Role of N-Acetylcysteine

Current
Therapeutics
Role of
N-Acetylcysteine
in the treatment of
Acute
Respiratory
Disorders
CURRENT THERAPEUTICS
Role of N-Acetylcysteine
in the treatment of Acute Respiratory Disorders
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Current Therapeutics
N-Acetylcysteine
in the treatment of Acute Respiratory Disorders
Role of
Contents
1. Introduction
3
2. Mucociliary System
4
3. Inflammatory Process
3.1 Role of Cigarette Smoke and Air Pollution
5
5
4. Immunomodulatory System
7
5. N-Acetylcysteine
5.1 Historical Use
5.2 Chemical Structure
5.3 Pharmacokinetic Profile
8
8
8
8
6. Mucolytic Activity
6.1 Clinical Trials
6.1.1 Children
9
9
12
7. Anti-Inflammatory and Antioxidant Activity
7.1 Patients with Chronic Obstructive Pulmonary Disease
7.2 Protection from the Effects of Cigarette Smoke or Air-borne Pollution
13
14
16
8. Immunomodulatory Activity
8.1 Clinical Trials
8.1.1 Effect on Influenza-like Symptoms
8.1.2 Effects on Aging-Related Changes in Immune Function
18
19
19
21
9. Tolerability
9.1 General Profile
9.2 Gastrointestinal Events
9.3 Laboratory Parameters
22
22
23
23
10. Dosage and Administration
24
11. Conclusions
25
12. References
26
1
1. Introduction
NAC was first developed and used as a mucolytic in
respiratory diseases, but subsequent research revealed its
antioxidant properties. NAC is therefore also effective in
reducing oxidative stress and inflammation in the
airways and lungs, produced by cigarette smoke or airborne pollution. Recently, NAC has also been shown to
stimulate activation of the immune system.
In addition to its use in the treatment of acute respiratory
conditions, NAC is used as part of the standard regimen in
themanagementofchronicobstructiverespiratorydisease,[1]
in the management of acetaminophen (paracetamol)
poisoning and in other indications;[1] however, a
discussion of these indications is beyond the scope of this
monograph.
The use of N-acetylcysteine (NAC) as an oral mucolytic
in the treatment of respiratory disorders has become an
accepted and widespread treatment option in many
countries worldwide.
The focus of this review is the use of oral NAC in treating
acute respiratory pathologies:
• productive (wet) cough
• acute bronchitis
• influenza.
The mechanisms of action of NAC in these indications
include mucolytic, anti-inflammatory, antioxidant and
immunomodulatory effects. NAC is recommended for
the treatment of acute respiratory conditions in a range of
patients including adults and children (figure 1).
Fig. 1
Acute respiratory
conditions for which
pharmacists can advise
using N-acetylcysteine
(NAC).
Acute bronchitis
Children aged < 12 years:
300-600 mg/day
NAC
Influenza
Patient presents
with acute
respiratory condition
Productive (wet) cough,
catarrh
3
Recommend
treatment with
oral NAC
(tablets, granules
or ready to-usesyrup)
Adults and children aged
> 12 years: 600 mg/day
Current Therapeutics
2. Mucociliary System
The mucociliary system has many functions including:[2-4]
• hydrating airways
• uptaking and transporting inhaled particles to the
pharynx
• biologically purifying against bacterial invasion
• maintaining bronchial tone.
Mucociliary transport is an important defense
mechanism in the human body; it moves airway mucous,
together with any trapped substances (e.g. inhaled
particles or endogenous debris), out of the lungs.[5] When
necessary, cough also helps to remove excessive airway
secretions. The fluidity of mucous is reduced by the
formation of disulfide bridges; this, in turn, impairs the
efficiency of mucociliary clearance and increases the
difficulty of expectoration (figure 2).[6,7]
In many acute respiratory conditions there is an excessive
secretion of mucous.[7,8] In addition, patients who smoke
cigarettes have an increase in tissues that secrete mucous,
increases in mucous production, and increased mucous
viscosity.[7]
Reducing excessive or thick mucous and improving
mucociliary transport is important as mucous retention
may lead to bacterial colonization, which may result in
pneumonia.[5-7] In influenza viral infections, rapid
movement of the mucous is useful in trapping and
physically removing the virus before it can penetrate the
blanket of mucous.[9] As involuntary cough affects quality
of sleep, improving mucous clearance will also help
reduce coughing and improve the health-related quality
of life of the patient.
Fig. 2
Effect of mucous
production in acute
respiratory conditions.
Airways inflammation
Increased mucous production
Formation of disulfide
bond and polymerization
Increased mucous viscosity
Difficulty in expectoration
Cough
Risk of infection
4
Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders
3. Inflammatory Process
Many mechanisms are involved in the inflammatory
process including mediators, gene expression, oxidative
stress and free radicals.[7,10-12] Oxidative stress, an
important part of the inflammatory response to both
environmental and internal signals, results from the
production of oxygen-free radicals and other oxidant
agents. Endogenous and exogenous oxidants (any
molecule with an unpaired electron on its outer orbit) are
capable of injuring the lung.[10,13] Free radicals are highly
reactive molecules that can either donate (reduce) or
abstract (oxidize) an electron to other nearby molecules.
These reactive species also activate transcription factors,
leading to the release of proinflammatory cytokines and
thus an increase in the inflammatory response.[7,14]
Therefore, it appears that oxidative stress and
inflammation are inseparable phenomena (figure 3).
Oxidative stress is responsible for alterations in many
components of the lungs, including the airway wall,
alveolar epithelial cell layer, lung matrix, pulmonary
microcirculation and transcription factors.[14] Oxidative
Fig. 3
Role of oxidative stress
and free radicals in
acute inflammation.
stress causes an amplified inflammatory response, lipid
peroxidation and cell membrane damage, which results
in acute inflammation, increased mucous secretion and
tissue damage (figure 3). In turn, each of these results in
clinical effects, such as difficult expectoration and risk of
infection, cough, bronchoconstriction, and decline in lung
function. In addition to initiating inflammation, cell and
tissue injury caused by oxidative stress maintains
inflammation.[12]
Antioxidants neutralize free radicals and restore the
reductive-oxidative (redox) balance and, therefore,
reduce the damage to cells and DNA caused by free
radicals.[10,13]
3.1 Role of Cigarette Smoke and Air
Pollution
Oxidants are produced by cells in the human body, but
cigarette smoke and atmospheric pollution are also a
source (figure 4).[7,10,13,15,16] Free radicals and potent
catalyzers of oxidation reactions (e.g. iron and other
Oxygen-free and nitrogen-free
radicals produced
Oxidative stress
Lipid peroxidation
Cell membrane
damage
Modified cellular redox equilibrium
Release of proinflammatory cytokines
5
Inflammation of
airways and lung
Current Therapeutics
transition metals) are present in large amounts in
cigarette smoke, leading to oxidative stress and airway
inflammation. Smokers have greater levels of some
systemic inflammatory markers than nonsmokers.
