What is NAC? Side Effects, Dosage, Mechanism, Reviews

What is the mechanism of action of N -acetylcysteine (NAC) in the treatment of acetaminophen toxicity/poisoning?

What is NAC? Side Effects, Dosage, Mechanism, Reviews

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Source: https://www.medscape.com/answers/820200-27203/what-is-the-mechanism-of-action-of-n--acetylcysteine-nac-in-the-treatment-of-acetaminophen-toxicitypoisoning

A Review on Various Uses of N-Acetyl Cysteine

What is NAC? Side Effects, Dosage, Mechanism, Reviews

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Biological Activities and Potential Oral Applications of N-Acetylcysteine: Progress and Prospects

What is NAC? Side Effects, Dosage, Mechanism, Reviews

N-Acetylcysteine (NAC), a cysteine prodrug and glutathione (GSH) precursor, has been used for several decades in clinical therapeutic practices as a mucolytic agent and for the treatment of disorders associated with GSH deficiency.

Other therapeutic activities of NAC include inhibition of inflammation/NF-κB signaling and expression of proinflammatory cytokines. N-Acetylcysteine is also a nonantibiotic compound possessing antimicrobial property and exerts anticarcinogenic and antimutagenic effects against certain types of cancer.

Recently, studies describing potentially important biological and pharmacological activities of NAC have stimulated interests in using NAC-based therapeutics for oral health care. The present review focused on the biological activities of NAC and its potential oral applications.

The potential side effects of NAC and formulations for drug delivery were also discussed, with the intent of advancing NAC-associated treatment modalities in oral medicine.

1. Introduction

N-acetylcysteine (NAC) possesses therapeutic effects over a wide range of disorders. These disorders include cystic fibrosis, acetaminophen poisoning, chronic obstructive pulmonary disease, chronic bronchitis, doxorubicin-induced cardiotoxicity, human immunodeficiency virus infection, heavy metal toxicity, and psychiatric/neurological disorders [1].

Being a N-acetyl derivative of the amino acid L-cysteine, NAC is a cysteine prodrug and glutathione (GSH) precursor that helps scavenge free radicals and bind metal ions into complexes [1] (Figure 1).

Because NAC possesses anti-inflammatory activity via inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and modulation of proinflammatory cytokine synthesis [2], it has been used for modulating oxidative stress- and inflammation-related diseases [3].

Although NAC is not an antibiotic, it possesses antimicrobial properties and breaks down bacterial biofilms of medically relevant pathogens [4]. These characteristics render NAC a potential candidate for managing oral diseases.

The oral cavity is the first point of entry for different forms of environmental insults, including toxic chemicals, microbial infections, and mechanical injury. These insults generate oxidative stress, induce inflammation, and may even initiate cancer (Figure 2).

Some dental materials such as resins, metals, and ceramics are cytotoxic and have the potential to induce oxidative stress, DNA damage, inflammatory reactions, and cell death via apoptosis [5–7]. Disturbances in the regulation of the host inflammatory responses to bacterial infection in the dental pulp and periodontal tissues result in pulpitis and periodontitis [8].

Cigarette smoking, alcohol consumption, and betel nut chewing increase the risk of oral cancer [9].

Mechanical stresses produced during physiological masticatory activities, orthodontic tooth movement, or occlusal trauma, as well as heat stresses caused by tooth cavity preparation, light-initiated resin polymerization, or laser irradiation, may create oxidative stresses and inflammatory reactions in the dental pulp, resulting in pulpal necrosis [10, 11].

Hence, there is a need for oral cells and tissues to efficiently detoxify xenobiotic toxicity, neutralize oxidative stress, kill invading pathogens, and eliminate inflammatory responses. In light of its potentially important biological and pharmacological activities, NAC has been advocated as a therapeutic agent in oral health care [12].

The present review focuses on the biological activities of NAC and its potential oral applications. The review also explores the potential side effects of NAC and its medical formulations. Understanding the actions of NAC and its biological effects on oral pathological processes is helpful in the design of future clinical trials and expedites clinical translation of the use of this drug in oral medicine.

2. Antioxidation Activity

Intracellular oxidative stress occurs when reactive oxygen species (ROS)/reactive nitrogen species (RNS) are produced beyond the cell’s antioxidation capacity. Excessive oxidative stress results in oxidative modification of proteins, lipids, DNA, and subsequent cell death [13].

This process contributes to numerous pathological conditions including oral diseases [14]. Antioxidants, either natural or synthetic, are effective in diminishing the cumulative effects of oxidative stress and NAC is of particular interest.

N-Acetylcysteine is a direct antioxidant that interacts with the electrophilic groups of free radicals through its free thiol side-chain. The rate constants of the reactions of NAC with various substrates under experimental conditions are summarized in Table 1.

Because NAC reacts rapidly with hydroxyl radical (·OH), nitrogen dioxide (·NO2), and carbon trioxide ion (CO3·−), it detoxifies ROS produced by leukocytes [15]. Although NAC does not react directly with nitric oxide (NO), it reacts with its reduced and protonated form, nitroxyl (HNO) [16].

In addition, NAC chelates transition metal ions such as Cu2+ and Fe3+, as well as heavy metal ions such as Cd2+, Hg2+, and Pb2+, through its thiol side-chain to produce complexes. This chelation process facilitates removal of these metal ions from the body [17].

