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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 2  |  Page : 153-161

Theophylline and leukotriene modifiers: Is there any compelling role in COPD?


1 Department of Pulmonary and Critical Care Medicine, Medeor JCS Institute of Pulmonary, Critical Care and Sleep Medicine, New Delhi, India
2 Department of Pulmonary Medicine, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
3 Department of General Medicine, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission15-Dec-2019
Date of Decision29-Jan-2020
Date of Acceptance25-Feb-2020
Date of Web Publication05-Jun-2020

Correspondence Address:
Prof. Rajendra Prasad
Erafs Lucknow Medical College and Hospital, Lucknow - 226 003, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijrc.ijrc_65_19

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  Abstract 


Chronic obstructive pulmonary disease (COPD) is considered to be an emerging global public health problem. Inhaled therapies are first-line maintenance treatment for COPD, whereas oral drug therapies are used as second or third line maintenance treatment. Oral drugs have modest bronchodilatory as well as anti-inflammatory activities but have lower potency as compared to inhaled therapies. Oral drug therapy can play an important role with several advantages that include distinctive pharmacologic mechanisms of action, prompt availability, ease of administration without the challenges of proper inhalational drug deposition in airways of lung and cost-effectiveness. Theophyllines and leukotriene modifiers are frequently prescribed oral drug therapies worldwide. Although evidence remains weak regarding the exact role of theophyllines in COPD, they are still used alone or as an add-on agent to inhaled therapies but at the expense of narrow therapeutic index leading to dose-dependent toxicities. Leukotriene modifiers are currently prescribed as add-on agents to inhaled therapies in moderate-to-severe asthma. However, the role of leukotriene modifiers in COPD is not very convincing with limited evidence. Overall, there is not any compelling evidence on the utility of theophyllines and leukotriene modifiers in the management of COPD.

Keywords: Chronic obstructive pulmonary disease, leukotriene modifiers, montelukast, theophylline


How to cite this article:
Singh A, Prasad R, Gupta N. Theophylline and leukotriene modifiers: Is there any compelling role in COPD?. Indian J Respir Care 2020;9:153-61

How to cite this URL:
Singh A, Prasad R, Gupta N. Theophylline and leukotriene modifiers: Is there any compelling role in COPD?. Indian J Respir Care [serial online] 2020 [cited 2020 Oct 22];9:153-61. Available from: http://www.ijrc.in/text.asp?2020/9/2/153/286100




  Introduction Top


Chronic obstructive pulmonary disease (COPD) is a chronic airway disorder characterized by persistent symptoms and airflow limitation with a lack of significant bronchodilator reversibility in majority of cases as evident on spirometry when performed under appropriate conditions.[1] COPD is considered to be an emerging public health problem with an estimated global prevalence of 11.7%.[2] It has been currently ranked fourth among leading causes of mortality worldwide but is projected to be the third leading cause in subsequent years.[3] More than 3 million deaths occurred ever year due to COPD accounting for 6% of all global deaths.[4] The disease is associated with significant morbidity and mortality carrying substantial and expanding socioeconomic burden worldwide.[5] The burden of COPD is increasing even in developing countries like India, although the magnitude of burden of disease is not exactly defined. The prevalence of COPD in India is estimated to be 3.67% with annual mortality rate of 500,000.[6],[7]

The use of drug therapy in COPD has expanded over the past several decades with a better outcome. Inhaled therapies play a pivotal role as these are typically preferred for the first-line maintenance treatment of COPD.[1],[8] The advantages of inhaled therapies include direct delivery of medications into the airways leading to improvement in efficacy, rapid onset of action, and lesser risk for systemic adverse effects.[8] Oral drug therapies are used for second or third line maintenance treatment of COPD. The most commonly used oral drugs are theophylline, leukotriene modifiers, macrolides, phosphodiesterase (PDE) inhibitors, and mucolytic agents. Oral drugs can play an important role as advantages include distinctive pharmacologic mechanisms of action, ease of administration, without the challenges of proper inhalational drug deposition in airways of lung and relatively cheaper than inhaled therapies.[8] These agents have anti-inflammatory or immunomodulatory effects as the predominant pharmacologic mechanism of action for clinical benefit. Other mechanisms include reduction of exacerbations and fairly rapid bronchodilation but less than that achieved with inhaled therapies. There is uncertainty regarding the role of theophylline and leukotriene modifiers either used alone or in combination in patients having COPD. This review highlights the current evidence regarding the role of theophylline and leukotriene modifiers in COPD.


