Leukotriene Receptor Antagonists

Marzena E. Krawiec, MD, Nizar J. Jarjour, MD


Semin Respir Crit Care Med. 2002;23(4) 

In This Article

Leukotriene Receptor Antagonists

The LTRAs selectively antagonize the cysLT1 receptor. Unlike 5-LO and FLAP inhibitors, the current LTRAs do not affect LTB4. Currently, there are three commercially available and structurally distinct drugs: montelukast (Singulair®, Merck, Whitehouse Station, NJ) and zafirlukast (Accolate®, AstraZeneca, Wilmington, DE) in the United States and pranlukast (Onon®, Ono Pharmaceuticals, Japan), which is available only in Asia. Montelukast can be used in children as young as 2 years of age and is dispensed once daily at bedtime. Three formulations are currently available including a 4 mg dose for ages 2 to 5, 5 mg for 6 to 14, and 10 mg for > 15 years. Zafirlukast is dosed twice daily, 20 mg b.i.d. for ages ≥ 12 years and 10 mg b.i.d. for ages 5 to 12 years. Based on its bioavailability in the presence of a standard meal, zafirlukast should be given a minimum of 1 hour before or 2 hours after a meal. Finally, pranlukast, previously only available for adult use, was recently launched for use in children in Japan as a syrup suspension.

Briefly, zileuton (Zyflo®, Abbott, Abbott Park, IL) is also commercially available as an LT modifying agent, however, it is specifically a 5-LO antagonist, rather than an LTRA.

Leukotriene Challenge Models

As previously discussed, inhalation of cysLTs can result in significant bronchoconstriction in both normal controls and asthmatic subjects. Therefore, the first efficacy trials evaluating the LTRAs required demonstration of these drugs' ability to inhibit cysLT-induced bronchoconstriction. One of the original efficacy trials compared the ability of single (40 mg) versus placebo administered at 2, 12, and 24 hours prior to challenge to inhibit LTD4-induced bronchoconstriction in normal subjects.[28] In this double-blind, crossover study, 18 patients were randomized to zafirlukast or placebo 3 to 7 days apart. Active treatment had no effect on baseline pulmonary function; however, compared with placebo, pretreatment with zafirlukast at all three time points significantly attenuated LTD4-induced bronchoconstriction based on specific airway conductance (SGaw) and forced expiratory volume in 1 second (FEV1) even in these normal subjects. In fact, zafirlukast increased the concentration of LTD4 required to reduce SGaw (specific airway conductance) by a factor of 117 when given 2 hours prior to challenge and a factor of 9 given 12 hours prior to challenge. Significant but smaller inhibition compared with placebo was reported with 24-hour pretreatment. The same group of investigators subsequently reported a progressive dose response for zafirlukast in 30 mild asthmatics randomized to single-dose zafirlukast (5, 10, 20, 40, or 100 mg) or placebo 12 hours prior to LTD4 inhalation challenge.[29] Furthermore, at doses of 10, 40, and 100 mg, the mean LTD4 provocation concentration resulting in a 20% fall in FEV1 (PC20FEV1) was increased 10-fold or greater (p < 0.05) compared with placebo. Similar efficacy and duration against LTD4-induced bronchoconstriction in both normal subjects with pranlukast[30] and mild asthmatics with montelukast[31] have also been reported.

Smith and colleagues more recently demonstrated that not only does zafirlukast effectively inhibit LTD4-induced bronchoconstriction in normal controls and mild asthmatics, it may also provide additional inhibition in moderate asthmatics already on maintenance therapy. Zafirlukast (20 mg) or placebo was administered on two consecutive days in six moderate asthmatic patients receiving inhaled beta2-agonists and inhaled corticosteroids (ICSs) (median dose 800 µg/day) in this double-blind, crossover trial.[32] Two hours following dosing, subjects underwent bronchoprovocation challenge with increasing concentrations of inhaled LTD4. Active therapy resulted in a 66-fold increase in the PC20FEV1 and 76-fold increase in the provocation dose resulting in PD20FEV1 compared with placebo, and also resulted in a decrease in mean recovery time following challenge. This would suggest that not only was zafirlukast effective in inhibiting LTD4-induced bronchoconstriction, it also provided additional benefit beyond maintenance ICS in terms of airway hyperresponsiveness.

