Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 100, Num. s1, 2005, pp. 161-165
Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol.100, Suppl. 1, March, 2005,
pp.
161-165
Local anaesthetic medication
for the treatment of asthma
Rodrigo A Siqueira,
Jorge CS Costa/*, Renato SB Cordeiro, Magda F Serra, Patrícia MR
e Silva, Marco A Martins/+
Laboratório
de Inflamação, Departamento de Fisiologia e Farmacodinâmica,
Instituto Oswaldo Cruz-Fiocruz, Av. Brasil 4365, 21040-900 Rio de Janeiro,
RJ, Brasil *Departamento de Síntese, Far-Manguinhos-Fiocruz, Rio de
Janeiro, RJ, Brasil
Financial Support: Faperj, CNPq, PDTIS-Fiocruz
+Corresponding author. E-mail:
mmartins@ioc.fiocruz.br
Received 8 November 2004
Accepted 30 December 2004
Code number: oc05044
It is presumed
that drugs able to prevent bronchial spasm and/or inflammation may have
therapeutic potential to control asthma symptoms. The local anaesthetic
lidocaine has recently received increased attention as an alternative form
of treatment for asthmatic patients. This paper reviews the major findings
on the topic and summarizes the putative mechanisms underlying the airway
effects of local anaesthetic agents. We think that lidocaine extends the
spectrum of options in asthma therapy, probably by counteracting both spasmogenic
and inflammatory stimuli in the bronchial airways. The possibility of development
of new anti-asthma compounds based on the synthesis of lidocaine derivatives
is also on the horizon.
Key words: local
anaesthetic - lidocaine - inflammation - asthma
Asthma is a chronic
inflammation of the lung airways caused by environmental factors in genetically
predisposed individuals. Episodic airway obstruction and reversible bronchial
hyperresponsiveness to non specific irritants are the major symptoms of the
disease, whose prevalence has remarkably increased worldwide over the past
two decades despite important advances in therapy (Busse & Rosenwasser
2003, Kay 2003, Barnes 2004). Among the potential reasons for causing the
increase in asthma prevalence are changes in the environment due to improved
hygiene (Umetsu et al. 2002), and lack of adherence to therapy by patients,
as well as by physicians who do not always follow guidelines on the established
anti-infammatory therapy in asthma (Apter & Szefler 2004, Barnes 2004).
Most of asthmatic patients are atopic, i.e., they have a genetic predisposition
to produce high levels of imunoglobulin (Ig) E against environmental antigens
and to mount an allergic inflammatory response. Inflammation is indeed central
in the pathogenesis of asthma. The antigen activates mast cells and TH2
cells in the airways, which in turn release preformed and neosynthetised
proinflammatory substances, including vasoactive amines, lipid mediators
and interleukins 4, 5, 9 and 13, deeply implicated in the early and late
phase reactions (Barnes 2004). An interesting aspect of the asthma pathogenesis
is the strong TH2 response in the airway mucosa resulting in accumulation
of a large number of eosinophils in tissue locations (Umetsu et al. 2002).
Experimental and clinical observations have linked eosinophil derivatives
with asthma dysfunctions such as epithelial cell damage and airway hyperresponsiveness.
Other pivotal pathological changes that appear to be associated with eosinophils
include subepithelial fibrosis, increased airway smooth muscle mass, angiogenesis
and increased mucus production caused by goblet-cell and submucosal-gland
hyperplasia (Busse & Rosenwasser 2003, Payne et al. 2003, Barnes 2004).
Therefore it is presumed that drugs able to prevent recruitment and/or activation
of mast cells, TH2 cells and/or eosinophils may have therapeutic
potential to control asthma.
CURRENT
TREATMENT STRATEGIES
It is a clinical
consensus that every patient with persistent asthma, regardless of disease
severity, should use a daily controller medication (Redding & Stoloff
2004). The therapeutic arsenal for asthma is relatively ample, basically
consisting of two classes of drugs: (i) the bronchodilators, including inhaled
long-acting β2-agonists (salmeterol
and formoterol), inhaled anticholinergics (ipratropium bromide and tiotropium
bromide) and theophylline (slow-release theophylline and aminophylline);
and (ii) the anti-inflammatory agents, including inhaled glucocorticosteroids
(budesonide, fluticasone propionate, beclomethasone dipropionate and mometasone),
anti-leukotrienes (montelukast, pranlukast and zafirlukast), cromones (sodium
cromoglycate and nedocromil sodium) and anti-IgE (omalizumab). Inhaled glucocorticosteroids
is by far the most effective treatment available for the control of mild,
moderate and severe asthma (Barnes 2004). They inhibit the transcription
of interleukins such as IL-4, IL-5, IL-13 and b chemokines, and it is likely
that switching off these key interleukins strongly contributes to the glucocorticosteroid
efficacy in controlling asthma (Caramori & Adcock 2003, Barnes 2004).
