Common side effects include nausea and vomiting when taken orally.[9] The skin may occasionally becomered anditchy with any route of administration.[9] A non-immune type ofanaphylaxis may also occur.[9] It appears to be safe in pregnancy.[9] For paracetamol overdose, it works by increasing the level ofglutathione, an antioxidant that can neutralize the toxic breakdown products of paracetamol.[9] When inhaled, it acts as amucolytic by decreasing the thickness of mucus.[15]
Intravenous and oral formulations of acetylcysteine are available for the treatment ofparacetamol (acetaminophen) overdose.[23] When paracetamol is taken in large quantities, a minor metabolite calledN-acetyl-p-benzoquinone imine (NAPQI) accumulates within the body. It is normallyconjugated byglutathione, but when taken in excess, the body's glutathione reserves are not sufficient to deactivate the toxic NAPQI. This metabolite is then free to react with key hepatic enzymes, thereby damagingliver cells. This may lead to severe liver damage and even death byacute liver failure.
In the treatment of paracetamol (acetaminophen) overdose, acetylcysteine acts to maintain or replenish depleted glutathione reserves in the liver and enhance non-toxic metabolism of acetaminophen.[24] These actions serve to protect liver cells from NAPQI toxicity. It is most effective in preventing or lessening hepatic injury when administered within 8–10 hours after overdose.[24] Research suggests that the rate of liver toxicity is approximately 3% when acetylcysteine is administered within 10 hours of overdose.[23]
Although IV and oral acetylcysteine are equally effective for this indication, oral administration is generally poorly tolerated due to the higher dosing required to overcome its low oralbioavailability,[25] its foul taste and odor, and a higher incidence ofadverse effects when taken orally, particularly nausea and vomiting. Prior pharmacokinetic studies of acetylcysteine did not consideracetylation as a reason for the low bioavailability of acetylcysteine.[26] Oral acetylcysteine is identical in bioavailability to cysteine precursors.[26] However, 3% to 6% of people given intravenous acetylcysteine show a severe,anaphylaxis-like allergic reaction, which may include extreme breathing difficulty (due tobronchospasm),a decrease in blood pressure, rash,angioedema, and sometimes also nausea and vomiting.[27] Repeated doses of intravenous acetylcysteine will cause these allergic reactions to progressively worsen in these people.
Several studies have found this anaphylaxis-like reaction to occur more often in people given intravenous acetylcysteine despite serum levels of paracetamol not high enough to be considered toxic.[28][29][30][31]
Acetylcysteine exhibitsmucolytic properties, meaning it reduces the viscosity and adhesiveness ofmucus. This therapeutic effect is achieved through the cleavage ofdisulfide bonds[32] withinmucoproteins (strongly cross-linkedmucins),[33] thereby decreasing the mucus viscosity and facilitating its clearance from the respiratory tract. This mechanism is particularly beneficial in conditions characterized by excessive or thickened mucus,[34] such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, rhinitis or sinusitis.[35] Acetylcysteine can be administered as a part of a complex molecule,Thiamphenicol glycinate acetylcysteine, which also containsthiamphenicol, an antibiotic.[36]
Inhaled acetylcysteine has been used formucolytic therapy in addition to other therapies in respiratory conditions with excessive and/or thick mucus production. It is also used post-operatively, as a diagnostic aid, and intracheotomy care. It may be considered ineffective incystic fibrosis.[37] A 2013 Cochrane review in cystic fibrosis found no evidence of benefit.[38]
Acetylcysteine has been used tocomplexpalladium, to help it dissolve in water. This helps to remove palladium from drugs or precursors synthesized by palladium-catalyzedcoupling reactions.[42]N-acetylcysteine can be used to protect the liver.[43]
Acetylcysteine can be used in Petroff's method of liquefaction and decontamination ofsputum, in preparation for recovery ofmycobacterium.[44] It also displays significant antiviral activity againstinfluenza A viruses.[45]
The most commonly reported adverse effects for IV formulations of acetylcysteine are rash,urticaria, anditchiness.[24]
Adverse effects for inhalational formulations of acetylcysteine include nausea, vomiting,stomatitis, fever,rhinorrhea, drowsiness, clamminess, chest tightness, and bronchoconstriction. Although infrequent, bronchospasm has been reported to occur unpredictably in some patients.[47]
Adverse effects for oral formulations of acetylcysteine have been reported to include nausea, vomiting, rash, and fever.[47]
