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Acetylcysteine
General information
Acetylcysteine (N-acetylcysteine) is used as a mucolytic and to treat paracetamol overdose.
Acetylcysteine splits disulfide bonds in mucoproteins and thus lowers mucus viscosity, resulting in a larger volume of sputum. It is normally administered by inhalation as a nebulized solution or aerosol, although it can also be taken orally. Acetylcysteine is also an antioxidant and may protect the lung from free radicals generated by inflammatory cells activated by influenza virus infection. Treatment for 6 months with acetylcysteine 600 mg bd significantly reduced the frequency and severity of influenza-like episodes. Adverse reactions were reported by 9% of patients who complained of dysuria, epigastric pain, nausea and vomiting, constipation or diarrhea, and flushing [SEDA-22, 195].
The place of mucolytic drugs in respiratory disease has recently been reviewed [ ]. The authors suggested that they have been inappropriately used in the past. As mucolytic agents do not improve lung function tests in COPD, the European Respiratory Society and the American Thoracic Society guidelines discourage their use in the treatment of COPD. Future trials should evaluate clinical symptoms and quality of life as well as lung function tests. Mucolytic agents should be evaluated earlier in the natural history of COPD, when mucus hypersecretion is the major feature and before lung function has deteriorated.
Acetylcysteine is used intravenously as an antidote for severe paracetamol poisoning, in which it acts as a thiol donor.
Oral acetylcysteine has been investigated for the treatment of cancer. Acetylcysteine 600 mg/day was compared with retinol 300 000 U/day, the combination, and a placebo in a total of 2191 patients treated for 2 years. Adverse reactions were reported by 14% of those who took acetylcysteine, compared with 23% of those who took retinol and 25% of those who took the combination. The most common adverse effect attributed to acetylcysteine was dyspepsia. In healthy volunteers, higher doses of acetylcysteine, 600 mg taken two or three times daily for 4 weeks, caused more adverse reactions 25% and 61% of the volunteers, respectively, reported gastrointestinal adverse reactions [SEDA-20, 184].
There has been a systematic review of published randomized studies of the use of N-acetylcysteine in chronic bronchitis [ ]. A total of 39 trials were considered, of which only nine were included in the meta-analysis. In all cases, oral N-acetylcysteine had been used in a dosage of 200–300 mg bd for 4–32 weeks. There were gastrointestinal adverse reactions (dyspepsia, diarrhea, and heartburn) in 10% of 2011 patients, and 6.5% withdrew because of their symptoms. However, the rate of gastrointestinal adverse reactions was higher in the placebo group (11% with a withdrawal rate of 7.1%). There was no exacerbation of chronic bronchitis in 49% of patients treated with acetylcysteine compared with 31% of placebo-treated patients, a relative benefit of 1.56 (95% CI = 1.37, 1.77). There was also symptom improvement with treatment: 61% reported improvement in symptoms with acetylcysteine compared with 35% with placebo.
Drug studies
Comparative studies
Three different methods for preventing contrast-induced nephropathy have been compared in 326 patients with chronic kidney disease: 0.9% saline infusion + N-acetylcysteine (n = 111), sodium bicarbonate infusion + N-acetylcysteine (n = 108), and 0.9% saline + ascorbic acid + N-acetylcysteine (n = 107) [ ]. The mean amounts of contrast medium (iodixanol) administered were 179, 169, and 169 respectively and risk scores (9.1, 9.5, and 9.3) were similar in the three groups. Contrast-induced nephropathy occurred in 11 of 111 patients (9.9%) after saline + N-acetylcysteine, in 2 of 108 (1.9%) after bicarbonate + N-acetylcysteine, and in 11 of 107 (10%) after saline + ascorbic acid + N-acetylcysteine. The authors concluded that sodium bicarbonate + N-acetylcysteine was superior to the other two methods that they had studied.
Of 87 adults with renal insufficiency who underwent emergency CT scanning, 43 were hydrated and given N-acetylcysteine 900 mg intravenously; the other 44 were hydrated only [ ]. There was a 25% or greater increase in serum creatinine concentration in two of the former and in nine of the latter. However, there was a 25% or greater increase in serum cystatin C concentration in seven and nine respectively. This disjunction between the effects of acetylcysteine on creatinine and cystatin led the authors to suggest that acetylcysteine might prevent the rise in serum creatinine after contrast administration without actually preventing contrast nephropathy.
It is not clear how effective acetylcysteine is in preventing contrast-induced nephropathy [ ], but in vitro acetylcysteine and ascorbic acid but not sodium bicarbonate prevented contrast-induced apoptosis [ ]. In a double-blind, placebo-controlled study patients with moderately impaired kidney function receiving low-osmolar, non-ionic contrast media were randomized to oral acetylcysteine 1.2 g/day for 2 days (n = 19), oral zinc 60 mg/day for 1 day (n = 18), or placebo (n = 17) [ ]. All received 0.45% saline 1 ml/kg/hour for 24 hours at the time of the procedure. There was a significant fall in serum creatinine in all patients during volume expansion, and creatinine did not increase after contrast administration. However, 2 days after contrast there was a significant rise in cystatin C concentration in those who were given zinc and placebo, but not after acetylcysteine. There was no difference in the incidence of nephropathy. The authors suggested that kidney function should be assessed by cystatin C in studies of contrast nephropathy, since creatinine can be misleading.
Two doses of N-acetylcysteine have been compared in 224 consecutive patients with chronic renal insufficiency (creatinine concentration over 130 μmol/l and/or creatinine clearance under 60 ml/minute), who were randomly assigned to receive N-acetylcysteine in the standard dose (600 mg orally bd; n = 110) or in a double dose (1200 mg orally bd; n = 114) for 2 days starting 24 hours before contrast administration (low-osmolar contrast media) [ ]. All received intravenous hydration with 0.45% saline for 12 hours before and after the procedure. There were increases of at least 0.44 μmol/l in creatinine concentration 48 hours after the procedure in 12/109 patients (11%) in the standard dose group and 4/114 patients (3.5%) in the double dose group (OR = 0.29; 95% CI = 0.09, 0.94). In the subgroup given a low dose of contrast (under 140 ml), there was no significant difference in renal function deterioration between the two groups. However, in the subgroup given a high dose of contrast (140 ml or more), nephrotoxicity was significantly more common after the single dose (19%) than the double dose (5.4%).
Fenoldopam mesylate (an agonist at dopamine D1 receptors) has been compared with double dose of N-acetylcysteine in 192 consecutive patients with chronic renal insufficiency, who were randomly assigned to receive 0.45% saline intravenously and N-acetylcysteine 1200 mg orally bd; n = 97) or fenoldopam (0.10 micrograms/kg/minute; n = 95) before and after a non-ionic, iso-osmolar contrast medium (iodixanol) [ ]. The baseline creatinine concentrations were similar (152 μmol/l and 155 μmol/l respectively). There was an increase of at least 44 μmol/l in creatinine concentration 48 hours after the procedure in 4 (4.1%) of 97 patients who were given N-acetylcysteine and in 13 (14%) of 95 patients who were given fenoldopam (OR = 0.27; 95% CI = 0.08, 0.85). The amount of contrast medium used in the two groups was similar (160 and 168 ml respectively). Thus, high-dose N-acetylcysteine may be more effective than fenoldopam.
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