  Search Strategy Top


Published studies related to role of theophylline and leukotriene modifiers in COPD were searched involving principal electronic databases (PUBMED, National Library of Medicine, EMBASE, Web of Science, Index Copernicus, Google scholar, and IndMed) from 1950 till now, using the index terms (Medical Subject Headings) in combination: “Chronic Obstructive Pulmonary Disease” or “COPD,” and “Theophyllines” or “Methylxanthines” or “Xanthine derivatives” and “Leukotriene modifiers” or “Leukotriene receptor antagonists” or “Montelukast” or “Zileuton.” Other terms such as “Oral drug therapies” and “Obstructive lung diseases” were also used. A manual search was also performed in addition. Twenty-five articles including three systematic reviews have been identified. All articles with resulting titles and abstracts were screened. The full text of relevant articles was read and kept for reference.


  Role of Theophyllines in Chronic Obstructive Pulmonary Disease Top


Theophylline is a drug extracted from a purine derivative (1, 3-dimethyl xanthine) and is naturally present in tea, cocoa, and beans. It was one of the drugs earlier used for the treatment of asthma, initially as aminophylline both in oral and intravenous forms. This drug had a very narrow therapeutic window as doses used at that time for bronchodilation, were also associated with severe gastrointestinal, cardiac, and central nervous system (CNS) adverse effects. Seizures, cardiac arrhythmias, and even mortality were also observed when blood concentrations became too high due to pharmacokinetic interactions. Subsequently, theophylline gained popularity with the availability of sustained release products and commercial automated assays that allowed convenient blood level monitoring. However, the utility of theophylline declined when inhaled bronchodilators were introduced since the past few decades.

Theophylline is usually prescribed at lower concentrations based on its anti-inflammatory effects in COPD and is a safer option currently than in the past. It usually acts as smooth muscle relaxant located in the bronchial airways and pulmonary blood vessels.[9] It also reduces the airway responsiveness to various agents such as histamine, adenosine, methacholine, and allergens. There are two major pharmacological mechanisms of action for theophylline which include broad spectrum PDE inhibition leading to increase in the concentration of intracellular cyclic adenosine monophosphate and guanosine monophosphate, activation of protein kinase A, inhibition of tumor necrosis factor alpha and leukotriene synthesis and another adenosine receptor antagonist leading to anti-inflammatory effects.[8],[9]

Other proposed mechanisms of action showing anti-inflammatory effects include inhibition of nuclear factor-kappa B leading to reduction of the expression of known inflammatory genes in COPD, enhancement of interleukin-10 secretion, increasing histone deacetylase 2 (HDAC 2) activity, inhibiting phosphoinositide 3-kinase-delta, decreasing poly (ADP-ribose) polymerase-1, and promotion of apoptosis of inflammatory cells such as T cells and neutrophils.[9],[10] All these actions occur at a higher therapeutic dosage ranging from 10 to 20 mcg/ml, whereas the effect on HDAC 2 is observed at a lower dosage ranging from 5 to 10 mcg/ml. Apart from anti-inflammatory effects, theophylline also exhibits mild bronchodilation (increase forced expiratory volume in 1 s [FEV1], decreased air-trapping, and improvement in gas exchange), decrease in work of breathing by improving diaphragm contractility, respiratory stimulation, promotion of mucociliary clearance, and suppression of cough.[11]

Desired therapeutic concentrations of theophylline for children and adults are 5–15 mcg/ml and 10–20 mcg/ml, respectively, whereas toxicity is increased when concentration exceeds 20 mcg/ml.[12] There are interactions with several drugs such as cimetidine, ciprofloxacin, erythromycin, clarithromycin, and rifampicin due to alterations in hepatic metabolism primarily with not only the CYP1A2 but also the CYP3A4 metabolizing enzymes. Therapeutic dose monitoring is required in various conditions such as congestive cardiac failure, liver disorders, viral infections, morbid obesity, atrial fibrillation, and smoking. Low doses of theophylline such as 100–200 mg twice daily as a sustained release with target blood levels of 5–10 mcg/mL is currently recommended considering the risk-benefit ratio. It is best to titrate the dose upward on initiation with monitoring of drug levels in blood as indicated for suspicion of toxicity. Dose-dependent toxicity is observed such as gastrointestinal (nausea, vomiting, and discomfort) and CNS (headache, sleeplessness, and seizures).[13] Gastrointestinal side-effects and diuresis have been observed due to PDE inhibition, whereas cardiac arrhythmias and seizures are due to adenosine receptor antagonism that occurs at very high plasma concentrations.

