Muscarinic Antagonists

Muscarinic antagonists block acetylcholine at muscarinic receptors in the airway and reduce vagal bronchoconstrictor tone and mucus secretion. Inhaled quaternary ammonium compounds are used as bronchodilators in COPD and asthma, with minimal systemic effect.

Mechanism. M3 receptors on smooth muscle cause contraction through Gq signalling and calcium release, and M3 receptors on submucosal glands drive secretion. M2 receptors on nerve endings limit acetylcholine release, so non-selective blockade (ipratropium) can partly offset benefit. Long acting agents dissociate slowly from M3 and quickly from M2.

Pharmacokinetics. Quaternary structure limits gut absorption, crossing of membranes and central nervous system penetration, so systemic effects are small compared with atropine. Renal excretion matters for tiotropium and glycopyrronium.

Atropine. Tertiary amine with systemic effects, not used as an inhaled bronchodilator. It is the antimuscarinic given in organophosphate poisoning, titrated to clear chest and drying of bronchial secretions.

Differences. Ipratropium has onset in 15 to 30 minutes, slower than salbutamol, so it is poor as sole rescue but adds to a beta 2 agonist in acute severe disease. Long acting agents give 24 hour bronchodilation (aclidinium 12 hours) and reduce COPD exacerbations.

Combining. Regular short acting and long acting antimuscarinics together duplicate effect and are not advised.

COPD. A long acting antimuscarinic is a first-line maintenance bronchodilator. Ipratropium is used for as-needed relief when beta 2 agonists are not tolerated.

Asthma. Tiotropium 2.5 mcg (2 puffs of 1.25 mcg) once daily by soft mist inhaler is an add-on at higher treatment steps for patients with exacerbations on inhaled corticosteroid with a long acting beta 2 agonist. Ipratropium is added to salbutamol in severe acute asthma.

Alternative reliever. Ipratropium helps when beta 2 agonists cause troublesome tachyarrhythmia or tremor.

Adverse effects. Dry mouth is most common. Constipation, urinary retention, blurred vision, tachycardia, cough and paradoxical bronchospasm occur. Acute angle closure glaucoma follows contact of nebulised drug with the eye, so use a mouthpiece or protect the eyes.

Contraindications and cautions. Hypersensitivity to atropine derivatives. Caution in prostatic hypertrophy, bladder outlet obstruction and narrow angle glaucoma. Dry powder products contain lactose with milk protein, which is a contraindication in severe milk protein allergy.

Cardiovascular safety. An early signal of excess mortality with soft mist tiotropium was not confirmed in later large comparisons with dry powder tiotropium.

Interactions. Added anticholinergic burden with tricyclic antidepressants, antipsychotics, antihistamines and bladder antimuscarinics. This matters most in older adults at risk of delirium.

Monitoring. Breathlessness, exacerbations, spirometry, urinary and eye symptoms, and technique.

Special groups. Renal impairment: tiotropium and glycopyrronium accumulate, so monitor for anticholinergic effects when creatinine clearance is under 60 mL/min. Umeclidinium and aclidinium need no adjustment. Pregnancy: limited data, use if benefit outweighs risk. Breastfeeding: low systemic absorption.

Referral and escalation. Eye pain, red eye or halos after nebulised therapy needs urgent ophthalmology review. Acute urinary retention needs catheterisation and drug withdrawal.