Inhaled Muscarinic Antagonists

SAMA vs LAMA

Inhaled muscarinic receptor antagonists are bronchodilators used in the treatment of severe asthma and COPD. They include the following:

• Short acting muscarinic receptor antagonists (SAMA), such as ipratropium, are used in short-term relief in mild COPD for reversible airway obstruction and in severe or life-threatening asthma (via nebuliser).
• Long acting muscarinic receptor antagonists (LAMA) include tiotropium, aclidinium, umeclidinium and glycopyrrolate. LAMAs have prolonged binding to muscarinic receptors and are used in the maintenance of COPD and in severe asthma. 

Mechanism of Action

Long-acting muscarinic antagonists (LAMAs) and short-acting muscarinic antagonists (SAMAs) are anticholinergic bronchodilators that act by inhibiting the effects of acetylcholine (ACh) in the airways. Parasympathetic (vagal) activity is the main bronchoconstrictive pathway in the lungs, and ACh released from nerve endings binds to muscarinic receptors on airway smooth muscle to promote contraction and mucus secretion. By competitively antagonising these receptors, both LAMAs and SAMAs reduce cholinergic tone, leading to relaxation of airway smooth muscle and bronchodilation.

Their primary site of action is the M3 muscarinic receptor located on bronchial smooth muscle. Activation of M3 receptors normally stimulates intracellular signalling via the inositol trisphosphate (IP3) and diacylglycerol (DAG) pathway, increasing intracellular calcium levels and causing muscle contraction. Muscarinic antagonists block this process, preventing calcium release and thereby inhibiting bronchoconstriction. Some agents also interact with M2 receptors on presynaptic cholinergic nerves, which modulate ACh release, but newer drugs are relatively more selective for M3 receptors to maximise bronchodilation while minimising interference with inhibitory feedback mechanisms. Inhaled antimuscarinics also inhibit mucus secretion in asthma. 

Short-acting muscarinic antagonists (SAMAs), such as ipratropium, are quaternary ammonium compounds that act locally in the airways when inhaled. They produce bronchodilation by blocking both M2 and M3 receptors, inhibiting vagally mediated reflex bronchoconstriction and reducing mucus secretion. Their onset of action is relatively rapid, but their duration is limited (typically 4-6 hours), necessitating multiple daily doses. The bronchodilator effect is primarily due to local drug concentrations in the lungs rather than systemic absorption, which helps limit systemic anticholinergic side effects.

Long-acting muscarinic antagonists (LAMAs), including agents such as tiotropium, aclidinium, glycopyrronium and umeclidinium, share the same fundamental mechanism but are characterised by prolonged duration of action. This is largely due to their slow dissociation from M3 receptors and sustained retention within lung tissue. Many LAMAs exhibit kinetic selectivity, dissociating more slowly from M3 than M2 receptors, which enhances bronchodilation while preserving autoregulatory control of ACh release. Their effects are dose-dependent and can last 24 hours or longer, allowing once-daily dosing in many cases.

Like SAMAs, LAMAs are inhaled quaternary ammonium compounds and therefore demonstrate relative broncho-selectivity with limited systemic exposure. Some agents, such as aclidinium, are rapidly hydrolysed in plasma, further reducing the risk of systemic anticholinergic effects. Overall, both SAMAs and LAMAs improve airflow by blocking cholinergic bronchoconstriction, but LAMAs provide more sustained bronchodilation and are typically used for maintenance therapy, whereas SAMAs are used for short-term symptom relief.

Created in BioRender. Boucher, M. (2026) https://BioRender.com/fj8d3in

Fig 1: Mechanism of Action of Bronchodilators such as β2 agonists, theophylline and muscarinic antagonists

Pharmacokinetics

Inhaled muscarinic antagonists act locally in the lung, and some have minimal systemic exposure (see table below). Due to this, there are limited drug interactions, however, if patients are experiencing antimuscarinic side effects, other medications should be assessed to determine whether there are any contributing drugs such as tricyclic antidepressants (TCAs).

Cautions and Adverse Effects

Long-acting muscarinic antagonists (LAMAs), also known as antimuscarinic bronchodilators, are widely used in respiratory conditions such as COPD and asthma. While generally well tolerated, their anticholinergic effects mean they must be used with caution in certain patient groups.

One important consideration is the risk of urinary retention. LAMAs can exacerbate symptoms in men with prostatic hyperplasia or those with bladder outflow obstruction, particularly in older adults. This is due to their inhibitory effect on bladder detrusor muscle contraction.

Caution is also required in individuals with renal impairment. For patients with a creatinine clearance <50 mL/min, manufacturers recommend that these drugs should only be used if the potential benefits outweigh the risks, as reduced clearance may increase systemic exposure.

Another key risk involves angle-closure glaucoma. Nebulized antimuscarinic agents can inadvertently come into contact with the eyes, potentially precipitating or worsening acute glaucoma. Appropriate administration technique and patient counselling are therefore essential; use of a mouthpiece rather than a mask with a nebuliser is recommended.

With inhalation therapies, there is a very rare risk of paradoxical bronchospasm, often attributed to non-active components in the formulation such as preservatives or propellants. Signs include immediate wheeze and shortness of breath after dosing, which can be treated with a fast-acting inhaled bronchodilator such as salbutamol. If this reaction occurs, therapy should be discontinued and an alternative sought. 

LAMAs are generally avoided in pregnancy and breastfeeding, unless specialist advice suggests otherwise, due to limited safety data.

Specific agents such as tiotropium require additional caution in patients with cardiovascular disease, including arrhythmias, heart failure, or a recent myocardial infarction (within the past six months). In these populations, there is evidence suggesting a possible increase in all-cause mortality, and treatment decisions should be made carefully.

Finally, combination therapy with ipratropium and salbutamol is contraindicated in patients with hypertrophic obstructive cardiomyopathy or tachyarrhythmias, due to the increased risk of adverse cardiac effects.

Adverse effects that can occur as a result of LAMA therapy include the above cautions, furthermore antimuscarinic effects such as dry mouth and constipation may also occur.

Overall, while LAMAs are effective therapies, careful patient selection and monitoring are essential to minimise potential risks.

By TeachMeSeries Ltd (2026)

Fig 2: Antimuscarinic/Anticholinergic Adverse Effects

References

1. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019. 
2. Muscarinic antagonists | Prescribing information | Chronic obstructive pulmonary disease | CKS | NICE Accessed 17/03/2026
3. Medicinal forms | Tiotropium | Drugs | BNF | NICE Accessed 17/03/2026
4. Braltus (tiotropium) 10mcg Inhalation Powder – Summary of Product Characteristics (SmPC) – (emc) | 4446 Accessed 17/03/2026
5. Eklira Genuair 322 micrograms inhalation powder – Summary of Product Characteristics (SmPC) – (emc) | 14790 Accessed 17/03/2026
6. Atrovent Inhaler CFC-Free – Summary of Product Characteristics (SmPC) – (emc) | 61 Accessed 17/03/2026
7. Seebri Breezhaler 44 micrograms inhalation powder (hard capsules) – Summary of Product Characteristics (SmPC) – (emc) | 2840 Accessed 17/03/2026
8. Incruse Ellipta 55 micrograms inhalation powder, pre-dispensed – Summary of Product Characteristics (SmPC) – (emc) | 3418 Accessed 17/03/2026