Mucolytic – Antidote for Acetaminophen Poisoning
Action And Clinical Pharmacology: The viscosity of respiratory mucous secretions depends primarily on the content of mucoprotein and to a smaller extent on the concentration of desoxyribonucleic acid (DNA). The proportion of DNA is increased with the presence of purulent material, due to cellular debris. The mucolytic action of acetylcysteine is related to the sulphydryl group in the molecule. This group probably opens disulphide bonds in mucus, thereby lowering the viscosity. The mucolytic activity of acetylcysteine is unaltered by the presence of DNA, and increases with increasing pH, with significant mucolysis occurring between pH 7 and 9.
Acetaminophen overdosage causes liver damage due to excessive formation of a highly reactive alkylating metabolite which binds irreversibly to protein molecules within the hepatocyte. After therapeutic doses, acetaminophen is excreted principally as the glucuronide and sulfate conjugates and only approximately 8% of the acetaminophen ingested is transformed into the toxic metabolite. Hepatic-reduced glutathione rapidly activates this metabolite, which is excreted by the kidneys as nontoxic cysteine and mercapturic derivatives. However, after an overdose of acetaminophen, (150 mg/kg or greater) the glucuronide and sulfate conjugation pathways are saturated and a larger fraction of the parent drug is metabolized to form the alkylating metabolite. Hepatic reduced glutathione stores are depleted and the excess metabolite causes hepatic damage and necrosis. Acetylcysteine probably protects the liver by maintaining or restoring the glutathione levels or by acting as an alternative substrate for conjugation with the reactive metabolite.
Indications And Clinical Uses: As a mucolytic agent: As adjuvant therapy for patients with abnormal, viscid or inspissated mucous secretions in such conditions as: chronic bronchopulmonary disease such as emphysema, chronic bronchitis, lung abscess, tuberculosis, bronchiectasis, and primary amyloidosis of the lung; acute bronchopulmonary disease such as pneumonia, bronchitis and tracheobronchitis; pulmonary complications of cystic fibrosis; tracheostomy care; pulmonary complications associated with surgery; use during anesthesia; post-traumatic chest conditions and pulmonary collapse; diagnostic bronchial studies such as bronchograms, bronchospirometry and bronchial wedge catheterization.
Use in the pathology laboratory: For the digestion of sputum in examinations for M. tuberculosis and for carcinoma cells.
As an antidote for acetaminophen poisoning: As an antidote to prevent or lessen hepatic injury which may occur following the ingestion of a potentially hepatotoxic quantity of acetaminophen.
Contra-Indications: In those patients who are sensitive or who have developed a sensitivity to acetylcysteine. There are no known contraindications to oral administration of acetylcysteine in the treatment of acetaminophen overdose.
Manufacturers’ Warnings In Clinical States: After proper administration of acetylcysteine an increased volume of liquefied bronchial secretions may occur. When cough is inadequate the airway must be maintained open by mechanical suction if necessary. When there is a large mechanical block due to foreign body or local accumulation, the airway should be cleared by endotracheal aspiration with or without bronchoscopy. Asthmatics under treatment with acetylcysteine should be watched carefully. If bronchospasm progresses, this medication should be immediately discontinued.
Generalized urticaria has been observed rarely in patients receiving oral acetylcysteine for acetaminophen overdose. If this and other allergic symptoms occur, treatment with acetylcysteine should be discontinued unless it is deemed essential and the allergic symptoms can otherwise be controlled. Although there are no data indicating that acetylcysteine adversely influences hepatic failure, this remains a theoretical possibility. Therefore, in the presence of hepatic failure due to acetaminophen overdose the degree of existing liver damage and the possible risk associated with the administration of acetylcysteine should be considered.
Precautions: After administration of acetylcysteine a slight disagreeable odor may be noticed initially. When a face mask is used, after nebulization, a stickiness on the face may be noticed; this is easily removed by washing with water.
Under certain conditions, acetylcysteine may change its color to a light purple in the open vial. This color change is due to a chemical reaction which does not significantly impair the mucolytic activity or the safety of the drug. After prolonged nebulization, extreme concentration of acetylcysteine in the solvent may occur. This might impede nebulization and efficient delivery of the drug. If this occurs, Sterile Water for Injection USP should be used to dilute the nebulizing solution.