Large doses in a mouse model showed that acetylcysteine could potentially cause damage to theheart andlungs.[48] They found that acetylcysteine wasmetabolized toS-nitroso-N-acetylcysteine (SNOAC), which increasedblood pressure in the lungs andright ventricle of the heart (pulmonary artery hypertension) inmice treated with acetylcysteine. The effect was similar to that observed following a 3-week exposure to an oxygen-deprived environment (chronichypoxia). The authors also found that SNOAC induced a hypoxia-like response in theexpression of several importantgenes bothin vitro andin vivo. The implications of these findings for long-term treatment with acetylcysteine have not yet been investigated. The dose used by Palmer and colleagues was dramatically higher than that used in humans, the equivalent of about 20 grams per day.[48] In humans, much lower dosages (600 mg per day) have been observed to counteract some age-related decline in thehypoxic ventilatory response as tested by inducing prolongedhypoxia.[49]
AlthoughN-acetylcysteine prevented liver damage in mice when taken before alcohol, when taken four hours after alcohol it made liver damage worse in a dose-dependent fashion.[50]
Acetylcysteine serves as aprodrug toL-cysteine, a precursor to the biologic antioxidantglutathione. Hence administration of acetylcysteine replenishes glutathione stores.[51]
L-cysteine also serves as a precursor tocystine, which in turn serves as a substrate for thecystine-glutamate antiporter onastrocytes; hence there is increasing glutamate release into the extracellular space. This glutamate in turn acts onmGluR2/3 receptors, and at higher doses of acetylcysteine,mGluR5.[57][58] Acetylcysteine may have other biological functions in the brain, such as the modulation of dopamine release and the reduction in inflammatory cytokine formation possibly via inhibitingNF-κB and modulating cytokine synthesis.[55] These properties, along with the reduction of oxidative stress and the re-establishment of glutamatergic balance, would lead to an increase in growth factors, such as brain-derived neurotrophic factor (BDNF), and the regulation of neuronal cell death through B-cell lymphoma 2 expression (BLC-2).[59]
The oral bioavailability of acetylcysteine is relatively low due to extensive first-pass metabolism in the gut wall and liver. It ranges between 6% and 10%.
Intravenous administration of acetylcysteine bypasses the first-pass metabolism, resulting in higher bioavailability compared to oral administration. Intravenous administration of acetylcysteine ensures nearly 100% bioavailability as it directly enters the bloodstream.
Acetylcysteine is extensively liver metabolized, CYP450 minimal, urine excretion is 22–30% with ahalf-life of 5.6 hours in adults and 11 hours in newborns.[medical citation needed]
Acetylcysteine is theN-acetyl derivative of the amino acidL-cysteine, and is a precursor in the formation of the antioxidantglutathione in the body. Thethiol (sulfhydryl) group confers antioxidant effects and is able toreducefree radicals.
Pure acetylcysteine is in a solid state at room temperature, appearing as a white crystalline powder or granules.[60] The solid form of acetylcysteine is stable under normal conditions, but it can undergo oxidation if exposed to air or moisture over time, leading to the formation of its dimeric form, diacetylcysteine, which can have different properties.[61] Acetylcysteine is highly hygroscopic, i.e., it absorbs moisture if exposed to open air.[60]
Acetylcysteine can sometimes appear as a light yellow cast powder instead of pure white due to oxidation. The sulfur-containing amino acids, like cysteine, are more easily oxidized than other amino acids. When exposed to air or moisture, acetylcysteine can oxidize, leading to a slight yellowish tint.[60]
Acetylcysteine in a form of a white or white with light yellow cast powder has apKa of 9.5 at 30 °C.[11]
N-acetyl-L-cysteine is soluble in water and alcohol, and practically insoluble in chloroform and ether.[62]
Acetylcysteine is highly soluble in water: it dissolves readily in water, forming a clear solution. The pH of a maximum-saturated acetylcysteine solution typically ranges between 6.0 and 7.5,[63] depending on temperature, purity of the compound, presence of other ions (that can affect the pH by interacting with acetylcysteine or altering the overall ionic strength of the solution), thus on the concentration of acetylcysteine itself: higher concentrations of acetylcysteine can lead to a lower pH due to the increased presence of the acetylcysteine molecule itself. This range of pH between 6.0 and 7.5 ensures that the solution is neither too acidic nor too alkaline, making it suitable for various medical applications. Aqueous solutions of acetylcysteine are compatible with 0.9% sodium chloride solution; compatibility with 5% and 10% glucose solutions is also good.[60]
As for the sunlight stability, acetylcysteine in dry powder form is relatively stable and does not degrade quickly when exposed to sunlight, but when dissolved in aqueous solution, acetylcysteine can degrade when exposed to sunlight, especially if the solution is not stored in a dark, cool place. Besides that, acetylcysteine in aqueous solution can undergo hydrolysis, leading to the breakdown of the amide bond in the molecule. Still, aqueous solutions of acetylcysteine are generally stable when stored properly: the solutions should be kept in tightly sealed containers and stored at controlled room temperature to prolong the stability.[64][60]
