OverviewThe basic scienceThe pharmacologyThe clinical basicsComplex pharmacology


Antimuscarinic drugs block muscarinic acetylcholine receptors. If restricted to the lung by inhalation and their chemical properties, these drugs cause bronchodilation and inhibition of mucus secretion with relatively few side-effects. The component of reversible bronchoconstriction present in COPD is adequately inhibited by these drugs, but might also be reversed using β2-agonists, as in asthma.

The basic science

The smooth muscle that surrounds the airways is innervated by cholinergic, parasympathetic nerves which cause bronchoconstriction and mucus secretion. The acetylcholine released from these nerve fibres acts on muscarinic receptors to mediate these effects in response to activation of sensory nerves which are activated by irritants and inflammatory mediators in the airways (Figure 1.) Blocking muscarinic receptors with anti-muscarinic drugs can ameliorate these effects. This has proven to be a particularly effective therapeutic strategy in treating COPD, and to a lesser extent asthma (see below).

Figure 1: Inhaled irritants or endogenous inflammatory mediators activate sensory nerve fibres which send signals to the central nervous system and trigger reflex firing of parasympathetic nerves in the airway. Parasympathetic, post-ganglionic cholinergic (releasing acetylcholine (ACh)) neurons are located within the airway wall and send fibres to airway smooth muscle and glands causing contraction and secretion respectively. Both of these actions occur when the released acetylcholine binds to muscarinic receptors on target cells. Anti-muscarinic drugs block these receptors, preventing acetylcholine from binding. NB: Preganglionic nerves carried to the airways in branches of the vagus nerve synapse on to post-ganglionic parasympathetic nerves and are themselves cholinergic (like all preganglionic neurons). The released acetylcholine in this case binds to nicotinic receptors which have a different pharmacological profile and are not affected by anti-muscarinic drugs.

The pharmacology

Currently available anti-muscarinic drugs are not selective for muscarinic receptors in the lung and may have some systemic effects. These effects are limited because the drugs are inhaled and are poorly absorbed from the lung. Dry mouth (saliva production is under cholinergic control) is the most common side-effect reported. Constipation and urinary retention (both also consistent with an anti-muscarinic effect) have also been reported but are rarer. When nebulised, there is a risk of anti-muscarinic drugs effecting cholinergic control of pupil diameter and accommodation.

The clinical basics

Short acting β2-agonist (SABA) and short-acting anti-muscarinic antagonists (SAMA) have been reported to be equally effective in COPD. The advice to prescribers is to try one of either class for several weeks and then swap them to see which has the most benefit and is better tolerated by the patient. SABA generally have a more rapid onset (15 minutes) as relievers that SAMA (30 minutes). SABA and SAMA act additively in most clinical trials, although it’s a small change and the clinical significance is unclear. The BTS guidelines only recommend combining the two drug classes in certain patients (e.g. those who don’t want, or are intolerant to glucocorticosteroids and are not adequately controlled by a SABA or SAMA alone).

Asthma and COPD are different inflammatory processes that produce different kinds of bronchoconstriction. COPD seems to have a significant cholinergic component, so anti-muscarinics are as effective in inhibiting bronchoconstriction as SABA are at reversing it. However, early clinical trials of these drugs in asthma revealed that SABA are a superior therapeutic in this disease. This is probably because more diverse inflammatory mediators are released in asthma, many of which directly contract airway smooth muscle.

Some studies suggest that anti-muscarinic drugs have a better cardiovascular safety profile in COPD than β2-agonists. This might be because COPD patients use their relievers several times a day, every day and because their chronic hypoxia doesn’t mix well with tachycardia (a common side-effect of β2-agonist use).

Complex pharmacology

There are 5 subtypes of muscarinic receptor (M1-M5), of which only two (M2 and M3) are of real pharmacological significance in the airways:

• M3 receptors are present on airway smooth muscle cells and mucus glands and mediate parasympathetic excitation of these tissues.
• M2 receptors act as autoreceptors on postganglionic nerve terminals and inhibit acetylcholine release. Therefore, blocking these receptors selectively would have the undesirable effect of increasing vagal excitation of smooth muscle and glands.

To date, no truly receptor subtype-selective anti-muscarinic drugs are in clinical use. The classic anti-muscarinic, atropine, is not used in respiratory disease because it crosses the blood-brain barrier and causes CNS effects. The SAMA Ipratropium has the advantage that while it is as non-selective as atropine it is poorly absorbed in the gastrointestinal tract (a proportion of any inhaled drug will inevitably be swallowed) and does not cross the blood brain barrier. Tiotropium is a long-acting muscarinic antagonist (LAMA) which is also relatively non-selective in the receptor subtypes to which it binds. However, the interesting property of this drug is that it binds only briefly to M2 receptors, but dissociates from M3 receptors much more slowly (24 hours). Thus, by the time the body has eliminated free tiotropium, the remainder still bound to M3 receptors keep working without affecting M2 receptors.

Listed in Cases