However, concerns regarding its long-term administration and steroid-resistance
have provided pivotal motivation for discovering new asthma therapies. Treatment
with combination inhalers containing a glucocorticosteroid and a long-acting β2-agonist
is becoming now the gold standard therapy for asthma. The β2-agonist
acts by binding to specific receptors expressed along the surface of the
bronchial smooth muscle cells. This agonist binding activates a complex intracellular
cascade of events that elevates cyclic AMP levels, leading to decrease in
intracellular calcium, smooth muscle relaxation and bronchodilation (Shore & Drazen
2003). Despite being the most effective way of opening the airways and providing
relief in the event of a severe asthma attack, the use of β2-agonist
as mono-therapy is no longer recommended, since a number of studies have
demonstrated that asthmatics who are chronically treated with bronchodilating
b-agonists alone sometimes experience a worsening of their condition (Lazarus
et al. 2001, Sears 2002, Ellis 2003).
LOCAL
ANAESTHETICS AND ALLERGIC INFLAMMATION
Local anaesthetics
block voltage-gated sodium channels in peripheral nerves causing reversible
inhibition of impulse transmission and blockade of neuronal function in a
circumscribed area of the body (Tetzlaff 2000). Lidocaine is largely used
in clinic as a short-acting local anaesthetic and antiarritmic agent (Tetzlaff
2000). Interestingly, lidocaine also inhibits the function of non-excitable
cells, particularly inflammatory cells, such as neutrophils, eosinophils,
macrophages, mast cells and TH2 cells, raising the promising possibility
of alternative clinical applications on the control of chronic inflammatory
diseases, including asthma (Hunt et al. 1996, Ohnishi et al. 1996, Okada
et al. 1998, Hollmann & Durieux 2000, Tanaka et al. 2002).
Ohnishi et al.
(1996) incidentally discovered that concentrations of lidocaine as high as
10 mM could be detected in the broncoalveolar lavage fluids recovered from
asthma patients subjected to bronchoscopy under lidocaine topical anesthesia,
and that such an effluent was a strong inhibitor of eosinophil viability
in vitro. It was further demonstrated that lidocaine preferentially inhibited
survival and activation of human eosinophils stimulated by cytokines, such
as IL-5, IL-3 and GM-CSF, in a concentration dependent-manner (IC50@ 110 µM). Such an effect did not seem to be accounted for by the blockade
of sodium channels and could not be explained by an action on either cytokine
receptor expression or cytokine-induced protein tyrosine phosphorilation
(Ohnishi et al. 1996, Okada et al. 1998). Of note, these effects were not
due to nonspecific cytotoxicity either, since (i) lidocaine inhibited eosinophil
survival by causing apoptosis rather than necrosis; (ii) the mechanism of
cell death was clearly time-dependent, requiring at least 24 h of exposure
to lidocaine; and (iii) eosinophil survival and superoxide production induced
by IgG, PAF or PMA were not modified by lidocaine, indicating that this local
anaesthetic was not a general inhibitor of eosinophils (Okada et al. 1998).
Other local anaesthetic agents such as tetracaine, dibucaine, benoxinate,
procaine and bupivacaine also inhibited IL-5-evoked eosinophil survival in
vitro but their pro-apoptotic performance did not reflect their respective
anaesthetic potencies (Okada et al. 1998). It is well established that lidocaine
at high concentrations can also block K+ channels (Illek et al.
1992, Yoneda et al. 1993, Olschewski et al. 1996). Therefore, Bankers-Fulbright
and coworkers studied the effect of three classes of K+ channel blockers
and reported that the sulfonylureas including glyburide, tolbutamide, and
glipizide (one class of K+ channel blockers) were the only ones able to mimic
the effect of lidocaine on the inhibition of cytokine-mediated eosinophil
survival and superoxide production in vitro. Similar functions of sulfonylureas
and lidocaine suggested that these agents might be working through a similar
mechanism blockade of K+ channel in order to evoke apoptosis of
eosinophils (Bankers-Fulbright et al. 1998).