Allergen Challenge Models

Inhalation of allergens in allergic patients with asthma results in bronchoconstriction in 15 to 20 minutes, an early asthmatic response (EAR), and, in 30 to 70% of patients, a subsequent bronchoconstriction, the late asthmatic response (LAR), occurring 3 to 12 hours after the challenge and resolving within 24 hours.[33] The cysLTs have been consistently increased in association with the EAR based on both urine and BAL studies.[34,35,36] Their association with the LAR is less clear. Recently, Macfarlane and colleagues demonstrated increases in induced sputum cysLT levels (baseline 3.45 ng/mL to 11.95 ng/ mL, p = 0.002) in 14 atopic asthmatics with LAR 24 hours following allergen challenge.[37]

Consistent demonstration of elevations in the cysLTs during allergen challenges has led to numerous studies to evaluate their ability to inhibit allergen-induced bronchoconstriction. All three of the commercially available LTRAs have demonstrated significant protection against bronchoconstriction. In general, inhibition was much more consistent during the EAR (50-90%) compared with the LAR (25-60%).[34,38,39,40]

The LTRA's mechanism of inhibition of the EAR appears to be related to bronchoprotection against LTD4-induced bronchoconstriction, whereas the mechanism of LAR inhibition is less clear and may involve inhibition of inflammatory cell influx and decreased edema formation in addition to protection against bronchoconstriction from LTD4. Interestingly, although montelukast (10 mg) was able to significantly inhibit the LAR (57% inhibition), no significant decrease in sputum eosinophils was noted following allergen challenge, suggesting that the effect was not through a decrease in eosinophilic inflammation.[34] On the other hand, 7-day treatment with zafirlukast was associated with a significant reduction in BAL lymphocytes and basophils (but not eosinophils) compared with placebo in 11 allergic asthmatic patients 48 hours following segmental allergen challenge (SAC).[41] Furthermore, stimulated superoxide release from purified alveolar macrophages ex vivo was significantly reduced 48 hours after SAC in the treatment group compared with placebo. This study would suggest that the link between the anti-inflammatory effects of the LTRAs and bronchoprotection during the LAR are still poorly defined. Further support for some anti-inflammatory effect during the LAR comes from a study with pranlukast in 10 mild asthmatics. The LAR was reduced in the pranlukast treated group with a mean protection in %FEV1 of 30.8%.[42] More interestingly, there was a small degree of protection against the allergen-induced increase in methacholine hyperresponsiveness. The increase in airway responsiveness normally present following allergen challenge is believed to be associated with an increase in inflammation, such that an improvement in this response could suggest an anti-inflammatory effect. Therefore, although the precise mechanism of protection against the LAR remains uncertain, it most likely involves some inhibitory effect on inflammatory processes and cysLT-induced bronchoconstriction.

Exercise-Induced Bronchoconstriction (EIB)

Greater than 70% of asthmatics experience EIB, making prevention of this bronchoconstriction an important area of efficacy for anti-asthma drugs, especially in children.[43] Increases in urinary LTE4 levels following exercise challenge in asthmatics have been inconsistent.[44,45,46] Despite this, the LTRAs have shown consistent inhibition of EIB in both children and adults.

Several studies in adults have shown the attenuation of EIB with the use of various LTRAs compared with placebo.[47,48] In one of the earliest studies using montelukast, 5 mg b.i.d. for 2 days inhibited the maximal decrease in FEV1 by > 50% (30% to 14% inhibition) compared with placebo in 19 nonsmoking patients with moderate asthma (FEV1 ≥ 65%). Furthermore, urinary excretion of LTE4 was significantly increased in the montelukast group (34.4 to 73.7 pg/mg creatinine; p < 0.05) compared with placebo.[46] More recently, 110 mild asthmatics treated with daily montelukast had significant improvement in maximal and total post-exercise bronchoconstriction compared with placebo(Fig. 2).[49] Similar inhibition against EIB has been demonstrated with the use of zafirlukast. In 24 adult asthmatics with EIB, zafirlukast (20 mg and 80 mg b.i.d.) was shown to provide significant protection against EIB at 2 hours (35 and 49% reduction in maximum post-exercise fall in FEV1, respectively) compared with placebo, but also at 8 hours (23 and 27% reduction in maximum post-exercise fall in FEV1).[50] This study not only showed significant inhibition of EIB using zafirlukast, it also demonstrated a potential dose-response benefit. Finally, similar efficacy of the LTRAs against EIB has been reported in two smaller pediatric studies.[51,52]

Figure 2.

Mean (± standard error) changes in forced expiratory volume in 1 second (FEV1) after exercise challenge following 12 weeks of treatment with montelukast or placebo. Treatment with montelukast was associated with a significant (p = 0.002) reduction in exercise-induced bronchoconstriction. (Adapted from Leff et al[49] with permission.)

