Long Acting Muscarinic Antagonists

Long acting muscarinic antagonists (tiotropium, glycopyrronium, umeclidinium and aclidinium) give 12 to 24 hour bronchodilation by slow dissociation from M3 receptors. They are first-line maintenance bronchodilators in COPD and an add-on in some asthma.

Mechanism. Competitive M3 blockade lowers cholinergic smooth muscle tone and gland secretion. Slow dissociation from M3 compared with M2 (kinetic selectivity) prolongs the effect without the M2 blockade that opposes benefit.

Pharmacokinetics. Absorbed drug is small, and most is excreted by the kidney. Tiotropium has a long terminal half life of several days, with steady state in about 1 week.

Differences. Aclidinium acts for 12 hours and is metabolised rapidly in plasma, giving low systemic exposure. Tiotropium has the most data, including exacerbation reduction. Glycopyrronium has rapid onset within minutes.

Combinations. With a long acting beta 2 agonist in a single inhaler (indacaterol with glycopyrronium, umeclidinium with vilanterol, olodaterol with tiotropium, formoterol with aclidinium), and with an inhaled corticosteroid as triple therapy.

COPD. Used as first-line maintenance when symptoms persist, and preferred to a long acting beta 2 agonist alone for preventing exacerbations. Move to a long acting antimuscarinic with a long acting beta 2 agonist if breathlessness persists. Add an inhaled corticosteroid when exacerbations continue and blood eosinophils are 300 cells/microlitre or more.

Asthma. Tiotropium 2.5 mcg (2 puffs of 1.25 mcg) once daily by soft mist inhaler, from 6 years, as an add-on in patients with exacerbations despite inhaled corticosteroid with a long acting beta 2 agonist. It is not used alone.

Not for rescue. A short acting beta 2 agonist is kept for acute symptoms.

Adverse effects. Dry mouth, constipation, urinary retention, blurred vision, tachycardia, cough, paradoxical bronchospasm.

Contraindications and cautions. Hypersensitivity. Dry powder capsules contain lactose with milk protein, so they are contraindicated in severe milk protein allergy. Caution in narrow angle glaucoma, prostatic hypertrophy and bladder outlet obstruction.

Interactions. Added anticholinergic burden with tricyclic antidepressants, antipsychotics, antihistamines and bladder antimuscarinics. Avoid with regular ipratropium.

Monitoring. Symptoms, exacerbations, spirometry, urinary and eye symptoms, and creatinine clearance in renal impairment.

Special groups. Renal impairment: tiotropium and glycopyrronium accumulate, so monitor for anticholinergic effects when creatinine clearance is under 60 mL/min and use glycopyrronium only if benefit outweighs risk when under 30 mL/min. Older adults: anticholinergic burden and delirium risk. Pregnancy: limited data. Breastfeeding: low systemic absorption, probably compatible.

Referral and escalation. Persistent exacerbations on dual bronchodilator therapy need review for an inhaled corticosteroid or specialist care. Urinary retention or eye pain needs urgent assessment and stopping of the drug.