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Pronunciation | /əˌsiːtəlˈsɪstiːn/ and similar ( /əˌsɛtəl-,ˌæsɪtəl-,-tiːn/ ) |
Trade names | ACC 200, Acetadote, Fluimucil, Mucomyst, others |
Other names | N-acetylcysteine; N-acetyl-L-cysteine; NALC; NAC |
AHFS/Drugs.com | Monograph |
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Routes of administration | By mouth, intravenous, inhalation |
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Pharmacokinetic data | |
Bioavailability | 10% (Oral) [6] |
Protein binding | 50 to 83% [7] |
Metabolism | Liver [7] |
Elimination half-life | 5.6 hours [5] |
Excretion | Kidney (30%), [7] faecal (3%) |
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ECHA InfoCard | 100.009.545 |
Chemical and physical data | |
Formula | C5H9NO3S |
Molar mass | 163.19 g·mol−1 |
3D model (JSmol) | |
Specific rotation | +5° (c = 3% in water) [9] |
Melting point | 109 to 110 °C (228 to 230 °F) [9] |
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Acetylcysteine, also known as N-acetylcysteine (NAC), is a medication that is used to treat paracetamol overdose and to loosen thick mucus in individuals with chronic bronchopulmonary disorders like pneumonia and bronchitis. [7] It has been used to treat lactobezoar in infants. It can be taken intravenously, by mouth, or inhaled as a mist. [7] Some people use it as a dietary supplement. [10] [11]
Common side effects include nausea and vomiting when taken by mouth. [7] The skin may occasionally become red and itchy with any route of administration. [7] A non-immune type of anaphylaxis may also occur. [7] It appears to be safe in pregnancy. [7] For paracetamol overdose, it works by increasing the level of glutathione, an antioxidant that can neutralise the toxic breakdown products of paracetamol. [7] When inhaled, it acts as a mucolytic by decreasing the thickness of mucus. [12]
Acetylcysteine was initially patented in 1960 and came into medical use in 1968. [13] [14] [15] It is on the World Health Organization's List of Essential Medicines. [16] [17] It is available as a generic medication. [18]
The sulfur-containing amino acids cysteine and methionine are more easily oxidized than the other amino acids. [19] [20]
Intravenous and oral formulations of acetylcysteine are available for the treatment of paracetamol (acetaminophen) overdose. [21] When paracetamol is taken in large quantities, a 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. [22] 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. [22] Research suggests that the rate of liver toxicity is approximately 3% when acetylcysteine is administered within 10 hours of overdose. [21]
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 oral bioavailability, [23] its foul taste and odour, and a higher incidence of adverse effects when taken by mouth, particularly nausea and vomiting. Prior pharmacokinetic studies of acetylcysteine did not consider acetylation as a reason for the low bioavailability of acetylcysteine. [24] Oral acetylcysteine is identical in bioavailability to cysteine precursors. [24] However, 3% to 6% of people given intravenous acetylcysteine show a severe, anaphylaxis-like allergic reaction, which may include extreme breathing difficulty (due to bronchospasm), a decrease in blood pressure, rash, angioedema, and sometimes also nausea and vomiting. [25] 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. [26] [27] [28] [29]
Inhaled acetylcysteine has been used for mucolytic ("mucus-dissolving") 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 in tracheotomy care. It may be considered ineffective in cystic fibrosis. [30] A 2013 Cochrane review in cystic fibrosis found no evidence of benefit. [31]
Acetylcysteine is used in the treatment of obstructive lung disease as an adjuvant treatment. [32] [33] [34]
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. [35] N-acetylcysteine can be used to protect the liver. [36]
Acetylcysteine can be used in Petroff's method of liquefaction and decontamination of sputum, in preparation for recovery of mycobacterium. [37] It also displays significant antiviral activity against the influenza A viruses. [38]
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 . [39]
The most commonly reported adverse effects for IV formulations of acetylcysteine are rash, urticaria, and itchiness. [22]
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. [40]
Adverse effects for oral formulations of acetylcysteine have been reported to include nausea, vomiting, rash, and fever. [40]
Large doses in a mouse model showed that acetylcysteine could potentially cause damage to the heart and lungs. [41] They found that acetylcysteine was metabolized to S-nitroso-N-acetylcysteine (SNOAC), 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. [41] In humans, a much lower dosages (600 mg per day) have been observed to counteract some age-related decline in the hypoxic ventilatory response as tested by inducing prolonged hypoxia. [42]
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. [43]
Acetylcysteine serves as a prodrug to L-cysteine, a precursor to the biologic antioxidant glutathione. Hence administration of acetylcysteine replenishes glutathione stores. [44]
L-cysteine 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. [50] [51] 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. [48] 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). [52]
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.
