Acetylcysteine

Medical uses Paracetamol overdose antidote Intravenous and oral formulations of acetylcysteine are available for the treatment of paracetamol (acetaminophen) overdose. When paracetamol is taken in large quantities, a toxic minor metabolite called N-acetyl-p-benzoquinone imine (NAPQI) accumulates within the body. It is normally conjugated by glutathione, 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 damaging liver cells. This may lead to severe liver damage and even death by acute 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. its foul taste and odor, and a higher incidence of adverse effects when taken orally, particularly nausea and vomiting. Prior pharmacokinetic studies of acetylcysteine did not consider acetylation as a reason for the low bioavailability of acetylcysteine. Oral acetylcysteine is identical in bioavailability to cysteine precursors. 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. Mucolytic agent Acetylcysteine exhibits mucolytic properties, meaning it reduces the viscosity and adhesiveness of mucus. This therapeutic effect is achieved through the cleavage of disulfide bonds within mucoproteins (strongly cross-linked mucins), 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, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, rhinitis or sinusitis. Acetylcysteine can be administered as a part of a complex molecule, thiamphenicol glycinate acetylcysteine, which also contains thiamphenicol, an antibiotic. Lungs Inhaled acetylcysteine is also used post-operatively, as a diagnostic aid, and in tracheotomy care. It may be considered ineffective in cystic fibrosis. A 2013 Cochrane review in cystic fibrosis found no evidence of benefit. Acetylcysteine is used in the treatment of obstructive lung disease as an adjuvant treatment. Other uses Acetylcysteine has been used to complex palladium, to help it dissolve in water. This helps to remove palladium from drugs or precursors synthesized by palladium-catalyzed coupling reactions. N-acetylcysteine can be used to protect the liver. Microbiological use Acetylcysteine can be used in Petroff's method of liquefaction and decontamination of sputum, in preparation for recovery of mycobacterium. It also displays significant antiviral activity against influenza A viruses. Acetylcysteine has bactericidal properties and breaks down bacterial biofilms of clinically relevant pathogens including Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis, Enterobacter cloacae, Staphylococcus epidermidis, and Klebsiella pneumoniae. ==Side effects==

The most commonly reported adverse effects for I.V. formulations of acetylcysteine are rash, urticaria, and itchiness. Adverse effects for oral formulations of acetylcysteine have been reported to include nausea, vomiting, rash, and fever. They found that acetylcysteine was metabolized to S-nitroso-N-acetylcysteine (''''), which increased blood pressure in the lungs and right ventricle of the heart (pulmonary artery hypertension) in mice treated with acetylcysteine. The effect was similar to that observed following a 3-week exposure to an oxygen-deprived environment (chronic hypoxia). The authors also found that SNOAC induced a hypoxia-like response in the expression of several important genes both in vitro and in 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. Although N-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. ==Pharmacology==

Pharmacodynamics Acetylcysteine serves as a prodrug to L-cysteine, a precursor to the biologic antioxidant glutathione. Hence administration of acetylcysteine replenishes glutathione stores. • Glutathione, along with oxidized glutathione (GSSG) and S-nitrosoglutathione (GSNO), have been found to bind to the glutamate recognition site of the NMDA and AMPA receptors (via their γ-glutamyl moieties), and may be endogenous neuromodulators. At millimolar concentrations, they may also modulate the redox state of the NMDA receptor complex. As such, since N-acetylcysteine is a prodrug of glutathione, it may modulate all of the aforementioned receptors as well. • Glutathione also modulates the NMDA receptor by acting at the redox site. Acetylcysteine also serves as a precursor to cystine, which in turn serves as a substrate for the cystine-glutamate antiporter on astrocytes; hence there is increasing glutamate release into the extracellular space. This glutamate in turn acts on mGluR2/3 receptors, and at higher doses of acetylcysteine, mGluR5. 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 inhibiting NF-κB and modulating cytokine synthesis. 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). As mentioned before, acetylcysteine clears mucus by opening disulfide bonds. Pharmacokinetics 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 a half-life of 5.6 hours in adults and 11 hours in newborns. Acetylcysteine is the N-acetyl derivative of the amino acid L-cysteine, and is a precursor in the formation of the antioxidant glutathione in the body. The thiol (sulfhydryl) group confers antioxidant effects and is able to reduce free radicals. ==Chemistry==

Pure acetylcysteine is in a solid state at room temperature, appearing as a white crystalline powder or granules. 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. Acetylcysteine is highly hygroscopic, i.e., it absorbs moisture if exposed to open air. N-acetyl-L-cysteine is soluble in water and alcohol, and practically insoluble in chloroform and ether. 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. 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. ==Society and culture==

, with brand 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 the Food and Drug Administration (FDA) of it being classified as a drug rather than a supplement. In April 2022, the FDA released draft guidance on its policy regarding products labeled as dietary supplements that contain N-acetyl-L-cysteine. Amazon subsequently re-listed NAC products as of August 2022. ==Research==

Acetylcysteine is under preliminary research for its potential to treat androgenetic alopecia (male baldness), with or without adjacent treatments such as with minoxidil. Acetylcysteine may have otoprotective properties and could be useful for preventing hearing loss and tinnitus in some cases. Acetylcysteine may be an adjunct therapy for the treatment of addiction to cocaine, nicotine, alcohol, and other drugs. Psychiatry Acetylcysteine has been studied for major psychiatric disorders, including bipolar disorder, Preliminary research indicates N-acetylcysteine may be useful in treating obsessive-compulsive disorder, specific drug addictions (cocaine), drug-induced neuropathy, trichotillomania, excoriation disorder, and a certain form of epilepsy (progressive myoclonic). Addiction Evidence to date does not support the efficacy for N-acetylcysteine in treating addictions to gambling, methamphetamine, or nicotine. COVID-19 Acetylcysteine has been studied as a possible treatment for COVID-19, but according to a paper published in 2023 it has not improved patient outcomes by common measures. == External links ==