Gastrointestinal complications—such as dyspepsia, mucosal irritation, peptic ulcers, and gastrointestinal bleeding—arise from two distinct mechanisms: (i) Local effects, driven by the direct contact of the drug with gastric mucosa, which may be mitigated by formulation strategies such as gastro-resistant coatings, enteric polymers, or site-specific delivery systems; (ii) Systemic effects, primarily resulting from cyclooxygenase-1 (COX-1) inhibition, which remain largely unaffected by oral formulation changes and require careful drug selection and dosing to manage risk. Here, PTGS1 is linked to peptic ulcer disease.