Crosstolerance

Cross-tolerance is a pharmacological phenomenon in which tolerance to the effects of one drug reduces the responsiveness to a second drug, typically because the two substances share similar mechanisms of action or metabolic pathways. It is a form of tolerance that can extend to other drugs within the same class or with overlapping targets, and it is distinct from tolerance to a single drug or from cross-sensitization, which involves different processes.

There are two main mechanisms. Pharmacodynamic cross-tolerance arises from adaptive changes in receptors or signaling pathways, such as receptor desensitization or downregulation, which lessen the effect of related drugs. Pharmacokinetic cross-tolerance occurs when repeated exposure to one drug alters the metabolism or distribution of another drug, for example through induction of metabolic enzymes, leading to lower systemic exposure to the second drug.

Common examples include opioids and sedative-hypnotics. Chronic morphine exposure can diminish the analgesic effect of morphine-like drugs such as heroin or fentanyl due to shared mu-opioid receptor mechanisms. Long-term alcohol use can blunt responses to benzodiazepines and other GABAergic agents because of overlapping effects on the GABA-A receptor system. Cross-tolerance can influence clinical decisions, such as opioid rotation or switching between sedatives, by requiring dose adjustments to achieve intended effects.

Clinical implications include an increased risk of underdosing or, conversely, overdose if potency is assumed to be equal across drugs. Cross-tolerance is influenced by drug properties, dosing, duration of exposure, and individual genetics and is not universal across all drug pairs.