Anticholinergics

The lung expresses at least three subtypes of muscarinic acetylcholine receptor. Ml receptors are located primarily in the parasympathetic ganglia, where their activation facilitates transmission through the ganglia, whereas M2 receptors are found on presynaptic cholinergic nerve terminals and function to inhibit acetylchdine release, and M3 receptors are present on the smooth muscle and elicit contraction [62]. Although anticholinergic drugs have had a long history of use in the treatment of asthma, the development of a successful antiasthmatic drug in this case has been slow. The major obstacle has been the lack of availability of compounds that produce optimal bronchodilation without accompanying side effects. Two drugs of this class, ipratropium bromide (19) and oxitropium bromide (20), which are structural analogues of atropine (21), have been studied extensively as alternatives to b2 stimulant drugs [63-65]. Although the distribution of cholinergic receptors in the human respiratory tract is not well understood, these quarternary drugs appear to exert their bronchodilatory activity mainly on the large airways, in contrast to b-andrenoceptor agonists, and probably produce bronchodilation by competitive inhibition of cholinergic receptors on bronchial smooth muscle, by antagonizing the action of acetylcholine at its membrane-bound receptor site. Thus, they block the bronchoconstrictor action of vagal efferent impulses; lung irritant receptors provide the chief efferent input for this vagal reflex. Because 19 and 20 are water-soluble quarternary ammonium derivatives, they lack the CNS stimulatory properties of atropine (21).

When given by inhalation, ipratropium bromide and oxitropium bromide are slower acting than b2-receptor stimulants but have a longer duration of action [66,67]. Both drugs are considerably more bronchoselective than atropine when given by inhalation and exhibit significantly less systemic anticholinergic side effects.

There is significant interest in identifying and developing either longer-acting, more potent nonselective muscarrinic receptor antagonists than ipratropium, such as tiotropium (22) and oxitropate (23), or more subtype-selective muscarinic receptor antagonists, such as darifenacin and revatropate (24). Revatropate is an M1/M3 receptor-selective muscarininc antagonist with about 50-fold lower potency against M2 receptors. In animal models, revatropate (24) inhibited acetylcholine-induced bronchoconstriction but, unlike ipratro-pium, did not potentiate vagally induced bronchoconstriction [68,69].

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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