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

frequency in vitro. Because inflammation leads to mucus hypersecretion,
anti-inflammatory treatments should reduce mucus
hypersecretion; ICS are very effective in reducing increased mucus
production in asthma.
Sensory nerves and neuropeptides are important in the secretory
activities of the submucosal gland (which predominates in proximal
airways) and goblet cell (more notable in peripheral airways).
Opioids and K + channel openers inhibit mucus secretion mediated
via sensory neuropeptide release; peripherally acting opioids may
be developed to control mucus hypersecretion due to irritants in the
future (Rogers, 2002).
Mucolytics
Several agents can reduce the viscosity of sputum in vitro. One group
are derivatives of cysteine that reduce the disulfide bridges that bind
glycoproteins to other proteins such as albumin and secretory IgA.
These drugs also act as antioxidants and may therefore reduce airway
inflammation. Only N-acetylcysteine (MUCOMYST, others) is available
in the U.S.; carbocysteine, methylcysteine, erdosteine, and
bromhexine are available elsewhere. Orally administered, these
agents are relatively well tolerated, but clinical studies in chronic
bronchitis, asthma, and bronchiectasis have been disappointing. A
systematic review of several small studies showed a small benefit in
terms of reducing exacerbations, with most of the benefit from N-
acetylcysteine; whether this relates to the mucolytic activity of N-
acetylcysteine or to its action as an antioxidant is unclear (Poole and
Black, 2001). A large controlled study of oral N-acetylcysteine in
COPD patients showed no effect in disease progress or in preventing
exacerbations, although there was some benefit in the patients
not treated with inhaled corticosteroids (Decramer et al., 2005), as
confirmed in a subsequent study of carbocysteine in COPD patients
not treated with other medications (Zheng et al., 2008). N-acetylcysteine
is not currently recommended for COPD management.
DNAse (dornase alfa, PULMOZYME) reduces mucus viscosity
in sputum of patients with cystic fibrosis and is indicated if there is
significant symptomatic and lung function improvement after a trial
of therapy (Henke and Ratjen, 2007). There is no evidence that dornase
alfa is effective in COPD or asthma, however.
The epidermal growth factor receptor (EGFR) plays a critical
role in airway mucus secretion from goblet cells and submucosal
glands and appears to mediate the mucus secretory response to several
secretagogues, including oxidative stress, cigarette smoke, inflammatory
cytokines, and activated TLRs (Burgel and Nadel, 2004). Small
molecule inhibitors of EGFR kinase, such as gefitinib and erlotinib,
have been developed for use as anticancer therapies and are currently
being assessed as treatments for mucus hypersecretion in COPD
patients.
Expectorants
Expectorants are oral drugs that are supposed to enhance the clearance
of mucus. Although expectorants were once commonly prescribed,
there is little or no objective evidence for their efficacy. Such
drugs are often emetics that are given in sub-emetic doses on the
basis that gastric irritation may stimulate an increase in mucus clearance
via a reflex mechanism. However, there is no good evidence
for this assumption. Lacking evidence for their efficacy, the FDA
has removed most expectorants from the market in a review of overthe-counter
drugs. With the exception of guaifenesin, no agents are
approved as expectorants in the U.S. In patients who find it difficult
to clear mucus, adequate hydration and inhalation of steam may be
of some benefit.
ANTITUSSIVES
Despite the fact that cough is a common symptom of airway
disease, its mechanisms are poorly understood, and
current treatment is unsatisfactory (Pavord and Chung,
2008). Viral infections of the upper respiratory tract are
the most common cause of cough; postviral cough is usually
self-limiting and commonly patient-medicated. Their
wide use notwithstanding, over-the-counter cough medications
are largely ineffective (Dicpinigaitis, 2009a).
Because cough is a defensive reflex, its suppression may
be inappropriate in bacterial lung infection. Before treatment
with antitussives, it is important to identify underlying
causal mechanisms that may require therapy.
Whenever possible, treat the underlying cause, not the cough.
Asthma commonly presents as cough, and the cough will usually
respond to ICS. A syndrome characterized by cough in association
with sputum eosinophilia but no airway hyperresponsiveness and
termed eosinophilic bronchitis also responds to ICS (Birring et al.,
2003). Nonasthmatic cough does not respond to ICS but sometimes
responds to anticholinergic therapy. The cough associated with postnasal
drip of sinusitis responds to antibiotics (if warranted), nasal
decongestants, and intranasal steroids. The cough associated with ACE
inhibitors (in ~15% of patients treated) responds to lowering the dose
or withdrawal of the drug and substitution of an AT 1
receptor antagonist
(Chapter 26). Gastroesophageal reflux is a common cause of
cough through a reflex mechanism and occasionally as a result of acid
aspiration into the lungs. This cough may respond to suppression of
gastric acid with an H 2
receptor antagonist or a proton pump inhibitor
(Chapter 45), although even large doses may not always be effective
(Chang et al., 2006). Some patients have a chronic cough with no obvious
cause, and this chronic idiopathic cough may be due to airway
sensory neural hyperesthesia (Haque et al., 2005).
Opiates. Opiates have a central mechanism of action on μ opioid
receptors in the medullary cough center, but there is some evidence
that they may have additional peripheral action on cough receptors
in the proximal airways. Codeine and pholcodine (not available in
the U.S.) are commonly used, but there is little evidence that they are
clinically effective, particularly on postviral cough; in addition, they
are associated with sedation and constipation (Dicpinigaitis, 2009a).
Morphine and methadone are effective but indicated only for
intractable cough associated with bronchial carcinoma. A peripherally
acting opioid agonist, 443C81, does not appear to be effective
for cough.
Dextromethorphan. Dextromethorphan is a centrally active N-methyl-
D-aspartate (NMDA) receptor antagonist. It may also antagonize
opioid receptors. Despite the fact that it is in numerous overthe-counter
cough suppressants and used commonly to treat cough,
it is poorly effective. In children with acute nocturnal cough, it is
not significantly different from placebo in reducing cough
1057
CHAPTER 36
PULMONARY PHARMACOLOGY