PATHOPHYSIOLOGICAL MECHANISMS LINKING CHRONIC STRESS TO ALTERED DRUG RESPONSE: A NARRATIVE REVIEW OF PHARMACOKINETIC AND PHARMACODYNAMIC CONSEQUENCES

Abstract

Introduction. Interindividual variability in drug response is conventionally attributed to genetic polymorphism, age, sex, organ function, comorbidity, adherence, diet and drug–drug interactions. This framework tacitly assumes that the physiological environment of pharmacotherapy is stable. Sustained psychological stress violates that assumption. Aim. To synthesise the mechanistic and clinical evidence on how chronic stress alters drug disposition and response, to compare the strength of that evidence across mechanisms, and to define what may reasonably be translated into clinical practice. Materials and methods. Narrative, mechanism-oriented synthesis of peer-reviewed literature identified in PubMed and Scopus for the period 2004–2026, across neuroendocrinology, immunology, gastroenterology, clinical pharmacology and psychiatry. Each mechanism was appraised against predefined criteria: level of evidence, direction and magnitude of effect, and translational readiness. Results. Sustained activation of the hypothalamic–pituitary–adrenal axis and of the sympathetic–adrenomedullary system reshapes cytochrome P450 activity in an isoform-specific manner, sustains low-grade inflammation capable of shifting the metabolic phenotype independently of genotype, increases intestinal permeability, modifies microbial biotransformation and efflux transport at the intestinal wall and the blood–brain barrier, and drives receptor desensitisation. The direction of change is not uniform, so the clinical presentation is context-dependent: reduced efficacy, increased toxicity, delayed response, or unstable variability. Effect magnitude differs across mechanisms by about an order of magnitude. Conclusions. Chronic stress is best conceptualised as a dynamic component of the individual exposome rather than as a behavioural confounder. The defensible clinical position is intensified monitoring and careful interpretation of apparent treatment failure, not dose adjustment on the mere presence of stress.