Polypharmacy and Drug–Drug Interactions in Chronic Obstructive Pulmonary Disease: A Narrative Clinical Review

Background: Chronic obstructive pulmonary disease (COPD) is commonly managed alongside multimorbidity, polypharmacy, recurrent treatment escalation, and older age, all of which increase vulnerability to drug–drug interactions (DDIs). We aimed to synthesize the main DDI domains relevant to COPD pharmacotherapy and to distinguish harmful DDIs from beneficial combination therapy and formal compatibility findings. Methods: We performed a narrative review using structured literature searches and citation tracking to evaluate COPD-related studies. We prioritized direct COPD-specific DDI evidence, while also including mechanistic, class-specific, and contextual studies when direct evidence was lacking. Retained evidence included observational cohorts, prescribing studies, pharmacokinetic trials, case reports, and systematic reviews. Results: The reviewed literature indicates that DDI vulnerability in COPD is driven less by isolated drug pairs than by overall regimen complexity, multimorbidity, aging, fragmented prescribing, and high-intensity treatment periods such as exacerbations, hospitalization, and discharge. Key DDI domains included cardiopulmonary co-treatment, QT-related vulnerability, and potential or clinically relevant interactions amplified during exacerbations. Inhaled therapies are not universally interaction-free, particularly with strong metabolic inhibitors. Psychotropics, frailty, dementia, and palliative care further increase clinical complexity. However, beneficial bronchodilator combinations and formal compatibility studies demonstrate that not all multidrug COPD regimens are harmful. Conclusions: In COPD, DDI assessment should focus on the full treatment regimen and not be limited to a set of iconic drug pairs. Clinicians must focus on exacerbation-related prescribing, QT-active drugs, theophylline exposure, psychotropic co-medication, and vulnerable subgroups such as older, frail, and palliative patients. Pharmacist-supported drug review, drug reconciliation, and selective deprescribing are key strategies for reducing clinically relevant DDI burden in COPD.