Newer derivatives, such as doxofylline (1,3 dioxolane-2-yl methyl) and acebrophylline (ambroxol + theophylline-7-acetate) with decreased affinity for adenosine receptors, have been showing similar efficacy but have better cardiovascular and CNS toxicity profile as compared to theophyllines. A network meta-analysis has observed doxofylline to be the best xanthine in the treatment of COPD in terms of therapeutic efficacy and toxicity profile, followed by aminophylline and theophylline.[14] This class of drugs is currently indicated as add-on therapy primarily in advanced COPD continuing to have symptoms despite optimum inhaled therapy including inhaled corticosteroids (ICS), long acting beta agonist (LABA), and long acting muscarinic antagonist to achieve symptomatic relief, improvement in quality of life and possible reduction in exacerbations.[1],[15] It can be used as an alternative in COPD patients noncompliant with inhalers for any reason.[15]

It has been proposed that there is the occurrence of steroid resistance even at higher doses in smokers with COPD due to neutrophilic infiltration of airways as well as sputum and also due to increase in survival life of neutrophils by inhibition of apoptosis. This could lead to impaired HDAC activity that can be restored by the addition of low-dose theophylline to ICS, showing the potential utility of drug.[16]

A single-blinded, prospective, randomized, placebo-controlled study reported reduction in dyspnea, improvement in exercise performance, and lung functions in 58 moderate-to-severe COPD patients when theophylline was added to LABA and ICS combination.[17] However, a recent randomized control trial reported that the addition of low-dose theophylline to ICS in COPD patients having high risk of exacerbation did not reduce the annual number of exacerbations as compared to placebo.[18] The findings do not support the use of low-dose theophylline as adjunctive therapy in the prevention of COPD exacerbations.

The existing Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines do not recommend oral or intravenous aminophylline in patients hospitalized with COPD exacerbations due to significant adverse effects.[1] Theophylline exerts minimal bronchodilatory effects in COPD with modest symptomatic improvement. It improved FEV1 when added to LABA, such as salmeterol compared with LABA alone. However, GOLD also does not recommend these drugs as a long-term controller for COPD unless other agents are unavailable or unaffordable.[1]


  Role of Leukotriene Modifiers in Chronic Obstructive Pulmonary Disease Top


The leukotriene modifiers are another class of oral drugs that include montelukast, zafirlukast, and zileuton.[19] All these drugs show anti-inflammatory activity by acting on different sites in 5-lipoxygenase pathway. The first two drugs are selective leukotriene receptor antagonists that selectively block the CysLT1 receptor leading to prevention of leukotriene specifically LTD4 and LTE4 from binding to the CysT1 receptor whereas the last is an inhibitor of the enzyme 5-lipo-oxygenase that is responsible for the production of leukotrienes (LTC4, LTD4, LTE4, and LTB4) which are potent bronchoconstrictors. The blockade of the leukotrienes leads to modest bronchodilation with an onset of action of 1–2 h. Zileuton has shown better improvement in FEV1 as compared to montelukast and zafirlukast because the former blocks the leukotriene pathway at the level of 5-lipoxygenase with additional effects occur on LTB4 as well as on the other leukotrienes.[19]

Clinical benefits include symptom relief, modest bronchodilation, reduction in exacerbations, and relief of allergic rhinitis symptoms. Dosing of these drugs is as follows: montelukast 10 mg once daily; zafirlukast 20 mg twice daily on empty stomach; and zileuton 600 mg 4 times daily or 1200 mg twice daily for extended-release product. Potential drug interactions include zafirlukast with warfarin leading to increase in prothrombin time, decrease in levels of zafirlukast co-administered with erythromycin and increase in levels of theophylline when given concurrently with zafirlukast and zileuton. All these drugs are generally well-tolerated but may be associated with headache, dyspepsia, nausea, pharyngitis, flu-like symptoms, sleep disturbances, hallucinations, and drowsiness. Deranged liver function test was reported with zileuton. Churg-Strauss syndrome was rarely reported with leukotriene modifiers. All these drugs are indicated as an alternative therapy for mild asthma and also as an add-on agents given in combination with other therapies such as ICS/LABA for moderate-to-severe asthma.[19],[20]

Montelukast is also indicated for the acute prevention of exercise-induced bronchoconstriction as well as for the treatment of aspirin-induced asthma and allergic rhinitis.[20] However, there is no current indication for using leukotriene modifiers in COPD as evidence is limited. These classes of drugs might show a promising role in patients of COPD. Studies have reported higher levels of LTB4 in the sputum of COPD patients than in controls and also overexpression of CysLT1 receptors in the bronchial mucosa of COPD patients having frequent exacerbations than in normal individuals or stable COPD.[21],[22],[23] In a subset of COPD patients with exacerbations, increased infiltration of bronchial mucosa with eosinophils has been observed, and montelukast with or without ICS might be effective in reducing the number of eosinophils.[8],[19],[21] A small retrospective series comprising 20 moderate-to-severe elderly COPD patients treated with montelukast on long-term basis reported modest benefit with reduced symptoms, emergency department visits, required doses of ICS but no change in lung function as compared to that group treated without montelukast.[24]