N-acetyl-L-cysteine is soluble in water and alcohol, and practically insoluble in chloroform and ether. [53]
It is a white to white with light yellow cast powder, and has a pKa of 9.5 at 30 °C. [9]
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. [54] [55] [56] [57] In April 2022, the FDA released draft guidance on FDA's policy regarding products labeled as dietary supplements that contain N-acetyl-L-cysteine. [58] Amazon subsequently re-listed NAC products as of August 2022. [59]
While many antioxidants have been researched to treat a large number of diseases by reducing the negative effect of oxidative stress, acetylcysteine is one of the few that has yielded promising results, and is currently already approved for the treatment of paracetamol overdose. [60]
Evidence for the benefit of acetylcysteine to prevent radiocontrast induced kidney disease is mixed. [73]
Acetylcysteine has been used for cyclophosphamide-induced haemorrhagic cystitis, although mesna is generally preferred due to the ability of acetylcysteine to diminish the effectiveness of cyclophosphamide. [74]
Acetylcysteine has been studied for major psychiatric disorders, [75] [52] [48] [62] including bipolar disorder, [75] major depressive disorder, and schizophrenia. [52] [48]
Tentative evidence exists for N-acetylcysteine also in the treatment of Alzheimer's disease, autism, obsessive-compulsive disorder, [76] specific drug addictions (cocaine), drug-induced neuropathy, trichotillomania, excoriation disorder, and a certain form of epilepsy (progressive myoclonic). [52] [48] [77] Preliminary evidence showed efficacy in anxiety disorder, attention deficit hyperactivity disorder and mild traumatic brain injury although confirmatory studies are required. [77] [78] [79] [80] Tentative evidence also supports use in cannabis use disorder. [81]
It is also being studied for use as a treatment of body-focused repetitive behavior. [82] [83]
Evidence to date does not support the efficacy for N-acetylcysteine in treating addictions to gambling, methamphetamine, or nicotine. [77] Based upon limited evidence, NAC appears to normalize glutamate neurotransmission in the nucleus accumbens and other brain structures, in part by upregulating the expression of excitatory amino acid transporter 2 (EAAT2), a.k.a. glutamate transporter 1 (GLT1), in individuals with addiction. [69] While NAC has been demonstrated to modulate glutamate neurotransmission in adult humans who are addicted to cocaine, NAC does not appear to modulate glutamate neurotransmission in healthy adult humans. [69] NAC has been hypothesized to exert beneficial effects through its modulation of glutamate and dopamine neurotransmission as well as its antioxidant properties. [48]
In bipolar disorder, N-acetylcysteine has been repurposed as an augmentation strategy for depressive episodes in light of the possible role of inflammation in the pathogenesis of mood disorders. Nonetheless, meta-analytic evidence shows that add-on N-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. [75] [84]
Acetylcysteine is being considered as a possible treatment for COVID-19. [85] [86] [87]
A combination of guanfacine and N-acetylcysteine has been found to lift the "brain fog" of eight patients with long COVID, according to researchers. [88]
A combination of glycine and N-acetylcysteine is suspected to have potential to safely replenish depleted glutathione levels in COVID-19 patients. [89]
Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression and pain management. It is a novel compound that was derived from phencyclidine in 1962 in pursuit of a safer anesthetic with fewer hallucinogenic effects.
Glutathione is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, peroxides, lipid peroxides, and heavy metals. It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side chain and cysteine. The carboxyl group of the cysteine residue is attached by normal peptide linkage to glycine.
Paracetamol is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely used over the counter medication. Common brand names include Tylenol and Panadol.
Riluzole is a medication used to treat amyotrophic lateral sclerosis and other motor neuron diseases. Riluzole delays the onset of ventilator-dependence or tracheostomy in some people and may increase survival by two to three months. Riluzole is available in tablet and liquid form.
Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation. It is a widely explored treatment option for many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxin consumption. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation. Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own. Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are glutamate antagonists and antioxidants, which aim to limit excitotoxicity and oxidative stress respectively.
Chronic liver disease in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis. "Chronic liver disease" refers to disease of the liver which lasts over a period of six months. It consists of a wide range of liver pathologies which include inflammation, liver cirrhosis, and hepatocellular carcinoma. The entire spectrum need not be experienced.
Cysteamine is a chemical compound that can be biosynthesized in mammals, including humans, by the degradation of coenzyme A. The intermediate pantetheine is broken down into cysteamine and pantothenic acid. It is the biosynthetic precursor to the neurotransmitter hypotaurine.
