N-Acetylcysteine (NAC) Jack Of All Trades, Master of None

Transcription

1 N-Acetylcysteine (NAC) Jack Of All Trades, Master of None Vineya Rai Consultant Intensivist Department of Anesthesia

2 NAC Structure Chemical formula : C 5 H 9 NO 3 S Molecular weight : g/mol Only L-NAC is active; L-NAC is metabolized to cysteine and not D- NAC. NAC is a derivative of the amino acid cysteine.

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4 NAC as an Antioxidant Reduces extracellular cystine cysteine which can be transported into the cell 10x faster than cystine and is a precursor in the biosynthesis of glutathione (GSH). The resulting free amino acid cysteine has a highly reactive sulfhydryl group. NAC replenishes hepatic glutathione stores conferring antioxidant activity (indirectly)

5 GSH has an important role in maintaining the redox state of the cell 1 It thereby exerts a profound protective effect on cells. Of the three amino acids in the GSH structure (glutamate, glycine, and cysteine), cysteine has the lowest intracellular concentration 2. Cysteine availability can limit the rate of GSH synthesis during times of oxidative stress. Kerksick C, Willoughby D. The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. J. Int. Soc. Sports Nutr. 2005;2: Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radical Biol. Med. 1989;6:

6 NAC can act directly ( as an antioxidant ) on reactive radicals. It is a powerful scavenger of Hypochlorous acid (HOCl) and is capable of reducing HO and H 2 O 2. Moldeus P & Cotgreave IA. Meth. Enzymol. 234: , 1994

7 NAC with Anti- Inflammation Inhibits neutrophil aggregation, suppression of macrophage activation, inhibition of leukocyte-endothelial cell adhesion and attenuation of the release of TNFα, IL-1β and IL-6. Inhibition of nuclear factor kappa B

8 NAC as Mucolytic Splitting of disulfide linkages between the glycopeptides in mucus and loosening of obstructive plugs.

9 Possible Clinical Uses paracetamol poisoning Drug induced liver injury (non PCM) Liver transplant Ischemia-Reperfusion Injury sepsis ARDS COPD Cystic Fibrosis acute myocardial infarction use in ameliorating nitrate tolerance. reducing the risks of radiographic contrast nephropathy enhance T cell function in HIV infected treatment of carbon monoxide poisoning Inhibit cigarette smoking Obstetrics (habitual abortion, gestational diabetes, pre-eclampsia ) Polycystic Ovarian Disease Influenza

10 NAC use in Acetaminophen poisoning After several early NAC trials showed promising results, subsequent human investigations have consisted mostly of observational studies due to ethical concerns of withholding a potential lifesaving treatment. There are no randomized controlled trials that evaluate NAC therapy for prevention of acetaminophen-induced hepatotoxicity

11 Pathophysiology of Acetaminophen Overdose Acetaminophen 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 11

12 Acetaminophen Sulfation Glucuronidation 5% 20-45% 40-65% Oxidation Remaining 5-15% Cyt P450 NAPQI Acetaminophen mercaptate compound Glutathione NORMAL METABOLISM

13 Acetaminophen Sulfation Glucuronidation SATURATED 5% SATURATED 20-45% SATURATED 40-65% Oxidation Remaining >>> % Cyt P450 NAPQI Acetaminophen - mercaptatecomp ound Glutathione METABOLISM IN OVERDOSE

14 Management of Acetaminophen Overdose Rumack-Matthews toxicity nomogram which plots serum concentration of acetaminophen against the time since ingestion in an attempt to prognosticate possible liver toxicity as well as allowing a clinician to decide whether to proceed with NAC treatment. 150 mcg/ml at 4 hours is possibly toxic

15 Rumack and Matthew Nomogram mg/l at 4 h, 100 mg/l at 8 h, 50 mg/l at 12 h, 30 mg/l at 15 h. Late Not valid after 24 hours 10 5 mcg/ml Hours After Acetaminophen Ingestion

16 An important factor in assessing the efficacy of NAC is the timing of therapy initiation in relation to the ingestion. Patients that ingest an acute overdose and have NAC therapy initiated within 8 hours do well and have less than a 10% incidence of hepatotoxicity and generally do not develop liver failure or die.

17 Route of administration 1. Oral preferred route for NAC therapy unless contraindications exist (e.g. aspiration, persistent vomiting). Dosage: 72 hour protocol Loading dose is 140 mg/kg Maintenance doses: 70 mg/kg Given every 4 hours x 17 doses starting 4 hours after loading dose Smilkstein MJ et al. N Engl J Med 319: , 1988.