Another study used montelukast on a short-term basis in moderate-to-severe COPD patients and reported that the addition of this drug to routine treatment protocol produced additional improvement on lung function, dyspnea score, and quality of life in patients with stable COPD suggesting need for an additional anti-inflammatory treatment.[25] A systematic review and meta-analysis in 2015 reviewed leukotriene inhibitor therapy for COPD and observed that there was a modest improvement in lung function and symptom scores and found no improvement in lung function and no reduction of myeloperoxidase/neutrophilic inflammation markers or LTB4.[26] A study reported that leukotriene synthesis inhibitor did not benefit COPD patients, although there was a modest reduction in neutrophilic inflammation with a 14-day therapy.[27] There is a lack of evidence to support the therapeutic efficacy of anti-leukotriene agents in COPD but more number of studies, including well-designed randomized controlled trials with larger sample size, are required.

A larger study reported that the addition of zileuton to routine care had no impact on treatment outcomes in patients hospitalized with exacerbations of COPD.[28] Patients with characteristics of both COPD and asthma sometimes referred to as asthma COPD overlap (ACO), may be more likely to benefit from montelukast therapy. A retrospective study of inner city veterans with COPD reported that 2 years of montelukast therapy is associated with decreased emergency department and urgent care utilization for exacerbations (from 34 to 22, 35%: P =0.03).[29] One well-designed trial in 39 smoking asthmatics likely representing ACO subgroup suggested that a better response to montelukast was observed as compared to ICS as compared to nonsmoking asthmatics.[30] Leukotriene modifiers have been prescribed frequently in patients of COPD in view of presumed diagnosis of ACO.[31] More studies are required to prove definite role of leukotriene modifiers in ACO.


  Conclusion Top


Whether theophyllines and leukotriene modifiers are still to be considered for treatment or to be withdrawn remains inconclusive. The existing review of literature supporting their roles remain weak, as shown in [Table 1].[1],[18],[26],[28],[32],[33],[34],[35],[36],[37] Despite the controversy about the exact role of these drugs whether used alone or in combination, they remain the most commonly used drugs worldwide on a traditional basis due to cost-effectiveness, availability, and ease of administration as compared to inhaled therapies. Studies have reported that most of the prescriptions by general practitioners are not always in accordance with GOLD guidelines. These two groups of drugs have been prescribed frequently either alone or along with inhaled therapies in multiple irrational combinations among COPD patients at various tertiary care centers leading to increased incidence of adverse drug reactions (ADRs).[38],[39],[40] Polypharmacy has been associated with multiple ADRs with few of them overlapping or being additive as one or more class of drugs can be responsible. The use of oral theophylline in particular requires cautious therapeutic monitoring and dose individualization.[41] There is a requirement of increased awareness among physicians regarding the rational use of these drugs among patients with COPD. In summary, there is no compelling evidence of benefit of theophyllines and leukotriene modifiers in the treatment of COPD. Their role needs to be justified by strong evidence.
Table 1: Review of literature showing existing role of theophyllines and leukotriene modifiers in chronic obstructive pulmonary disease

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  Phenotyping of Chronic Obstructive Pulmonary Disease: Future Prospects Top


COPD has now been considered to be a heterogeneous disease, such as asthma and lung cancer. The concept of heterogeneity arises from the fact that COPD patients manifest with diverse clinical features (symptoms, comorbidities, and frequency of exacerbation) for a similar degree of airflow limitation based on FEV1. The concept of universal therapy for all seems to be outdated and personalized therapy is required. Several phenotypes have been proposed based on expanding evidence over the last decade.[42],[43],[44],[45] However, only few of them have been validated as described in [Table 2]. Categorization of all COPD patients into a particular phenotype seems to be practically difficult as many of them will have overlapping clinical manifestations and comorbidities. The phenotyping approach to COPD based on various parameters related to three domains (severity, activity, and impact) will potentiate targeted therapy that can guide clinicians to prescribe appropriate drugs. This approach will promote precision medicine in COPD leading to change in clinical practice but larger trials are required for validation in the near future.
Table 2: Validated and proposed phenotypes of chronic obstructive pulmonary disease with treatment options

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Conflicts of interest

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Ram FS, Jardin JR, Atallah A, Castro AA, Mazzini R, Goldstein R, et al. Efficacy of theophylline in people with stable chronic obstructive pulmonary disease: A systematic review and meta-analysis. Respir Med 2005;99:135-44.  Back to cited text no. 11
    
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[PUBMED]  [Full text]  
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  [Table 1], [Table 2], [Table 1], [Table 2]



 

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