Glutathione protects cells against electrophilic compounds by acting as both a reducing agent and an antioxidant.124 NAC improves oxygen delivery38,55,146,163,164 and utilization in extrahepatic organs such as the brain, heart, and kidney, probably by improving blood flow in the microvasculature, although the exact mechanism is unclear.83,133 In addition, NAC increases hepatic mitochondrial ATP production in mice129 and demonstrates a suppressive action on macrophages, neutrophils, leukocyte endothelial cell adhesion, and cytokines.75 Pharmacokinetics/Pharmacodynamics Administered NAC is present in plasma in the reduced or oxidized state and is either free or bound to plasma proteins or with other thiols and SH groups to form mixed disulfides such as NAC–cysteine.111 NAC has a relatively small volume of distribution (0.5 L/kg), and protein binding is 83%. NAC is metabolized to many sulfur containing compounds such ascysteine, glutathione, methionine, cystine, and disulfides, as well as conjugates of electrophilic compounds, that are not routinely measured.47,105,111 Thus, the pharmacodynamic study of NAC is complex. In addition, the pharmacokinetics of NAC are complicated based on whether total or free NAC is being measured.111 Pharmacokinetics of Oral N-Acetylcysteine. Oral NAC is rapidly absorbed, but its bioavailability is low (10%–30%) because of significant first-pass metabolism.47,105,111 The mean time to peak serum concentration is 1.4 ± 0.7 hours. The mean elimination half-life is 2.5 ± 0.6 hours and is linear with increasing dose up to 3200 mg/m2/day given as a single daily dose. Inter- subject serum NAC concentrations vary tenfold.105 Chronic administration leads to a decrease in plasma concentrations from a Cmax of 8.9 mg/L (55 µmol/L) at the end of 1 month to 5.1 mg/L (31 µmol/L) at the end of 6 months.105 Conflicting in vitro30,73,127 and in vivo28,45,101,117 data regarding the concomitant use of PO NAC and activated charcoal suggest that the resultant bioavailability of NAC is either decreased or unchanged. This interaction is likely of limited clinical importance, and PO or IV NAC can be initiated without concern for activated charcoal interaction (Chap. 35). Pharmacokinetics of IV N-Acetylcysteine. When only free NAC was analyzed, healthy volunteers given 600 mg IV NAC achieved peak serum NAC concentration of 49 mg/L (300 µmol/L) with a half-life of 2.27 hours compared with a peak serum concentration of 2.6 mg/L (16 µmol/L) after 600 mg PO.24Serum concentrations after IV administration of an initial loading dose of 150 mg/kg over 15 minutes reach approximately 500 mg/L (3075 µmol/L).111 A steady-state serum concentration of 35 mg/L (10–90 mg/L) is reached in approximately 12 hours with the standard IV protocol.111 Approximately 30% is eliminated renally. Once in the blood, IV and PO NAC have a similar half-life (2–2.5 hours). This half-life is increased in the setting of severe liver failure or end-stage kidney disease because of a reduction in clearance.67,100 Intravenous vs. Oral Administration. As in the case of many issues related to APAP toxicity, the choice of PO versus IV NAC is complex. The available information suggests that each has advantages and disadvantages, and each may be more appropriate than the other in certain settings. Because no controlled studies have compared IV with PO NAC, conclusions about the relative benefit of each are largely speculative. With the exception of fulminant hepatic failure, for which only the IV route has been investigated, IV and PO NAC administration are equally efficacious in treating patients with APAP toxicity.114 Some data suggest that IV NAC may be slightly more efficacious when given less than 12 hours after an overdose and that PO NAC is significantly more efficacious when given after 16 hours after overdose; however, this study compared patient groups that differed by decade of treatment and by country. It remains unclear if these differences are true or clinically relevant.114,172,173 In addition, any difference in outcome for patients who are treated after 16 hours almost certainly is related to theduration and total dose of NAC therapy rather than the route itself. The decision of which route to use should depend on the rate of adverse events, safety, availability, and ease of use. Efficacy should not be a consideration. Safety is the best understood of these issues. Nausea and vomiting may occur in up to 20% of patients treated with PO NAC compared to 7% with IV NAC.57 Diarrhea and headache are prevalent, but there is no credible evidence of more serious complications resulting from PO NAC. Reports of skin rash and unusual complications are rare.97 In contrast, IV NAC is associated with a 14% to 18%72 rate of anaphylactoid reactions, although rates of 2% to 6% are reported in retrospective trials.63,68,168,175 Most of these reactions are mild and include rash, flushing, nausea, and vomiting.10,72,130,140,177Anaphylactoid reactions may be severe in approximately 1% of cases72,94,176 and in rare instances may lead to hypotension and death.7,17,35,68,89,93,106,140,173,174 Anaphylactoid reactions are attributed to both the dose and concentration of NAC and are caused by a non IgE mediated release of histamine from mast cells and mononucleocytes.32 APAP inhibits mast cell histamine release; therefore, a higher APAP concentration at the time of NAC delivery decreases the risk of anaphylactoid reactions.32,166 The anaphylactoid reaction rate is decreased by using a more dilute NAC solution68,72,175 and by slowing NAC infusions in some studies.28 In one prospective study, prolongation of the loading infusion from 15 to 60 minutes did not decrease the anaphylactoid rate significantly (from 18% to 14%).48,63,72,88 Minor reactions, such as rash, generally do not require treatment, rarely recur, and do not preclude administration of subsequent NAC doses.11,140,175,178 Even when urticaria, angioedema, and respiratory symptoms develop, they usually are easily treated, and NAC can be subsequently restarted with a very low incidence of recurrence.11,108,130,178Although proper dosing of IV NAC is very safe, it nevertheless must be considered less safe than PO NAC because of the possibility of severe anaphylactoid reactions, the risk of dosing errors,56,58,98 and the possibility of incomplete or delayed treatment because of anaphylactoid reactions.63,108 IV NAC is dosed using a complex three-bag preparation system (see Dosing and Administration below) that has led to an up to 33% error rate including 19% of patients having a greater than 1 hour interruption of NAC.56 Attempts at simplifying this system are described but have not been adequately studied for general use67,136 (Table A3–1).
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