Several comparisons of the LTRAs with traditional EIB therapies exist. Interestingly, however, no direct comparison with the established prophylactic treatment for EIB, short-acting beta2-agonists, exists. The LTRAs, as a group, appear to have efficacy comparable to sodium cromoglycate in the inhibition of EIB.[53,54] Coreno and colleagues compared single doses of salmeterol [50 µg metered dose inhaler (MDI)], montelukast (10 mg), zafirlukast (20 mg), and placebo in 10 patients with EIB. The study was performed random-order, blinded, and double-dummy and suggested that the only benefit salmeterol provided was a quicker onset of action compared with the 1-hour onset of action of the LTRAs. All three drugs showed similar efficacy against EIB.[55] In a much larger study, an 8-week treatment trial compared montelukast (10 mg) to salmeterol (50 mg BID) in 197 mild asthmatics with EIB.[56] The exercise challenges were done approximately 10 hours after dosing with salmeterol and 20 hours after montelukast. Although montelukast and salmeterol produced comparable protection against EIB at 3 days, montelukast was superior to salmeterol in attenuating the maximal percent fall in post-exercise FEV1 at 4 and 8 weeks (p ≤ 0.001). Such a prolonged bronchoprotective effect of the LTRA was mirrored in 191 adult asthmatics treated with montelukast or salmeterol (50 mg b.i.d.). Once again, on days 1 to 3, similar and statistically significant reduction in maximal percentage decrease in FEV1 were seen with both the long-acting beta2-agonist and the LTRA. By week 8, however, the percent inhibition in the maximal decrease in FEV1 was 57.2% in the montelukast group compared with 33% in the salmeterol group (p = 0.002).[57] This difference was not surprising because salmeterol has demonstrated tachyphylaxis to bronchoprotection against exercise challenge over time, especially when the exercise challenges are performed more than 6 hours after dosing.[58,59]

Aspirin-Induced Asthma

The cysLTs are believed to play a significant role in the pathogenesis of aspirin-induced asthma, a subtype of asthma seen primarily in adults. LTC4 levels are increased in nasal lavage fluid,[60] urine,[61,62] blood,[63] BAL,[64] and bronchial mucosa[65] following aspirin challenge in aspirin-sensitive asthma (ASA) compared with aspirin-tolerant asthmatics and normal controls. One recent study suggested that the level of urinary LTE4 excretion correlated with the severity of respiratory response.[62] Pretreatment with pranlukast protected against aspirin-induced bronchoconstriction by significantly decreasing hypersensitivity to sulpyrine (p < 0.0001) and bronchial hyperresponsiveness (p < 0.005) to methacholine compared with placebo in 16 mild to moderate ASA cases. Active treatment, however, showed minimal effect on reducing urinary LTE4 excretion.[66] In an earlier double-blind study, six ASA patients were randomized to placebo or pranlukast (225 mg) followed by bronchial provocation with dipyrone. A 15-fold difference in the PD20FEV1 was reported in the pranlukast-pretreated group compared with placebo (p = 0.001).[67]

In a double-blind, placebo-controlled, parallel-group study, 80 moderate ASA patients (mean FEV1 69%) were randomized to montelukast (10 mg) or placebo for 1 month.[68] Chronic therapy with montelukast resulted in a significant improvement in FEV1 (8.55 ± 1.92 %, p < 0.05), am peak expiratory flow (PEF), beta2-agonist use, and nocturnal symptoms compared with placebo. More recently, however, Stevenson and colleagues demonstrated that 9/10 ASA patients treated with 8 to 12 days of montelukast (10 mg) failed to be fully protected against bronchospasm during oral aspirin challenge at threshold and then escalating doses. Ninety percent of these patients experienced at least naso-ocular reactions during their second oral aspirin challenge, whereas 40% experienced asthmatic reactions despite pretreatment with montelukast.[69] Additionally, pranlukast was also less effective in a more recent chronic dosing study. Pranlukast therapy (225 mg b.i.d.) for 4 weeks almost doubled the mean PD20FEV1 to methacholine in seven moderate to severe ASA patients; however, pre- and postspirometric data, FEV1, and forced vital capacity (FVC), did not differ in these patients.[70] In addition, there have been isolated case reports of ASA patients ingesting full-strength, nonsteroidal anti-inflammatory drugs (NSAIDs) on the assumption that treatment with LTRAs would prevent any reaction.[71,72] These reports would suggest that LTRAs are ineffective in inhibiting the adverse response to standard dose therapy and that the ASA patient should continue to avoid the use of NSAIDs. Furthermore, although cysLTs appear to be important mediators of aspirin-induced bronchoconstriction, the efficacy of the LTRAs for prevention appears to be variable.


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