Acetylcysteine

Acetylcysteine is a peripheral antitussive agent.

Acetylcysteine is used as a mucolytic agent in patients with certain lung conditions and as an antidote for acetaminophen overdose. It is also used to treat acute hepatic failure, prevention of contrast-induced nephropathy and topical treatment of keratoconjunctivitis sicca.

Acetylcysteine is Rapidly and almost completely absorbed from the gastrointestinal tract. Bioavailability: 4-10% (oral) and Crosses the placenta. Plasma protein binding: 66-87%.

it Undergoes extensive first-pass metabolism to form cysteine (active metabolite), N,N-diacetylcysteine and N-acetylcysteine; cysteine undergoes further metabolism to form glutathione and other metabolites.

and get excreted Via urine (13-38%; almost entirely as inactive metabolites).

The onset of action of acetylcysteine is within 5-10 minutes.

The duration of action was >1 hour.

The Tmax was Approx 1-3 hours (oral).

Acetylcysteine shows common side effects like Nausea, vomiting, stomatitis; diarrhoea, abdominal pain

Acetylcysteine is available in the form of tablet and solution

Acetylcysteine is available in India, Germany, Canada, Italy.

Acetylcysteine is an N-acetyl derivative of the amino acid L-cysteine. It exhibits its mucolytic action through its free sulfhydryl group that breaks up the disulfide linkages of mucoproteins, thus reducing mucous viscosity; this action may also benefit patients with ocular mucus abnormality. In paracetamol poisoning, acetylcysteine acts as a hepatoprotective agent by maintaining or restoring the hepatic glutathione levels, or by acting as an alternate substrate for conjugation with, and therefore detoxification of, the toxic intermediate metabolite (N-acetyl-p-benzoquinoneimine) of paracetamol.

Acetylcysteine is available in the form of tablet and solution.

Acetylcysteine is used as a mucolytic in patients with certain lung conditions and as an antidote for acetaminophen overdose.

Acetylcysteine acts as a hepatoprotective agent by restoring hepatic glutathione, serving as a glutathione substitute, and enhancing the nontoxic sulfate conjugation of acetaminophen.

Acetylcysteine is approved for use in the following clinical indications

Certain lung conditions and as an antidote for acetaminophen overdose.

Although not approved there have been certain off label use documented for Acetylcysteine which includes

Acute hepatic failure, prevention of contrast-induced nephropathy and topical treatment of keratoconjunctivitis sicca.

Oral

As a mucolytic

Adult: As adjunctive therapy for respiratory tract disorders associated with excessive, viscous mucus: As granules for oral solution: 200 mg 2-3 times daily. As effervescent tab: 600 mg once daily. Treatment duration may vary depending on the nature and severity of the disease. Dosage recommendations may vary among countries and individual products (refer to specific product guidelines).

Child: 2-6 years As granules for oral solution: 100 mg 2-4 times daily; >6 years Same as adult dose. Treatment or dosage recommendations may vary among countries and individual products (refer to specific product guidelines).

Reconstitution: Effervescent tab: Dissolve tab in a glass of water before administration. Granules for oral solution: Dissolve the contents of the sachet into a glass of water and stir with a spoon if necessary.

Incompatibility: Incompatible with certain metals (e.g. Fe, Cu), rubber, amphotericin B, ampicillin Na, erythromycin lactobionate, some tetracyclines, iodised oil, chymotrypsin, trypsin, and hydrogen peroxide.

Oral

Paracetamol poisoning

Adult: Initiate treatment as soon as possible following the overdose or within 24 hours of ingestion. As 5% oral solution (diluted 20% solution) or effervescent tab (diluted in appropriate volume of water): Loading dose: 140 mg/kg. Maintenance: 70 mg/kg 4 hourly for 17 doses. If emesis occurs within 1 hour of administration, repeat the dose. Refer to specific product guidelines for further dosing information.

Child: Same as adult dose.

Reconstitution: Effervescent tab: Dissolve tab in a glass of water before administration. As 5% oral solution: Dilute the 20% solution with diet cola or other diet soft drinks to achieve a final concentration of 5%. Refer to detailed product guidelines for specific instructions on preparation.

