DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Pulmonary
Pharmacology
Peter J. Barnes
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 2
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 H
2) lymphocytes
(Figure 36–1) (Barnes, 2008b). Mast cell activation
by allergens and physical stimuli releases
bronchoconstrictor mediators, such as histamine,
leukotriene D 4
, and prostaglandin D 2
, 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 H
2 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 through the release of
>100 inflammatory mediators (Barnes et al., 1998a).
Complex cytokine networks, including chemokines and
growth factors, play important roles in orchestrating the
inflammation process (Barnes, 2008a).