Details About Overdose or Poisoning Generic Salt :: Acetylcysteine N Acetylcysteine, NAC
Acetylcysteine (N-Acetylcysteine [NAC])
Drug Pharmacology ::
I. Pharmacology. Acetylcysteine (N-acetylcysteine[NAC]) is a mucolytic agent that acts as a sulfhydryl group donor,substituting for the liver’s usual sulfhydryl donor, glutathione. Itrapidly binds (detoxifies) the highly reactive electrophilicintermediates of metabolism or it may enhance the reduction of thetoxic intermediate, NAPQI, to the parent, acetaminophen. It is mosteffective in preventing acetaminophen-induced liver injury when givenearly in the course of intoxication (within 8 to 10 hours), but mayalso be of benefit in reducing the severity of liver injury by severalproposed mechanisms (improved blood flow and oxygen delivery, modifiedcytokine production, free radical or oxygen scavenging) even when givenafter 24 hours. This proposed role of NAC as a glutathione precursor,direct sulfhydryl binding agent, and antioxidant has also been thebasis for its investigational use for poisonings from agents associatedwith a free radical or oxidative stress mechanism of toxicity or thatbind to sulfhydryl groups. It may be used empirically when the severityof ingestion is unknown or serum concentrations of the ingested drugare not immediately available.
Drug Indications ::
Indications
Acetaminophen overdose.
Casereports of or investigational use in carbon tetrachloride, chloroform,acrylonitrile, doxorubicin, arsenic, gold, amanitin mushroom, carbonmonoxide, chromium, cyanide, paraquat, and methyl mercury poisoning.
Pennyroyaloil and clove oil poisoning (case reports). The mechanism of hepaticinjury by pennyroyal oil and clove oil are similar to that ofacetaminophen, and empiric use of NAC seems justified for anysignificant pennyroyal oil or clove oil ingestion.
Cisplatin nephrotoxicity and prevention of radiocontrast-induced nephropathy.
Drug Contra-Indications ::
III. Contraindications. Knownacute hypersensitivity or IgE-mediated anaphylaxis (rare).Anaphylactoid reactions, while similar in clinical effects, may beprevented or ameliorated as discussed below.
Drug Adverse Effects ::
IV. Adverse effects
Acetylcysteine typically causes nausea and vomiting when given orally. Ifthe dose is vomited, it should be repeated. The dose calculation andproper dilution (to 5%) should be verified (this effect may be dose andconcentration dependent). Use of a gastric tube, slower rate ofadministration, and a strong antiemetic agent (eg, metoclopramide,Metoclopramide; ondansetron, Ondansetron) may be necessary.
Rapid intravenousadministration can cause flushing, rash, angioedema, hypotension, andbronchospasm (anaphylactoid reaction). Death (status epilepticus,intracranial hypertension) was reported in a 30-month-old childaccidentally receiving a massive dose intravenously (2,450 mg/kg over 6hours, 45 minutes), and fatal bronchospasm occurred in an adult withsevere asthma. Reactions might be reduced by giving each dose slowly(over at least 60 minutes) in a dilute (3–4%) solution (this effect isdose and concentration dependent) and exercising extreme caution inasthmatics (avoid IV use or carefully titrate with more dilutesolutions and slower infusion rates). If an anaphylactoid reactionoccurs, stop the infusion immediately and treat with diphenhydramine(see Diphenhydramine) if urticaria and or angioedema is present, andepinephrine (see Epinephrine) for more serious reactions (shock,bronchoconstriction). Once symptoms have resolved, the infusion may berecommenced at a slower infusion rate (by further dilution and givenover at least 1 hour). Note: dilutional hyponatremia and seizuresdeveloped in a 3-year-old after IV administration from excess freewater (see pediatric dilution precautions below).
Use in pregnancy. FDAcategory B. (See Table III–1) There is no evidence for teratogenicity.Use of this drug to treat acetaminophen overdose is consideredbeneficial to both mother and developing fetus. However, maternalhypotension or hypoxia due to a serious anaphylactoid reaction from IVadministration may harm the fetus.
Drug Lab Interactions ::
Drug or laboratory interactions
Activatedcharcoal adsorbs acetylcysteine and may interfere with its systemicabsorption. When both are given orally together, data suggest that peakacetylcysteine levels are decreased by about 30% and that the time toreach peak level may be delayed. However, these effects are notconsidered clinically important.
NAC can produce a false-positive test for ketones in the urine.
Drug Dose Management ::
Dosage and method of administration
Oral loading dose. Give140 mg/kg of the 10% (1.4 ml/kg) or 20% (0.7 ml/kg) solution diluted toapproximately 5% in juice or soda to enhance palatability: dilute theloading dose of 10% NAC with 1.4 mL/kg of juice or soda (for 20% NACdilute with 2 mL/kg of juice/soda). (See Table III–2 for oral dilutionguidelines)
Maintenance oral dose. Give70 mg/kg (as a 5% solution) every 4 hours. To make an approximately 5%solution, dilute the maintenance dose of 10% NAC (0.7 mL/kg) with 0.7mL/kg of juice or soda (for 20% NAC dilute 0.35 mL/kg with 1 mL/kg ofjuice/soda). (See Table III–2 for oral dilution guidelines). Theconventional protocol for treatment of acetaminophen poisoning in theUnited States calls for 17 doses of oral NAC given over approximately72 hours. However, successful shorter protocols in Canada and Europeutilize intravenous NAC for only 20 hours for uncomplicated poisoningswithout evidence of liver injury treated within 8 hours of ingestion.We use a shorter oral NAC regimen consisting of the usual loading dosefollowed by 70 mg/kg every 4 hours for five doses (20 hours). If thereis evidence of hepatic toxicity, NAC should be continued untilresolution of toxic effects (ie, liver function tests are clearlyimproving).
