Common side effects include nausea and vomiting when taken orally.[10] The skin may occasionally becomered anditchy with any route of administration.[10] A non-immune type ofanaphylaxis may also occur.[10] It appears to be safe in pregnancy.[10] For paracetamol overdose, it works by increasing the level ofglutathione, an antioxidant that can neutralize the toxic breakdown products of paracetamol.[10] When inhaled, it acts as amucolytic by decreasing the thickness of mucus.[17]
Intravenous and oral formulations of acetylcysteine are available for the treatment ofparacetamol (acetaminophen) overdose.[25] When paracetamol is taken in large quantities, a toxic 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.[6] 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.[6] Research suggests that the rate of liver toxicity is approximately 3% when acetylcysteine is administered within 10 hours of overdose.[25]
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,[26] 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.[27] Oral acetylcysteine is identical in bioavailability to cysteine precursors.[27] 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.[28] 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.[29][30][31][32]
Acetylcysteine exhibitsmucolytic properties, meaning it reduces the viscosity and adhesiveness ofmucus. This therapeutic effect is achieved through the cleavage ofdisulfide bonds[33] withinmucoproteins (strongly cross-linkedmucins),[34] 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,[35] such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, rhinitis or sinusitis.[36] Acetylcysteine can be administered as a part of a complex molecule,thiamphenicol glycinate acetylcysteine, which also containsthiamphenicol, an antibiotic.[37]
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.[38] A 2013 Cochrane review in cystic fibrosis found no evidence of benefit.[39]
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.[43]N-acetylcysteine can be used to protect the liver.[44]
Acetylcysteine can be used in Petroff's method of liquefaction and decontamination ofsputum, in preparation for recovery ofmycobacterium.[45] It also displays significant antiviral activity againstinfluenza A viruses.[46]
The most commonly reported adverse effects for I.V. formulations of acetylcysteine are rash,urticaria, anditchiness.[6]
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.[48]
Adverse effects for oral formulations of acetylcysteine have been reported to include nausea, vomiting, rash, and fever.[48]
Large doses in a mouse model showed that acetylcysteine could potentially cause damage to theheart andlungs.[49] 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.[49] 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.[50]
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.[51]
Acetylcysteine serves as aprodrug toL-cysteine, a precursor to the biologic antioxidantglutathione. Hence administration of acetylcysteine replenishes glutathione stores.[52]
Acetylcysteine 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.[58][59] 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.[56] 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).[60]
As mentioned before, actylcysteine clears mucus by opening disulfide bonds.[33]
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.[61] 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.[62] Acetylcysteine is highly hygroscopic, i.e., it absorbs moisture if exposed to open air.[61]
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.[61]
Acetylcysteine in a form of a white or white with light yellow cast powder has apKa of 9.5 at 30 °C.[12]
N-acetyl-L-cysteine is soluble in water and alcohol, and practically insoluble in chloroform and ether.[63]
Acetylcysteine dissolves readily in water, forming a colorless solution. The pH of a 1% acetylcysteine solution in water typically ranges between 2.0 and 2.8.[64] Solutions with higher concentrations of acetylcysteine have lower pH. Aqueous solutions of acetylcysteine are compatible with 0.9% sodium chloride solution; compatibility with 5% and 10% glucose solutions is also good.[61]
As for photochemical stability, acetylcysteine in dry powder form is relatively stable and does not degrade quickly when exposed to light, but in aqueous solution, acetylcysteine can degrade when exposed to sunlight. In addition, 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.[65][61]
Acetylcysteine has been reported to have a pH of 2.2 when administered through inhalation.[66]
Acetylcysteine capsules sold by the supplement companyLife ExtensionOver-the-counter (OTC) Acetylcysteine pills inChina, withbrand name Fluimucil
Acetylcysteine was first studied as a drug in 1963.Amazon removed acetylcysteine for sale in the US in 2021, due to claims by theFood and Drug Administration (FDA) of it being classified as a drug rather than a supplement.[67][68][69][70] In April 2022, the FDA released draft guidance on its policy regarding products labeled as dietary supplements that containN-acetyl-L-cysteine.[71] Amazon subsequently re-listed NAC products as of August 2022.[72]
Acetylcysteine is under preliminary research for its potential to treatandrogenetic alopecia (male baldness), with or without adjacent treatments such as withminoxidil.[73] Acetylcysteine may have otoprotective properties and could be useful for preventinghearing loss andtinnitus in some cases.[74][75]
Acetylcysteine may be anadjunct therapy for the treatment of addiction to cocaine, nicotine, alcohol, and other drugs.[76]
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.[77][82]
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