Air-borne pollutants (e.g. from fossil fuel combustion
products, diesel exhaust particles and residual oil fly ash)
contribute to respiratory illness in urban and industrial
areas.[7] Particulate air pollution has proinflammatory
activities (e.g. release of inflammatory markers and
Fig. 4
Role of cigarette smoke
and atmospheric
pollution on oxidative
stress and inflammation
in airways and lung.
generation of free radicals) similar to those seen with
cigarette smoke. The lung can be protected by:[10,13,16,17]
• reducing the oxidant burden (e.g. limiting exposure to
cigarette smoke or air-borne pollutants)
• increasing antioxidant defenses by increasing normal
antioxidants (e.g. enzymes [superoxide dismutases,
catalase, glutathione peroxidase] and vitamins E and C)
or by administering exogenous antioxidants, such as
NAC, that have well established antioxidant properties.
Inhaled by individual
Oxygen- and nitrogen-free
radicals and other highly reactive
compounds
Oxidative stress
Acute inflammation
of airways and lungs
Cigarette smoke
6
Air-borne pollution
(e.g. particulate air pollution,
ozone, heavy metals)
Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders
4. Immunomodulatory System
The pathogenesis of influenza and other viral infections
and the age-related deterioration of the immunomodulatory system are related, in part, to:[14,18-23]
• redox imbalance
• oxidative stress
• increases in inflammatory mediators.
The epithelial cell layer of the respiratory tract undergoes
pathological change during influenza virus infection.[20]
When respiratory cells are infected with pathogenic
viruses, oxidant production in respiratory cells increases.
At the same time, stores of naturally occurring
antioxidants, in particular glutathione, are depleted.
Oxidants are involved in the activation of transcription
factors for inflammatory protein genes and the
development of pulmonary cell damage.[19-21] Moreover,
oxidative stress alters the local immune response,
increasing the risk of infection.[14,21]
Therefore, antioxidants have a role in the treatment of
viral infections: they defend against viral-induced
oxidation by reactive species and also prevent the release
of inflammatory mediators.[14,19] This improves immune
function and prevents pulmonary cell damage under
conditions of oxidative stress.[19]
A redox imbalance, which leads to oxidative stress
resulting in a deterioration of the function of immune
cells (e.g. neutrophil and lymphocyte activity) occurs
with aging.[22,23] Antioxidant treatment may, therefore,
restore the function of some immune systems in older
patients by directly affecting the immune system or
indirectly as a result of its antioxidant properties.
7
Current Therapeutics
5. N-Acetylcysteine
Table I Summary of the pharmacokinetic properties of oral
N-acetylcysteine (NAC)[25]
5.1 Historical Use
NAC has been used in clinical practice since the 1960s.
A 5% to 10% NAC solution administered by aerosol or
instillation into the bronchopulmonary tree was shown to
be an effective mucolytic in various respiratory diseases.
Since the 1970s, pleasant-tasting oral NAC preparations
have been available in many countries of the world. The
oral formulations are effective in treating respiratory
disorders with thick and productive cough, and are well
accepted by patients.
[1]
Parameter
Comments
Absorption
Characteristics
Rapid and complete
Plasma protein binding
Found in body as free NAC
and reversibly bound to
plasma proteins through
disulfide links
Bioavailability of free
NAC after hepatic first
passage
≈10%
5.2 Chemical Structure
Distribution
NAC is a precursor of both the naturally occurring
simple amino acid cysteine and reduced glutathione.[24]
Due to the presence of the acetyl substituted amino
group, NAC is less easily oxidized to inactive cystine
than cysteine.[1] NAC is a thiol (sulfhydryl)-providing
compound; the thiol group ruptures disulfide bridges in
mucoproteins and is responsible for its mucolytic
activity (section 6).[1]
Primary spread
Aqueous environment of
the extracellular space
Primary location
Liver, kidneys, lungs and
bronchial mucous
Metabolism
Initial
Rapidly deacetylized in the
intestinal wall and
through hepatic first
passage to active L-cysteine
Secondary
Metabolized to inactive
forms
5.3 Pharmacokinetic Profile
Tables I and II provide a brief summary of the
pharmacokinetic properties of orally administered
NAC.[25] The pharmacokinetics of oral NAC appear to be
dose proportional, and NAC does not accumulate in the
plasma after repeated dosing.[26]
Following oral administration, NAC is quickly and
completely absorbed from the gastrointestinal tract. It
undergoes rapid, extensive metabolism in the gut wall
and liver.[27] The active NAC metabolites (cysteine and
reduced glutathione), and not NAC itself, are likely to be
responsible for most of the observed pharmacological
and clinical effects. The plasma concentration of free
cysteine increases significantly after administration of
NAC. The elimination half-life of free cysteine in the
plasma is ≈0.81 hours.
NAC may be present in plasma and tissues as:[27]
• the parent compound or active (cysteine and reduced
glutathione) or inactive metabolites
• a releasable fraction bound to proteins by disulfide
linkages
• a fraction incorporated into protein chains.
Clearance
Renal
≈30%
Primary metabolites
excreted
Cystine and cysteine
Table II Summary of the pharmacokinetic properties of
N-acetylcysteine (NAC) 30mg/kg[25]
Parameter
Free and
bound NAC
Free NAC
9
Cmax (nmol/mL)
67
Time to Cmax (h)
0.75–1
Area under the curve
(nmol/mL × h)
163
12
Elimination half-life (h)
1.3
0.46
Cmax = peak plasma concentration
8
Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders
6. Mucolytic Activity
Table III Summary of mucolytic effects of N-acetylcysteine in
in vitro studies, animal models and studies in patients with excess
respiratory mucous
NAC has two primary mechanisms of action as a
mucolytic (figure 5):[24]
• direct mucolytic activity. The thiol groups in NAC
rupture the disulfide bridges of proteins in the mucous,
resulting in smaller units of the protein and, therefore,
reduced viscosity and mucous that is easier to
expectorate
• activation of mucociliary clearance. The physiological
transport of mucous and, therefore, its removal is
improved by NAC.
The favourable effects of NAC as a mucolytic have been
shown in numerous in vitro and animal-model studies
and studies in patients (table III).[28-40] NAC reduced the
viscosity of mucous, improved its transport and
increased sputum volume.