Acetylcysteine was first studied as a drug in 1963. Amazon removed acetylcysteine for sale in the US in 2021, due to claims by the FDA of it being classified as a drug rather than a supplement.[65][66][67][68] In April 2022, the FDA released draft guidance on FDA's policy regarding products labeled as dietary supplements that containN-acetyl-L-cysteine.[69] Amazon subsequently re-listed NAC products as of August 2022.[70]
While manyantioxidants have been researched to treat a large number of diseases by reducing the negative effect ofoxidative stress, acetylcysteine is one of the few that has yielded promising results, and is currently already approved for the treatment of paracetamol overdose.[71]
In mousemdx models ofDuchenne's muscular dystrophy, treatment with 1–2% acetylcysteine in drinking water significantly reduces muscle damage and improves strength.[71]
It is being studied in conditions such asautism, where cysteine and related sulfur amino acids may be depleted due to multifactorial dysfunction of methylation pathways involved inmethionine catabolism.[72]
Animal studies have also demonstrated its efficacy in reducing the damage associated with moderate traumatic brain or spinal injury, and also ischaemia-induced brain injury. In particular, it has been demonstrated to reduce neuronal losses and to improve cognitive and neurological outcomes associated with these traumatic events.[73]
Research on acetylcysteine usage seems to show a positive efficiency in treatingandrogenetic alopecia (male baldness), with or without adjacent treatments such as the use of topicalminoxidil solution.[74]
Research on mouse models also shows that acetylcysteine could be "used as an efficient and safe therapeutic option for hair loss induced bychemotherapy".[75]
It has been suggested that acetylcysteine may help people withaspirin-exacerbated respiratory disease by increasing levels of glutathione allowing faster breakdown ofsalicylates, although there is no evidence that it is of benefit.[76]
Small studies have shown acetylcysteine to be of benefit to people withblepharitis.[77] It has been shown to reduce ocular soreness caused bySjögren's syndrome.[78]
Research has found that acetylcysteine may have otoprotective properties and could potentially be useful for preventinghearing loss andtinnitus in some cases.[79][80] A 2011 study showed thatN-acetylcysteine may protect the human cochlea from subclinical hearing loss caused by loud noises such as impulse noise.[81] In animal models, it reduced age-related hearing loss.[citation needed]
It has been shown effective in the treatment ofUnverricht-Lundborg disease in an open trial in four patients. A marked decrease in myoclonus and some normalization of somatosensory evoked potentials with acetylcysteine treatment has been documented.[82][83]
Addiction to certain addictive drugs (includingcocaine,heroin,alcohol, andnicotine) is correlated with a persistent reduction in the expression ofexcitatory amino acid transporter 2 (EAAT2) in thenucleus accumbens (NAcc);[84] the reduced expression of EAAT2 in this region is implicated in addictive drug-seeking behavior.[84] In particular, the long-term dysregulation of glutamate neurotransmission in the NAcc of long-term, drug-dependent users is associated with an increase in vulnerability torelapse after re-exposure to the addictive drug or its associateddrug cues.[84] Drugs that help to normalize the expression of EAAT2 in this region, such asN-acetylcysteine, have been proposed as anadjunct therapy for the treatment of addiction to cocaine, nicotine, alcohol, and other drugs.[84]
It has been tested for the reduction of hangover symptoms, though the overall results indicate very limited efficacy.[85][86]
A double-blind placebo controlled trial of 262 patients has shown NAC treatment was well-tolerated and resulted in a significant decrease in the frequency of influenza-like episodes, severity, and length of time confined to bed.[87]
N-acetylcysteine has been widely believed to prevent adverse effects of long termKetamine use on the bladder and kidneys, and there is growing body of evidence to support this.[88]
Acetylcysteine has been used forcyclophosphamide-induced haemorrhagiccystitis, althoughmesna is generally preferred due to the ability of acetylcysteine to diminish the effectiveness of cyclophosphamide.[90]
Inbipolar disorder,N-acetylcysteine has been repurposed as an augmentation strategy for depressive episodes in light of the possible role of inflammation in the pathogenesis ofmood disorders. Nonetheless, meta-analytic evidence shows that add-onN-acetylcysteine was more effective than placebo only in reducing depression scales scores (low quality evidence), without positive effects on response and remission outcomes, limiting its possible role in clinical practice to date.[91][100]
Acetylcysteine has been studied as a possible treatment forCOVID-19, but has not improved patient outcomes by common measures.[101][102]
A combination ofguanfacine andN-acetylcysteine has been found to lift the "brain fog" of eight patients withlong COVID, according to researchers, but the results are inconclusive and have not been confirmed by other studies.[103]
A combination ofglycine andN-acetylcysteine is suspected to have potential to safely replenish depletedglutathione levels in COVID-19 patients.[104]
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