Mucolytic – Antidote for Acetaminophen Poisoning
Action And Clinical Pharmacology: The viscosity of pulmonary mucous secretions depends on the concentrations of mucoprotein and to a lesser extent deoxyribonucleic acid (DNA). The latter increases with increasing purulence owing to cellular debris. The mucolytic action of acetylcysteine is related to the sulfhydryl group in the molecule. This group probably “opens” disulfide linkages in mucus thereby lowering the viscosity. The mucolytic activity of acetylcysteine is unaltered by the presence of DNA, and increases with increasing pH. Significant mucolysis occurs between pH 7 and 9.
Acetaminophen is rapidly absorbed from the upper gastrointestinal tract with peak plasma levels occurring between 30 and 60 minutes after therapeutic doses and usually within 4 hours following an overdose. The parent compound, which is non-toxic, is extensively metabolized in the liver to form principally the sulfate and glucuronide conjugates which are also non-toxic and are rapidly excreted in the urine.
A small fraction of the ingested dose is metabolized in the liver by the cytochrome P-450 mixed function oxidase enzyme system to form a reactive, potentially toxic, intermediate metabolite which preferentially conjugates with hepatic glutathione to form the non-toxic cysteine and mercapturic acid derivatives which are then excreted by the kidney.
Therapeutic doses of acetaminophen do not saturate the glucuronide and sulfate conjugation pathways and do not result in formation of sufficient reactive metabolite to deplete glutathione stores.
However, following ingestion of a large overdose (150 mg/kg or greater) the glucuronide and sulfate conjugation pathways are saturated resulting in a larger fraction of the drug being metabolized via the P-450 pathway. The increased formation of reactive metabolite may deplete the hepatic stores of glutathione with subsequent binding of the metabolite to protein molecules within the hepatocyte resulting in cellular necrosis. Acetylcysteine probably protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with and thus detoxification of the reactive metabolite.
Indications And Clinical Uses: As adjuvant therapy for patients with abnormal, viscid, or inspissated mucous secretions in such conditions as: chronic bronchopulmonary disease (chronic emphysema, emphysema with bronchitis, chronic asthmatic bronchitis, tuberculosis, bronchiectasis and primary amyloidosis of the lung); acute bronchopulmonary disease (pneumonia, bronchitis, tracheobronchitis); pulmonary complications of cystic fibrosis; post-tracheostomy care; pulmonary complications associated with surgery; use during anesthesia; post-traumatic chest conditions; atelectasis due to mucous obstruction; diagnostic bronchial studies (bronchograms, bronchospirometry and bronchial wedge catheterization).
Administered orally or i.v., 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 it.
There are no contraindications to oral or i.v. 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 open airway must be maintained 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 occurs and other allergic symptoms appear, treatment with acetylcysteine should be discontinued unless it is deemed essential and the allergic symptoms cannot be otherwise controlled.
If encephalopathy due to hepatic failure is evident, acetylcysteine treatment should be discontinued to avoid further administration of nitrogenous substances. There are no data indicating acetylcysteine adversely influences hepatic failure; however, this remains a theoretical possibility.
Precautions: With the administration of acetylcysteine as a mucolytic agent, the patient may initially notice a slight disagreeable odor which soon is not noticeable. With a face mask, there may be a stickiness on the face after nebulization which is easily removed by washing with water.
Acetylcysteine is not compatible with rubber and metals, particularly iron, copper and nickel. Silicone and lacquered rubber and plastic are satisfactory for use with acetylcysteine.
Under certain conditions, a color change may take place in the solution of acetylcysteine in the open vial. The light purple color is the result of a chemical reaction which does not significantly impair the safety or mucolytic efficacy of acetylcysteine.
Continued nebulization of an acetylcysteine solution with a dry gas will result in an increased concentration of the drug in the nebulizer because of evaporation of the solvent. Extreme concentration may impede nebulization and efficient delivery of the drug. Dilution of the nebulizing solution with Sterile Water for Injection USP, as concentration occurs, will obviate this problem.
Occasionally severe and persistent vomiting occurs as a symptom of acute acetaminophen overdose. Treatment with oral 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. Dilution of the acetylcysteine with cola drinks minimizes the propensity of oral acetylcysteine to aggravate vomiting.
Drug/Laboratory Interaction: Acetylcysteine may cause a false-positive reaction with reagent dipstick tests for urinary ketones.
Adverse Reactions: Adverse reactions have been included in order of frequency: stomatitis, nausea and rhinorrhea. Sensitivity and sensitization to acetylcysteine have been reported very rarely. A few susceptible patients, particularly asthmatics (see Warnings), may experience varying degrees of bronchospasm associated with the administration of nebulized acetylcysteine. Most patients with such bronchospasm are quickly relieved by the use of a bronchodilator given by nebulization.
Oral or i.v. administration of acetylcysteine, especially in the large doses needed to treat acetaminophen overdose, in order of frequency may result in nausea, vomiting and other gastrointestinal symptoms. Hypersensitivity reactions following the i.v. administration of acetylcysteine have been reported. Symptoms include rashes, facial edema, urticaria, hypotension and bronchospasm.