NAC also had a beneficial effect on mucous induced by
cigarette smoke (table III). It improved mucociliary
action,[28] decreased the length of time necessary to
reverse mucous cell hyperplasia[29] and inhibited
hypersecretion of mucous in the larynx and trachea.[30]
In vitro
Reduced viscosity of mucous[31-34]
Direct and immediate effect on decreasing the
viscoelastic properties of bronchial secretions [35]
Inhibited Na+ absorption across human nasal epithelial
cells, which may increase mucous fluidity[36]
Reduced the deleterious effect of cigarette smoke
extract on mucociliary action[28]
Animal models
Increased mucous velocity and ciliary beat frequency[37]
Increased the volume of respiratory tract fluid and
decreased viscosity of sputum[38]
Reduced the time required to reverse smoke-induced
mucous cell hyperplasia[29]
Inhibited cigarette smoke-induced hypersecretion of
mucous in larynx and trachea[30]
Studies in patients
More effective than saline in reducing sputum viscosity
and consistency and increasing sputum volume in
patients with chronic bronchial disease[2,39]
6.1 Clinical Trials
Improved mucociliary transport in heavy smokers with
hypersecretory bronchitis and reduction in mucociliary
transport[40]
The efficacy of NAC as a mucolytic in patients with
respiratory conditions, such as chronic obstructive
pulmonary disease (COPD) or chronic bronchitis, is well
established.[7,24,41] Oral NAC has favorable effects on
mucous and cough in patients, including children, with
acute or chronic respiratory disorders.
The focus of this monograph is the relatively short-term
(10–15 days) use of oral NAC in the treatment of acute
respiratory conditions.[42-44] In these trials, the efficacy of
treatment was assessed using the differences between
baseline and endpoint values in various clinical
parameters.[42-44] Sputum viscosity, cough severity,
difficulty of expectoration and dyspnea were each
scored on a 3- or 4-point scale, where the lowest scores
of 0 or 1 indicate ‘normal‘ function (e.g. absence of
cough) or few symptoms (e.g. very fluid sputum) and 3
points indicates highly pathological conditions (e.g.
very viscous sputum or intense cough during the day or
night).
NAC reduces the viscosity of expectorations, which
reduces the expectoration difficulties and the severity of
productive cough. In the short-term clinical trials, oral
NAC 200mg three times daily used alone or
concomitantly with antibiotics (amoxicillin 1.5[42] or 2
g/day[43,44]), decreased the consistency of sputum,
facilitated its expectoration and reduced cough and
thoracic physical symptoms.[42-44]
NAC was more effective than placebo in the largest of
the short-term trials.[42] In this trial in 215 patients with
acute bronchitis, superinfections of chronic bronchitis,
or complicated bronchitis in patients with severe
chronic respiratory insufficiency, patients received NAC
200mg three times daily for 10 days. Compared with
baseline, patients receiving NAC showed significant
improvements in all parameters (sputum expectoration,
sputum viscosity, cough and peak expiratory flow rate
[PEFR]). Moreover, NAC was significantly more
effective than placebo in decreasing sputum viscosity,
9
Current Therapeutics
Fig. 5
Primary mechanisms of
action
of N-acetylcysteine
(NAC) as
a mucolytic.
NAC
NAC
Direct mucolytic activity
NAC breaks disulfide bonds, rendering the mucous
less viscous and easier to expectorate
from baseline in clinical parameters with NAC
compared with placebo in patients with acute
bronchitis. The increase in the volume of sputum shown
in the group receiving NAC was probably due to the
0
–0.2
–0.4
–0.6
–0.8
–1
–1.2
–1.4
–1.6
–1.8
–2
100
90
80
70
60
50
40
30
20
10
0
Sputum viscosity
Cough severity
NAC
6
***
***
*
Change from baseline (mL/day)
Change from baseline (L/min)
Change from baseline (score)
increasing sputum expectoration, preventing cough and
increasing PEFR (all p < 0.0001).
The greatest efficacy was shown in patients with acute
or chronic bronchitis. Figure 6 shows the improvements
Fig. 6
Efficacy of oral
N-acetylcysteine (NAC)
in the treatment of
patients with acute
bronchitis. Mean changes
from baseline at day 10
for various clinical
parameters in patients
with acute bronchitis
receiving oral NAC
200mg three times daily
or placebo in a 10-day
trial.[42]
* p < 0.01, ** p ≤ 0.005,
*** p ≤ 0.0001 vs placebo.
Activation of mucociliary clearance
NAC improves the physiological transport
of mucous, facilitating its removal
4
2
0
–2
–4
–6
–8
–10
Peak expiratory flow rate
10
Placebo
Sputum volume
**
Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders
Table IV Efficacy of oral N-acetylcysteine (NAC) in the treatment of acute respiratory diseases in children in selected clinical trials
Acute respiratory condition
Treatment regimen
Results
Biscatti et al.
Acute respiratory tract
infections
Oral NAC 100–300mg/day
(according to age) or
placebo for 6 days
All patients received the
most suitable antibacterial
agent
Fever, cough, dyspnea
and thoracic moist rates
returned to normal in a
significantly shorter time
with NAC than with
placebo
Hofman[48] (49)
Asthma, sinobronchial syndrome
or severe, purulent bronchitis
Not stated
Subjective improvement
in all patients
Improved sinusitis when it
was not chronic and
purulent
Improved most cases of
bronchitis
Nikolic´ & Korac´[45] (20)
Bronchitis (afebrile acute
recurrent bronchitis frequently
accompanied by signs of
bronchial allergy; febrile
recurrent or catarrhal bronchitis;
or simple catarrhal bronchitis)
Oral NAC 100 or 200mg
three times daily
(according to age) for 4
days
Only patients with acute
febrile bronchitis received
antibacterials
Shortened the duration
of catarrhal inflammation
of the throat and cough
Returned vital capacity
and pulmonary air flow
values to normal in
patients with simple or
recurrent catarrhal
bronchitis after 4 days of
treatment
Ribeiro et al.[46] (67)
Obstructive bronchial diseases
(atelectasis, bronchiolopathy,
pseudobronchiectasis,
bronchiectasis, cystic fibrosis,
lung abscess, chronic bronchitis,
combined pathology)
NAC 10–50mg/kg/day in 2
or 3 divided doses for
7–110 days (mean 26 days)
All patients had previously
received other treatments
without success or only
partial success
Improvement shown in
most patients
The majority (>80%) of
patients had excellent-togood clinical and
radiological results
(fig. 8)
Fig. 7
Efficacy of oral
N-acetylcysteine (NAC)
in the treatment of
patients with bronchitis.
Mean changes from
baseline at day 10 for
various clinical
parameters in patients
receiving oral NAC
200mg three times daily,
placebo or bromhexine
8mg three times daily in a
10-day trial.[43]
* p < 0.05, ** p ≤ 0.01,
*** p < 0.001 vs baseline.
0
Sputum viscosity
Cough severity
Difficulty in
expectoration
–0.2
–0.4
–0.6
*
–0.8
**
–1
**
–1.2
***
–1.4
***
***
NAC
Bromhexine
Placebo
Change from baseline (mL)
(50)
Change from baseline (score)
[47]
Change from baseline (mL/day)
Study (no. of children)
Sputum volume
0
–5
–10
–15
–20
*
–25
400
350
300
250
200
150
100
50
0
*
**
Forced expiratory
volume in 1 sec
11
Forced vital
capacity
Current Therapeutics
and dyspnea to a significantly greater extent than
bromhexine (all p < 0.05). For example, compared with
bromhexine, NAC reduced sputum viscosity more
rapidly and effectively (p < 0.001). Moreover, NAC was
more effective than bromhexine in treating patients in
both of the treatment groups (i.e. when NAC was used
concomitantly with antibacterial treatment in patients
with acute respiratory infections and to an even greater
degree in those with chronic non-infectious respiratory
conditions).
decrease in mucous viscosity, which facilitated drainage
of bronchial secretions.
