N Acetylcysteine
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N-acetylcysteine (NAC) is an antidote and mucolytic agent with FDA approval for acetaminophen overdose and adjunctive mucolytic therapy. It works by increasing glutathione stores to prevent liver toxicity from acetaminophen or by lowering mucus viscosity. NAC is available as an intravenous or inhaled solution and oral capsules. The intravenous route is preferred for severe overdose or inability to take oral medications. Common side effects include nausea and vomiting. While its efficacy for other off-label uses like contrast-induced nephrotoxicity prevention is unclear, it is generally well-tolerated with minimal drug interactions.
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N Acetylcysteine
- 1. N-acetylcysteine (NAC)Trennette R. GilbertUniversity of Southern NevadaCollege of Pharmacy
- 2. Description N-acetyl derivative of L-cysteine Pharmacologic category Antidote Mucolytic 2
- 3. Indications 3 FDA labeled indications Acetaminophen (APAP) overdose Adjunctive mucolytic therapy Diagnostic bronchial studies Off-label use Prevention of contrast-induced nephrotoxicity (CIN) Helicobacter pylori infection
- 4. Pathophysiology of APAP Overdose 4 APAP primarily metabolized via glucoronidation or sulphation Secondary metabolism by CYP 450 system In OD, primary route saturated -> CYP 450 system -> NAPQI production NAPQI converted to non-toxic form by glutathione In OD, glutathione stores consumed -> excess NAPQI -> covalent binding to hepatocytes
- 5. Mechanisms of Action 5 APAP overdose NAC -> cysteine-> glutathione (GSH) Prevention of CIN Possibly minimizes vasoconstriction and oxidative stress Mucolysis Lowers mucus viscosity Free sulfhydryl group opens disulfide bonds in mucoproteins H. pylori infection May increase delivery of medications by ↓ mucus viscosity
- 6. Dosage Forms 6 Injection solution (Rx) Acetadote 20% (30 ml) Inhalation solution (Rx) Mucomyst, generic 10%, 20% (4 ml, 10 ml, 30 ml) Capsules (OTC) Generic 600 mg (60, 120) Extemporaneous compounding Inhalation solution may be used as IV Inhalation solution may also be mixed w/soda to yield 5% oral solution
- 7. IV vs. PO 7 Both routes are effective, differences minimal IV route preferred if: Vomiting Contraindication to oral administration of medication Hepatic failure Refuses oral administration Pricing: Acetadote = $145.77/vial (30 ml) NAC 10%, 20% inhalation solution = $1.32/vial (4 ml)
- 8. Contraindications 8 Hypersensitivity to acetylcysteine
- 9. Warnings/Precautions 9 Inhaled form may cause increased bronchial secretions, bronchospasm Emesis Oral form may aggravate vomiting Encephalopathy If present, consider discontinuing administration of NAC Odor Has slight disagreeable odor
- 10. Adverse Reactions Inhalation Drowsiness Chills/fever N/V Bronchospasm Rhinorrhea Unpleasant odor IV Anaphylactoid reactions N/V 10
- 11. Drug Interactions 11 No significant interactions Adsorbed by activated charcoal
- 12. Pharmacokinetics 12 Absorption Bioavailability of oral form is low Distribution Vdss = 0.47 L/kg Plasma protein binding = 83% Metabolism Deacetylated in the liver to cysteine Elimination T1/2 = (Adults) 5.5 hours, (Newborns) 11 hours Primarily non-renal (70%), renal (30%)
- 13. Pharmacokinetics - Special Populations 13 Pregnant women In limited reports, shown to cross placenta Pregnancy risk category: B Hepatic dysfunction May influence pharmacokinetics T1/2 shown to increase by 80% Renal clearance decreased by 30%
- 14. Dosing 14 APAP toxicity Children and adults (> 40 kg) Loading dose should be given Oral: 140 mg/kg IV: 150 mg/kg infused over 60 minutes Maintenance doses Oral: 70 mg/kg q 4 hours x 17 doses IV: 50 mg/kg infused over 4 hours, then 100 mg/kg infused over 16 hours (Total 300 mg/kg infused over 21 hours) Patients < 40 kg Fluid volume should be reduced Weight-based dilution
- 15. Dosing cont… Respiratory conditions Diagnostic bronchial studies 1 – 2 ml of 20% or 2 – 4 ml of 10% 2 – 3 times prior to procedure Prevention of CIN 600 – 1200 mg PO BID x 2 days (begin day before procedure) 15
- 16. Stability 16 IV solution Stable for 24 hours after dilution w/D5W Inhalation solution Vials must be refrigerated after opening Must be used w/in 96 hours Opened vials may change color Does not affect safety or efficacy
- 17. Monitoring Parameters 17 Anaphylaxis APAP overdose APAP levels q 4 – 6 hours LFTs Scr, BUN PT, INR
- 18. Therapeutic Efficacy 18 APAP overdose No trials to evaluate efficacy Low incidence of hepatotoxicity when given early Mucolysis Studies suggest small benefit Prevention of CIN Conflicting results in available data There is a trend towards benefit