18 Route of administration 2. IV Intravenous acetylcysteine 20 hour protocol (total dose 300 mg/kg) Loading dose is 150 mg/kg over 15 to 60 minutes Maintenance dose: 50 mg/kg infusion over four hours; the last 100 mg/kg are infused over the remaining 16 hours of the protocol

19 NAC in Drug induced liver injury (DILI ) DILI refers to acute or chronic liver injury that may occur as a consequence of using drugs and herbal, viral hepatitis or dietary supplements. DILI does not involve glutathione depletion.

20 The proposed pathogenic mechanisms in idiosyncratic DILI include direct cell injury, immune mediated damage and mitochondrial injury. Mitochondria are involved in protecting hepatocytes against oxidative stress from oxygen-free radicals in the liver. The damage and loss of mitochondria leads to an accumulation of oxygen-free radicals and subsequent oxidative cell damage. NAC maybe of benefit in this context through its antioxidant effect 1 Additional benefits of NAC involve the improvement of systemic haemodynamic and tissue oxygen delivery, as well as other favourable effects on the injured liver 2. 1Harrison PM, Keays R, Bray GP, Alexander GJM, Williams R. Improvedoutcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Lancet. 1990;335: Harrison P, Wendon J, Williams R. Evidence of increased guanylate cyclase activation by acetylcysteine in fulminant hepatic failure. Hepatology. 1996;23:

21 NAC in non NAI- ALF Prospective, randomized, double-blind, placebocontrolled trial of NAC for adult NAI-ALF patients, which was conducted at 24 participating sites in the United states for eight years from 1998 to 2006.

22 Methods randomly assigned to groups that were given NAC or placebo (dextrose) infusion for 72 hours. A total of 173 patients received NAC (n=81) or placebo (n=92) The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation.

23 Results There was no difference in the overall survival at three weeks between NAC (70%) vs placebo groups (66%) (P = 0.238). Transplant-free survival was significantly better in NAC patients with coma grades I II who received NAC compared with placebo (52% vs 30%, P = 0.010). However, no difference was found in coma grades III IV (P = 0.912)

24 A total of 47 adult patients were prospectively enrolled with NAI-ALF and oral NAC was given. Compared these results with records of NAI-ALF patients admitted from 2000 to 2003 (n = 44) who were not given NAC ( historical controls). The primary outcome was reduction in mortality with the use of NAC in NAI-ALF. The secondary outcomes were to evaluate safety of NAC and to assess factors predicting mortality

25 Results A total of 34 (37.36%) patients survived; 22 (47%) in NAC group and 12 (27%) in control group. (P = 0.05). Limitations The main shortcoming of the study was its design, that is, prospective study with historical control, which is intrinsically flawed in that the groups being compared are not treated at same time in point.

26 Comparing efficacy and safety between NAC and control in the treatment of NAI-ALF. Identified by searching Pubmed ( ) and EMBASE ( ) using the search terms acetylcysteine or NAC and NAI-ALF. Primary outcome was overall survival. Secondary outcomes included liver transplantation-free survival, post transplantation survival, length of ICU and hospital stays, and the relationship with coma grade. Safety profiles were also analyzed.

27 4 clinical trials were selected for meta-analysis. 331 patients received NAC (oral or intravenously) and 285 patients in control group were included for meta-analysis. No statistical difference between NAC group and control group for overall survival [236/331 (71%) vs 191/285 (67%); 95% CI 1.16 ( ); P = 0.42]. Significant differences between NAC group and control group regarding the survival with native liver [112/273 (41%) vs 68/226 (30%); 95% CI 1.61 ( ); P = 0.01] and post-transplantation survival [78/91 (85.7%) vs 50/70 (71.4%); 95% CI 2.44 ( ); P = 0.03].

28 Conclusion NAC is safe for NAI-ALF. It can prolong patients survival with native liver without transplantation and survival after transplantation, but it cannot improve the overall survival. Additional studies are needed to determine the optimal dose and duration of NAC therapy, predictors of response, and the physiologic basis for these improved outcomes

29 NAC in Prevention of Contrast Induced Nephropathy ( CIN ) Pathophysiology of CIN remains incompletely understood. It is hypothesized that renal vasoconstriction leading to renal medullary ischemia and direct toxicity to the kidney tubules mediated via reactive oxygen species may cause CIN Parfrey P (2005) The clinical epidemiology of contrast-induced nephropathy. Cardiovasc Intervent Radiol28 Suppl 2S3 11

30 NAC in Prevention of Contrast Induced Nephropathy ( CIN ) NAC is a direct scavenger of free radicals, improves blood flow through: nitric oxide mediated pathways vasodilation Precursor for the synthesis of glutathione The antioxidant and vasodilatory properties of NAC are thought to provide protection against CIN.

