Mucolytics

Mucolytics reduce the viscosity or elasticity of airway mucus to ease clearance, and some also have antioxidant or anti-inflammatory action. They are used in chronic bronchitis, COPD with frequent exacerbations, bronchiectasis and cystic fibrosis. Benefit is modest, and the best evidence is for fewer exacerbations rather than better lung function.

Classification. Thiol agents (acetylcysteine, erdosteine), mucoregulators (carbocisteine), secretolytics (ambroxol, bromhexine) and a DNA-degrading enzyme (dornase alfa). Hypertonic saline and mannitol are osmotic agents that aid clearance by a different mechanism.

Mechanism. Acetylcysteine and erdosteine break disulphide bonds between mucin polymers and scavenge free radicals. Carbocisteine restores the balance of sialomucins and fucomucins and lowers viscosity. Ambroxol and bromhexine increase serous secretion, ciliary beat and surfactant production. Dornase alfa cleaves extracellular DNA released by neutrophils in purulent sputum.

Pharmacokinetics. Oral acetylcysteine bioavailability is under 10 percent because of first pass metabolism. Carbocisteine is well absorbed, with a half life of about 2 hours. Ambroxol is metabolised by CYP3A4 and excreted by the kidney. Dornase alfa acts locally with little systemic absorption.

Differences. Carbocisteine, acetylcysteine and erdosteine have the most evidence for fewer exacerbations in COPD, with a larger effect in patients not taking an inhaled corticosteroid. Evidence for ambroxol and bromhexine is weak. Only dornase alfa has proven benefit in cystic fibrosis.

Intravenous acetylcysteine. It is the antidote for paracetamol poisoning, given as three consecutive infusions over 21 hours: 150 mg/kg over 1 hour, 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours, with dosing weight capped at 100 kg. Nebulised acetylcysteine is not advised for routine clearance because it causes bronchospasm.

COPD and chronic bronchitis. Consider carbocisteine, acetylcysteine or erdosteine in patients with chronic productive cough and 2 or more exacerbations in the last year despite optimised inhaled therapy. Review at 3 to 6 months and stop if exacerbations or sputum difficulty do not improve.

Cystic fibrosis. Dornase alfa 2.5 mg nebulised once daily improves FEV1 and reduces exacerbations. Hypertonic saline 7 percent is an alternative or added agent, given after a bronchodilator.

Bronchiectasis not due to cystic fibrosis. Dornase alfa is not advised because it increased exacerbations and worsened lung function. Airway clearance physiotherapy and hypertonic saline are the usual options.

Acute cough and bronchitis. No proven benefit, and mucolytics are not needed.

Region. Many mucolytics are sold without prescription and used for long periods. Exclude tuberculosis before treating a chronic productive cough, especially in HIV or in settings with high tuberculosis burden.

Adverse effects. Nausea, dyspepsia, diarrhoea and rash. Inhaled acetylcysteine and dornase alfa cause cough, voice change and bronchospasm. Ambroxol and bromhexine are linked with rare severe skin reactions, including Stevens Johnson syndrome, so stop at the first rash.

Contraindications and cautions. Carbocisteine and acetylcysteine in peptic ulcer, because of gastric mucosal irritation. Acetylcysteine in asthma with bronchospasm risk. Hypersensitivity to any component.

Interactions. Few of importance. Cough suppressants should not be combined with mucolytics, because suppressed cough causes retention of secretions.

Monitoring. Sputum volume and ease of clearance, exacerbation count, gastrointestinal symptoms and any skin reaction.

Special groups. Pregnancy: avoid in the first trimester, and use later only when needed. Breastfeeding: limited data, avoid unless needed. Children: not advised under 2 years because of the risk of excess secretions and respiratory depression, and many products restrict use under 6 years. Older adults: gastrointestinal bleeding risk with peptic disease. Renal and hepatic impairment: reduce the dose of ambroxol or extend the interval in severe impairment.

Referral and escalation. Persistent purulent sputum, haemoptysis, weight loss or fever needs infection and tuberculosis assessment. Frequent exacerbations despite treatment need specialist review. Rash with mucosal involvement needs emergency care.