Postgrad Med J 2000;76:767–773 767 Postgrad Med J: first published as 10.1136/pgmj.76.902.767 on 1 December 2000. Downloaded from Leukotriene receptor antagonist therapy O J Dempsey Abstract Leukotriene receptor antagonists (LTRA) Box 1: Biological eVects of cysteinyl are a new class of drugs for asthma treat- leukotrienes ment, available in tablet form. Their x Bronchoconstriction (100–10000 times unique mechanism of action results in a more potent than histamine). combination of both bronchodilator and x Bronchial smooth muscle anti-inflammatory eVects. While their hyperresponsiveness, for example to optimal place in asthma management is allergen. still under review, LTRA represent an x Inflammatory cell recruitment, for important advance in asthma pharmaco- example eosinophils. therapy. Vascular permeability (leading to tissue (Postgrad Med J 2000;76:767–773) x oedema and airflow obstruction). Keywords: leukotriene receptor antagonist; asthma; x Mucus formation (leading to further montelukast; zafirlukast airflow obstruction). Asthma and Allergy Leukotriene receptor antagonists (LTRA) are a Research Group, new class of drugs for asthma treatment, avail- Department of Clinical able in tablet form.12Their unique mechanism Methods Pharmacology and of action results in a combination of both Fully published papers and review articles Therapeutics, between 1966 and January 2000 were sought Ninewells Hospital and bronchodilator and anti-inflammatory eVects. While their optimal place in asthma manage- using appropriate index terms and the National Medical School, Library of Medicine’s computerised search University of Dundee, ment is still under review, LTRA represent an Dundee DD1 9SY, UK important advance in asthma pharmaco- service (providing access to Medline, Pre- Medline, and other related databases). Studies O J Dempsey therapy. In this article I provide a brief published only in abstract form (and thus sub- overview of evidence supporting their use in Correspondence to: ject to less rigorous peer review) are not Dr Dempsey patients with chronic asthma, focusing on two discussed. [email protected] leukotriene receptor antagonists, montelukast and zafirlukast, currently licensed for use in the Submitted 6 March 2000 Background Accepted 19 April 2000 United Kingdom. The term “slow reacting substance of anaphy- laxis” (SRS-A), coined by Brocklehurst in Phospholipids in cell 1960, is still familiar to many physicians.3 The http://pmj.bmj.com/ membrane chemical structure of SRS-A, however, was not Phospholipase A 2 identified until 1979 by Samuelsson and Arachidonic acid colleagues, who discovered that it consisted of a family of biologically active fatty acids Cyclo-oxygenase 5-Lipoxygenase/FLAP derived from arachidonic acid metabolism in many cells, including eosinophils, mast cells, 45 Prostaglandins and lymphocytes (fig 1). The term “leuko- on September 28, 2021 by guest. Protected copyright. 5-HPETE Thromboxanes triene” is apt, given their synthesis in leucocytes 5-Lipoxygenase/FLAP and their chemical structure (containing three conjugated double bonds, that is, a triene). Of LTB4 LTA4 particular importance in the patient with LTA4 hydrolase LTC synthase asthma are leukotrienes C4,D4, and E4.As 4 these contain the amino acid residue cysteine, LTC4 they are sometimes referred to collectively as the cysteinyl leukotrienes. γ-Glutamyl transpeptidase Cysteinyl leukotrienes are important biologi- CYSTEINYL cal mediators in asthma, interacting with at LTD LEUKOTRIENE 4 least one specific receptor in the lungs, which 67 RECEPTOR has now been fully identified, leading to vari- Dipeptidase ous important biological eVects (box 1). Of these, potent bronchoconstriction is well rec- LTE4 ognised, but they also have a variety of eVects that are proinflammatory.8 Thus leukotrienes MONTELUKAST are capable of inducing several key features of ZAFIRLUKAST asthma. Furthermore, studies have shown that leukotrienes are produced in excessive quanti- Figure 1 Arachidonic acid metabolism. Cysteinyl leukotrienes (LTC4,LTD4,LTE4) ties in patients with asthma, reinforcing the interact with a specific receptor, which is blocked by antagonists such as montelukast or zafirlukast. FLAP,5-lipoxygenase activating protein; HPETE, view that they are important biological 5-hydroxyperoxyeicosatetraenoic acid. mediators.9 www.postgradmedj.com 768 Dempsey Postgrad Med J: first published as 10.1136/pgmj.76.902.767 on 1 December 2000. Downloaded from bile. The terminal half lives of the two drugs are Zafirlukast CH3 N five and 10 hours, respectively. O Zafirlukast can inhibit the hepatic micro- CH 3 somal cytochrome P450 isoenzymes CYP2C9 O N O H and CYP3A at therapeutic concentrations, N which clinically may result in drug interactions H with other drugs using