An intravenous preparation(Acetadote, Cumberland Pharmaceuticals) was approved in 2004 by theU.S. FDA and is indicated if the patient is unable to tolerate the oralformulation because of vomiting, ileus, intestinal obstruction, orother GI problems.
1.The package insert recommends the following 20 hour regimen foruncomplicated poisonings treated within 8 hours (in adults): 150 mg/kgin 200 mL of 5% dextrose in water (D5W) over 15 minutes, followed by 50 mg/kg in 500 mL of D5W over 4 hours and then 100 mg/kg in 1000 mL of D5Wover 16 hours. However, anaphylactoid reactions have been reported(including death in an obese asthma patient, whose dose was based ontotal body weight rather than ideal body weight) and we usuallyrecommend that the loading dose be given over at least 45–60 minutes.(see Table III–3 for IV Acetadote administration guidelines andprecautions)
2. Pediatricpatients should have an alternate dilution volume or use of asaline-containing solution to avoid over-hydration and hyponatremia(see Table III–3 for IV Acetadote administration guidelines andprecautions).
3. Many patients can be switched to an oral regimen after the first 1–2 IV doses, if vomiting has ceased.
4. If Acetadote is not available, then the oral preparation may be administered by the IV route (using an inline micropore filter).
Contact a medical toxicologist or regional poison center ([800]222-1222) for advice and see the formulations section below forpreparation and administration.
Dosage during dialysis. Although acetylcysteine is removed during dialysis, no change in dosage is necessary.
E. Dosage for prevention of radiocontrast-induced nephropathy.Give 600 mg of PO NAC twice on the day before and the day of theprocedure (4 doses total). This is coupled with IV hydration using 1/2NS at 1 mL/kg/h for 12 hours before and after the administration of thecontrast agent.
Drug Chemical Formulations ::
Formulations
OralThe usual formulation is as a 10% (100-mg/mL) or 20% (200-mg/mL)solution, supplied as an inhaled mucolytic agent (Mucomyst, orgeneric). This form is available through most hospital pharmacies orrespiratory therapy departments. This preparation is notFDA approved for parenteral use. In rare circumstances when intravenousadministration of this preparation is required and Acetadote is notavailable, dilute the loading dose to a 3–4% solution (In D5W),use a micropore (0.22-micron) filter, and administer over 45–60minutes. To make a 4% solution, dilute the loading dose of 10% NAC (1.4mL/kg = 140 mg/kg) with 2.1 mL/kg of D5W (for 20% NAC dilute 0.7 mL/kg with 2.8 mL/kg of D5W).
Thenew intravenous formulation (Acetadote) is available as a 20% solutionin 30 mL (200 mg/mL) vials in a carton of 4 vials. Note: specialprecautions are needed to avoid accidental overdose or over-dilutionwith D5W in pediatric patients (see Table III–3 for IV Acetadote administration guidelines and precautions).
Suggested minimum stocking levelfor treatment of a 70-kg adult for the first 24 hours: 20% (oral)solution, 7 vials (30 mL each) and or 20% (IV) solution, 1 carton of 4vials (30 ml each). We suggest that both preparations be stocked andthat the oral solution be used preferentially in most cases.
Table III–2. Dilution Guidelines for Oral Administration of NAC
Volume of NACApproximate volume of soda/juice needed to make 5% solutionLoading Dose (140 mg/kg) Using 20% NAC (200 mg/ml) solution0.7 mL/kg2 mL/kgUsing 10% NAC (100 mg/ml) solution1.4 mL/kg1.4 mL/kgMaintenance dose (70 mg/kg) Using 20% NAC (200 mg/ml) solution0.35 mL/kg1 mL/kgUsing 10% NAC (100 mg/ml) solution0.7 mL/kg0.7 mL/kg
Table III–3. Dilution Guidelines for Intravenous Administration of Acetadote
Dose of Acetadote (20% = 200 mg/mL solution) Volume of diluent (D5W)b needed.
Duration of infusionLoading Dose (150 mg/kg) 0.75 mL/kga
3 mL/kg (pediatrics) up to 200 mL (adults) Recommend over at least 45–60 minutes to reduce risk of anaphylactoid reactions.First Maintenance dose (50 mg/kg) 0.25 mL/kg 1 mL/kg (pediatrics) up to 500 ml (adults) Over 4 hours.Second Maintenance dose (100 mg/kg) 0.5 mL/kg 2 mL/kg (pediatrics) up to 1000 ml (adults) Over 16 hours.
aWe suggest use of ideal body weight for loading dose calculation in patients with morbid obesity (BMI > 40).
bManufacturer indicates that NAC is also stable in 0.45% NS @ room temperature for 24 hours.