Chapter 15 Bronchodilators

Peter M.A. Calverley

Bronchodilator drugs are among the most widely used respiratory medicines, and substantial developments, particularly in duration of action, have increased their effectiveness in recent years. Essentially these drugs act to increase airway caliber and permit faster and more effective lung emptying. The concept of bronchodilatation has evolved as well, and the designation “bronchodilator” is now largely synonymous with any drug that acts relatively rapidly to cause relaxation of airway smooth muscle.

Breathlessness and wheezing are cardinal symptoms of many respiratory diseases, and from the 19th century it was recognized that smoking cigarettes made from the leaves of the plant Atropa belladonna lessened the symptoms of asthma. This therapy was largely superseded when epinephrine (adrenaline) was purified in the early 20th century. Subsequently, synthetic analogues of epinephrine were developed, as was atropine, the first synthetic antimuscarinic agent. Both atropine and epinephrine could be added to organ baths containing airway smooth muscle, and their potency in relieving or preventing induced smooth muscle contraction could be measured. These developments led to the current understanding of the control of airway smooth muscle, as shown in Figure 15-1. Changes in airway smooth muscle length translate into changes in airway caliber—an especially important issue when airway diameter is reduced, as in chronic obstructive pulmonary disease (COPD) (Figure 15-2). In clinical practice, this aspect of pulmonary function is assessed indirectly as an increase in the forced expiratory volume in 1 second (FEV₁) after drug administration. When a bronchodilator is given orally, the time to onset of action (i.e., improvement in lung function) is prolonged, reflecting the absorption and circulation of the drug; this time can be considerably shortened when treatment is administered by inhalation. Of note, not all drugs that increase FEV₁ do so by changing airway smooth muscle activity; for example, antiinflammatory agents can reduce the mucosal thickening and thickening of the airway wall, thereby leading to improvements in FEV₁. These processes take some time to develop, however, because agents such as corticosteroids have both nuclear and extranuclear effects on protein synthesis, which reduce the number of proinflammatory messenger molecules. Hence, for practical purposes, bronchodilators can be considered as those drugs with a proven direct effect on airway smooth muscle and a relatively rapid onset of effect (minutes to several hours) in clinical circumstances in which some measure of airway resistance is the marker for effectiveness.

Figure 15-1 Control of airway smooth muscle in humans. Preganglionic and postganglionic parasympathetic nerves release acetylcholine (ACh) and can be activated by airway and extrapulmonary afferent nerves. There is no direct sympathetic innervation to the airways. Mediators released from inflammatory cells directly activate airway smooth muscle cells, as well as acting through a cholinergic reflex. This may explain why antimuscarinics are less effective than β₂-agonists as bronchodilators in asthma, because the latter drugs counteract the effect of all bronchoconstrictors.

(From Barnes PJ: β₂-Agonists, anticholinergics, and other nonsteroid drugs. In Albert RK, editor: Clinical respiratory medicine, ed 3, Philadelphia, Mosby, 2008.)

Figure 15-2 Cholinergic control of airways in chronic obstructive pulmonary disease (COPD). The normal airway has a certain degree of vagal cholinergic tone caused by tonic release of acetylcholine, which is blocked by muscarinic antagonists. This effect may be exaggerated in patients who have COPD, because of fixed narrowing of the airways as a result of geometric factors. The absolute increase in forced expiratory volume in 1 second (FEV₁) after administration of these agents is similar to that seen in healthy smokers, but the relative change is much greater, reflecting the lower initial airway diameter.

(From Barnes PJ: β₂-agonists, anticholinergics, and other nonsteroid drugs. In Albert RK, editor: Clinical respiratory medicine, ed 3, Philadelphia, Mosby, 2008.)

This chapter presents an overview of the principal classes of bronchodilator drugs, including their mechanisms of action and specific indications. As background for these considerations, it is useful first to examine why these drugs should be so useful in respiratory disease, and to identify those settings in which they should be deployed.