NAC is more effective than bromhexine or placebo when
used together with antibacterials, whereas bromhexine
and placebo have similar efficacy.[43] In a 10-day trial in 54
patients with acute infections complicating COPD or
acute respiratory infections, oral NAC 200mg three times
daily significantly improved most clinical parameters of
mucous, cough and functional parameters from baseline
(figure 7). Mean changes from baseline in several
parameters (sputum viscosity, cough, difficulty of
expectoration and forced expiratory volume in 1 second
[FEV1]) were significantly greater with NAC than with
placebo or bromhexine 8mg three times daily (all
p < 0.05). In contrast, there were no significant differences
between placebo and bromhexine in changes from
baseline for any parameter.[43] Changes in functional
respiratory parameters are secondary to the clearing of
the airways; the combination of NAC and an antibacterial
cleared the airways better than antibacterials alone or
combined with bromhexine, leading to improvements in
FEV1 and forced vital capacity values (figure 7).
NAC was also more effective than bromhexine in a 15day trial in 60 patients with non-infectious chronic
bronchitis or acute respiratory infections.[44] NAC reduced
sputum thickness, difficulty in raising sputum, cough
Excellent
60
Good
50
40
% of patients
Fig. 8
Efficacy of N-acetylcysteine
(NAC) in the treatment of
obstructive bronchial diseases in
children. The proportion of
patients with clinical or
radiological results classified as
excellent, good or bad following
treatment with NAC 10–50
mg/kg/day in 2 or 3 divided doses
for 7 to 110 days (mean 26
days).[46] Patients had previously
received other treatments without
success or only partial success.
6.1.1 Children
Oral NAC was also effective in treating children with
acute respiratory conditions in clinical trials (table IV).[45-48]
Although it is difficult to evaluate objective parameters
of mucolytic activity in children (e.g. they may not fully
cooperate in spirographic testing or mucous collection),
objective and/or subjective improvements in a variety
of parameters were shown with treatment with oral
NAC in children with a range of diseases of the
respiratory system.[45-48] For example, both clinical and
radiological results were favourable with oral NAC in
children with a variety of obstructive respiratory
diseases (figure 8 and table IV).[45-48] Oral NAC is,
therefore, a useful option in the treatment of respiratory
diseases in pediatric patients.
30
20
10
0
Clinical results
12
Radiological results
Bad
Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders
7. Anti-Inflammatory and Antioxidant Activity
The mechanism of action of NAC as an anti-inflammatory
is complex and involves both antioxidant activity and reestablishment of redox equilibrium (figure 9).[7,14]
Oxidants and free radical attack cause inflammatory
damage (section 3); therefore, agents with antioxidant
activity, such as NAC, will inhibit the inflammatory
process. NAC not only acts directly as an antioxidant, but
also has indirect antioxidant properties as it is a precursor
to biosynthesis of the antioxidant glutathione (figure
10).[7,16] Pulmonary tissues have a variety of both
intracellular and extracellular antioxidant defense
systems in order to counterbalance the production of free
radicals and cope with the normal oxidative burden
within the lungs. Antioxidant defense systems include
antioxidant molecules and enzymatic systems, the most
important of which is glutathione and its related complex
enzymatic systems.[7,12,24] Glutathione directly detoxifies
reactive species by conjugation and/or reduction; the
enzyme systems enhance chemical detoxification by
catalyzing conjugation reactions and reductions.[16]
Fig. 9
Pathway showing the
mechanism of action of
N-acetylcysteine (NAC)
as an antioxidant and reestablisher of reductiveoxidative (redox)
equilibrium in the
presence of oxidative
stress.
Glutathione has also been implicated in numerous
cellular functions.[12,14] Inflammation is mediated by
inducible transcription factors that switch on the genes
for inflammatory proteins. Reactive species activate this
transcription, leading to the release of proinflammatory
cytokines.[7] Therefore, to neutralize reactive species and
prevent activation of transcription of inflammatory
protein genes, the cellular redox equilibrium between
reduced glutathione and its oxidized species glutathione
disulfide must be maintained (figure 10).[7,14]
It is essential to maintain adequate intracellular levels of
glutathione to overcome the harmful effects of reactive
species. Depletion of glutathione is caused by its
antioxidant activity and also by elimination of oxidized
glutathione from the cells. Once oxidized glutathione is
eliminated from the cell, it is not available to be
regenerated to reduced glutathione via the reductase
pathway. The rate-limiting substrate in the synthesis of
glutathione is cysteine.[7,12,24] Cysteine is difficult to
administer as it is poorly absorbed, has low solubility in
Oxygen- and nitrogen-free radicals produced
Oxidative stress
NAC
Increases intracellular
and extracellular
antioxidant defenses
Re-establishes cellular
redox equilibrium
Controls activation of
transcription of
inflammatory genes
Prevents lipid
peroxidation and cell
membrane damage
Prevents inflammation
of airways and lungs
13
Controls release of
proinflammatory
cytokines
Current Therapeutics
inflammatory response than agents that inhibit only the
inflammation mediators involved in the last steps of the
inflammatory process.[7]
The anti-inflammatory and antioxidative actions of NAC
have been shown in many in vitro and animal-model
studies (table V).[49-60]
water and undergoes rapid hepatic metabolism.[14]
However, additional cysteine may be delivered by the
administration of NAC because it is a precursor to
cysteine (figure 10). NAC increases the endogenous
supply of cysteine, either by deacetylation of NAC or
through reduction by NAC of endogenous cystine into
cysteine.[16] Relative to cysteine, NAC is well absorbed
intestinally, has good water solubility, is stable to
oxidation and is well tolerated.
Administration of NAC results in increased levels of
endogenous cysteine that:
• stimulate glutathione synthesis when there is an
increased demand
• enhance the activity of enzymes dependent on
glutathione
• promote antioxidant activity.
NAC, therefore, maintains the redox-equilibrium
between reduced glutathione and oxidized glutathione
and acts directly as an antioxidant, which leads to
complete airway protection against oxidative stress and
inflammation (figure 9).
NAC inhibits the activation of some redox-sensitive
signal transduction factors.[14] Therefore, NAC prevents
the release of proinflammatory cytokines (figure 9) and, as
a result, would have longer-term effects on the
Fig. 10
Reductive-oxidative
(redox) equilibrium
between reduced
glutathione and
glutathione disulfide. In
the presence of oxidative
stress, there is a lack of
sufficient reduced
glutathione to neutralize
the reactive species and,
therefore, redox
equilibrium is not
maintained.
N-acetylcysteine (NAC)
restores redox equilibrium
by increasing levels of
endogenous cysteine,
resulting in increased
levels of glutathione.