Occasionally severe and persistent vomiting occurs as a symptom of acute acetaminophen overdose. The administration of acetylcysteine may aggravate the vomiting. Patients at risk of gastric hemorrhage (e.g., esophageal varices, peptic ulcers, etc.) should be evaluated concerning the risk of upper gastrointestinal hemorrhage versus the risk of developing hepatic toxicity and treatment with acetylcysteine given accordingly. The propensity of oral acetylcysteine to aggravate vomiting is minimized when it is administered diluted in cola drinks.
Acetylcysteine should be used with caution in asthma or where there is a history of bronchospasm.
Acetylcysteine may cause a false-positive reaction with reagent dipstick tests for urinary ketones.
Acetylcysteine is not compatible with rubber and metals, particularly iron, copper and nickel. Silicone rubber and plastic are satisfactory for use with acetylcysteine.
Adverse Reactions: Adverse effects include stomatitis, nausea and rhinorrhea. Sensitivity and sensitization to acetylcysteine have been reported very rarely. Asthmatics and other susceptible patients may experience varying degrees of bronchospasm associated with the administration of nebulized acetylcysteine. In most cases, this is quickly relieved by the use of a bronchodilator given by nebulization.
Rash, asthma and anaphylactoid reactions have been reported with i.v. use. These occur most commonly either during or at the end of the period of an initial high-dose infusion, and may in fact be dose-related. If the anaphylactoid manifestations are mild, and the patient is at high risk of liver toxicity, consideration should be given to continuing the acetylcysteine infusion at a reduced rate. However, this should be given only after discussion with a physician with substantial experience in the treatment of acetaminophen poisoning for a full consideration of possible risks and benefits and with appropriate supportive equipment available.
Oral administration of the large doses needed to treat acetaminophen overdose may result in nausea, vomiting and other gastrointestinal disorders. Rash, with or without mild fever has been reported rarely.
Hypokalemia and ECG changes have been noted in patients with acetaminophen poisoning irrespective of treatment given. Monitoring of plasma potassium is therefore recommended.
Dosage And Administration: As a Mucolytic Agent: Parvolex is a 20% solution which may be diluted to a lesser concentration with either sterile normal saline or sterile distilled water.
Nebulization (face mask, mouthpiece, tracheostomy): When nebulized into a face mask, mouthpiece or tracheostomy, 1 to 10 mL of the 20% solution may be given every 2 to 6 hours; the recommended dose for most patients is 3 to 5 mL of the 20% solution 3 to 4 times a day.
Nebulization (tent, croupette): In special circumstances it may be necessary to nebulize into a tent or croupette, and this method must be individualized to take into account the available equipment and the patient’s particular needs. This form of administration requires very large volumes of the solution occasionally as much as 300 mL during a single treatment period. If a tent or croupette must be used, the recommended dose is the volume of 20% solution which will maintain a very heavy mist in the tent or croupette for the desired period. Administration for intermittent or continuous prolonged periods, including overnight, may be desirable.
Direct Instillation: When used by direct instillation, 1.5 mL of a 10 to 20% solution may be given as often as every hour. When used for the routine nursing care of patients with tracheostomy, 1 to 2 mL of a 10 to 20% solution may be given every 1 to 4 hours by instillation into the tracheostomy.
Acetylcysteine may be introduced directly into a particular segment of the bronchopulmonary tree by inserting (under local anesthesia and direct vision), a small plastic catheter into the trachea.
Acetylcysteine may also be given through a percutaneous intratracheal catheter.
Diagnostic Bronchograms: For diagnostic bronchial studies, 2 or 3 administrations of 1 to 2 mL of the 20% solution should be given by nebulization or by instillation intratracheally, prior to the procedure.
Administration of Aerosol: Acetylcysteine is usually administered as a fine nebulae for its local effect and the nebulizer used should be capable of providing optimal quantities of a suitable range of particle sizes.
Certain materials used in nebulization equipment react with acetylcysteine. The most reactive are metals (particularly iron and copper) and rubber. Where materials may come into contact with acetylcysteine solutions, parts made of glass or plastic should be used.
The nebulized solution may be breathed directly from the nebulizer. Nebulizers may also be attached to plastic face masks, plastic face tents, plastic mouthpieces, conventional plastic oxygen tents or head tents. Suitable nebulizers may also be fitted for use with the various intermittent positive pressure breathing (IPPB) machines.
The nebulizing equipment should be cleaned immediately after use; the residues may occlude the fine orifices or corrode metal parts.
