"Off-target" Mechanisms of ADRs

Very few drugs are completely selective; consequently, they can interact with different receptor types. An “off target” ADR can occur when a drug interacts with an unintended receptor either in an intended or in an unintended tissue.⁶ For example, a β2-adrenergic receptor agonist used to treat asthma may interact with β1-adrenergic receptors in the heart and increase heart rate; and β1-adrenergic receptor blocking agents targeting the heart may also antagonize β2-adrenergic receptors in lungs and cause bronchoconstriction.

Two other examples of “off-target” ADRs, uncovered during post-marketing surveillance, resulted in the withdrawal of both drugs from the market. Terfenadine, an H1-histamine receptor blocking agent interacted with unintended receptors (potassium channels) in an unintended tissue (heart) to generate fatal cardiac arrhythmias.⁶ The anorectic agent, fenfluramine, targeting 5-HT serotonin receptors in the brain also interacted with 5-HT2B receptors in the heart causing myofibroblast proliferation and fatal valvular damage.⁶