7.1 Patients with chronic obstructive
pulmonary disease
The anti-inflammatory and antioxidative actions of NAC
have also been demonstrated in studies in patients with
COPD (table VI).[14,16,49,50,61-68] Markers of oxidative stress and
inflammation were reduced in the red blood cells,
sputum and blood of these patients.[66-68]
Oral NAC decreased levels of C-reactive protein, which is
a marker of inflammation, in patients with acute
exacerbations of COPD.[68] This double-blind 10-day
study compared the efficacy of two dosage regimens of
oral NAC (600 or 1200mg/day) with that of placebo in
reducing the levels of C-reactive protein and other
indicators of inflammation in 122 patients with an acute
exacerbation of COPD.
Levels of C-reactive protein decreased to a greater extent
with NAC than with placebo at day 5 and day 10 of the
trial (figure 11). The improvement was greater with the
NAC
N-acetylcysteine
Cysteine
Reduced glutathione
Reactive
species
Neutral
species
Glutathione
reductase
Oxidized glutathione
14
Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders
Table V Summary of the protective function of N-acetylcysteine against cigarette smoke or air-borne pollution in in vitro studies, animal
models and studies in cigarette smokers
In vitro
Protected against oxidant-mediated cytotoxicity induced by cigarette smoke[49]
Decreased toxicity due to tobacco smoke[50]
Improved the survival of cultured human bronchial cells exposed to tobacco smoke condensate[51]
Protected against the loss of pulmonary glutathione and cell toxicity associated with cigarette smoke[51]
Glutathione and cysteine protected macrophage cells from the effects of tobacco smoke[52]
Reduced stimuli-induced superoxide radical generation by human alveolar macrophages from smokers[53]
Animal models
Attenuated secretory cell hyperplasia induced by tobacco smoke[54]
Protected against acetaldehyde lethality; more effective on an equivalent mole basis than L-cysteine or L-ascorbic
acid[55]
Protected against chloroacetaldehyde and metabolically formed acrolein[55]
Prevented thickening of the airway wall and improved distribution of ventilation in a model of cigarette smokeinduced alterations to small airways[56]
Prevented lung inflammation after short-term exposure to inhaled concentrated ambient particles[57]
Increased levels of interferon-γ and normalized interferon-γ : interleukin-4 ratios[58]
Studies in healthy smokers
Reduced the levels of some markers of inflammation[59]
Reduced the stimulated production of free oxygen radicals[53]
Exhibited defensive mechanism against aggressive agents[60]
Baseline
2.5
Day 5
Day 10
100
90
Normalized CRP levels (% of patients)
2
CRP (mg/100mL)
Fig. 11
Effect of oral
N-acetylcysteine
(NAC) 600 or 1200
mg/day on levels of a
marker of inflammation
(C-reactive protein; CRP).
Levels of CRP at baseline
and at day 5 and day 10
of treatment and the
proportion of patients that
achieved normal CRP
levels at day 10 in
patients with an acute
exacerbation of chronic
obstructive pulmonary
disease.[68]
* p < 0.001 vs baseline;
† p < 0.001 vs placebo;
‡ p = 0.002 vs NAC
600mg/day.
1.5
1
0.5
*
*
*
†‡
80
70
60
50
40
30
20
10
*†‡
0
0
NAC 600
NAC 1200
15
Placebo
NAC 600 NAC 1200 Placebo
Current Therapeutics
Table VI Summary of antioxidant and anti-inflammatory effects
of N-acetylcysteine in in vitro studies and animal models
1200mg/day regimen than with the 600mg/day regimen.
The proportion of patients that achieved normal C-reactive
protein levels was significantly greater with NAC 1200
mg/day than with NAC 600mg/day or placebo (figure 11).
NAC 1200mg/day also reduced interleukin-8 levels,
another marker of inflammation, to a significantly greater
extent than NAC 600mg/day or placebo (both p = 0.01).[68]
Other parameters of disease severity (including the
frequency and severity of severe cough and difficulty in
expectoration) also improved with treatment with
NAC.[68] In contrast, the group receiving placebo did not
show significant improvement from baseline in these
parameters.
In vitro
Supported intracellular glutathione synthesis[16]
Acted as a scavenger of reactive species[16,61]
Decreased oxidant-mediated cytotoxicity[49,50]
Inhibited activation of a mitogen-activated protein
kinases resulting in reduced release of chemokines[62]
Protected cells against death induced by exposure to
noxious stimuli[63]
Protected against programmed cell death (apoptosis)
associated with exposure to inadequate amounts of
trophic factors[63]
Altered lung oxidant : antioxidant imbalance[14]
Animal models
7.2 Protection from the Effects of Cigarette
Smoke or Air-borne Pollution
Reduced pulmonary response to endotoxin in a model
of adult respiratory disease syndrome[61]
Prevented the release of granulocyte aggregates
following endotoxin-induced lung injury[64]
NAC is useful in respiratory conditions caused by
oxidative stress and inflammation in the airways that are
induced by cigarette smoke and air-borne pollution
(section 3.1).[7] When excessive amounts of oxidants are
inhaled from cigarette smoking or air-borne pollution,
the normal oxidant burden in the lungs is increased and
oxidative stress may occur, resulting in lung injury.[16]
Inadditiontoitsbeneficialeffects as a mucolytic (section 6),
NAChasantioxidantproperties and the ability to maintain
the glutathione redox equilibrium (figure 9). Acting as a
direct antioxidant and a precursor of glutathione synthesis,
NAC has a beneficial effect by increasing the antioxidant
Improved immune function in a model of premature
ageing[65]
Studies in patients with chronic obstructive pulmonary
disease (COPD)
Reduced markers of oxidative stress in red blood cells
in patients[66]
Decreased markers of inflammation in sputum and
blood in patients with stable COPD[67]
Decreased levels of activated protein C, a marker of
inflammation, in patients with acute exacerbations of
COPD[68]
Fig. 12
Benefits of
N-acetylcysteine (NAC)
on countering the
airway effects of
cigarette smoke or
air-borne pollution.
Inhaled by individual
Oxidative stress
Oxygen- and nitrogen-free
radicals and other highly reactive
compounds
Mucous production
NAC
Neutralized oxidants
and maintenance of
cellular reductiveoxidative equilibrium
Airways inflammation
prevented
Decreased mucous
viscosity and improved
mucociliary transport
Eased expectoration
Reduction in cough
and other symptoms
16
Cigarette smoke
Air-borne pollution
(e.g. particulate air pollution,
ozone, heavy metals)
Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders
had beneficial effects on markers of inflammation in
healthy smokers (table V). In three studies in healthy
smokers,[53,59] the effects of treatment with oral NAC
200mg three times daily on bronchoalveolar lavage fluid
were assessed. NAC significantly reduced the levels of
some markers of inflammation[59] and reduced the
stimulated production of free oxygen radicals.[53]
Following NAC treatment, there was an increase in
lymphocyte concentrations, improvement in the
phagocytic activity of alveolar macrophages and an
increase in leukotriene B4 secretion.[60] These activities
indicated that NAC has important defense mechanisms
against toxic agents.
status in patients with pulmonary inflammation induced
by cigarette smoke or air-borne pollution. Exposure to
particulate matter induces transcription of many
proinflammatory genes;[57] therefore, the activity of NAC
in maintaining cellular redox equilibrium will also play a
role in its protective effects. The various mechanisms of
action of NAC will result in the inhibition of the
inflammatory process induced by cigarette smoke or
air-borne pollution and improve the clearance of mucous
(figure 12).
