Associate professor of medical sciences Department of Toxicology N-Acetylcysteine Dr Rokhsareh Meamar MD, Ph.D Associate professor of medical sciences Department of Toxicology

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 and possibly liver failure from chronic valproic acid use. Finally, NAC may be useful in the management of adults with fulminant hepatic failure caused by nontoxicologic etiologi. However, although a study using historic controls suggests that NAC improves survival in children with non–APAP-related acute liver failure

INTRODUCTION N-Acetylcysteine (NAC) was originally marketed in 1963 as Mucomyst® for inhalation use as a mucolytic due to its ability to break disulfide bonds in mucoprotein complexes in chronic bronchopulmonary disease Radical-scavenging properties of NAC has extended into the treatment of non-toxicology related critical illnesses, such as septic shock, coronary artery disease ,hepatic failure of any cause, respiratory distress syndrome, abdominal aortic aneurysm repair, necrotizing enterocolitis , and sickle cell disease.

BIOCHEMICAL TOXICITY  Metabolism of APAP occurs within the hepatic microsomes. At therapeutic doses, 90 percent of acetaminophen is metabolized in the liver to sulfate and glucuronide conjugates via sulfotransferase (SULT) and UDP-glucuronosyl transferases (UGT) . These conjugated metabolites are then excreted in the urine. Approximately 2 percent is excreted in the urine unchanged. The remaining acetaminophen is metabolized via oxidation by the hepatic cytochrome P450 (CYP2E1, CYP1A2, CYP3A4 subfamilies) mixed function oxidase pathway into a toxic, highly reactive, electrophilic intermediate, N-acetyl-p-benzoquinoneimine (NAPQI)

Mechanism of toxicity NAPQI arylates and binds covalently to the cysteine groups on hepatic macromolecules, particularly mitochondrial proteins, forming NAPQI-protein adducts. This process is irreversible. The formation of these adducts leads to oxidative hepatocyte injury, alteration of the mitochondrial ATP-synthase α-subunit, and hepatocellular centrilobular necrosis . Toxic free radicals (eg, peroxynitrite) form nitro-tyrosine adducts within the mitochondria .

PHARMACOLOGY 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. Alternatively, NAC may act as a glutathione substitute, providing thiol groups to bind N-acetyl-p-benzoquinoneimine, or encourage the reduction of this metabolite back to acetaminophen, thus sparing hepatocytes

Mechanism of Action 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

Pharmacokinetics Pharmacokinetics of Oral N-Acetylcysteine. Oral NAC is rapidly absorbed, but its bioavailability is low (10%–30%) because of significant first-pass metabolism .With such a large first-pass effect with a possible enhancement of portal circulation by direct delivery to the liver and the fact that the target organ of acetaminophen is the liver 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 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.

Specific Indications for IV NAC In addition to decisions based on cost, duration, safety, and ease of use, three situations exist for which the available information suggests IV NAC is preferable to PO NAC: (1) Fulminant hepatic failure (2) Inability to tolerate PO NAC (3) APAP poisoning in pregnancy (4)Intractable vomiting (5) Patients who refuse oral administration

Evaluation after acute overdose After a single acute overdose of an immediate-release preparation, a serum acetaminophen concentration should be drawn four hours after reported ingestion. If the ingestion was more than four hours prior to presentation, the serum acetaminophen concentration should be measured immediately. The concentration should be evaluated according to the modified Rumack-Matthew nomogram to determine the need for NAC therapy .Serum concentrations drawn before four hours may not represent peak values, and should not be used

ANTIDOTE: ACETYLCYSTEINE  N-acetylcysteine is the accepted antidote for acetaminophen poisoning and is given to all patients at significant risk for hepatotoxicity. Indications for N-acetylcysteine therapy include: Serum acetaminophen concentration drawn at four hours or more following acute ingestion of an immediate-release preparation is above the "treatment" line of the treatment nomogram for acetaminophen poisoning . A suspected single ingestion of greater than 150 mg/kg (7.5 g total dose regardless of weight) in a patient for whom the serum acetaminophen concentration will not be available until more than eight hours from the time of the ingestion. Patient with an unknown time of ingestion and a serum acetaminophen concentration >10 mg/L  (66 micromole/L) Patient with a history of APAP ingestion and ANY evidence of liver injury. Patients with delayed presentation (>24 hours after ingestion) consisting of laboratory evidence of liver injury (ranging from mildly elevated aminotransferases to fulminant hepatic failure) and a history of excessive acetaminophen ingestion.

Evaluation after repeated (chronic) overdose When the diagnosis of chronic acetaminophen intoxication is suspected, the goal of evaluation is to identify patients who need NAC treatment based upon a combination of historical, clinical, and laboratory data. Serum concentrations of acetaminophen in this setting do not correlate with toxicity and the treatment nomogram for acetaminophen poisoning should not be used. However, the presence of unmetabolized acetaminophen in patients with other findings suggestive of liver toxicity is a potential indication for NAC administration.