Incompatibility: Incompatible with certain metals (e.g. Fe, Cu), rubber, amphotericin B, ampicillin Na, erythromycin lactobionate, some tetracyclines, iodized oil, chymotrypsin, trypsin, and hydrogen peroxide.

Inhalation

As a mucolytic

Adult: As adjunctive therapy for respiratory tract disorders associated with excessive, viscous mucus: As 10% solution: 6-10 mL 3-4 times daily; if necessary, may give 2-20 mL 2-6 hourly. As 20% solution: 3-5 mL 3-4 times daily; if necessary, may give 1-10 mL 2-6 hourly. In preparation for diagnostic bronchial studies (bronchograms, bronchospirometry, bronchial wedge catheterisation): 2-4 mL of 10% solution or 1-2 mL of 20% solution to be given 2-3 times before the procedure. Doses are given via nebulisation (e.g. through a face mask or mouthpiece). Refer to specific product guidelines for further instructions on administration.

Reconstitution: As 20% solution: May dilute to a lesser concentration with 0.9% NaCl or sterile water for inj or inhalation.

Incompatibility: Incompatible with certain metals (e.g. Fe, Cu), rubber, amphotericin B, ampicillin Na, erythromycin lactobionate, some tetracyclines, iodised oil, chymotrypsin, trypsin, and hydrogen peroxide.

Endotracheal

As a mucolytic

Adult: As adjunctive therapy for respiratory tract disorders associated with excessive, viscous mucus: As 10% or 20% solution: 1-2 mL as often as every hour via direct instillation. Use in the routine nursing care of patients with tracheostomy: As 10 or 20% solution: 1-2 mL 1-4 hourly via instillation into the tracheostomy. Alternatively, 2-4 mL of 10% solution or 1-2 mL of 20% solution may be given 1-4 hourly through percutaneous intratracheal catheter. In preparation for diagnostic bronchial studies (bronchograms, bronchospirometry, bronchial wedge catheterisation): 2-4 mL of 10% solution or 1-2 mL of 20% solution to be given 2-3 times before the procedure.

Reconstitution: As 20% solution: May dilute to a lesser concentration with 0.9% NaCl or sterile water for inj or inhalation.

Incompatibility: Incompatible with certain metals (e.g. Fe, Cu), rubber, amphotericin B, ampicillin Na, erythromycin lactobionate, some tetracyclines, iodised oil, chymotrypsin, trypsin, and hydrogen peroxide.

Intravenous

Paracetamol poisoning

Adult: 21-hour regimen: Initially, 150 mg/kg in 200 mL of diluent via infusion over 1 hour, followed by 50 mg/kg in 500 mL of diluent infused over the next 4 hours and then 100 mg/kg in 1,000 mL of diluent infused over the next 16 hours. Treatment may be continued using the same dose and rate as the 3rd infusion depending on the individual clinical evaluation. Refer to specific product guidelines for further dosing information.

Child: 21-hour regimen: 5-20 kg: Initially, 150 mg/kg in 3 mL/kg of diluent via infusion over 1 hour, followed by 50 mg/kg in 7 mL/kg of diluent infused over 4 hours and then 100 mg/kg in 14 mL/kg of diluent infused over 16 hours; 21-40 kg: Initially, 150 mg/kg in 100 mL of diluent infused over 1 hour, followed by 50 mg/kg in 250 mL of diluent infused over 4 hours and then 100 mg/kg in 500 mL of diluent infused over 16 hours; ≥41 kg: Same as adult dose. Volume of the diluent must be adjusted to consider the age and weight of the patient. Recommendations may vary among countries and individual products (refer to specific product guidelines).

Reconstitution: IV: Dilute with 5% dextrose in water, 0.9% NaCl, sterile water for inj, or 0.45% NaCl solutions.

Incompatibility: Incompatible with certain metals (e.g. Fe, Cu), rubber, amphotericin B, ampicillin Na, erythromycin lactobionate, some tetracyclines, iodised oil, chymotrypsin, trypsin, and hydrogen peroxide.