In in vitro and animal-model studies, the action of NAC
as an antioxidant offered protection against cigarette
smoke or air-borne pollution (table V). Oral NAC also
17
Current Therapeutics
8. Immunomodulatory Activity
Table VII Summary of the immunomodulatory activity of
N-acetylcysteine in in vitro studies and animal models and studies
in patients
NAC has shown beneficial effects on the immune system
inmanyinvitrostudiesandanimalmodels(tableVII),[9,18-21,69,70]
and also in studies in patients. The antioxidant activity of
NAC appears to play a role in its efficacy in improving
immune function.[19,69] The pathogenesis of influenza and
other infections, and age-related decreases in immune
function involves oxidative stress, redox imbalance and
the production of inflammatory cytokines (section 4).
NAC may also have a direct action on immune cells; it
improves the local immune response by protecting the
function of lymphocytes and macrophages when exposed
to reactive oxygen species in vitro.[21,69,70] In addition, it is
the precursor to glutathione, which has been shown to
play a pivotal role in regulating, directly or indirectly,
antimicrobial activity in immune cells (particularly
macrophages).[71] In mice models of respiratory influenza,
NAC increased the resistance to the virus and reduced
influenza-associated mortality.[9,18] Beneficial effects on
immune function were also shown in patients at risk of
influenza infection (section 8.1) and in postmenopausal
women (section 8.2). Therefore, NAC can protect against
viral infection by improving the defenses against the
Fig. 13
Immunomodulatory
effects of
N-acetylcysteine (NAC).
In vitro
Protected lymphocytes from the toxic activity of
reactive oxygen species[21]
Improved immune function of macrophages from mice
with endotoxin-induced oxidative stress[69]
Improved immune function of lymphocytes from mice
with endotoxin-induced oxidative stress[70]
Animal models
Increased the resistance to influenza virus[9]
Pretreatment reduced the virus-induced activation of
oxidase-sensitive transcription factors[20]
Pretreatment reduced the release of inflammatory
cytokines[20]
Reduced the mortality of mice intranasally infected
with influenza virus[18]
Increased the antiviral activity of ribavirin in a
synergistic manner[19]
virus and by protecting against the development of
inflammation in the lung (figure 13).
Viral infections
Oxidative stress
Redox imbalance
Increase in inflammatory mediators
Decreased function of immune cells
NAC
Increased antioxidant
ability and restablished
cellular redox
equilibrium
Increased function of
immune cells
Prevented cell
membrane damage and
controlled release of
proinflammatory
cytokines
Decreased frequency
and severity of
infections
18
Improved defenses
against infections
Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders
with NAC than with placebo.[72] Of the 46 influenza-like
episodes in the NAC-treatment group, 72% were
classified as mild, 25% as moderate, and 2% as severe. In
comparison, of the 99 episodes within the placebo group,
48%, 47%, and 6% were classified as mild, moderate, or
severe, respectively.
The incidence of specific local influenza-like symptoms
(coryza/rhinorrhea, sore throat, catarrh and cough) and
general influenza-like symptoms (headache, myalgia)
was significantly lower with NAC than with placebo
(all p < 0.05).[72] This indicates that NAC, in addition
to its mucolytic effects, also has antioxidant and
immunomodulatory activity.
Relative to placebo, NAC also significantly reduced the
length of time spent in bed due to influenza-like
symptoms.[72] Indeed, 9 of the 10 patients with influenzalike symptoms who were not bedridden were receiving
NAC. Conversely, of the 25 patients who were
bedridden for ≥ 6 days, only 3 patients were in the
NAC-treatment group.
The frequency of seroconversion towards influenza virus
was similar in the NAC and placebo-treatment groups
(29% vs 24%), indicating that NAC did not prevent
subclinical infections. However, significantly fewer NAC
recipients developed a symptomatic form of the condition
(figure 15). This indicates that NAC had a protective effect
with respect to clinically evident disease. In those patients
who did not undergo seroconversion towards the virus
(71% vs 76%), the proportion of patients experiencing an
influenza-like episode was numerically, but not
8.1 Clinical Trials
8.1.1 Effect on Influenza-like Symptoms
NAC reduced both the frequency and severity of
influenza-like episodes in a randomized, double-blind
trial (table VIII).[71] Treatment with oral NAC 600mg
twice daily for 6 months attenuated influenza-like
symptomatology relative to placebo in patients without
chronic respiratory diseases (the majority of the 190
evaluable patients were aged ≥ 65 years).[72] The frequency
of influenza-like symptoms was significantly less with
NAC than with placebo (figure 14). When assessed on a
monthly basis, significant between-group differences in the
frequency of influenza-like episodes were shown during
the period of greatest seasonal incidence of influenza in
Europe (i.e. during the winter months of December to
March [2–4 months after beginning treatment]).
The severity of influenza-like symptoms was also less
Table VIII Summary of the immunomodulatory activity of
N-acetylcysteine in patients with nonrespiratory chronic
degenerative diseases[71]
Decreased the severity of influenza-like episodes
Decreased the incidence of specific local and general
influenza-like symptoms
Decreased the length of time spent in bed due to
influenza-like symptoms
Protective effect with respect to clinically evident
disease
Shift from anergy to normergy in cell-mediated
immunity
60
NAC
Placebo
50
Influenza-like episodes (% of patients)
Fig. 14
Efficacy of oral N-acetylcysteine
(NAC) 600mg twice daily
compared with placebo in the
attenuation of influenza-like
symptoms. Proportion of
patients experiencing influenzalike symptoms during the total
duration of ≥ 5 months
treatment and on a monthly
basis.[71]
* p < 0.05, ** p < 0.01,
*** p = 0.0006 vs placebo.
40
30
***
20
*
10
**
**
0
Total treatment
duration
1 month
2 months
3 months
Monthly assessment
19
4 months
5 months
6 months
Current Therapeutics
significantly, lower with NAC than with placebo (figure 15).