Prolonged Nebulization: When 3/4 of the initial volume of acetylcysteine solution has been nebulized a quantity of Sterile Water for Injection USP (approximately equal to the volume of solution remaining) should be added to the nebulizer. This obviates any concentration of the agent in the residual solvent remaining after prolonged nebulization.
Storage of Open Vials: If only a portion of the solution in the vial is used, to minimize contamination the remainder should be stored in a refrigerator and used within 96 hours.
Compatibility: Acetylcysteine may be mixed with the topical anesthetics lidocaine HCl (4%) and amethocaine HCl (2%); the x-ray contrast media propyliodone and the bronchodilator isoprenaline. It is incompatible with iodized oil (Lipiodol).
Antibiotics which may be mixed with acetylcysteine include polymyxin B sulfate, streptomycin sulfate, methicillin sodium, novobiocin sodium and dihydrostreptomycin sulfate. If it is deemed advisable to prepare an admixture it should be administered immediately after preparation. Do not store mixtures.
Antibiotics found to be incompatible when mixed in solution with acetylcysteine include tetracyclines HCl, oxytetracycline HCl, erythromycin lactobionate and oleandomycin. These agents may be administered by nebulization from separate solutions if necessary.
As An Antidote for Acetaminophen Poisoning: Acetylcysteine should be administered immediately if 24 hours or less have elapsed from the reported time of ingestion of an overdose of acetaminophen, regardless of the quantity reported to have been ingested.
Note: The critical ingestion-treatment interval for complete protection against severe liver damage is 8 hours. Efficacy diminishes progressively thereafter and treatment between 15 and 24 hours post-ingestion of acetaminophen is usually ineffective. However, it does not appear to worsen the condition of patients and it should not be withheld, since the reported time of ingestion may not be correct.
It should be kept in mind that after a fatal dose of acetaminophen, the patient may appear relatively well initially and may even continue normal activities for a day or two before the onset of hepatic failure.
General Management: In the case of patients admitted within 4 hours of ingestion, the stomach should be emptied promptly by lavage or by inducing emesis with syrup of ipecac. Syrup of ipecac should be given in a dose of 15 to 30 mL for children and 30 to 45 mL for adults, accompanied by drinking copious quantities of water. The dose should be repeated if emesis does not occur within 20 minutes. In the case of mixed drug overdose, activated charcoal may be indicated. However, since activated charcoal will absorb acetylcysteine and reduce its effectiveness, gastric aspiration and lavage should be performed before administering acetylcysteine orally.
On admission, blood should be drawn for determination of acetaminophen plasma levels, which will serve as a basis for determining the need for continuation of treatment with acetylcysteine. AST, ALT, bilirubin, prothrombin time, creatinine, BUN, blood sugar and electrolytes also should be determined in order to monitor hepatic and renal function and electrolyte and fluid balance.
I.V. Treatment With Acetylcysteine: Single use vials when used i.v. Discard unused portion. Acetylcysteine should be given i.v. in an initial dose of 150 mg/kg in 5% dextrose (see Table I for volume) over 15 minutes, followed by 50 mg/kg in 500 mL of 5% dextrose over 4 hours and 100 mg/kg in 1 L of 5% dextrose over the next 16 hours (total dose: 300 mg/kg in 20 hours). The treatment with acetylcysteine may also be continued if the acetaminophen assay reveals nontoxic plasma levels.
Acetaminophen Assays: Interpretation and Methodology: An overdose of acetaminophen of 150 mg/kg or greater may result in liver damage. However, no reliance can be placed on the number of tablets claimed to have been taken by the patient and early specific clinical manifestations of acetaminophen poisoning. As well, maximal biochemical abnormalities of liver function are usually manifested only 3 to 5 days after ingestion. Therefore, plasma or serum acetaminophen concentrations determined as early as possible, but no sooner than 4 hours following an acute overdose, are essential in assessing the potential risk of hepatotoxicity. Chronic alcohol ingestion and/or concomitant barbiturate therapy may induce a greater formation of the toxic metabolite for any given dose of acetaminophen. This should be kept in mind when therapy is based upon blood levels of acetaminophen.
The possibility of chronic alcohol ingestion and/or concomitant barbiturate therapy should be considered when evaluating the possibility of discontinuing treatment, since in these instances blood levels of the parent drug may underestimate the true risk of hepatotoxicity.