Ophthalmic

Dry eye

Acetylcysteine is available in various strengths as 4 mL, 10 mL, 30 mL

Acetylcysteine is available in the form of tablet and solution.

• Dosage Adjustment in Kidney Patient

Oral, IV: There are no dosage adjustments provided in the manufacturer's labeling.

• Dosage Adjustment in Hepatic impairment Patient

Oral, IV: There are no dosage adjustments provided in the manufacturer's labeling.

• Dosage Adjustment for Pediatric Patients

Acetaminophen poisoning

Initiation of therapy:

• Ideally, in patients with an acute acetaminophen ingestion, treatment should begin within 8 hours of ingestion or as soon as possible after ingestion. If there will be a delay in obtaining a serum acetaminophen concentration, initiate treatment as soon as possible and reevaluate the need for continued acetylcysteine upon receipt of the results. In patients who meet the criteria for acetylcysteine therapy based on the initial serum acetaminophen concentration, there is no reason to obtain additional acetaminophen concentrations, even in a patient who ingested an extended-release product. In patients with a suspected acute ingestion where the time of ingestion is unknown, the serum acetaminophen concentration is unobtainable or uninterpretable within 8 hours of ingestion, the patient presents >8 hours after ingestion, or there is clinical evidence of toxicity, initiate treatment immediately and re-evaluate the need for acetylcysteine upon receipt of the results (if applicable). In patients who present following repeated supratherapeutic ingestions (RSTI) and treatment is deemed appropriate, acetylcysteine should be initiated immediately. It is critical that there is no delay in the administration of the loading dose of acetylcysteine and no delays in the administration of bags 2 and 3.
• Note: There is no reason to withhold activated charcoal in a patient with an acetaminophen overdose. If activated charcoal is administered within 1 to 2 hours postingestion of acetaminophen, it may provide additional hepatoprotection in patients requiring N-acetylcysteine treatment for acetaminophen overdose .
• Duration of therapy:
• Discontinue treatment if the initial serum acetaminophen concentration indicates the patient is at "low" risk for hepatotoxicity when plotted on the Rumack-Matthew nomogram. In those patients who require a follow-up acetaminophen concentration, do not discontinue treatment if the follow-up serum acetaminophen concentration indicates the patient is at "low" risk for hepatotoxicity. In patients who continue to experience symptoms of hepatotoxicity or elevated liver function tests at the conclusion of a 72-hour oral or 21-hour IV regimen, extending the treatment course may be appropriate; however, when and to which patients additional doses should be administered is unclear. Possible candidates for extended therapy include patients with a suspected massive overdose, concomitant ingestion of other substances, or patients with preexisting liver disease. In patients with persistently elevated acetaminophen concentrations, persistently elevated liver function tests, or an elevated INR, additional acetylcysteine should be administered. Typically, an additional "third dose" or "third bag" (IV: 100 mg/kg [maximum dose: 10 g/dose] infused over 16 hours) is administered; however, this dose may be inadequate in some patients. Regardless of the treatment regimen selected, serum acetaminophen concentrations, liver function, and clinical status should be evaluated during and prior to the end of the treatment regimen to determine if treatment discontinuation is appropriate. Some experts suggest continuing therapy until there are undetectable acetaminophen concentrations, improving hepatic aminotransferases, and improving prognostic markers (eg, creatinine, lactate pH, prothrombin time/INR, phosphate). In patients with a low risk for acetaminophen-induced hepatotoxicity, an abbreviated 12-hour N-acetylcysteine dosing regime has been compared to a 20-hour protocol; no difference was shown in measured acetaminophen metabolites or clinical outcomes. A two-bag regimen with the same total dose of 300 mg/kg has been used, but is not FDA-approved . Consultation with a poison control center or clinical toxicologist is highly recommended to determine optimal patient care.
• Oral: Effervescent tablet or solution for oral administration (using injectable/nebulizer formulation):
• Note: There is no data for use of the OTC supplement tablets for acetaminophen poisoning. Dosing below is based on effervescent tablet or a solution for oral administration that is prepared from the solution for oral inhalation:
• Infants, Children, and Adolescents: 72-hour regimen: Consists of 18 doses; total dose delivered: 1,330 mg/kg.
• Loading dose: Oral: 140 mg/kg; maximum dose: 15 g/dose.
• Maintenance dose: Oral: 70 mg/kg every 4 hours for 17 doses; maximum dose: 7.5 g/dose; repeat dose if emesis occurs within 1 hour of administration; Note: Although not FDA approved, some experts may recommend a shortened course of oral acetylcysteine therapy (<72 hours of treatment) under certain circumstances. Consultation with a poison control center or clinical toxicologist is highly recommended when considering the discontinuation of oral acetylcysteine prior to the conclusion of a full 18-dose course of therapy.
• IV: Acetadote:
• Three-bag method: Infants, Children, and Adolescents: 21-hour regimen: Consists of 3 doses; total dose delivered: 300 mg/kg.
• Loading dose: IV: 150 mg/kg infused over 60 minutes; maximum dose: 15 g/dose.
• Second dose: IV: 50 mg/kg infused over 4 hours; maximum dose: 5 g/dose.
• Third dose: IV: 100 mg/kg infused over 16 hours; maximum dose: 10 g/dose.
• Two-bag method: Limited data available: Note: The "two-bag method" has been associated with fewer and milder nonallergic anaphylactic reactions as compared to the manufacturer's labeled dosing.
• Children ≥12 years and Adolescents: 20-hour regimen: Consists of 2 doses; total dose delivered: 300 mg/kg; maximum total dose: 30 g:
• First dose: IV: 200 mg/kg infused over 4 hours.
• Second dose: IV: 100 mg/kg infused over 16 hours.

