Suspected Adverse Drug Reactions Associated with Leukotriene Receptor Antagonists Versus First-Line Asthma Medications: A National Registry–Pharmacology Approach

Background/Objectives: The aim of this study was to determine the suspected adverse drug reaction (ADR) profile of leukotriene receptor antagonists (LTRAs; montelukast and zafirlukast) relative to first-line asthma medications such as short-acting beta agonists (SABAs; salbutamol) and inhaled corticosteroid (ICS; beclomethasone) in the United Kingdom. to determine the chemical and pharmacological rationale for the suspected ADR signals. Methods: Properties of the asthma medications (pharmacokinetics and pharmacology) were datamined from the chemical database of bioactive molecules with drug-like properties, the European Molecular Biology Laboratory (ChEMBL). Suspected ADR profiles of the asthma medications were curated from the Medicines and Healthcare products Regulatory Authority (MHRA) Yellow Card interactive Drug Analysis Profiles (iDAP) and concatenated to the standardised prescribing levels (using Open Prescribing data) between 2018 and 2023. Results: Total ADRs per 100,000 Rx (p < 0.001) and psychiatric system organ class (SOC) ADRs (p < 0.001) reached statistical significance. Montelukast exhibited the greatest ADR rate at 15.64 per 100,000 Rx. Conclusions: Relative to the controls, montelukast displays a range of suspected system organ class level ADRs. For the credible and previously reported psychiatric ADRs, montelukast is statistically significant (p < 0.001). A mechanistic hypothesis is proposed based on polypharmacological interactions in combination with cerebrospinal fluid (CSF) levels attained. Montelukast had the highest nervous disorder ADR rate at 1.71 per 100,000 Rx, whereas beclomethasone and salbutamol had lower rates (0.43 and 0.14, respectively). These ADRs share a similar background to psychiatric ADRs with CSF penetrability involved and affecting the dopamine axis. This work further supports the monitoring of montelukast for rare but important neuropsychiatric side effects.