31 NAC in Prevention of Contrast Induced Nephropathy ( CIN ) The first study showed a benefit of NAC in the prevention of CIN published in Since then, more than 40 studies have been performed, including approximately 15 metaanalyses

32 2308 patients undergoing an intravascular angiographic procedure with at least 1 risk factor for contrast-induced acute kidney injury (age >70 years, renal failure, diabetes mellitus, heart failure, or hypotension) to acetylcysteine 1200 mg or placebo. The study drugs were administered orally twice daily for 2 doses before and 2 doses after the procedure. Circulation Sep 13;124(11):1250-9

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34 Results The incidence of contrast-induced acute kidney injury (primary end point) was 12.7% in the acetylcysteine group and 12.7% in the control group (relative risk, 1.00; 95% confidence interval, 0.81 to 1.25; P=0.97). A combined end point of mortality or need for dialysis at 30 days was also similar in both groups (2.2% and 2.3%, respectively; hazard ratio, 0.97; 95% confidence interval, 0.56 to 1.69; P=0.92).

35 Conclusion This large randomized trial, acetylcysteine did not reduce the incidence of contrastinduced acute kidney injury. Acetylcysteine also did not show statistically significant beneficial effects on other end points such as all-cause mortality and need for dialysis at 30 days.

36 NAC in ARDS The antioxidant defence is at least partly depleted in ARDS, as illustrated by a rapid fall in intracellular glutathione. Depletion of antioxidants increases the lung's vulnerability to oxidative injury, and restoration of antioxidant defences therefore is an attractive strategy. NAC is capable of repleting glutathione Bernard, GR, Wheeler, AP, Arons, MM, et al. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group. Chest 1997; 112:164. 1

37 Prospective, randomized, double blind, placebocontrolled trial compared procysteine to NAC and placebo in 46 patients. Both procysteine and NAC effectively restored glutathione stores and appeared to decrease the duration of lung injury. Survival was not enhanced, although the size of this study was too small to rule out a benefit. Such treatment may shorten the duration of acute lung injury, but larger studies are needed to confirm this.

38 One double blind, randomized, placebocontrolled trial of 66 ARDS patients compared NAC to placebo and found no improvement in oxygenation or survival

39 NAC in COPD The imbalance of oxidant/antioxidant agents (redox balance) plays an important role in COPD pathogenesis. Inhaled cigarette smoke, the main exogenous source of oxidative stress in COPD, stimulates elastase activity and induces apoptosis, resulting in lung damage and emphysema. It also induces inflammation.

40 Proposed mechanism of action of NAC in COPD Oral NAC is a mucolytic agent with direct/indirect antioxidant and anti-inflammatory properties that may be beneficial in COPD. NAC acts directly as a reactive oxygen species scavenger and acts as a precursor of reduced glutathione (GSH).

41 Proposed mechanism of action of NAC in COPD NAC restores cellular redox status and modulates the inflammatory pathway in COPD by inhibiting redox sensitive cell-signal transduction and pro inflammatory gene expression. As a mucolytic drug, it may, by means of decreasing viscosity of the sputum, clean the bronchi leading to a decrease in dyspnoea and improved lung function.

42 This 1-year, double-blind, randomized, placebo-controlled trial was conducted in Kwong Wah Hospital, Hong Kong Patients were recruited from the COPD clinic from March 1,2010, to February 28, Subjects aged 50 to 80 years, with stable COPD and post bronchodilator spirometry FEV 1 /FVC ratio, 0.7 were included in the study. Eligible patients experiencing an acute exacerbation were treated appropriately and they were recruited 4 weeks after remission of their exacerbation. NAC 600mg BD VS placebo.

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44 Conclusion High-dose NAC (600 mg bid) was a well tolerated treatment. It significantly decreased small airways resistance, as shown by improvements in FEF 25%-75% and FOT( forced oscillation technique) and reduced exacerbation frequency in patients with stable COPD. Despite most previous studies failing to show a beneficial effect with NAC 600 mg daily in COPD this study demonstrated that 1-year, high-dose, NAC (600 mg bid) improved small airways function in patients with COPD.

