Objective <p>The effectiveness of pressurized metered-dose inhalers (pMDIs) relies on correct inhalation technique. While prior studies investigated idealized breathing, the impact of real-life irregularities remains less understood. This study explores how real-life irregularities—pausing, coughing, and premature exhalation—alter aerosol transport and deposition in the airways.</p> Methods <p>Large-eddy simulations combined with a discrete phase model were performed on a realistic male airway geometry extending from the oral cavity to the fourth bronchial generation. Computational predictions were validated against <i>in vitro</i> experiments conducted under constant inhalation.</p> Results <p>Breathing irregularities substantially modified airflow dynamics and shifted deposition toward the upper airways. Coughing generated the strongest vortical structures and turbulence, followed by premature exhalation. Deposition in the left lung decreased from 19.9% during standard COPD inhalation to 2.1% during exhalation and 0.9% during coughing, while mouth–throat deposition increased to 35.2% during coughing compared to 14.5% under the COPD baseline condition. Exhalation caused higher overall particle loss (27.9%) than coughing (24.1%), but coughing produced more pronounced inertial impaction in the upper airways. Fine particles (&lt; 2&#xa0;µm) were largely exhaled (approximately 80%), whereas particles in the 2–5&#xa0;µm range—considered optimal for deep lung delivery—were redirected and lost under disturbed flow conditions.</p> Conclusions <p>Irregular breathing patterns markedly decrease deep lung deposition and increase upper airway losses. Repeated puffs without adequate intervals may exacerbate this problem, leading to excessive upper-airway deposition and increasing the likelihood of side effects. These findings provide guidance for physicians to tailor puff number and timing, improving therapeutic efficacy while minimizing risks to patient safety.</p>