Acetylcysteine
Acetylcysteine, also known as "N"-acetylcysteine (NAC), is a medication that is used to treat paracetamol (acetaminophen) overdose, and to loosen thick mucus in individuals with chronic bronchopulmonary disorders like pneumonia and bronchitis. It has been used to treat lactobezoar in infants. It can be taken intravenously, by mouth, or inhaled as a mist. Some people use it as a dietary supplement. Common side effects include nausea and vomiting when taken by mouth. The skin may occasionally become red and itchy with any route of administration. A non-immune type of anaphylaxis may also occur. It appears to be safe  in pregnancy. For paracetamol overdose, it works by increasing the level of glutathione, an antioxidant that can neutralise the toxic breakdown products of paracetamol. When inhaled, it acts as a mucolytic by decreasing the thickness of mucus. Acetylcysteine was initially patented in 1960 and came into medical use in 1968. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication and is inexpensive. Uses. Paracetamol overdose. Intravenous and oral formulations of acetylcysteine are available for the treatment of paracetamol (acetaminophen) overdose. 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. 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. Research suggests that the rate of liver toxicity is approximately 3% when acetylcysteine is administered within 10 hours of overdose. 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, 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. Oral acetylcysteine is identical in bioavailability to cysteine precursors. 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. 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 IV acetylcysteine despite serum levels of paracetamol not high enough to be considered toxic. Lungs. 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. 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. Kidney and bladder. Evidence for the benefit of acetylcysteine to prevent radiocontrast induced kidney disease is mixed. 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. Psychiatry. Acetylcysteine has been studied for major psychiatric disorders, including bipolar disorder, major depressive disorder, and schizophrenia. Tentative evidence exists for "N"-acetylcysteine also in the treatment of Alzheimer's disease, autism, obsessive-compulsive disorder, specific drug addictions (cocaine), drug-induced neuropathy, trichotillomania, excoriation disorder, and a certain form of epilepsy (progressive myoclonic). Preliminary evidence showed efficacy in anxiety disorder, attention deficit hyperactivity disorder and mild traumatic brain injury although confirmatory studies are required. Tentative evidence also supports use in cannabis use disorder. Bipolar disorder. 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. Addiction. Evidence to date does not support the efficacy for "N"-acetylcysteine in treating addictions to gambling, methamphetamine, or nicotine. 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), glutamate transporter 1 (GLT1), in individuals with addiction. 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. NAC has been hypothesized to exert beneficial effects through its modulation of glutamate and dopamine neurotransmission as well as its antioxidant properties. Microbiological use. Acetylcysteine can be used in Petroff's method i.e. liquefaction and decontamination of sputum, in preparation for recovery of mycobacterium. It also displays significant antiviral activity against the  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". 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"-actelylcysteine can be used to protect the liver. Side effects. The most commonly reported adverse effects for IV formulations of acetylcysteine are rash, urticaria, and itchiness. Up to 18% of patients have been reported to experience anaphylaxis reaction, which are  defined as rash, hypotension, wheezing, and/or shortness of breath. Lower rates of anaphylactoid reactions have been reported with slower rates of infusion. 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. Adverse effects for oral formulations of acetylcysteine have been reported to include nausea, vomiting, rash, and fever. Large doses in a mouse model showed that acetylcysteine could potentially cause damage to the heart and lungs. 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 . Nonetheless, positive effects on age-diminished control of respiration (the hypoxic ventilatory response) have been observed previously in human subjects at more moderate doses. Although "N"-acetylcysteine prevented liver damage 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. 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 mGluR receptors, and at higher doses of acetylcysteine, mGluR. Acetylcysteine also possesses some anti-inflammatory effects possibly via inhibiting NF-κB and modulating cytokine synthesis. Pharmacokinetics. 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 neonates. Chemistry. 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. It is a white to white with light yellow cast powder, and has a pKa of 9.5 at 30 °C. Dosage forms. Acetylcysteine is available in different dosage forms for different indications: The IV injection and inhalation preparations are, in general, prescription only, whereas the oral solution and the effervescent tablets are available over the counter in many countries. Acetylcysteine is available as a health supplement in the United States, typically in capsule form. Society and culture. NAC was  first studied as a drug in 1963. Amazon removed NAC for sale in the US in 2021, due to claims by the FDA of it being classified as a drug rather than a supplement. Research. 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. Psychiatry. Acetylcysteine has been studied for a number of psychiatric disorders. Several reviews found tentative evidence for "N"-acetylcysteine in the treatment of  Alzheimer's disease, autism, bipolar disorder, drug-induced neuropathy, major depressive disorder, obsessive-compulsive disorder, schizophrenia, specific drug addictions (cocaine), trichotillomania, excoriation disorder, and a certain form of epilepsy (progressive myoclonic). Preliminary evidence showed efficacy in anxiety disorder, attention deficit hyperactivity disorder and mild traumatic brain injury although confirmatory studies are required. Tentative evidence also supports use in cannabis use disorder. Bipolar disorder. 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.