Respiratory conditions, adjuvant therapy: Note: Patients should receive an aerosolized bronchodilator 10 to 15 minutes prior to acetylcysteine:

• Nebulized inhalation:
• Face mask, mouthpiece, tracheostomy:
• Infants: 1 to 2 mL of 20% solution (may be further diluted with sodium chloride or sterile water for inhalation) or 2 to 4 mL of 10% solution (undiluted); administer 3 to 4 times daily.
• Children: 3 to 5 mL of 20% solution (may be further diluted with sodium chloride or sterile water for inhalation) or 6 to 10 mL of 10% solution (undiluted); administer 3 to 4 times daily.
• Adolescents: 3 to 5 mL of 20% solution (may be further diluted with sodium chloride or sterile water for inhalation) or 6 to 10 mL of 10% solution (undiluted); administer 3 to 4 times daily; usual dosing range: 20% solution: 1 to 10 mL or 10% solution: 2 to 20 mL every 2 to 6 hours.
• Tent, croupette: 10% or 20% solution: Dose must be individualized; dose is volume of solution necessary to maintain a very heavy mist in tent or croupette; in some cases, may require up to 300 mL solution/treatment.
• Direct instillation: Children and Adolescents:
• Endotracheal: 1 to 2 mL of 10% to 20% solution every 1 to 4 hours as needed.
• Percutaneous endotracheal catheter: 1 to 2 mL of 20% or 2 to 4 mL of 10% solution every 1 to 4 hours via syringe attached to catheter.

Diagnostic bronchogram: Children and Adolescents: Nebulization or endotracheal: 1 to 2 mL of 20% solution or 2 to 4 mL of 10% solution administered 2 to 3 times prior to procedure.

Distal intestinal obstruction syndrome (previously known as meconium ileus equivalent): Limited data available; dosing regimens variable (polyethylene glycol has become more widely used for this indication):

Oral:

Children <10 years: 30 mL of 10% solution diluted in 30 mL juice or soda 3 times/day for 24 hours.

Children 10 years and Adolescents: 60 mL of 10% solution diluted in 60 mL juice or soda 3 times/day for 24 hours.

Note: Prior to treatment, administer a phosphosoda enema. A clear liquid diet should be used during the 24-hour acetylcysteine treatment.

