Drug interactions occur when one drug influences the behavior and effects of another, potentially enhancing or diminishing their effects or creating new therapeutic or adverse outcomes. Clinicians must be aware of drug interactions, especially during the perioperative period when using anesthetic agents to ensure patients have a safe, painless procedure.
Three primary types of interactions between anesthetic agents can be distinguished: (1) additivity, (2) infra-additivity (or antagonism), and (3) supra-additivity (or “synergy”). Additivity occurs when the combined effect of anesthetic agents equals the sum of their individual effects, often indicating a shared site of action. Infra-additivity, or antagonism, occurs when the combined effect is less than the sum of the individual effects, potentially reflecting conflicting mechanisms. In contrast, synergy occurs when the combined effect is greater than the sum of the individual effects, suggesting that the drugs act on different sites or mechanisms. Interactions between anesthetic agents that lead to synergy, in particular, offer potential advantages by reducing the required doses of individual agents, thereby minimizing dose-dependent side effects (1).
Anesthetic drug synergy often results from the interaction of agents acting on different receptor systems. For example, intravenous (IV) anesthetics that act on different sites frequently demonstrate synergistic effects. A hypnotic-hypnotic interaction between propofol, which potentiates GABA responses and directly activates GABA-A receptor function (reducing neuronal excitability), and midazolam, a short-acting benzodiazepine that enhances GABA-A receptor function at a different site, produces synergy that enhances hypnosis and immobility. This combination results in a more profound effect than either drug alone, allowing for lower doses of both agents. Similarly, one of the most well-studied synergistic interactions in anesthesia is between opioids and hypnotic agents. Opioids such as remifentanil, an ultra-short-acting opioid that exerts its effects through μ-opioid receptors to produce potent analgesia, synergize with propofol, which modulates GABA-A receptors, to enhance hypnosis and sedation, thereby increasing the clinical utility of both drugs (1, 2).
Another notable synergistic interaction in anesthesia is between inhaled anesthetics such as sevoflurane, desflurane, and isoflurane. These agents, which block excitatory channels and enhance inhibitory ligand-gated ion channels, exhibit synergistic effects when combined with IV agents. For instance, IV-administered opioids synergize with inhaled agents to suppress movement during surgery. Studies of drug interactions have demonstrated that this reduces the minimum alveolar concentration (MAC)—a standard measure of inhaled anesthetic potency—required for anesthesia. This allows for reduced doses of both drugs (1, 2, 3).
Not all anesthetic drug combinations result in synergy. Notably, among inhaled agents themselves, interactions are generally additive or infra-additive, suggesting a shared mechanism of action. This lack of synergy supports the theory that all inhaled anesthetics may target a
common site to achieve anesthesia. Ketamine, an IV-administered NMDA receptor antagonist, exhibits behavior that often stands out as an exception to the synergistic effects of IV drugs. It interacts either additively or infra-additively with other anesthetics, particularly those that enhance GABA-A receptors (1).
Synergy is significant in its ability to reduce the dosages of individual anesthetic agents, thereby minimizing side effects such as hypotension, respiratory depression, or delayed recovery. However, synergy is not without risks. Profound ventilatory depression, for instance, may occur when combining midazolam with fentanyl. Careful consideration is necessary to balance the benefits of synergy against potential adverse effects (1).
References
1. Hendrickx, J. F., Eger, E. I., 2nd, Sonner, J. M., & Shafer, S. L. (2008). Is synergy the rule? A review of anesthetic interactions producing hypnosis and immobility. Anesthesia and analgesia, 107(2), 494–506. https://doi.org/10.1213/ane.0b013e31817b859e
2. Tafur-Betancourt, L. A. (2017). The hidden world of drug interactions in anesthesia. Colombian journal of anesthesiology, 45(3), 216-223. https://doi.org/10.1016/j.rcae.2017.06.004
3. Vereecke H.M., & Proost J.H., & Eleveld D.J., & Struys M.F. (2015). Drug interactions in anesthesia. Johnson K.B.(Ed.), Clinical Pharmacology for Anesthesiology. McGraw-Hill Education. https://accessanesthesiology.mhmedical.com/content.aspx?bookid=1181§ionid=65651789
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