CLINICAL
FINDINGS WITH LIDOCAINE TREATMENT
Since eosinophils
are expected to play a pivotal role in the pathogenesis of asthma, studies
on the putative beneficial effect of nebulized lidocaine in adults and children
with asthma have been carried out. Administration of nebulized lidocaine
four times daily in 20 adult patients with severe asthma, who had side effects
of exogenous hypercortisolism, allowed for the complete elimination of steroid
treatment in 13 of 20 patients (Hunt et al. 1996). A pilot study involving
six pediatric patients with severe asthma added support to the interpretation
that nebulized lidocaine in doses of 40 to 100 mg (0.8 to 2.5 mg/kg/dose)
four times daily had indeed steroid-sparing actions (Decco et al. 1999).
The results indicated that during a mean of 11.2 months of therapy (range
7 to 16 months) 5 of the 6 patients completely discontinued their oral steroids
within an average time of 3.4 months. Similar findings were also reported
by Rosario and coworkers, while treating a 12-year-old severe steroid-dependent
asthmatic with nebulized lidocaine (Rosario et al. 2000). The side effects
observed in these patients were limited to transient oropharyngeal anaesthesia
and bitter taste.
In a more recent
evaluation, Hunt et al. (2004) reported the results of a placebo-controlled
8-week study in 50 adult subjects with mild-to-moderate asthma. The patients
were randomized (25 receiving lidocaine and 25 receiving placebo) and their
inhaled steroids were progressively withdrawn over 4 weeks. The analysis
revealed a significant benefit for lidocaine treatment (4%, 100 mg) four
times daily compared with placebo (saline), particularly concerning FEV1 symptom
scores, night-time awakening, b-agonist use, and blood eosinophils. There
were no serious adverse effects in either group, but 15 subjects (9 receiving
lidocaine and 6 receiving placebo) did not complete the full 8-week trial.
Reasons for withdrawal included worsening asthma symptoms (4 receiving lidocaine
and 6 receiving placebo) and treatment intolerance (4 receiving lidocaine).
From the latter group, one had a cold feeling in the throat, one reported
a feeling of claustrophobia, one had cough, one had wheezing after lidocaine,
and only the last presented a 16% decrease in FEV1 (Hunt et al.
2004). In line with previous studies, Harrison and Tattersfield (1998) reported
that patients with mild-to-moderate asthma did not bronchoconstrict significantly
more than to 0.9% NaCl (saline). However, the possibility that patients with
more severe asthma might have more marked bronchoconstriction could not be
discarded. It should be emphasized that at least five single-dose studies
have demonstrated broncoconstriction following lidocaine inhalation (Miller & Awe
1975, Weiss & Patwardhan 1977, Fish & Peterman 1979, McAlpine & Thomson
1989, Bulut et al. 1996), indicating that the putative use of lidocaine for
the treatment of asthma should be investigated with caution.
EFFECTS
OF LIDOCAINE ON THE AIRWAYS
The effects of
lidocaine on the airways are heterogeneous and complex. It is well established
that in patients with asthma, airway instrumentation such as endotracheal
intubations can cause life-threatening bronchospasm (Caplan et al. 1990),
and that lidocaine when administered either intravenously or as an aerosol
significantly attenuates that sort of reflex bronchoconstriction (Groeben
et al. 1999). Inhaled lidocaine can also diminish the response to an inhalational
provocation with hyperosmolar saline solution (Makker & Holgate 1993),
histamine (Groeben et al. 2000), water (Loehning et al. 1976) and under conditions
of exercise-induced asthma (Enright et al. 1980). On the other hand, a number
of studies has pointed out that aerosolization of lidocaine itself produces
an initial bronchoconstriction in a significant proportion of patients with
asthma and hyperirritable airways, as attested by reduction in FEV1 and
other respiratory parameters (Miller & Awe 1975, Weiss & Patwardhan
1977, Fish & Peterman 1979, McAlpine & Thomson 1989, Bulut et al.