Compatibility: The physical and chemical compatibility of acetylcysteine solutions with other drugs commonly administered by nebulization, direct instillation, or topical application, has been studied.
Acetylcysteine should not be mixed with all antibiotics. For example, the antibiotics tetracycline HCl, oxytetracycline HCl and erythromycin lactobionate were found to be incompatible when mixed in the same solution. These agents may be administered from separate solutions if administration of these agents is desirable.
Dosage And Administration: As a Mucolytic Agent: The 20% solution may be diluted to a lesser concentration with either sterile normal saline or Sterile Water for Injection, USP. Any unused portion of a vial should be refrigerated and used within 96 hours.
Nebulization-face mask, mouth piece, tracheostomy: When nebulized into a face mask, mouth piece 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 daily.
Nebulization-tent, croupette: In special circumstances it may be necessary to nebulize into a tent or croupette, and this method of use 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 solution that 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 to 2 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. Two to 5 mL of the 20% solution may then be instilled by means of a syringe connected to the catheter.
Acetylcysteine may also be given through a percutaneous intratracheal catheter. One to 2 mL of the 20% solution may be given every 1 to 4 hours by a syringe attached to the 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: Materials: Acetylcysteine may be administered using conventional nebulizers made of plastic or glass. Certain materials used in nebulization equipment react with acetylcysteine. The most reactive of these are certain metals (notably iron and copper), and rubber. Where materials may come into contact with acetylcysteine solution, parts made of the following acceptable materials should be used: glass, plastic, aluminum, anodized aluminum, chromed metal, tantalum, sterling silver or stainless steel. Silver may become tarnished after exposure, but this is not harmful to the drug action or the patient.
Nebulizing Gases: Compressed tank gas (air) or an air compressor should be used to provide pressure for nebulizing the solution. Oxygen may also be used but should be used with usual caution in patients with severe respiratory disease and CO2 retention.
As an Antidote for Acetaminophen Poisoning: In the case of an overdosage of acetaminophen, acetylcysteine should be administered immediately if 24 hours or less have elapsed from the reported time of ingestion. To be effective in protecting against severe liver damage, therapy with acetylcysteine must be started within 10 hours of acetaminophen ingestion. There is some evidence of progressively diminished efficacy thereafter, possibly lasting up to 24 hours.
It should be borne 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.
The following procedure is recommended: 1. 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 in 20 minutes.
2. In the case of a mixed drug overdose activated charcoal may be indicated. However, if activated charcoal has been administered, perform gastric lavage before administering oral acetylcysteine treatment. Activated charcoal will absorb acetylcysteine and reduce its effectiveness.
3. Draw blood for acetaminophen plasma assay and for baseline AST, ALT, bilirubin, prothrombin time, creatinine, BUN, blood sugar and electrolytes. The acetaminophen assay provides a reliable prognostic indication of potential hepatotoxicity and serves as a basis for determining the need for continuing with the maintenance doses of acetylcysteine treatment. The laboratory measurements are used to monitor hepatic and renal function and electrolyte fluid balance.
4. Administer the loading dose of acetylcysteine according to route of administration employed.
5. Read information regarding oral and i.v. maintenance doses.
6. If the patient vomits the oral loading dose or any oral maintenance dose within 1 hour of administration, repeat that dose.
7. If the patient is unable to retain the orally administered acetylcysteine, the antidote may be administered by duodenal intubation or by the i.v. route.
8. Repeat AST, ALT, bilirubin, prothrombin time, creatinine, BUN, blood sugar and electrolytes daily if acetaminophen plasma level is in the potentially toxic range.
Preparation of solution for oral administration: Oral administration requires dilution of the 20% solution with cola drinks, or other soft drinks, to a final concentration of 5%. If administered via gastric tube or Miller-Abbott tube, water may be used as the diluent. The dilutions should be freshly prepared and utilized within 1 hour. Remaining undiluted solutions in opened vials can be stored in the refrigerator up to 96 hours.
Preparation of solution for i.v. administration: Acetylcysteine may be used for i.v. administration following acetaminophen overdose according to Dosage Guidelines. Dilutions recommended should be prepared with 5% Dextrose and Water, as appropriate. Acetylcysteine for i.v. use should be considered as a single-dose container. Solutions recommended should be freshly prepared and used only over times stated.
Supportive treatment of acetaminophen overdose: Maintain fluid and electrolyte balance based on clinical evaluation of state of hydration and serum electrolytes. Treat as necessary for hypoglycemia. Administer vitamin K1 if prothrombin time ratio exceeds 1.5 or fresh frozen plasma if the prothrombin time ratio exceeds 3.0. Diuretics and forced diuresis should be avoided.
Hemodialysis or peritoneal dialysis have not been found helpful.
Availability And Storage: Each rubber-stoppered, glass vial contains: a sterile 20% solution of acetylcysteine. Vials of 10 and 30 mL.
MUCOMYST® Roberts Acetylcysteine Mucolytic – Antidote for Acetaminophen Poisoning