Rectal enema: Children: Varying dosages; 100 to 300 mL of 4% to 6% solution 2 to 4 times daily; 50 mL of 20% solution 1 to 4 times daily and 5 to 30 mL of 10% to 20% solution 3 to 4 times daily have been used; rectal enemas appear to have less favorable results than oral administration . Note: Higher concentrations (10% to 20%) appear to increase fluid in the bowel and lead to increased incidence of adverse effects

Hypersensitivity to acetylcysteine or any component of the formulation.

Effervescent tablet: There are no contraindications listed in the manufacturer's labeling.

Concerns related to adverse effects:

• Anaphylactoid reactions: Acute flushing and erythema have been reported; usually occurs within 30 to 60 minutes and may resolve spontaneously. Serious anaphylactoid reactions (some fatal) have also been reported and are more commonly associated with IV administration, but also occur with oral administration. When used for acetaminophen overdose, the incidence is reduced when the initial intravenous loading dose is administered over 60 minutes. The acetylcysteine infusion may be interrupted until the treatment of allergic symptoms is initiated; the infusion can then be carefully restarted. Treatment for anaphylactoid reactions should be immediately available. Conversely, patients with high acetaminophen concentrations (>150 mg/L) may be at a reduced risk for anaphylactoid reactions

• Fluid overload: IV administration can cause fluid overload, potentially resulting in hyponatremia, seizure and death. To avoid fluid overload in patients ≤40 kg and those requiring fluid restriction, decrease volume of diluent proportionally.

Disease-related concerns:

• Asthma/bronchospasm: Use caution in patients with asthma or history of bronchospasm; these patients may be at increased risk of hypersensitivity reactions.

• Common Adverse effects:

Nausea, vomiting, stomatitis; diarrhoea, abdominal pain, Pyrexia, chest tightness; malaise, facial pain.

• Less Adverse effects:

Rhinorrhoea; throat tightness, pharyngitis, rhonchi, cough, stridor (IV); tracheal and bronchial tracts irritation.

• Rare Adverse effects:

bronchospasm; serious skin reactions (e.g. Stevens-Johnson syndrome, Lyell's syndrome), generalised urticaria

Concomitant use with antitussives may lead to a build-up of secretions due to suppressed cough reflex; avoid concurrent use. May increase the vasodilatory and platelet aggregation-inhibiting effect of glyceryl trinitrate.

The common side effects of Acetylcysteine include the following Nausea, vomiting, stomatitis; diarrhoea, abdominal pain.

Symptoms: Nausea, vomiting, diarrhea, anaphylactoid reaction and bronchospasm (IV).

Management: Symptomatic and supportive treatment.

Pharmacodynamic

Acetylcysteine is an N-acetyl derivative of the amino acid L-cysteine. It exhibits its mucolytic action through its free sulfhydryl group that breaks up the disulfide linkages of mucoproteins, thus reducing mucous viscosity; this action may also benefit patients with ocular mucus abnormality. In paracetamol poisoning, acetylcysteine acts as a hepatoprotective agent by maintaining or restoring the hepatic glutathione levels, or by acting as an alternate substrate for conjugation with, and therefore detoxification of, the toxic intermediate metabolite (N-acetyl-p-benzoquinoneimine) of paracetamol

Pharmacokinetics

• Absorption: Rapidly and almost completely absorbed from the gastrointestinal tract. Bioavailability: 4-10% (oral). Time to peak plasma concentrations: Approx 1-3 hours (oral).
• Distribution: Crosses the placenta. Plasma protein binding: 66-87%.
• Metabolism: Undergoes extensive first-pass metabolism to form cysteine (active metabolite), N,N-diacetylcysteine and N-acetylcysteine; cysteine undergoes further metabolism to form glutathione and other metabolites.
• Excretion: Via urine (13-38%; almost entirely as inactive metabolites). Elimination half-life: Oral: 6.25 hours (total acetylcysteine). IV: 5.6 hours (total acetylcysteine); 2 hours (reduced acetylcysteine).

• https://www.rxlist.com/dopram-drug.htm
• https://www.mims.com/india/drug/info/Acetylcysteine?type=full&mtype=generic
• https://go.drugbank.com/drugs/DB00561
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003846/