MANAGEMENT OF CHRONIC POISONING No hepatic injury and no unmetabolized acetaminophen – These children may be discharged home. Their caregivers should receive instruction to avoid acetaminophen for the remainder of the current illness No liver injury but with unmetabolized acetaminophen – Children without liver injury, but with unmetabolized acetaminophen, are at risk for hepatic injury because they have the potential to generate more toxic metabolite through the cytochrome oxidase system. These patients warrant monitoring of serum alanine aminotransferase, prothrombin time, and supportive care in the hospital. Consultation with a regional poison control center or medical toxicologist should be obtained for recommendations regarding antidotal therapy with N-acetylcysteine (NAC). Liver injury (with or without unmetabolized acetaminophen) – Children with a history of multiple supratherapeutic doses of acetaminophen that is associated with hepatic injury with or without unmetabolized acetaminophen should receive NAC and supportive care in the hospital. The optimal mode of delivery and the duration of NAC therapy in this setting have not been established in controlled trials . The end-point of therapy in this setting is either resolution of symptoms or liver transplantation .

We then stop acetylcysteine???  If the patient fulfills all three of the following conditions: Asymptomatic (eg, no right upper quadrant pain) Acetaminophen concentration is non-detectable The serum transaminase activity is decreasing significantly (has decreased to the normal range or to <50 percent of the peak value), If these conditions are not met, treatment should be continued until the conditions above are fulfilled (serum acetaminophen undetectable and serum transaminase is normal or <50 percent of peak value).

Drug Interactions There are no known significant interactions

Effectiveness   Serious hepatotoxicity is uncommon and death extremely rare if N-acetylcysteine is administered within eight hours following acetaminophen overdose

Simplified 20 hour IV protocol Administer an initial loading dose of 150 mg/kg IV over 15 to 60 minutes (we recommend 60 minutes). Next, administer a 4 hour infusion at 12.5 mg/kg per hour IV (ie, total of 50 mg/kg over 4 hours). Finally, administer a 16 hour infusion at 6.25 mg/kg per hour IV (ie, total of 100 mg/kg over 16 hours).

72 hour oral protocol  A loading dose of 140 mg/kg PO ; maximum dose: 15 g/dose followed A dose of 70 mg/kg PO every four hours for a total of 17 doses maximum dose: 7.5 g/dose; repeat dose if emesis occurs within 1 hour of administration The dose does not need to be adjusted if the patient has been treated with activated charcoal.

MUCOSOLVIN 200mg Tablet OSLYT 600 mg Tablet HINDONAC injection 200mg/ml, 25 ml EXI-NAC 2g/10mL FLUIMUCIL 600mg/Effervescent

NAC Solution for injection (Acetadote): Store intact vials at 20°C to 25°C (68°F to 77°F). Following reconstitution, solution is stable for 24 hours at room temperature. A color change may occur in opened vials (light pink or purple) and does not affect the safety or efficacy. Discard unused portion.

Pregnancy Implications  Adverse events have not been observed in animal reproduction studies. Based on limited reports using acetylcysteine to treat acetaminophen overdose in pregnant women, acetylcysteine has been shown to cross the placenta and may provide protective concentrations in the fetus.

Adverse Effects Nausea and vomiting may occur in up to 20% of patients treated with PO NAC compared to 7% with IV NAC. 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. Anaphylactoid reactions may be severe in approximately 1% of cases The main disadvantage of the NAC PO formulation is the high rate of vomiting and the concern that vomiting may delay therapy. Delays in administration of NAC are correlated with an increased risk of hepatotoxicity

Adverse reactions Anaphylaxis (Anaphylactic reaction) Patients who experience flushing without pruritus or urticaria do not require intervention and the infusion can be continued, unless more severe signs develop. Patients who develop urticaria should have the infusion stopped and be treated with intramuscular epinephrine, diphenhydramine, and glucocorticoid medication . The infusion can be restarted at the prior rate once the urticaria resolves. Patients with angioedema or respiratory symptoms should have the infusion stopped and be treated with epinephrine, diphenhydramine, glucocorticoid medication and if wheezing, albuterol . In patients for whom signs and symptoms resolve, the infusion may be started at the prior rate one hour after the administration of epinephrine. Patients who develop hypotension or other persistent systemic anaphylaxis symptoms after IV acetylcysteine therapy should have the infusion stopped and receive treatment for anaphylaxis . IV NAC should not be restarted. Oral NAC therapy should be provided as an alternative. These patients will generally tolerate oral acetylcysteine. If the patient cannot be treated with oral acetylcysteine, the clinician should consult a medical toxicologist or poison control center for guidance.