45 Use of NAC as a mucolytic in ICU NAC is a mucolytic agent that breaks disulfide bonds of mucus, reducing its viscosity and elasticity,(nac is referred to as slime loosener ) and has anti-inflammatory properties in experimental models 1. As a result of its mucolytic properties, many practitioners advocate its use in the ICU for assistance in the clearance of airway secretions. Ackerman MH: The use of bolus normal saline instillations in artifical airways: is it useful or necessary? Heart Lung 1985, 14:

46 Use of NAC as a mucolytic in ICU Although there are limited data on the use of NAC in ICU patients, it is important for clinicians to recognize the potential deleterious effects of this practice. In vitro, NAC may antagonize aminoglycoside and β- lactam antibiotics. NAC at concentrations less than 10% inhibits the growth of Pseudomonas strains in vitro, potentially causing false-negative sputum cultures Parry MF, Neu HC: Effect of N-acetylcysteine on antibiotic activity and bacterial growth in vitro. J Clin Microbiol 1977, 5:58-61.

47 Delivery via aerosol thins airway secretions but does not change pulmonary function or sputum volume in patients with stable chronic bronchitis Furthermore, aerosolized NAC can cause bronchoconstriction and inhibit ciliary function Dueholm M, Nielsen C, Thorshauge H, Evald T, Hansen NC, Madsen HD, Maltbek N: N-acetylcysteine by metered dose inhaler in the treatment of chronic bronchitis: a multi-centre study. Respir Med 1992, 86: Dorsch W, Auch E, Powerlowicz P: Adverse effects of acetylcysteine on human and guinea pig bronchial asthma in vivo and on human fibroblasts and leukocytes in vitro.int Arch Allergy Appl Immunol 1987, 82:

48 Direct tracheal instillation of NAC is more effective than aerosol inhalation in the treatment of atelectasis caused by mucoid impaction; may induce the rapid accumulation of liquefied secretions that must be suctioned immediately to prevent asphyxia Despite its widespread use, few data are available to support NAC as a mucolytic agent. Urschel HC Jr, Paulson DL, Shaw RR: Mucoid impaction of the bronchi. Ann Thorac Surg 1966, 2:1-16.

49 NAC in HIV Glutathione has been implicated in the proliferation of T cells, in the differentiation of T and B cells, and in cytotoxic T cell and natural killer cell activity. Glutathione levels are reduced in the plasma, lung epithelium and T cells in HIV infection.

50 Administration of NAC improves T cell glutathione levels, though whether this improves function or outcome has not yet been elucidated, although one study has shown improved natural killer (NK) and T cell activities. Breitkreutz R, Pittack N, Schuster D, et al. Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials J Mol Med 2001;78;

51 NAC in Acute Coronary Syndrome When perfusion is restored to ischaemic tissues, there exists a state of oxidative stress following the accumulation of toxic metabolites of anaerobic respiration. This involves the production of free radicals with strong oxidative properties, such as hydrogen peroxide and superoxide anions, which can injure tissues (e.g. cell wall lipid peroxidation). The restoration of perfusion can thus paradoxically have detrimental effects on tissues

52 In a small study, the addition of NAC was compared with the standard treatment of glyceryltrinitate and streptokinase, in patients presenting with acute myocardial infarction (AMI). Using echocardiography, cardiac index was significantly better in the NAC group. Larger studies have not been performed to confirm this finding and NAC does not feature in most treatment protocols used for patients with AMI. Arstall MA, Young J, Stafford I, Betts WM, Horowitz JD. N-acetylcysteine in combination with nitroglycerine and streptokinase for the treatment of evolving acute myocardial infarction. Safety and biochemical effects. Circulation 1995;92:

53 NAC in Cancer According to research findings, certain types of cancer including lung, skin, head and neck, mammary, and liver can be potentially treated with NAC Many in vitro studies conducted on human melanoma, prostate, and astrocytoma cell lines have helped to prove NAC s efficacy as a chemo-preventive agent. NAC has been found to be effective in inhibiting cell growth and proliferation in all mentioned cell lines. Cell culture and animal studies indicate that NAC administration can selectively protect normal cells, but not malignant ones, from chemotherapy and radiation toxicity. De Flora S et al. Toxicol. Lett. 53: W4/L2, De Flora S et al. Respiration 50: S43-S49, De Flora S et al. Int J Cancer 67: , Redondo et al. Cytokine 12: , Chiao JW et al. Int J Oncol. 16: , 2000.

54 Conclusion NAC has antioxidant properties that may be useful in many clinical conditions. Currently, it can only be recommended as therapy for paracetamol poisoning. It can be considered for use in other forms of drug induced ALF, especially if your center does not have a transplant facility. Its use in CIN prophylaxis should be discontinued and replaced.. In many other disorders, it is still under evaluation NAC IS JACK OF ALL TRADE AND MASTER OF NONE ONE

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