NAPQI, also known as NAPBQI or N-acetyl-p-benzoquinone imine, is a toxic byproduct produced during the xenobiotic metabolism of the analgesic paracetamol (acetaminophen). It is normally produced only in small amounts, and then almost immediately detoxified in the liver.
Glutathione synthetase (GSS) is the second enzyme in the glutathione (GSH) biosynthesis pathway. It catalyses the condensation of gamma-glutamylcysteine and glycine, to form glutathione. Glutathione synthetase is also a potent antioxidant. It is found in many species including bacteria, yeast, mammals, and plants.
Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat postpartum depression. It is given by injection into a vein.
Quisqualic acid is an agonist of the AMPA, kainate, and group I metabotropic glutamate receptors. It is one of the most potent AMPA receptor agonists known. It causes excitotoxicity and is used in neuroscience to selectively destroy neurons in the brain or spinal cord. Quisqualic acid occurs naturally in the seeds of Quisqualis species.
Thiocolchicoside is a muscle relaxant with anti-inflammatory and analgesic effects. Its mechanism of action is unknown, but it is believed to be act via antagonism of nicotinic acetylcholine receptors (nAchRs). However, it also appears to be a competitive antagonist of GABAA and glycine receptors. As such, it has powerful convulsant activity and should not be used in seizure-prone individuals.
Bucillamine is an antirheumatic agent developed from tiopronin. Activity is mediated by the two thiol groups that the molecule contains. Research done in USA showed positive transplant preservation properties. Bucillamine is currently being investigated for COVID-19 drug repurposing.
Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the NFE2L2 gene. NRF2 is a basic leucine zipper (bZIP) protein that may regulate the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation, according to preliminary research. In vitro, NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encoding cytoprotective proteins. NRF2 induces the expression of heme oxygenase 1 in vitro leading to an increase in phase II enzymes. NRF2 also inhibits the NLRP3 inflammasome.
Glutamate–cysteine ligase (GCL) EC 6.3.2.2), previously known as γ-glutamylcysteine synthetase (GCS), is the first enzyme of the cellular glutathione (GSH) biosynthetic pathway that catalyzes the chemical reaction:
Cystine/glutamate transporter is an antiporter that in humans is encoded by the SLC7A11 gene.
Paracetamol poisoning, also known as acetaminophen poisoning, is caused by excessive use of the medication paracetamol (acetaminophen). Most people have few or non-specific symptoms in the first 24 hours following overdose. These symptoms include feeling tired, abdominal pain, or nausea. This is typically followed by absence of symptoms for a couple of days, after which yellowish skin, blood clotting problems, and confusion occurs as a result of liver failure. Additional complications may include kidney failure, pancreatitis, low blood sugar, and lactic acidosis. If death does not occur, people tend to recover fully over a couple of weeks. Without treatment, death from toxicity occurs 4 to 18 days later.
N-Acetylcarnosine (NAC) is a naturally occurring compound chemically related to the dipeptide carnosine. The NAC molecular structure is identical to carnosine with the exception that it carries an additional acetyl group. The acetylation makes NAC more resistant to degradation by carnosinase, an enzyme that breaks down carnosine to its constituent amino acids, beta-alanine and histidine.
Nitrotyrosine is a product of tyrosine nitration mediated by reactive nitrogen species such as peroxynitrite anion and nitrogen dioxide. Nitrotyrosine is identified as an indicator or marker of cell damage, inflammation as well as NO (nitric oxide) production. Nitrotyrosine is formed in the presence of the active metabolite NO. Generally in many disease states, oxidative stress increases the production of superoxide (O2−) and NO forming peroxynitrite (ONOO−) a destructive free radical oxidant. The production of ONOO− is capable of oxidizing several lipoproteins and of nitrating tyrosine residues in many proteins. It is difficult to determine the production of ONOO− so, usually nitrotyrosine in proteins are the detectable marker for indirectly detecting ONOO−. It is detected in large number of pathological conditions and is considered a marker of NO-dependent, reactive nitrogen species-induced nitrative stress. Nitrotyrosine is detected in biological fluids such as plasma, lung aspirants-BALF (Broncho alveolar lining fluid) and urine. Increased level of nitrotyrosine is detected in rheumatoid arthritis, septic shock and coeliac disease. In all these studies nitrotyrosine was undetected in healthy subjects. Nitrotyrosine is also found in numerous other disease-affected tissues, such as the cornea in keratoconus. Peroxynitrite and/or nitrative stress may participate in the pathogenesis of diabetes.
Boldine is an alkaloid of the aporphine class that can be found in the boldo tree. It is the most abundant aporphine alkaloid found in Boldo. Boldine is also found in Lindera aggregata.