1996). Bronchoconstriction following lidocaine inhalation was also assessed
using high-resolution computed tomography in Basenji-Greyhound dogs with
hyperreactive airways (Bulut et al. 1996). Analyzing airway caliber before
and after the administration of lidocaine aerosol, a 27% decrease from baseline
was observed. Intravenous administration of lidocaine did no cause airway
changes but clearly prevented initial broncoconstriction evoked by aerosolized
lidocaine in these animals (Bulut et al. 1996). In asthmatics, bronchoconstriction
caused by lidocaine aerosol was clearly reversed with aerosolized atropine,
isoproterenol (Fish & Peterman 1979) or sabutamol (Harrison & Tattersfield
1998, Groeben et al. 2000). Moreover, combined lidocaine and salbutamol inhalation
protected against histamine-evoked bronchoconstriction in mild asthmatics
to a much greater extent than pretreatment with either drug alone (Groeben
et al. 2000). These findings pointed out that in the case of using lidocaine
for the control of asthma, the treatment should be accompanied by a b-adrenergic
aerosol. The combined inhalation might prevent the putative irritant effects
of lidocaine, and yield an improved bronchial hyperreactivity blockade due
to the synergistic interaction of these substances (Harrison & Tattersfield
1998, Groeben et al. 2000).
Several mechanisms
may explain the attenuation of bronchoconstriction by lidocaine but none
of them has been definitively proven in vivo. Aerosolized lidocaine is theoretically
capable of blocking neurogenic reflexes in the lung, and the neural blockade
of vagal reflex pathways may indeed explain its ability to attenuate the
response to different stimuli evoking bronchoconstriction (Enright et al.
1980, Makker & Holgate 1993, Groeben et al. 2000). Actually, the lidocaine
protective effect occurs at plasma concentrations much lower than those required
for intravenous lidocaine to impair airway broncocon-striction, in line with
the interpretation that this effect is accounted for by topical airway anaesthesia.
If this is the case, the protective effect should be presumably independent
of the local anaesthetic used. While trying to clarify this point, Gloeben
et al. (2001) tested three local anaesthetics with distinct anaesthetic potencies
(Groeben et al. 2001). They reported that inhaled lidocaine and ropivacaine
significantly attenuated histamine-evoked bronchoconstriction whereas dyclonine,
despite its longer lasting and more intense local anaesthesia, did not. In
addition, inhaled dyclonine was by far the most irritant for the airways
(Groeben et al. 2001). These findings were double-folded illustrative. First
because they made clear that the protective effect of lidocaine on bronchospasm
might indeed be dissociated from its local anaesthetic activity. Second because
they raised the possibility that lung anaesthesia might indeed account for
the airway irritant properties of this class of agents.
Lidocaine effects
on bronchial hypearreactivity might also be accounted for by a direct relaxant
effect on airway smooth muscle (Downes & Loehning 1977, Weiss et al.
1978, Okumura & Denborough 1980, Kai et al. 1993). Kai et al. (1993)
reported that lidocaine had direct spasmolytic properties by inhibition of
calcium influx and release of stored calcium. Accordingly, circulating concentrations
of lidocaine of more than 100 µM had marked airway relaxant effects
(Kai et al. 1993).
CONCLUSION
There is renewed
interest in lidocaine for treatment of atopic asthma. Inhaled lidocaine has
glucocorticosteroid-sparing properties in atopic asthmatics as demonstrated
by significant reduction in symptoms, bronchodilator use and blood eosinophilia.
Lidocaine has marked effects in several settings beyond neuronal blockade,
and some of these alternative actions may also be beneficial to asthma control.
There is clear evidence for anti-inflammatory and spasmolitic properties.
Inhibitory effects of lidocaine on eosinophil survival and activation, mast
cell secretor function, as well as CD4+ T-cell proliferation and cytokine
generation, seem to be most important. Lidocaine also significantly attenuates
the response to direct stimulation of airway smooth fibers in a mechanism
closely associated with blockade of calcium influx. On the other hand, inhalation
of lidocaine initially evokes a significant decrease in FEV1 in
the majority of asthmatic volunteers, an effect sensitive to β2-agonist
pretreatment. As in the case of glucocorticosteroid therapy, treatment with
combination inhalers, containing lidocaine and a long-acting β2-agonist,
may turn out to be the safer and more reliable alternative. In addition,
since airway anesthesia alone does not necessarily attenuate bronchial hyperreativity,
further research should be directed to (i) clarify the mode of action of
lidocaine on both inflammation and airway obstruction and (ii) structure-activity
studies, particularly concerning non anaesthetic lidocaine analogues.
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