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

Allergen
Cold air
1053
Exercise
PAF
Aspirin
(in AS asthmatics)
Mast cell
Eosinophil
SO 2
CHAPTER 36
Arachidonic acid
5´-lipoxygenase
Cysteinyl-leukotrienes
(LTC 4 , LTD 4 , LTE 4 )
CysLT 1
receptors
5-LO INHIBITORS
Zileuton
LT ANTAGONISTS
Montelukast
Pranlukast
Zafirlukast
PULMONARY PHARMACOLOGY
Plasma
exudation
Mucus
secretion
Bronchoconstriction
Eosinophil
recruitment
Figure 36–11. Effects of cysteinyl-leukotrienes on the airways and their inhibition by anti-leukotrienes. AS, aspirin sensitive; 5-LO,
5-lipoxygenase; LT, leukotriene; PAF, platelet-activating factor.
symptoms, with a reduction in the use of rescue inhaled 2
agonists.
Several studies show evidence for a bronchodilator effect, with an
improvement in baseline lung function, suggesting that leukotrienes
are contributing to the baseline bronchoconstriction in asthma,
although this varies among patients. However, anti-leukotrienes are
considerably less effective than inhaled corticosteroids in the treatment
of mild asthma and cannot be considered the treatment of first
choice (Ducharme, 2003). Anti-leukotrienes are indicated as an addon
therapy in patients who are not well controlled on ICS. The added
benefit is small, equivalent to doubling the dose of ICS, and less
effective than adding a LABA (Ducharme et al., 2006).
In patients with severe asthma who are not controlled on high
doses of ICS and LABA, anti-leukotrienes do not appear to provide
any additional benefit (Robinson et al., 2001). Theoretically, antileukotrienes
should be of particular value in patients with aspirinsensitive
asthma because they block the airway response to aspirin
challenge; however, their benefit is no greater here than in other
types of asthma (Dahlen et al., 2002). Anti-leukotrienes are effective
in preventing exercise-induced asthma, with efficacy similar to
that of LABA (Coreno et al., 2000). Anti-leukotrienes also have a
weak effect in rhinitis that may be additive with the effects of an
antihistamine (Nathan, 2003).
Studies have demonstrated weak anti-inflammatory effects
of anti-leukotrienes in reducing eosinophils in sputum and biopsies
(Minoguchi et al., 2002), but this is much less marked than with ICS
and there is no additional anti-inflammatory effect when added to
an ICS (O’Sullivan et al., 2003). Anti-leukotrienes therefore appear
to act mainly as anti-bronchoconstrictor drugs, and they are clearly
less broadly effective than 2
agonists because they antagonize only
one of several bronchoconstrictor mediators.
In COPD, Cys-LTs are not elevated in exhaled breath condensate,
and cys-LT1 receptor antagonists have no role in the therapy
of COPD (Barnes, 2004). By contrast, LTB 4
, a potent neutrophil
chemoattractant, is elevated in COPD, indicating that 5-LO
inhibitors that inhibit LTB 4
synthesis may have some potential benefit
by reducing neutrophil inflammation. However, a pilot study
failed to indicate any clear benefit of a 5-LO inhibitor in COPD
patients (Gompertz and Stockley, 2002).
Adverse Effects. Zileuton, zafirlukast, and montelukast are all associated
with rare cases of hepatic dysfunction; thus liver-associated
enzymes should be monitored. Several cases of Churg-Strauss syndrome
have been associated with the use of zafirlukast and montelukast.
Churg-Strauss syndrome is a very rare vasculitis that may
affect the heart, peripheral nerves, and kidney and is associated with
increased circulating eosinophils and asthma. It is uncertain whether
the reported cases are due to a reduction in oral or inhaled corticosteroid
dose or are a direct effect of the drug. Cases of Churg-Strauss
syndrome have been described in patients on anti-leukotrienes who