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

NORMAL
ACh
Vagus
nerve
Vagus
nerve
Resistance
1
r 4
Control vagal tone
Highly
constricted
+ Muscarinic
antagonist
Less highly
constricted
COPD
ACh
by inhalation and may therefore have a more prolonged effect. Thus,
it may be useful in some patients with nocturnal asthma.
Combination inhalers of an anticholinergic and 2
agonist,
such as ipratropium/albuterol (COMBIVENT, DUONEB, others), are popular,
particularly among patients with COPD. Several studies have
demonstrated additive effects of these two drugs, thus providing an
advantage over increasing the dose of 2
agonist in patients who
have side effects.
Tiotropium bromide is a long-acting anticholinergic drug that
is suitable for once-daily dosing as a DPI (SPIRIVA) or via a soft mist
mini-nebulizer device (not available in the U.S.) (Barr et al., 2006).
Tiotropium binds to all muscarinic receptor subtypes but dissociates
very slowly from M 3
and M 1
receptors, giving it a degree of kinetic
receptor selectivity for these receptors compared with M 2
receptors,
from which it dissociates more rapidly. Thus, compared with
ipratropium, tiotropium is less likely to antagonize M 2
-mediated
inhibition of ACh release (the resulting increase in ACh could counteract
the blockade of M 3
receptor–mediated bronchoconstriction)
(Chapter 9). It is an effective bronchodilator in patients with COPD
and is more effective than ipratropium four times daily without any
loss of efficacy over a 1-year treatment period. Over a 4-year period,
tiotropium improves lung function and health status and reduces
exacerbations and all-cause mortality, although there is no effect on
disease progression (Tashkin et al., 2008). As a result, tiotropium is
becoming the bronchodilator of choice for COPD patients.
1045
CHAPTER 36
PULMONARY PHARMACOLOGY
Figure 36–7. Anticholinergic drugs inhibit vagally mediated airway
tone, thereby producing bronchodilation. This effect is small
in normal airways but is greater in airways of patients with
chronic obstructive pulmonary disease (COPD), which are structurally
narrowed and have higher resistance to airflow because
airway resistance is inversely related to the fourth power of the
radius (r). ACh, acetylcholine.
when control of asthma is not adequate with nebulized 2
agonists.
A muscarinic antagonist should be considered when there are problems
with theophylline or when inhaled 2
agonists cause a troublesome
tremor in elderly patients.
In COPD, anticholinergic drugs may be as effective as or
even superior to 2
agonists. Their relatively greater effect in COPD
than in asthma may be explained by an inhibitory effect on vagal
tone, which, although not necessarily increased in COPD, may be the
only reversible element of airway obstruction and one that is exaggerated
by geometric factors in the narrowed airways of COPD
patients (Figure 36–7). Anticholinergic drugs reduce air trapping and
improve exercise tolerance in COPD patients.
Therapeutic Choices. Ipratropium bromide (ATROVENT, others) is
available as a pMDI and nebulized preparation. The onset of bronchodilation
is relatively slow and is usually maximal 30-60 minutes
after inhalation, but may persist for 6-8 hours. It is usually given by
MDI three to four times daily on a regular basis, rather than intermittently
for symptom relief, in view of its slow onset of action.
Oxitropium bromide (not available in the U.S.) is a quaternary
anticholinergic bronchodilator that is similar to ipratropium
bromide in terms of receptor blockade. It is available in higher doses
Adverse Effects. Inhaled anticholinergic drugs are generally well
tolerated. On stopping inhaled anticholinergics, a small rebound
increase in airway responsiveness has been described, but the clinical
relevance of this is uncertain. Systemic side effects after ipratropium
bromide and tiotropium bromide are uncommon during
normal clinical use because there is little systemic absorption.
Because cholinergic agonists can stimulate mucus secretion, there
has been concern that anticholinergics may reduce secretion and lead
to more viscous mucus. However, ipratropium bromide, even in high
doses, has no detectable effect on mucociliary clearance in either
normal subjects or in patients with airway disease. A significant
unwanted effect is the unpleasant bitter taste of inhaled ipratropium,
which may contribute to poor compliance. Nebulized ipratropium
bromide may precipitate glaucoma in elderly patients due to a direct
effect of the nebulized drug on the eye. This may be prevented by
nebulization with a mouthpiece rather than a face mask. Reports of
paradoxical bronchoconstriction with ipratropium bromide, particularly
when given by nebulizer, were largely explained as effects of
the hypotonic nebulizer solution and by antibacterial additives, such
as benzalkonium chloride and ethylenediaminetetraacetic acid
(EDTA). This problem has not been described with tiotropium.
Occasionally, bronchoconstriction may occur with ipratropium
bromide given by MDI. It is possible that this is due to blockade of
prejunctional M 2
receptors on airway cholinergic nerves that normally
inhibit acetylcholine release. Tiotropium causes dryness of the
mouth in 10-15% of patients, but this usually disappears during continued
therapy. Urinary retention is occasionally seen in elderly
patients.
Future Developments. Anticholinergics are the bronchodilators of
choice in COPD and therefore have a growing market. Several longacting
muscarinic antagonists are now in clinical development,