ACC 600 HOT

Indications

• Paracetamol overdose
• Chronic obstructive pulmonary disease (COPD)
• Cystic fibrosis
• Bronchiectasis
• Mucolytic therapy for excessive mucus production

Dosage

Children: For paracetamol overdose in children, the initial dose is 150 mg/kg IV over 15 minutes, followed by 50 mg/kg IV over 4 hours, and then 100 mg/kg IV over 16 hours. Refer to BNF for Children for detailed dosing.

Adults: For paracetamol overdose, the initial dose is 300 mg IV over 15 minutes, followed by 600 mg IV over 4 hours, and then 1200 mg IV over 16 hours. Refer to specific guidelines for other indications.

Mechanism of action

Acetylcysteine works by breaking disulfide bonds in mucoproteins, leading to the depolymerization of mucus and reducing its viscosity, making it easier to clear from the airways.

Pharmacodynamics

Acetylcysteine enhances mucociliary clearance and helps restore depleted glutathione levels, which is critical in the detoxification of harmful substances in the liver, particularly in cases of paracetamol toxicity.

Pharmacokinetics

When administered orally, acetylcysteine is rapidly absorbed and metabolized in the liver. It has a half-life of approximately 1 to 2 hours, with its effects lasting longer due to its metabolites. The major route of excretion is via the urine.

Contra-indications

• Severe asthma
• History of peptic ulceration

Adverse effects

• Nausea
• Vomiting
• Abdominal pain
• Diarrhea
• Skin rashes
• Anaphylactic reactions

Interactions

• May increase INR in patients on anticoagulants

Precautions

• Use with caution in patients with asthma
• Monitor for allergic reactions

Pregnancy

Use only if clearly needed; benefits must outweigh risks.

Breast-feeding

Considered safe; minimal transfer into breast milk.

Storage

Store in a cool, dry place away from light.

Formulations

• Oral solution
• Injectable solution

Mechanism of action

A number of possible mechanisms for the mucolytic activity of acetylcysteine have been proposed. Acetylcysteine's sulfhydryl groups may hydrolize disulfide bonds within mucin, breaking down the oligomers, and making the mucin less viscous. Acetylcysteine has also been shown to reduce mucin secretion in rat models. It is an antioxidant in its own right but is also deacetylated to cysteine, which participates in the synthesis of the antioxidant glutathione. The antioxidant activity may also alter intracellular redox reactions, decreasing phosphorylation of EGFR and MAPK, which decrease transcription of the gene MUC5AC which produces mucin. In the case of acetaminophen overdoses, a portion of the drug is metabolized by CYP2E1 to form the potentially toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). The amount of NAPQI produced in an overdose saturates and depletes glutathione stores. The free NAPQI promiscuously binds to proteins in hepatocytes, leading to cellular necrosis. Acetylcysteine can directly conjugate NAPQI or provide cysteine for glutathione production and NAPQI conjugation. Acetylcysteine exerts its mucolytic action through its free sulfhydryl group, which opens the disulfide bonds and lower the viscosity of the mucus. This action increases with increasing pH and is most significant at pH 7 to 9. The mucolytic action of acetylcysteine is not affected by the presence of DNA. Acetylcysteine may protect against acetaminophen overdose-induced hepatotoxicity by maintaining or restoring hepatic concentrations of glutathione. Glutathione is required to inactivate an intermediate metabolite of acetaminophen that is thought to be hepatotoxic. In acetaminophen overdose, excessive quantities of this metabolite are formed because the primary metabolic (glucuronide and sulfate conjugation) pathways become saturated. Acetylcysteine may act by reducing the metabolite to the parent compound and/or by providing sulfhydryl for conjugation of the metabolite. Experimental evidence also suggests that a sulfhydryl-containing compound such as acetylcysteine may directly inactivate the metabolite.

Pharmacodynamics

Acetylcysteine is indicated for mucolytic therapy and in the management of acetaminophen overdose. It has a short duration of action as it is given every 1-8 hours depending on route of administration, and has a wide therapeutic window. Patients should be counselled regarding diluting oral solutions in cola for taste masking, the risk of hypersensitivity, and the risk of upper gastrointestinal hemorrhage.