Chapter 36: Pulmonary Pharmacolog

INTRODUCTION

Pulmonary pharmacology concerns understanding how drugs act on the lung and the pharmacological therapy of pulmonary diseases. Much of pulmonary pharmacology is concerned with the effects of drugs on the airways and the therapy of airway obstruction, particularly asthma and chronic obstructive pulmonary disease (COPD), which are among the most common chronic diseases in the world. Both asthma and COPD are characterized by chronic inflammation of the airways, although there are marked differences in inflammatory mechanisms and response to therapy between these diseases (Barnes, 2008b). After a brief introduction to asthma and COPD, this chapter discusses the pharmacotherapy of obstructive airways disease, particularly bronchodilators, which act mainly by reversing airway smooth muscle contraction, and anti-inflammatory drugs, which suppress the inflammatory response in the airways. This chapter focuses on the pulmonary pharmacology of β₂ agonists and corticosteroids; the basic pharmacology of these classes of agents is presented elsewhere (Chapters 12 and 42). In presenting the details of pharmacotherapy of asthma and COPD, the chapter also covers the physiology and molecular pathology surrounding these conditions, deriving knowledge of the diseases by assessing their responses to various classes of drugs.

This chapter also discusses other drugs used to treat obstructive airway diseases, such as mucolytics and respiratory stimulants, and covers the drug therapy of cough, the most common respiratory symptom, as well as drugs used to treat pulmonary hypertension. Drugs used in the treatment of lung infections, including tuberculosis (Chapter 56), are covered elsewhere.

MECHANISMS OF ASTHMA

Asthma is a chronic inflammatory disease of the airways that is characterized by activation of mast cells, infiltration of eosinophils, and T helper 2 (T_H2) lymphocytes (Figure 36–1) (Barnes, 2008b). Mast cell activation by allergens and physical stimuli releases bronchoconstrictor mediators, such as histamine, leukotriene D₄, and prostaglandin D₂, which cause bronchoconstriction, microvascular leakage, and plasma exudation (Chapters 32 and 33). Increased numbers of mast cells in airway smooth muscle are a characteristic of asthma. Many of the symptoms of asthma are due to airway smooth muscle contraction, and therefore bronchodilators are important as symptom relievers. Whether airway smooth muscle is intrinsically abnormal in asthma is not clear, but increased contractility of airway smooth muscle may contribute to airway hyperresponsiveness, the physiological hallmark of asthma. The mechanism of chronic inflammation in asthma is still not well understood. It may initially be driven by allergen exposure, but it appears to become autonomous so that asthma is essentially incurable. The inflammation may be orchestrated by dendritic cells that regulate T_H2 cells that drive eosinophilic inflammation and also IgE formation by B lymphocytes. Airway epithelium plays an important role through the release of multiple inflammatory mediators and through the release of growth factors in an attempt to repair the damage caused by inflammation. The inflammatory process in asthma is mediated ...