- 19. References 19 Acetadote [package insert]. Nashville, TN:Cumberland Pharmaceuticals, Inc.; February 2006. Gurbuz AK, Ozel AM, Ozturk R, Yildirim S, Yazgan Y, Demirturk L. Effect of N-acetyl cysteine on Helicobacter pylori. South Med J. 2005;98:1095-1097 Lacy, CF, Armstrong, LL, Goldman, MP, Lance, LL. Drug information handbook.17th ed. Hudson: Lexi-Comp, Inc.; c2008. Acetylcysteine; p. 32-4. N-Acetylcysteine, a Novel Treatment for Helicobacter pylori Infection. Dig Dis Sci. 2004 Nov-Dec;49(11-12):1853-61. Pombrio JM, Giangreco A, Li L, Wempe MF, Anders MW, Sweet DH, Pritchard JB, Ballatori N. Mercapturic acids (N-acetylcysteine S-conjugates) as endogenous substrates for the renal organic anion transporter-1. Mol Pharmacol. 2001 Nov;60(5):1091-9. Up to date online. Prevention of contrast-induced nephropathy. Rudnick, MR, Tumlin, JA. 2009 Sep. Dribben WH, Porto SM, Jeffords BK. Stability and microbiology of inhalant N-acetylcysteine used as an intravenous solution for the treatment of acetaminophen poisoning. Ann Emerg Med. 2003 Jul;42(1):9-13
Notes de l'éditeur
- NAC is a derivative of the amino acid cysteine.It is classified as a mucolytic and an antidote.
- It is FDA approved as an antidote for APAP overdose, as adjunctive therapy for respiratory conditions, and as a mucolytic for diagnostic bronchial studies.The off-label uses are for the prevention of contrast-induced nephropathy and asAn adjunct in the treatment of H. pylori infections
- Before I go over the mechanism of action, I thought I should explain the reason why NAC is useful as an antidote.APAP has 2 routes of metabolism, the primary route is through glucoronidation or sulphation which would make APAP more water soluble so that it may then be excreted in the urine. The secondary route involves the CYP 450 system which converts APAP to a highly reactive oxide called NAPQI. From there, NAPQI is quickly converted to mercapturic acid by glutathione and is excreted in the urine. However, in an overdose situation, the amount of APAP is high enough to overwhelm the primary route and its metabolism is shunted to the CYP system which increases the production of NAPQI, however because of the sharp increase, our glutathione stores also become overwhelmed and the end result is excess NAPQI that may covalently bind to hepatocytes and cause hepatic necrosis.
- It is useful in an overdose because essentially what we are doing when we administer NAC is giving exogenous glutathione. In our cells, NAC is converted to cysteine which is a precursor of glutathione.The exact mechanism of how NAC prevents CIN has not been fully elucidated, however the theory is that it minimizes vasoconstriction and oxidative stress.In addition to antioxidant benefits, It may also be used as a mucolytic.NAC contains a free sulfhydryl group that may open disulfide bonds in mucoproteins. Disulfide bonds increase the rigidity of proteins and support its secondary structure. Therefore, by breaking the structure of the protein, the mucus becomes less “bulky” or viscous. And for this same reason it has been thought to be beneficial in the treatment H. pylori infection because it may increase delivery of medications to the gut by decreasing mucus viscosity, however there is not a lot of strong evidence to support this.
- The only available injectable form of NAC is Acetadote 20% which is not generically available.The inhalation solution is available generically and as brand Mucomyst in concentrations of 10% and 20%.There are also capsules available over the counter, however these are considered dietary supplements and are not regulated by the FDA. If Acetadote is not available, the inhalation solution may be used intravenously however, each dose must be infused through a filter and the dosing is different. To make NAC more palatable, it may be mixed with juice or soda and taken orally.
- Both routes are effective in the treatment of APAP overdose, however, if the patient is vomiting, has a condition that makes giving oral medications not feasible, has hepatic failure, or refuses oral meds, then IV is the preferred route.Some of the benefits of oral therapy include:Minimal anaphylactoid reactionsThe oral form undergoes the first pass effect which allows it to achieve high concentrations in the liverMay be an alternative for patients with previous anaphylactoid reactions to IV formLess dosing errors Less expensive than IV formSome benefits of IV therapy include:Less N/VMay result in shorter hospital stay More stable than oral form. Once compounded, the oral form is only stable for 1 hour.Cost is another aspect we should consider when determining which route is best. 1 vial of acetadote is 145.77 and 1 vial of the inhalation is 1.32.
- The only contraindication for the use of NAC is hypersensitivity to it or any component of the formulation.
