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

1058 (Dicpinigaitis, 2009a). It can cause hallucinations at higher doses
and has significant abuse potential.
Benzonatate. (TESSALON, others), a local anesthetic, acts peripherally
by anesthetizing the stretch receptors located in the respiratory
passages, lungs, and pleura. By dampening the activity of these
receptors, benzonatate may reduce the cough reflex at its source. The
recommended dose is 100 mg, three times/day, and up to 600
mg/day, if needed. Although clinical studies shortly after its approval
showed some efficacy, benzonatate, 200 mg, was not effective in
suppressing experimentally-induced cough in a recent clinical trial
(Dicpinigaitis et al., 2009b). Side effects include dizziness and dysphagia.
Seizures and cardiac arrest have occurred following an acute
ingestion. Severe allergic reactions have been reported in patients
allergic to para-aminobenzoic acid, a metabolite of benzonatate.
Other Drugs. Several other drugs reportedly have small benefits in
protecting against cough challenges or in reducing cough in pulmonary
diseases (Dicpinigaitis, 2009a). These drugs include moguisteine
(not available in the U.S.), which acts peripherally and
appears to open ATP-sensitive K + channels; baclofen, a GABA B
-
selective agonist; and theobromine, a naturally occurring methylxanthine.
Although the expectorant guaifenesin is not typically known
as a cough suppressant, it is significantly better than placebo in
reducing acute viral cough and inhibits cough-reflex sensitivity in
patients with upper respiratory tract infections (Dicpinigaitis et al.,
2009b).
Novel Antitussives. There is clearly a need to develop new more
effective therapies for cough, particularly drugs that act peripherally
in order to avoid sedation. There are close analogies between chronic
cough and sensory hyperesthesia, so new therapies are likely to arise
from pain research (Barnes, 2007).
Transient Receptor Potential V1 Antagonists. TRPV1 (previously
called the vanilloid receptor) is a member of the transient receptor
potential (TRP) family of ion channels activated by capsaicin, H + , and
bradykinin, all of which are potent tussive agents. TRPV1 antagonists
block cough induced by capsaicin and bradykinin and are effective in
some models of cough (McLeod et al., 2008). A side effect of these
drugs is loss of temperature regulation and hyperthermia, which has
prevented clinical development.
Transient Receptor Potential A1 Antagonists. TRPA1 is emerging as
a more promising novel target for antitussives. This channel is activated
by oxidative stress and many irritants and may be sensitized by
inflammatory cytokines (Taylor-Clark et al., 2009). Several selective
TRPA1 antagonists are now in development.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
DRUGS FOR DYSPNEA AND
VENTILATORY CONTROL
Drugs for Dyspnea
Bronchodilators should reduce breathlessness in patients
with airway obstruction. Chronic oxygen may have a
beneficial effect, but in a few patients dyspnea may be
extreme. Drugs that reduce breathlessness may also
depress ventilation in parallel and may therefore be dangerous
in severe asthma and COPD. Some patients show
a beneficial response to dihydrocodeine and diazepam;
however, these drugs must be used with great caution
because of the risk of ventilatory depression. Slowrelease
morphine tablets may also be helpful in COPD
patients with extreme dyspnea (Currow and Abernethy,
2007). Nebulized morphine may also reduce breathlessness
in COPD and could act in part on opioid receptors
in the lung. Nebulized furosemide has some efficacy in
treating dyspnea from a variety of causes, but the evidence
is not yet sufficiently convincing to recommend
this as routine therapy (Newton et al., 2008).
Ventilatory Stimulants
Several classes of drug stimulate ventilation and are indicated
when ventilatory drive is inadequate. Nikethamide
and ethamivan were originally introduced as respiratory
stimulants, but effective doses are close to those causing
convulsions so the use of these agents has ceased. More
selective respiratory stimulants have been developed and
are indicated if ventilation is impaired as a result of overdose
with sedatives, in postanesthetic respiratory depression,
and in idiopathic hypoventilation. Respiratory
stimulants are rarely indicated in COPD because respiratory
drive is already maximal and further stimulation of
ventilation may be counterproductive because of the
increase in energy expenditure caused by the drugs.
Doxapram (DOPRAM, others). At low doses (0.5 mg/kg IV), doxapram
stimulates carotid chemoreceptors; at higher doses it stimulates
medullary respiratory centers. Its effect is transient; thus, intravenous
infusion (0.3-3 mg/kg per minute) is needed for sustained effect.
Unwanted effects include nausea, sweating, anxiety, and hallucinations.
At higher doses, increased pulmonary and systemic pressures
may occur. Both the kidney and the liver participate in the clearance
of doxapram, which should be used with caution if hepatic or renal
function is impaired. In COPD, the infusion of doxapram is restricted
to 2 hours. The use of doxapram to treat ventilatory failure in COPD
has now largely been replaced by noninvasive ventilation (Greenstone
and Lasserson, 2003).
Almitrine. Almitrine bismesylate is a piperazine derivative that
appears to selectively stimulate peripheral chemoreceptors and is
without central actions (Winkelmann et al., 1994). It is ineffective in
patients with surgically removed carotid bodies. Almitrine stimulates
ventilation only when there is hypoxia. Long-term use of
almitrine is associated with peripheral neuropathy, limiting its availability
in most countries.
Acetazolamide. The carbonic anhydrase inhibitor acetazolamide
(Chapter 25) induces metabolic acidosis and thereby stimulates ventilation,
but it is not widely used because the metabolic imbalance it
produces may be detrimental in the face of respiratory acidosis. It has
a very small beneficial effect in respiratory failure in COPD patients
(Jones and Greenstone, 2001). The drug has proved useful in prevention
of high altitude sickness (Basnyat and Murdoch, 2003).