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

Abstract

AbstractAimsTo determine the suspected adverse drug reaction (ADR) profile of leukotriene receptor antagonists (LTRAs: montelukast and zafirlukast) relative to first-line asthma medications short-acting beta agonists (SABA: salbutamol) and inhaled corticosteroid (ICH: beclomethasone) in the United Kingdom. To determine chemical and pharmacological rationale for the suspected ADR signals.MethodsProperties of the asthma medications (pharmacokinetics and pharmacology) were datamined from the chemical database of bioactive molecules with drug-like properties, European molecular Biology laboratory (ChEMBL). Suspected ADR profiles of the asthma medications was curated from the Medicines and Healthcare products Regulatory Authority (MHRA) Yellow Card interactive drug analysis profiles (iDAP) and concatenated to the standardised prescribing levels (Open Prescribing) between 2018-2023.ResultsTotal ADRs per 100,000Rx(P< .001) and psychiatric system organ class (SOC) ADRs (P< .001) reached statistical significance. Montelukast exhibited the greatest ADR rate at 15.64 per 100,000Rx. The low lipophilic ligand efficiency (LLE = 0.15) of montelukast relative to the controls may explain the promiscuity of interactions with off-target G-coupled protein receptors (GPCRs). This included the dopamine signalling axis, which in combination with bioaccumulation in the cerebrospinal fluid (CSF) to achieve Cmaxbeyond a typical dose can be ascribed to the psychiatric side effects observed. Cardiac ADRs did not reach statistical significance but inhibitory interaction of montelukast with the MAP kinase p38 alpha (a cardiac protective pathway) was identified as a potential rationale for montelukast withdrawal cardiac effects.ConclusionRelative to the controls, montelukast displays a range of suspected system organ class level ADRs. For psychiatric ADR, montelukast is statistically significant (P< .001). A mechanistic hypothesis is proposed based on polypharmacological interactions in combination with CSF levels attained. This work further supports the close monitoring of montelukast for neuropsychiatric side effects.