Physiologic Basis for Bronchodilator Action

Under resting conditions in healthy people, the work of breathing performed by the respiratory muscles is relatively small. Inspiration is an active process, and sufficient flow has to be generated by overcoming respiratory resistive, elastive, and frictional loads to ensure adequate alveolar ventilation. Expiration is passive and ends when the expiratory recoil pressure of the lungs and the chest wall are balanced. There is little expiratory flow resistance within the bronchial tree, and expiratory flow limitation (no increase in flow despite increasing expiratory driving pressure) is detected only during the last part of the maximum forced expiration (Figure 15-3, top). Ventilation increases during exercise but not to the point at which flow limitation significantly limits performance.

Figure 15-3 Expiratory flow limitation in health and disease. Top, The pressure change within and outside the airway in health. Intraluminal driving pressure producing expiratory flow declines owing to frictional resistance. The opposing triangles mark the point at which pressures within and outside the airway are equal (choke point) when expiratory flow limitation is present. This occurs outside of the thorax in healthy people (dotted line) and only during a maximum forced expiration. Bottom, The resistive pressure drop is greater, the choke point is more proximal in the airway, and expiratory flow limitation occurs within the thorax and can be present in tidal breathing. The bronchodilator moves the choke point distally and thus may abolish resting flow limitation altogether or allow more lung emptying to occur before onset of flow limitation.

Airway resistance is influenced significantly by the caliber of the bronchial tree (see Figure 15-2). In health, most of the resistance lies in the region of the larynx, with less than 20% coming from the periphery of the lung. The evidence points to resting airway smooth muscle tone that decreases physiologically during exercise to reduce the resistive work required when ventilation has to increase. Bronchodilator drugs abolish this smooth muscle tone in both healthy persons and patients with disease. In healthy people, the increase in FEV₁ after administration of a β-agonist is between 50 and 120 mL, a value similar to that in patients with COPD, whose baseline FEV₁ usually is much lower. By contrast, in patients with asthma, in which airway smooth muscle bulk is greater and resting muscle tone may be increased by indirect reflex mechanisms, the response to bronchodilator drugs is more dramatic, and substantial increases in lung function occur after the acute administration of a bronchodilator. The improvement in lung emptying that results from bronchodilation has important effects on the operating lung volume and hence on the work of breathing.

In general, wheezing reflects areas of local flow limitation within the airway. Expiratory flow limitation can occur in the absence of audible wheeze and contributes to the slow emptying of the lungs and the higher lung volumes that lead to breathlessness and chest tightness in obstructive lung disease. Expiratory flow limitation may be abolished completely after a bronchodilator drug in asthma (see Figure 15-3), although asthmatic symptoms often will recur when the effects of the bronchodilator wear off (see further on). In COPD, the absolute change in lung function is much smaller than in asthma, and flow limitation often persists, particularly in severe disease, although to a less severe degree. These subtle changes in lung mechanics, however, can produce clinically relevant changes in operating lung volumes, particularly in the end-expiratory lung volume, which is significantly elevated in many patients with COPD and constitutes is a good guide to the degree of exercise impairment experienced by affected persons. A further effect of bronchodilator drugs is to increase the threshold at which symptoms are induced. This increased threshold is important in the prevention of exercise-induced asthma and also in the reduction of symptoms produced more predictably by exercise, as occurs when patients with COPD undertake certain daily activities. This ability to increase baseline lung function and reduce the impact of external stimuli on the airways is likely to be important in explaining why bronchodilator drugs are associated with fewer exacerbations of airways disease when given in effective doses over the long term.

A different situation obtains in patients with restrictive lung function secondary to diffuse pulmonary fibrosis or chest wall disorders, in which the work of breathing is increased because of the greatly increased elastic load on the inspiratory muscles and the airways are largely spared from involvement. In such patients, bronchodilator drugs will have little effect on breathlessness, and their use is associated with unwanted side effects, rather than clinical benefit. Thus, bronchodilators are indicated only for the relief of symptoms that are caused by obstructive lung disease and not when a restrictive disorder is the dominant clinical problem.

Pharmacologic Basis of Bronchodilator Action

Although by definition the focus of action of bronchodilator drugs is the airway smooth muscle, a number of other secondary or incidental effects occur that can be clinically useful. The balance of these nonbronchodilator effects differs significantly between the two main classes of bronchodilator drugs.

