The pathological triad of pulmonary disease consists of: bronchospasm, airway inflammation, and retained secretion. Respiratory pharmacology deals with agents used to treat this “pathological triad.” Medications used to treat these conditions can be divided into different categories based on their mechanism of action. They include bronchodilators, anticholinergics, corticosteroids, mucolytics, and decongestants just to name a few. Other agents used to treat pulmonary disease such as oxygen, antibiotics, local anesthetics, respiratory stimulants, and muscle relaxers are beyond the scope of this chapter.

Bronchodilators are essential in the treatment of airway disorders. They are the primary treatment for the management of chronic obstructive pulmonary disease (COPD) and are critical in the symptomatic management of asthma. Bronchodilators work through a direct relaxation effect on airway smooth muscle cells. Three major classes of bronchodilators exist at the present time: β(beta)2-adrenoreceptor (AR) agonists, cholinergic receptor antagonists, and xanthines. This chapter will discuss the first 2 treatments, which can be used individually or in combination, as is currently preferred in order to minimize systemic effects. Fast- and short-acting agents are best used for acute symptom relief, whereas long-acting agents are best for maintenance therapy. Treatment adherence has been improved by new formulations that allow once-daily administration.

Understanding the neurological innervation of the airway is key to understanding how bronchodilators work. Airway tone is mainly controlled by parasympathetic nerves carried by the vagus nerve. Postganglionic parasympathetic cholinergic and non-noradrenergic noncholinergic (NANC) fibers innervate airway smooth muscles (ASM), providing the dominant control of the muscle tone and airway caliber as well as airway glands and microvasculature.

There is no direct sympathetic innervation of ASM, but there is innervation of the airway vasculature. Acetylcholine (ACh) is the classic neurotransmitter of the parasympathetic nervous system at both the ganglionic and neuroeffector junctions, which then activate the cholinergic/muscarinic receptors.

Five different subtypes of muscarinic receptors (mAChRs) have been identified (M1-M5), and they are expressed in almost every cell type of the airway and lung tissue, including airway and vascular smooth muscle, different glandular and surface epithelium cells, endothelial cells, and inflammatory cells.

β(beta)-ARs are present in high concentrations in lung tissue and are divided into 3 types: β(beta)1, β(beta)2, and β(beta)3. The majority of pulmonary β(beta)-ARs are of the β(beta)2-AR subtype, localized in the ASM, epithelium, vascular smooth muscle, and submucosal glands. They are more prevalent in small airways than large airways but are also expressed on many inflammatory and immune cells, whereas β(beta)1-ARs are located in the gland and alveoli. There is a uniform distribution of β(beta)-ARs on the alveolar wall with a 2:1 ratio of β(beta)1/β(beta)2.

β(beta)2-ARs are coupled to Gs (part of the G protein-coupled receptors), where stimulation by β(beta)2-AR agonist activate the adenyl cyclase and increase cyclic adenosine monophosphate (cAMP) levels, which in turn increase protein kinase A (PKA) activity. This reduces the intracellular calcium level and activates large conductance potassium channels leading to relaxation of airway smooth muscle.

Ephedrine from the plant ephedra equisetina was used for more than 2000 years for the short-term treatment of respiratory symptoms. The discovery of epinephrine and isoproterenol followed, but due to the fact that these drugs were non-selective alpha- and beta-adrenergic receptor agonists, they caused unwanted side effects and warranted the need of selective β(beta)-AR receptors agonist.