CompoundsRate constant (M−1 s−1)Experimental conditionsReference
CO3·−≈1.0 × 1071.8 × 108pH = 7; RTpH = 12; RT[90]
HNO5.0 × 105pH = 7.4; 37°C[91]
HOCl>107pH ≈ 7.4; 21–24°C[92]
HOSCN7.7 × 103pH = 7.4; 22°C[93]
H2O20.16 ± 0.010.85 ± 0.09pH = 7.4; 25°CpH = 7.4; 37°C[94][95]
·NO2≈2.4 × 108≈1.0 × 107pH > pKa; RTpH = 7.4; RT[96]
O2·−68 ± 6

Source: https://www.hindawi.com/journals/omcl/2018/2835787/

What is NAC? Side Effects, Dosage, Mechanism, Reviews

What is NAC? Side Effects, Dosage, Mechanism, Reviews

NAC is essential for the human body’s antioxidant defenses. Read on to learn about how it works, what dosages have worked, and what the dangers are.

What is NAC?

Your body uses N-acetyl cysteine (NAC) to make its own antioxidants. Medically, it is used to treat acetaminophen toxicity; it is almost 100% effective as long as it’s given within the first eight hours after overdose [1, 2].

For all other purposes, NAC is an unapproved supplement. Preliminary evidence may look promising (and in some cases, very promising!), but future studies may find that NAC is actually ineffective for some of these purposes.

It’s important to talk to your doctor before adding NAC to your health strategies, as it may have unexpected interactions.

Antioxidant Activity

NAC (short for N-Acetyl Cysteine) is transformed into the amino acid cysteine in the body.

Why should you care about cysteine? For one, it is the most important amino acid (along with glycine and glutamine) for the formation of glutathione, the body’s strongest antioxidant [1].

In other words, if glutathione is “the mother of all antioxidants,” then cysteine would be the grandmother.

Since cysteine levels can determine how much and how fast glutathione is made, NAC is essential in replenishing levels of this antioxidant. Glutathione (reduced glutathione or GSH) removes free radicals from cells and activates detox pathways [3, 4].

Cysteine also contains sulfur, which is essential for glutathione to work. Aside from boosting glutathione, NAC can directly fight free radicals [1, 5].

Its antioxidant effects protect DNA, cells, tissues, and organs from damage, inflammation, and harmful substances. For this reason, its benefits range from brain protection to liver support to balancing mood. NAC can also break down and soften mucus, which can improve symptoms of lung diseases [1, 6].

Importantly, NAC has been thoroughly researched. The number of clinical, animal, and cell studies that explored the benefits of NAC are almost impossible to list. There are close to a thousand clinical trials of NAC alone!

However, while most studies on NAC have found at least marginal benefits, a lot have had mixed results. That’s why the FDA still considered the evidence insufficient to recommend NAC for most health conditions.

Side Effects

NAC seems to be a safe substance with few known side effects. Occasionally, oral supplements can cause digestive issues such as [7, 8, 9]:

  • Nausea
  • Vomiting
  • Diarrhea
  • Constipation

NAC blocks an enzyme called DAO (by about 20%). Since DAO breaks down histamine, it is possible that NAC may trigger a histamine reaction in some people. Low DAO can cause food sensitivities, skin reactions, flushing, asthma, gastrointestinal problems, and other symptoms [10, 11, 12].

Because of the sulfur-containing cysteine, NAC does smell bad (sulfur smells rotten eggs), which makes the powder form unappealing for most people.

Sensitive Groups

People with severe liver damage can’t make glutathione (GSH) from cysteine and may need to take GSH itself [13].

Since NAC can impact the platelets and reduce coagulation, consult your doctor if you [14]:

  • Have a bleeding disorder
  • Are having surgery soon
  • Take blood-thinning medications

In rats, high doses of NAC (12 mg/kg/day) impaired the blood vessels in the brain. Clinical trials haven’t confirmed this effect [15, 16].

Children and pregnant women should avoid NAC unless prescribed by their doctor.

Supplement Dosage

Remember that NAC is not approved by the FDA for any purpose except to treat acetaminophen toxicity. That means that there is no official safe dose of NAC.

1800 – 2,400mg of NAC was very common across clinical studies, typically divided into 2-3 doses throughout the day.

Some studies for fighting addiction and mental health issues used doses closer to 3,000 mg/day.

For general wellness or gut health, 600 mg a day is the typical dose.

A maximum safe dose of NAC has yet to be determined.

Is It In Food?

The simple answer is no.

NAC is not found in foods. However, you can get cysteine — the amino acid NAC releases — from various foods.

L-cysteine in Food

As an amino acid, cysteine is found in protein-rich foods. The other sulfur-containing amino acid is methionine, which also helps make glutathione [17].

Food sources of cysteine (which also provide methionine) include [17]:

  • Red meat and poultry (equal cysteine/methionine ratio)
  • Eggs (higher in cysteine)
  • Fish (higher in methionine)
  • Dairy (higher in methionine)
  • Grains and starch-rich foods (higher in cysteine than in methionine)
  • Soybeans (lower in both amino acids than animal proteins)

Additionally, your body can make cysteine from other sulfur-containing compounds found in foods, such as [17]:

  • Garlic
  • Onions
  • Broccoli and other cruciferous vegetables

Your body uses sulfur for sulfation, a crucial detox pathway, and to make other important compounds SAM. You detox drugs such as acetaminophen (Tylenol) via sulfation, and they deplete your glutathione reserves [17].

This means that reducing your intake of acetaminophen-containing OTC painkillers Tylenol can lower the strain on your liver, lower your dietary sulfur requirements, and allow your body to make better use of sulfur compounds.

Further Reading

Source: https://selfhacked.com/blog/n-acetyl-cysteine-nac/