these enzymes. Simi- S CH larly, as montelukast is metabolised by CYP O OO3 3A4, caution should be exercised, particularly Montelukast COONa in children when montelukast is co- administered with inducers of this enzyme, as listed in table 1. OH Another clinically relevant point is that S co-administration of food with zafirlukast can reduce oral bioavailability by approximately N Cl 40%, which means that patients should avoid taking this preparation soon before or after Figure 2 Structure of zafirlukast (top) and montelukast food (see table 1). This may have implications (bottom). for patient compliance. Interestingly, inhaled or oral corticosteroids have not been shown to attenuate leukotriene CLINICAL EFFICACY IN ASTHMA production significantly in vivo. This led to The optimal place of LTRA in asthma interest in the development of specific leuko- management is still under review. This reflects triene modifying asthma drugs, which might their recent introduction and the relative confer additional benefits even in patients paucity of fully published comparative studies, already receiving an optimal dose of inhaled 10 particularly compared with existing asthma corticosteroid. Several drug classes were treatments. For simplicity, in this article I will developed, aVecting various sites in the leuko- describe as their use in stud- triene biosynthetic cascade, of which the most first line treatment ies in conjunction with “as required” short act- successful have been receptor antagonists. ing â2 agonists. Their use in patients already Leukotriene receptor antagonists receiving inhaled corticosteroids and “as re- quired” short acting agonists will be STRUCTURE â2 Montelukast and zafirlukast are two of the described as second line treatment. most commonly prescribed LTRA available worldwide. Their structures are shown in fig 2. First line treatment studies—chronic asthma PRESCRIBING INFORMATION LTRA v PLACEBO 13–22 Prescribing information is given in table 1.11 12 These studies are summarised in table 2. http://pmj.bmj.com/ Montelukast and zafirlukast share some phar- Most of the patients in these studies were ster- macokinetic properties including rapid oral oid naive, and hence the description “first line absorption (three hours to peak plasma con- treatment studies”; however, some did include centrations), near maximal (99%) plasma pro- a minority of patients receiving low dose tein binding, and, after extensive hepatic inhaled corticosteroids or oral theophyllines, or biotransformation, excretion principally in the both.13–16 20 Table 1 Prescribing information on September 28, 2021 by guest. Protected copyright. Generic name Montelukast11 Zafirlukast12 Trade name SingulairTM AccolateTM Indications (UK) 1. Add on treatment in patients with mild to moderate persistent Treatment of asthma asthma, inadequately controlled on inhaled corticosteroids and short acting â2 agonists alone 2. Exercise induced bronchoconstriction Contraindications Acute asthma Acute asthma Pregnancy / lactation Pregnancy / lactation Severe hepatic impairment Hepatic impairment Moderate to severe renal impairment Age group > 6 years old > 12 years old No dose adjustment in the elderly No dose adjustment in the elderly Formulation Tablet (paediatric tablet chewable and cherry flavoured) Tablet Dose 5mg (if aged 6–14 years) 20 mg 10 mg (if > 14 years) Frequency Once daily Twice daily Special instructions Adult dose can be taken with food Avoid1hbeforeand2hafter meals Paediatricdose:avoid1hbeforeand2hafter meals Drug interactions None with oral contraceptive pill, warfarin, digoxin, theophylline, or Patients on warfarin may have ⇑ prothrombin times (monitor INR) terfenadine Coadministration with CYP 3A4 hepatic enzyme inducers (eg Aspirin may ⇑ zafirlukast levels phenytoin, phenobarbitone, rifampicin) may ⇓ montelukast levels ⇓ Zafirlukast levels with erythromycin, terfenadine, theophylline www.postgradmedj.com Leukotriene receptor antagonists Table 2 First line treatment—leukotriene receptor antagonists v placebo: randomised, placebo controlled, parallel group studies Treatment Age range duration FEV1 Inclusion criteria‡ and Study n (years) (weeks) (% predicted) intercurrent treatment Treatment(s) Primary endpoint(s) Results Montelukast 13 Altman 343 18–65 6 40–80 â2 use > 1puV/day; 36% on M 10 mg, 100 mg, or 200 mg od; FEV1 Mall doses*>P ⇑ ICS, 15% on theo M10mgor50mgbd;P For M10mg, mean % in FEV1 = 11.4% No dose (or dosage interval) relation with eYcacy 14 Knorr 336 6–14 8 50–85 36% on ICS M 5 mg od; P FEV1 M** > P ⇑ For M5mg, mean % in FEV1 = 8.2% Also significant ⇑ in quality of life 15 www.postgradmedj.com Noonan 281 18–65 3 40–80 â2 use > 1puV/day; 24% on M 2 mg, 10 mg, or 50 mg od; P FEV1 Mall doses*>P ⇑ ICS, 19% on theo For M10mg, mean % in FEV1 = 13.5%