Page 362 - Basic _ Clinical Pharmacology ( PDFDrive )

348 SECTION IV Drugs with Important Actions on Smooth Muscle

100

Early reaction Late reaction
FEV 1

75
0 8
Time (h)

Smooth muscle Blood vessel

Airway wall

Cell infiltration

Histamine PGD 2 IL-4 ECP Proteases
Tryptase LTC 4 IL-5 MBP PAF
PAF GM-CSF
TNF
TGF

IgE

Mast cell T lymphocyte Eosinophil Neutrophil

ALLERGEN
FIGURE 20–1 Conceptual model for the immunopathogenesis of asthma. Exposure to allergen causes synthesis of IgE, which binds to
mast cells in the airway mucosa. On re-exposure to allergen, antigen-antibody interaction on mast cell surfaces triggers release of mediators
of anaphylaxis: histamine, tryptase, prostaglandin D 2 (PGD 2 ), leukotriene (LT) C 4 , and platelet-activating factor (PAF). These agents provoke
contraction of airway smooth muscle, causing the immediate fall in forced expiratory volume in 1 second (FEV 1 ). Re-exposure to allergen also
causes the synthesis and release of a variety of cytokines: interleukins (IL) 4 and 5, granulocyte-macrophage colony-stimulating factor (GM-CSF),
tumor necrosis factor (TNF), and tissue growth factor (TGF) from T cells and mast cells. These cytokines in turn attract and activate eosinophils
and neutrophils, whose products include eosinophil cationic protein (ECP), major basic protein (MBP), proteases, and platelet-activating factor.
These mediators cause the edema, mucus hypersecretion, smooth muscle contraction, and increase in bronchial reactivity associated with the
late asthmatic response, indicated by a second fall in FEV 1 3–6 hours after the exposure.

leukotriene receptor antagonists), or interfere with the action of This therapy, once expected to be effective for all forms of asthma,
inflammatory cytokines (anti-IL-5 and anti-IL-13 monoclonal is now recognized to be more effective for allergic than nonallergic
antibodies). Other drugs that might be expected to be effective asthma (see Future Directions of Asthma Therapy below).
in all forms of asthma are those that relax airway smooth mus-
cle (sympathomimetic agents, phosphodiesterase inhibitors) or
inhibit the effect of acetylcholine released from vagal motor nerves ■ BASIC PHARMACOLOGY
(muscarinic antagonists, also described as anticholinergic agents).
Another approach to asthma treatment is aimed at reducing OF AGENTS USED IN THE
the level of bronchial responsiveness. Because increased respon- TREATMENT OF ASTHMA
siveness appears to be linked to airway inflammation and because
airway inflammation is a feature of late asthmatic responses, this The drugs most used for asthma management are adrenoceptor
strategy is implemented both by reducing exposure to the aller- agonists or sympathomimetic agents (used as “relievers” or bron-
gens that provoke inflammation and by prolonged therapy with chodilators) and inhaled corticosteroids (used as “controllers” or
anti-inflammatory agents, especially inhaled corticosteroids (ICS). anti-inflammatory agents). Their basic pharmacology is presented