- When NAC is inhaled, it may cause bronchospasm which may be mitigated by giving a bronchodilator such as albuterol or ipratropium 10 – 15 minutes prior to administration.The oral form may cause nausea and vomiting and so giving to someone who is actively vomiting may not be the best thing to do. Hepatic failure may result in encephalopathy which can be exacerbated by NAC because it is nitrogenous substance and may lead to uremic encephalopathy. There have been no reports of this, the risk is theoretical but should still be considered. The oral formulation has a slight disagreeable odor that may affect palatability and may cause patients to refuse it. We use the Rumack-Matthew nomogram to predict the liklihood of a patient developing hepatotoxicity after an acute APAP overdose. This nomogram does not apply to all situations. If the time of ingestion is unknown, or the patient has been chronically overdosing, the nomogram does not apply. The nomogram may be used in cases of extended-release APAP overdose, however, multiple levels should be obtained and then plotted on the nomogram.Treatment with NAC is most effective when administered within 8 hours of ingestion. If APAP levels are not available or if ingestion time is unknown, NAC should be given immediately, however after 8 hours post-ingestion treatment efficacy declines.
- The most important adverse reactions to the inhalation are bronchospasm and n/v. Asthmatic patients are at higher risk of developingbronchospasm. Approximately 10 – 20 % of patients receiving NAC will have an anaphylactoid reaction to the IV form and patients with asthma are at a higher risk. These reactions are most commonly seen w/in 30 – 60 minutes of starting the infusion.If the reaction is just flushing, the infusion should continue, however if other symptoms are present such as rash, hypotension, or shortness of breath, the NAC infusion may be interrupted until the symptoms are adequately treated. [If they return or progress, stop NAC and consider calling the poison control center’s APAP over dose line for health care providers 1-800-525-6115]Treatment of anaphylactoid reactions:Diphenhydramine 1mg/kg IV up to 50 mgCimetidine 5 mg/kg up to 300 mg Oral ephedrine 0.5 mg/kg up to 25 mg
- There are no significant drug interactions, however NAC is adsorbed to activated charcoal.
- NAC is a protein so it’s oral bioavailability is low due to catabolism in the gut.The volume of distribution at steady state is 0.47 L/kg and it is approximately 83% protein bound in plasma.NAC is metabolized to other substances such as cysteine and other conjugates.Elimination of total acetylcysteine is primarily through extrarenal sources, however 30% of it’s elimination is though the kidneys. The elimination half-live is about 5.5 hours in adults and 11 hours in newborns. **Elimination is 3% fecal**
- IN pregnant women, NAC has been shown to cross the placenta.And The pharmacokinetics of NAC are different in patients with hepatic dysfunction. The half-life is increases by 80% and the renal clearance decreases by 30%. Although we know this, there are no data to support a dosage adjustment in these patients or patients with renal dysfunction.
- The dosing of NAC can be somewhat complicated which may lend itself to dosing errors.Patients that weigh more than 40 kg should receive a loading of 140 mg/kg by mouth or 150 mg/kg IV [in 200 ml D5W] infused over 60 minutes. The oral maintenance dose is 70 mg/kg for 17 additional doses. The IV maintenance dose is 50 mg/kg [in 500 ml D5W] infused over 4 hours, then 100 mg/kg [in 1 L D5W] infused over 16 hours for a total of 300 mg/kg infused over 21 hours)Patients that weigh less than 40 kg should receive the same dose of NAC, however the volume of D5W used to dilute the drug is less to avoid fluid overload which may lead to hyponatremia, seizure, and death.
- The dosing for respiratory conditions is straight forward, for infants, the dose is 200 – 400 mg inhaled via nebulizer 3 – 4 times a day.For children and adults, the dose is 600 mg – 1 g inhaled via nebulizer 3 – 4 times a day. Either the 10% or 20% solution may be used, however, you must note the difference in volume needed.For diagnostic pulmonary procedures the dose is 200 – 400 mg (using either the 10% or 20% solution) inhaled via nebulizer 2 – 3 time before the procedure.To prevent CIN, the inhalation solution may be given by mouth mixed in soda or juice twice a day for 2 days beginning the day before the procedure.**When mixed w/juice or soda, final concentration must be 5%**
- Once the IV solution has been diluted, it is only stable for 24 hours. The inhalation solution is stable for 96 hours once the vial has been opened as long as it is kept in the refrigerator.When NAC is exposed to air, the solution may change to a light purple color. This has no effect on its stability or efficacy and should not be cause for alarm. The recommended diluent is D5W, however, NS, ½ NS, or SWFI may also be used.
- While patients are on NAC, we should monitor them for signs and symptoms of anaphylaxis.Specifically for patients with APAP overdose, we should monitor their APAP levels and renal and liver function tests as well as their INR.
- There have been no placebo-controlled trials conducted to evaluate the efficacy of NAC in APAP overdose because that would be unethical but, the trials that have been conducted show that there is a low incidence of hepatotoxicity when it is given early.Trials to evaluate NAC effectiveness as a mucolytic demonstrate that NAC does provide small benefit in the treatment of respiratory conditions such as COPD.While NAC is used to prevent CIN, there are conflicting results in numerous trials. In the largest meta-analysis conducted, NAC was shown to significantly lower the risk of renal dysfunction.