β-Agonists

Based on the classical work of Ahlquist in defining different subtypes of adrenoreceptors, a range of relatively specific β-agonist agents were developed. Because β₂-receptors are almost the only subtype expressed on human airway smooth muscle, it makes sense to use highly selective β-agonists and there is no place for nonselective agents in clinical practice today. The chemical structures of the principal β-agonists are shown in Figure 15-4.

Figure 15-4 Chemical structures of commonly used bronchodilator drugs. A, β₂-Agonists. B, Antimuscarinic drugs.

β₂-Agonists produce bronchodilatation by directly stimulating β₂-receptors in airway smooth muscle, which leads to relaxation. This can be demonstrated in vitro by the relaxant effect of β-agonists on human bronchi and small airways—an effect confirmed in humans by a rapid decrease in airway resistance after administration of drug by inhalation. β-Receptors have been demonstrated in airway smooth muscle by direct receptor-binding techniques, and autoradiographic studies indicate that β-receptors are localized to smooth muscle of all airways from the trachea to the terminal bronchioles, although a wide distribution within the lungs as a whole, including the alveoli, is characteristic.

The β-receptor is a seven transmembrane–spanning G protein. Binding of the β₂-agonist to the disulfide bonds on the extracellular surface leads to activation of adenylate cyclase and a consequent increase in intracellular cyclic adenosine-3′,5′-monophosphate (cAMP). This leads in turn to activation of a specific kinase (protein kinase A) that phosphorylates several target proteins within the cell, resulting in several specific effects:

• A fall in the intracellular calcium ion (Ca²⁺) concentration by active removal of Ca²⁺ from the cell into intracellular stores

• Inhibition of phosphoinositide hydrolysis

• Direct inhibition of myosin light chain kinase

• Opening of large-conductance, calcium-activated potassium channels (K_Ca) that repolarize the smooth muscle cell and may stimulate the sequestration of Ca²⁺ into intracellular stores

• β₂-Agonists act as functional antagonists and reverse bronchoconstriction, irrespective of the contractile agent. This is an important property, because multiple bronchoconstrictor mediators (inflammatory mediators and neurotransmitters) are released in asthma.

β₂-Agonists may have other effects on airways, and β₂-receptors are localized to several different airway cells. Thus, additional effects may include the following:

• Inhibition of mediator release from mast cells and other inflammatory cells

• Inhibitory effects on neutrophil migration and activation

• Reduction and prevention of microvascular leakage and, consequently, development of bronchial mucosal edema after exposure to mediators such as histamine and leukotrienes

• Increased mucus secretion from submucosal glands and ion transport across airway epithelium (effects that may enhance mucociliary clearance, thereby reversing the defect in clearance found in asthma)

• Reduction in neurotransmitter release from airway cholinergic nerves, thus reducing cholinergic reflex bronchoconstriction

• Inhibition of the release of bronchoconstrictor and inflammatory peptides, such as substance P, from sensory nerves

How relevant any of these effects are to the observed clinical effects in disease is hard to determine. They may be more important in preventing bronchoconstriction from other stimuli in asthmatic patients than in directly influencing airway dimensions. The immediate impact on airway smooth muscle remains the most important of these various mechanisms, as illustrated in Figure 15-5. Recognized polymorphisms of the β-receptor show variable responses to agonist drugs in vitro. Translation of these observations into clinically noticeable differences in response in the clinical setting has been difficult, however, and at present these observations remain primarily of academic interest.

Figure 15-5 Direct and indirect bronchodilator effects of β₂-agonists. These agents stimulate β₂-receptors throughout the bronchial tree but cause bronchodilatation directly by means of activation of β₂-receptors on airway smooth muscle and also indirectly by inhibition of mediator release from mast cells. The latter mechanism is more likely to operate in allergic asthmatic patients, but its relative significance is unknown. LTD₄, leukotriene D₄.

(From Barnes PJ: β₂-Agonists, anticholinergics, and other nonsteroid drugs. In Albert RK, editor: Clinical respiratory medicine, ed 3, Philadelphia, Mosby, 2008.)