Following NAC treatment, there was a progressive,
significant shift from anergy to normergy in an
evaluation of cell-mediated immunity.[72] In general,
anergy was defined as a lack of skin reactivity to any of
the 7 tested antigens; hypoergic as skin reactivity to ≤ 2 of
the 7 antigens; and normergy as skin reactivity to ≥ 3
antigens. As is common in elderly patients, a relatively
high proportion of the patients in both of the treatment
groups were anergic (≈20%) or hypoergic (≈48%) at the
beginning of the trial. Throughout the study, there was
significant increase from the baseline in the proportion of
patients who were normergic in the NAC treatment
NAC
90
Placebo
80
Influenza-like episodes (% of patients)
Fig. 15
Efficacy of oral N-acetylcysteine
(NAC) 600mg twice daily
compared with placebo in
patients with or without
seroconversion towards
influenza virus. Proportion of
patients experiencing influenzalike symptoms as related to
seroconversion towards
influenza virus.[71]
* p < 0.0001 vs placebo.
group, but not in the placebo treatment group (figure 16).
The change in the proportion of normergic patients was
significantly greater with NAC than with placebo
(p < 0.05).
These changes in cell-mediated immunity confirm the
immunomodulatory properties of NAC. Patients who are
elderly and/or have chronic pathological conditions are
particularly vulnerable to viral respiratory diseases, as
there is a general impairment in immune defenses, loss of
antioxidants and reduced function of immunocompetent
systems. Therefore, NAC may be of benefit in boosting the
immune response in elderly and high-risk individuals
during the influenza season.
70
60
50
40
30
*
20
10
0
Seroconversion
Baseline
60
6 months
*†
50
Normergy (% of patients)
Fig. 16
Effect of oral N-acetylcysteine
(NAC) 600mg twice daily
compared with placebo on cellmediated immunity. Proportion
of patients with cell-mediated
normergy at baseline and after 6
months of treatment.[71]
* p < 0.001 vs baseline;
† p < 0.05 vs placebo.
No seroconversion
40
30
20
10
0
NAC
20
Placebo
Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders
lymphoproliferation in response to PHA and IL-2
liberation. The immune function values at the end of
treatment in the older group were either significantly
better or similar to baseline values in the younger group.
This indicates that, in older people, NAC can restore some
immune functions.
8.1.2 Effects on Aging-Related Changes in Immune
Function
NAC improved age-related deterioration of immune
function in a study in 36 postmenopausal women (18
aged 50–60 years and 18 aged > 70 years).[22,23] The women,
who were in overall good health, received oral NAC
600mg once daily for 2 months.
NAC significantly improved the immune function of
neutrophilsandoflymphocytes(tableIX),[22,23] indicating that
there was a decrease in the oxidative stress of the cell and
rejuvenation of immune function.[22,23] Improvements from
baseline were significant for all values in each of the age
groups and in the combined treatment groups (figure 17).[73]
Immune function of neutrophils and lymphocytes in the
older women was restored to that of younger women.[73]
Improvements from baseline in age-depressed immune
function in the group aged >70 years were generally
greater than those in the group aged 50–60 years (figure 17).
At the beginning of treatment, baseline values for immune
function parameters had deteriorated in the older
age group compared with values in the younger age
group, being significantly different in the case of
Effect on neutrophils[22]
Effect on lymphocytes[23]
Reduced adhesion
Reduced adhesion
Reduced superoxide levels Reduced secretion of
tumour necrosis factor-α
Stimulated mobility
towards the infectious
center
Stimulated mobility
towards the infectious
center
Stimulated phagocytosis of Stimulated production of
strange particles
interleukin-2
Stimulated the
proliferation response to
phytohemagglutinin
Stimulated ‘natural killer’
activity
Combined groups
100
Age 50-60y
Age >70y
Change from baseline (%)
90
80
70
60
50
40
30
20
10
0
0
Neutrophil
chemotaxis
Neutrophil
adhesion
Lymphocyte
chemotaxis
Lymphocyte
adhesion
–5
Change from baseline (%)
Fig. 17
Effect of oral
N-acetylcysteine (NAC)
600mg/day on markers of
immune function.
Percentage change from
baseline in immune function
values in postmenopausal
women receiving oral NAC
600mg/day for 2 months.[72]
Values are shown for the
combined treatment groups
and in groups stratified
by age (50-60 years
and > 70 years).
IL = interleukin;
NK = natural killer;
PHA = phytohemagglutinin;
SO = superoxide;
TNF = tumour necrosis
factor-α. All changes from
baseline were significant
(p ≤ 0.05).
Table IX Effects of oral N-acetylcysteine on the immune function of
neutrophils and leukocytes in postmenopausal women.
–10
–15
–20
–25
–30
–35
–40
21
Phagocytosis
Proliferation
response to PHA
TNF
production
IL-2
production
Basal SO
levels
NK
activity
Stimulated
SO levels
Current Therapeutics
9. Tolerability
9.1 General Profile
patients (4%) had minor adverse effects, and all patients
considered there were no safety issues.
Oral NAC has a general tolerability profile similar to that
of placebo.[41,74] Adverse events occur infrequently, are
generally mild in severity and resolve without medical
intervention. When they do occur, adverse events include
gastrointestinal effects (e.g. pyrosis, nausea, vomiting,
and diarrhea), headache, fever, and hypersensitivity
reactions (e.g. urticaria).[25]
In a summary of tolerability data from nine randomized,
controlled clinical trials of oral NAC 300–600mg/day
administered for 6 to 180 days in adults or children with
respiratory conditions,[74] there was no difference between
NAC and placebo in the incidence of adverse events
(based on adverse events leading to the withdrawal of
treatment). These events were generally gastrointestinal
in nature (gastric pyrosis, nausea, dyspepsia, diarrhea,
stypsis, and rarely vomiting). The exceptions to
gastrointestinal events were urticaria and itching in one
patient receiving NAC and two patients receiving
placebo.
Similar results were shown in a meta-analysis of 23
randomized, controlled trials of oral mucolytic drugs,
primarily NAC, in patients with stable bronchitis or
COPD.[41] The frequency of adverse events was similar
between mucolytic and placebo recipients.
The frequency of adverse events suspected to be
associated with oral NAC have been estimated from
spontaneous or solicited reports from physicians in
clinical practice in Europe (table X).[74]
The once-daily effervescent tablet formulation of NAC
600mg is at least as effective and well tolerated as NAC
200mg three times daily.[75] Higher dosages of NAC than
those commonly used as mucolytics are also well
tolerated.[72] In the study of oral NAC as an influenza
prophylactic, the proportion of patients reporting
adverse events was not significantly different between
NAC 600mg twice daily and placebo (9% vs 5%).[72]
Moreover, there were no significant differences between
treatment groups for any of the individual adverse events.
