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

1037
Cell
membrane
β 2 agonist
Methylxanthines
R 1 C C NH
HO
ATP
OH R 2
K +
Iberiotoxin
AC
GTP
Cyclic AMP
PDE
5 AMP
β γ
α s
PKA
G s
β 2 AR
G s
Ca 2+ -activated K + channel activation
PLC-IP 3 -Ca 2+ pathway activity
Na + /Ca 2+ exchange
Na + ,Ca 2+ -ATPase
MLCK
CHAPTER 36
PULMONARY PHARMACOLOGY
Figure 36–5. Molecular actions of β 2
agonists to induce relaxation of airway smooth muscle cells. Activation of 2
receptors ( 2
AR)
results in activation of adenylyl cyclase (AC) via a stimulatory G protein (G s
), leading to an increase in intracellular cyclic AMP and
activation of PKA. PKA phosphorylates a variety of target substrates, resulting in opening of Ca 2+ -activated K + channels (K Ca
), thereby
facilitating hyperpolarization, decreased phosphoinositide (PI) hydrolysis, increased Na + /Ca 2+ exchange, increased Na + ,Ca 2+ - ATPase
activity, and decreased myosin light chain kinase (MLCK) activity. 2
Receptors may also couple to K Ca
via G s
. PDE, cyclic nucleotide
phosphodiesterase.
the contractile agent. This is an important property for the treatment
of asthma because many bronchoconstrictor mechanisms (neurotransmitters
and mediators) are likely to be contributory. In COPD
the major mechanism of action is likely to be reduction of cholinergic
neural bronchoconstriction.
2
Receptors are localized to several different airway cells,
where they may have additional effects. Thus, 2
agonists may cause
bronchodilation in vivo not only via a direct action on airways smooth
muscle, but also indirectly by inhibiting the release of bronchoconstrictor
mediators from inflammatory cells and of bronchoconstrictor neurotransmitters
from airway nerves. These mechanisms include:
• Prevention of mediator release from isolated human lung mast
cells (via 2
receptors).
• Prevention of microvascular leakage and thus the development
of bronchial mucosal edema after exposure to mediators, such
as histamine and leukotriene D 4
.
• Increase in mucus secretion from submucosal glands and ion
transport across airway epithelium; these effects may enhance
mucociliary clearance, and thereby reverse the defective clearance
found in asthma.
• Reduction in neurotransmission in human airway cholinergic
nerves by an action at presynaptic 2
receptors to inhibit acetylcholine
release. This may contribute to their bronchodilator
effect by reducing reflex cholinergic bronchoconstriction.
Although these additional effects of 2
agonists may be relevant
to the prophylactic use of these drugs against various challenges,
their rapid bronchodilator action is probably attributable to
a direct effect on airway smooth muscle.
Anti-Inflammatory Effects
Whether 2
agonists have anti-inflammatory effects in asthma is controversial.
The inhibitory effects of 2
agonists on mast cell mediator
release and microvascular leakage are clearly anti-inflammatory,
suggesting that 2
agonists may modify acute inflammation.
However, 2
agonists do not appear to have a significant inhibitory
effect on the chronic inflammation of asthmatic airways, which is
suppressed by corticosteroids. This has now been confirmed by several
biopsy and bronchoalveolar lavage studies in patients with
asthma who are taking regular 2
agonists (including long-acting
inhaled 2
agonists), that demonstrate no significant reduction in the
number or activation in inflammatory cells in the airways, in contrast
to resolution of the inflammation that occurs with ICS. This may be
related to the fact that effects of 2
agonists on macrophages,
eosinophils, and lymphocytes are rapidly desensitized.
Clinical Use
Short-Acting 2
Agonists. Inhaled short-acting 2
agonists
are the most widely used and effective bronchodilators in