Oral Treatment With Acetylcysteine: Administer the loading dose of acetylcysteine, 140 mg/kg of body weight. (Prepare acetylcysteine for oral administration as described in Table III). Four hours after the loading dose administer the first maintenance dose (70 mg/kg/body weight) of acetylcysteine. The maintenance dose is then repeated at 4 hour intervals for a total of 17 doses unless the acetaminophen assays reveal a nontoxic level as discussed below.
If the patient vomits the loading dose or any one of the maintenance doses within 1 hour of administration, repeat that dose.
If the patient is unable to retain the orally administered acetylcysteine, the antidote may be administered by duodenal intubation.
Liver function tests should be repeated daily if acetaminophen levels are within the potentially toxic range as discussed below.
Preparation of Acetylcysteine Solution for Oral Administration: The original 20% solution should be diluted to a 5% solution with cola drinks, or other soft drinks. Each diluted solution should be consumed within an hour of preparation. Remaining undiluted solutions in open vials may be stored under refrigeration for up to 96 hours.
If acetylcysteine is to be administered by gastric tube, water may be used as a diluent. The relative amounts of the 20% solution of acetylcysteine and of diluent to be mixed according to body weight of the patient
Supportive Treatment of Acetaminophen Overdose: 1. Maintain fluid and electrolyte balance based on clinical evaluation of state of hydration and serum electrolytes. 2. Treat as necessary for hypoglycemia. 3. Administer vitamin K1 if prothrombin time ratio exceeds 1.5 or with fresh frozen plasma if the prothrombin time ratio exceeds 3.0. 4. Diuretics and forced diuresis should be avoided. Hemodialysis or peritoneal dialysis have not been found helpful.
Acetaminophen Assays – Interpretation and Methodology: Hepatic toxicity may result from the acute ingestion of 150 mg/kg or more of acetaminophen. The reported quantity of a drug ingested after an overdose is often inaccurate and is not a reliable guide to therapy of the overdose. Therefore, plasma or serum acetaminophen concentrations, determined as early as possible, but no sooner than 4 hours following ingestion of an acute overdose, are essential in assessing the potential risk of hepatotoxicity.
Do not wait for assay results to begin acetylcysteine treatment. For any given dose of acetaminophen, a greater formation of toxic metabolite may occur if there is a history of chronic alcohol ingestion and/or concomitant barbiturate therapy. This should be kept in mind when therapy is based on acetaminophen blood levels interpretation of acetaminophen assays: (Refer to manufacturer’s package insert for nomogram).
1. Acetaminophen plasma concentrations above the solid line which connects 200 µg/mL at 4 hours with 50 µg/mL at 12 hours are associated with a possibility of hepatic toxicity if an antidote is not administered. 2. Plasma levels above the broken line may be associated with hepatic toxicity; therefore, treatment with acetylcysteine is indicated. 3. If plasma levels of acetaminophen are below the broken line the risk of hepatic toxicity is minimal and acetylcysteine treatment can be discontinued.
When discontinuation of treatment with acetylcysteine is contemplated, the possibility of chronic alcohol ingestion and/or concomitant barbiturate therapy should be kept in mind, since under these circumstances blood levels of the parent compound may underestimate the true risk of hepatotoxicity.
Suitable assay procedures for measuring acetaminophen levels in plasma are listed below. These methods detect only parent acetaminophen and not conjugated.
1. Blair, D. and Rumack, B.H.: Clin. Chem. 23(4); 743-745 (April) 1977.
2. Howie, D., Andriaenssens, P.I. and Prescott, L.F.: Journ. Pharm. and Pharmacol. 9 (4) 235-237; (April) 1977.
3. Prescott, L.F.: Journ. Pharm. and Pharmacol. 23 (10); 804-808 (Oct.) 1971.
4. Glynn, J.P. and Kendal, S.E.: The Lancet. 1:1147-1148, (17 May) 1975.
Availability And Storage: Each mL of sterile solution contains: acetylcysteine 200 mg, disodium edetate 0.5 mg/mL and sodium hydroxide to adjust pH. Preservative-free, lacquered rubber stoppered glass vials of 10 and 30 mL, trays of 10. Store at room temperature (15 to 30Â°C) if unopened. Single use vials when used i.v. Discard unused portion. If previously opened, do not use i.v. When used for inhalation or oral administration, unused portions should be stored in a refrigerator and used within 96 hours.
PARVOLEX® Bioniche Acetylcysteine Mucolytic – Antidote for Acetaminophen Poisoning
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