Oral NAC is also well tolerated in children.[46] In the study
in children with obstructive bronchial diseases,[46] oral
NAC was well tolerated by 96% of patients (64 of 67
patients reported good acceptance and safety). Only three
Table X Adverse events possibly associated with oral N-acetylcysteine
(NAC) based on reports by prescribing physicians in Europe[74]
Rating
Adverse event
Occasional (1–10% of
patients)
Gastric events (pyrosis,
nausea), intestinal events
(diarrhea, stypsis) and
dyspepsia
Rare (<1% of patients)
Urticaria/itching, anorexia,
vomiting, abdominal
distension and
dizziness/malaise
Once only
Asthma worsening,
dyspnea and lessening of
phenprocoumon effects
Once only but causal
association with NAC
deemed unlikely by
reporting physicians
Alopecia and menorrhagia
Table XI Laboratory indices that were not changed following
treatment with oral N-acetylcysteine in clinical trials in patients
with respiratory conditions or in healthy volunteers[74]
22
Parameter
Indices
Coagulation
Prothrombin, thrombin,
Factors VII and X,fibrinogen,
platelet aggregation
Hematological
Hematocrit, hemoglobin,
red blood cells, white blood
cells, platelets, erythrocyte
sedimentation rate
Hepatic
Aspartate aminotransferase,
alanine aminotransferase,
alkaline phosphatase,
orthinine carbamyl
transferase, bilirubin
Fecal
Occult blood
Immunoglobulins
Serum IgA, IgG, IgM, sputum
IgA
Other blood chemistry
Serum protein fractions,
cholesterol, glucose
Renal
Blood urea nitrogen, serum
creatinine, urinalysis
Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders
9.2 Gastrointestinal Events
gastroduodenal lesions (edema, hyperemia, erosions or
ulcerations) or pathological changes.[76]
Although most adverse events are gastrointestinal in nature,
therapeutic doses of oral NAC do not cause a loss of blood in
the gastrointestinal tract.[74] Moreover, oral NAC taken on a
full or empty stomach does not adversely affect the stomach
or duodenum as assessed by gastroduodenal endoscopy or
histological examination.[76] In a placebo-controlled endoscopic study of therapeutic dosages of oral NAC (200mg
two to three times daily for 14 days) in patients with
bronchopneumopathies, NAC was not associated with any
9.3 Laboratory Parameters
Oral NAC was not associated with changes in values of
laboratory tests in clinical trials in patients with
respiratory conditions (table XI).[74] Oral NAC did not
affect hematological, coagulation, platelet aggregation,
hepatic, renal, immunoglobulin, serum protein fractions,
cholesterol or glucose values.
23
Current Therapeutics
10. Dosage and Administration
NAC is available as an over-the-counter product in the
form of granules or effervescent tablets for oral solution,
and oral solution.[25]
A summary of product information is presented in
table XII.[25]
Oral NAC is indicated in acute respiratory conditions
associated with cough (e.g. productive cough, acute
bronchitis and influenza; figure 1).[25] It reduces the
viscosity and facilitates expulsion of mucous secretions
and has a protective action on the respiratory system.
Table XII Summary of product information for oral N-acetylcysteine (NAC)[25]
Indications for use in respiratory
conditions
Respiratory conditions characterized by the formation of dense, difficult-toexpectorate secretions
Mechanism of action
Mucolytic, antioxidant and anti-inflammatory
Usual dosage in acute conditions
Children (aged 2–12y)
Adults
Adverse effects
Contraindications
All formulations
Granules and effervescent tablets
Granules
Ready-to-use syrup
Precautions
All formulations
Effervescent tablets
Potential drug interactions
300-600mg/day
600mg/day divided into one or more administrations (e.g. 200mg three times
daily or 600mg as a single dose)
Occur rarely
Gastrointestinal effects: pyrosis, nausea, vomiting, diarrhea
Other: urticaria, headache, fever
Predisposed patients: hypersensitivity reactions (e.g. urticaria, bronchospasm)
Unpleasant breath odor: probably due to the breaking of mucous disulfide
bonds
Hypersensitivity to any of the ingredients
Active gastroduodenal ulcer
Phenylketonuria: these formulations contain aspartame (as an excipient),
which metabolizes to phenylalanine
Fructose intolerance: this formulation contains sorbitol (as an excipient),
which metabolizes to fructose
Confirmed hypersensitivity to preservative agents E218 or E211: this
formulation contains E218 and E211
Asthma, a past history of bronchospasm or other serious respiratory
insufficiency, as NAC may increase obstruction of the respiratory tract or
induce bronchospasm
Risk of gastrointestinal bleeding (e.g. history of peptic ulceration or
esophagus varices), as oral NAC may induce vomiting
Pregnancy: animal studies did not show any teratogenic effects, but the
administration of NAC during pregnancy must be supervised by a physician
Breast feeding: there is a lack of data on the passage of NAC into breast
milk, however discontinuation of lactation is advised when receiving NAC
therapy
Hypertension or other conditions in which salt use is to be avoided: this
formulation contains 140mg sodium (350mg sodium chloride); therefore, use
one of the salt-free formulations
Concomitant treatment with certain antibacterials or metal salts: a 2-hour
interval should separate their administration
Availability
Granules for oral solution
Ready-to-use oral solution
Effervescent tablets for oral solution
100, 200 and 600mg sachets
2% (100mg/5mL)
200 and 600mg
Storage
All products
Ready-to-use-syrup after opening
Away from light in a dry place at room temperature
15 days at room temperature
24
Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders
11. Conclusions
mucous. In addition, its antioxidant, anti-inflammatory,
and immunomodulatory effects offer protection against
inhaled oxidants, are beneficial in attenuating influenzalike symptoms and rejuvenate immune function of
neutrophils and lymphocytes in older patients.
An overall summary of the clinical benefits of the use of
NAC in treating acute respiratory conditions is presented
in table XIII.
The oral formulation of NAC is convenient and easy-touse, and represents a useful option in the treatment of
patients with acute respiratory conditions (figure 1). NAC
safely and effectively reduces mucous and cough in adults
andchildrenwithacute respiratory disorders. Its mucolytic
effects in breaking disulfide bonds in mucous and
enhancing mucociliary transport are useful in respiratory
conditions associated with dense difficult-to-expectorate
Table XIII Summary of the overall clinical benefits of oral N-acetylcysteine (NAC) in the treatment of acute respiratory conditions
• Mucolytic, antioxidant, anti-inflammatory and
immunomodulatory effects
• Mucolytic effect involves decreasing mucous viscosity and
improving mucociliary transport
• Antioxidant effects are both direct and indirect
• Anti-inflammatory effects involve antioxidant properties,
re-establishment of the cellular reductive-oxidative
equilibrium and preventing the release of inflammatory
cytokines
• May be used in combination with
antibacterials in patients with acute
respiratory infections with mucopurulent
sputum
• Confers protection against cigarette
smoking and air-borne pollution
• Decreases the severity and frequency of
influenza-like symptoms in high-risk
patients
• Immune effects involve antioxidant protection against
oxidative stress and improving the function of some
immune cells
• Restores age-related deterioration of
immune function
• Effective in a wide range of acute respiratory disorders in
adults and children
• Tolerability profile similar to that of
placebo
• Very well tolerated in adults and children
25
Current Therapeutics
12. References
1. Ziment I. Acetylcysteine: a drug with an interesting past and a
fascinating future. Respiration 1986; 50 Suppl. 1: 26-30
22. Arranz L, Rodríguez A, Fernández C, et al. Un tratamiento de 2 meses
con N-acetilcisteína mejora la función leucocitaria en mujeres mayores de
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