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

1036
NOREPINEPHRINE
HO CH CH 2 NH 2
HO
OH
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
EPINEPHRINE
ISOPROTERENOL
ALBUTEROLOL
SALMETEROL
FORMOTEROL
HO CH CH 2 NH
HO
OH CH 3
differs from epinephrine only in the terminal amine group; in general,
further modification at this site confers receptor selectivity.
Further substitution of the terminal amine resulted in
2
receptor selectivity, as in albuterol (salbutamol) and terbutaline.
Exogenous catecholamines are rapidly metabolized by catechol-Omethyl
transferase (COMT), which methylates in the 3-hydroxyl
position, and accounts for the short duration of action of catecholamines.
Modification of the catechol ring, as in albuterol and
terbutaline, prevents this degradation and therefore prolongs the
effect. Catecholamines are also broken down in sympathetic nerve
terminals and in the GI tract by monoamine oxidase (MAO), which
cleaves the side chain. Isoproterenol, which is a substrate for MAO,
is metabolized in the gut, making absorption variable. Substitution
in the amine group confers resistance to MAO and ensures reliable
absorption. Many other 2
-selective agonists have now been introduced
and, although there may be differences in potency, there are
no clinically significant differences in selectivity. Inhaled 2
-selective
drugs in current clinical use (apart from rimiterol [not available in the
U.S.] that is broken down by COMT) have a similar duration of
action (3-6 hours). The inhaled long-acting inhaled 2
agonists
salmeterol and formoterol have a much longer duration of effect,
providing bronchodilation and bronchoprotection for >12 hours
(Kips and Pauwels, 2001). Formoterol has a bulky substitution in
the aliphatic chain and has a moderate lipophilicity, which appears
to keep the drug in the membrane close to the receptor, so it behaves
as a slow-release drug. Salmeterol has a long aliphatic chain, and its
long duration may be due to binding within the receptor binding cleft
(“exosite”) that anchors the drug in the binding cleft. Once-daily 2
agonists, such as indacaterol, with a duration of action >24 hours, are
now in development (Cazzola and Matera, 2008).
HO CH CH 2 NH
HO
OH CH(CH 3 ) 2
HOH 2 C CH CH 2 NH
HO
OH C(CH 3 ) 3
HOH 2 C CH CH 2 NHCH 2 (CH 2 ) 5 OCH 2 (CH 2 ) 3
HO
OH
HCONH CH CH 2 NHCH CH 2 OCH 3
HO
OH CH 3
Figure 36–4. Chemical structure of some adrenergic agonists showing development from catecholamines by substitutions on the catechol
nucleus and side chain.
Mode of Action
Occupation of 2
receptors by agonists results in the activation of
the G s
-adenylyl cyclase-cAMP-PKA pathway, resulting in phosphorylative
events leading to bronchial smooth muscle relaxation
(Figure 36–5). Agonists produce bronchodilation by directly stimulating
2
receptors in airway smooth muscle, and in vitro relax
human bronchi and lung strips (indicating an effect on peripheral
airways). In vivo there is a rapid decrease in airway resistance. 2
Receptors have been localized to airway smooth muscle of all airways
by direct receptor binding techniques and autoradiographic
mapping studies.
The molecular mechanisms by which agonists induce
relaxation of airway smooth muscle include:
• Lowering of [Ca 2+ ] i
concentration by active removal of Ca 2+
from the cytosol into intracellular stores and out of the cell
• Acute inhibition of the PLC-IP 3
pathway and its mobilization of
cellular Ca 2+ (prolonged use can upregulate expression of PLC 1
)
• Inhibition of myosin light chain kinase activation
• Activation of myosin light chain phosphatase
• Opening of a large conductance Ca 2+ -activated K + channel
(K Ca
), which repolarizes the smooth muscle cell and may stimulate
the sequestration of Ca 2+ into intracellular stores. 2
Receptors may also couple to K Ca
via G s
so that relaxation of
airway smooth muscle may occur independently of an increase
in cAMP.
Several actions of 2
agonists are mediated not by PKA but
by other cAMP-regulated proteins, such as the exchange protein activated
by cAMP (EPAC) (Holz et al., 2006). 2
Agonists act as functional
antagonists and reverse bronchoconstriction irrespective of