Author: Mónica M. Bernardo
Medscape News Europe
Anesthetics remain safe, but they are not universally effective. Sex, genetics, body composition, and brain function influence how anesthetics are metabolized and tolerated, so the challenge lies in tailoring those drugs to each patient’s biology.
Anesthesia is one of the cornerstones of modern medicine, but its effects are not the same in all patients, nor do they always manifest the same way in the same person. Historically, anesthetic practice has relied on relatively stable models — weight, age, sex, comorbidities, and clinical experience — to predict drug response. However, recent research shows that this response results from a complex interaction of pharmacokinetics, pharmacodynamics, genetics, pathophysiology, preexisting brain state, and even psychosocial factors — all of which are variable and dynamic.
In October 1846, in the amphitheater at Massachusetts General Hospital in Boston, William T.G. Morton, young dentist, publicly demonstrated that inhaling ether in the proper dose could eliminate pain without compromising the patient’s vital functions. That experiment marked the birth of modern anesthesia and transformed surgery forever.
Almost two centuries later, general anesthetics make more than 300 million surgeries a year worldwide possible (between 2 and 3 million in Spain), and they are considered safe and routine. Yet the exact mechanism by which these drugs “switch off” consciousness is still not fully known, which helps explain why anesthetic responses can vary even in the same patient.
Today’s anesthesiology is moving toward personalization based on biomarkers, pharmacogenetics, advanced monitoring, and dynamic phenotyping — a paradigm shift that will allow clinicians to better manage each patient’s biological individuality before surgery. There is no doubt that the body’s response will depend largely on its ability to absorb, distribute, metabolize, and eliminate drugs — processes that are part of pharmacokinetics. Variability in these phases explains differences in the effective dose, duration of effect, and recovery times, even with standardized protocols.
Pharmacokinetic Influences
Advanced age, cardiovascular, liver, or kidney disease, and nutritional status are the main factors that affect the volume of distribution, metabolism, and elimination of anesthetics and are linked to variability in anesthetic depth and recovery.
But they are not the only factors. Recent scientific evidence also indicates that sex and sex hormones influence individual sensitivity to anesthetics. A study in mouse models, published in Proceedings of the National Academy of Sciences (2024), showed that testosterone and its conversion to estradiol modulate the response to volatile anesthetics, with greater sensitivity in men than in women at constant doses — an effect mediated by brain circuits involved in regulating consciousness. Human data, reported in Current Issues in Molecular Biology (2025), suggest differences in speed of recovery and responses to opioids and neuromuscular blockers between men and women, although clinical relevance depends on the specific drug.
Body composition is another factor that influences anesthetic efficacy. In individuals with obesity, changes in the ratio of fat to lean mass alter the volume of distribution of propofol (one of the most studied anesthetics) and other lipophilic drugs, modifying plasma concentrations after a standard dose. Thus, greater total body volume and increased cardiac output directly affect the clinical behavior of anesthetics.
Finally, liver or kidney comorbidities affect drug metabolism and elimination, requiring dose adjustments and close monitoring. Renal clearance can be reduced in people with chronic kidney disease, altering elimination of metabolites and, occasionally, active drugs that depend on renal excretion. All of this contributes to why the same patient may respond differently to the same anesthetic regimen on different occasions.
Pharmacogenomics
Beyond pharmacokinetics, other factors that can explain variability in anesthetic effects relate to the patient’s genes — that is, pharmacogenomics.
A study published in Pharmacogenetics and Genomics (2025) revealed that polymorphisms in genes encoding metabolizing enzymes, such as cytochromes P450 and UDP-glucuronosyltransferases, directly affect the clearance rate, achieved plasma concentration, and duration of clinical effect.
Variants in CYP2B6, CYP2C9, and UGT1A9 have been associated with differences in propofol pharmacokinetics, affecting clearance and the total dose required to achieve and maintain an adequate anesthetic depth. Polymorphisms in CYP3A4 and CYP3A5 influence the response to midazolam.
These differences are particularly relevant in contexts of prolonged sedation or critical illness, where small variations in clearance can lead to drug accumulation, delayed awakening, or greater hemodynamic instability.
Beyond metabolism, genetics also affects the pharmacologic targets of anesthetics. Polymorphisms in subunits of the gamma-aminobutyric acid type A receptor, such as GABRA1, have been linked to differences in propofol sensitivity and in the hemodynamic effects associated with its administration. These findings reinforce the idea that anesthetic response depends not only on how much drug reaches the brain but also on how the brain processes it at the molecular level.
Neurocognitive Factors and Inflammation
The brain’s response is also highly heterogeneous and is modulated by neurocognitive factors that determine both tolerance to certain anesthetic depths and the risk for postoperative cognitive dysfunction (POCD), as noted in an article published in Nature (2025). POCD is a key indicator of this differential vulnerability of the brain to anesthetic and surgical stress. This indicator shows that similar anesthetic exposures can have very different consequences depending on the patient’s baseline condition. Advanced age, longer anesthesia duration, lower education level, and a history of cerebrovascular disease increase the risk for postoperative brain damage, suggesting that not all brains tolerate standard anesthesia in the same way.
In patients with lower cognitive reserve or prior brain injury, standard anesthetic exposures can have a greater functional impact, forcing a rethinking of the concept of a “safe dose” as a variable dependent on the individual’s neurobiological context.
Another study, published in Frontiers in Aging Neuroscience (2025), found that surgery-induced neuroinflammation is a key mechanism in this variability. Elevated levels of mediators such as interleukin-6, interleukin-8, or C-reactive protein have been linked to higher risk for postoperative cognitive decline, while modulators of the inflammatory response such as dexamethasone have been shown to reduce its incidence.
All this underlines the anesthetic effect also depends on the brain’s inflammatory and functional state. Vulnerability is dynamic, so a patient’s risk can change between procedures because of aging, emerging cognitive decline, or new cerebrovascular events. This helps explain why responses to the same anesthetic combination can differ over time.
Anxiety Influence
In addition to the biological and pharmacologic factors discussed, psychological variables that influence the subjective experience of sedation and analgesia must also be considered in the anesthetic response. Recent literature on placebo and nocebo effects (2025) shows that patient expectations, anxiety levels, and certain personality traits can modify pain perception and the state of hypnosis, even when the dose and anesthetic protocol are identical.
Experimental and neuroimaging studies have shown that traits such as introversion, extraversion, or emotional control are associated with different patterns of brain activation during pain modulation. In this context, nocebo effects (linked to negative expectations) can be intense and persistent, diminishing analgesic placebo effects. This could explain why some patients report insufficient sedation or greater postoperative pain despite technically adequate anesthesia.
A patient’s psychological state can vary from one procedure to another. Increased anxiety, prior negative surgical experiences, or different preoperative information can markedly change the subjective response to the same anesthesia, demonstrating that the emotional context is a key component of anesthetic variability.
Depth Monitoring
To reduce that variability, depth-of-anesthesia monitoring using EEG has emerged, with tools that use the bispectral index. This strategy seeks to individualize dosing and improve clinical safety during surgery, but the problem is that these tools themselves show substantial variability.
Factors such as age, neurologic comorbidity, and concurrent medications affect the relationship between anesthetic concentration and EEG changes, so two patients with the same index value can be at different levels of hypnosis. Likewise, the same patient can show different EEG patterns in different surgeries.
Although EEG monitoring helps adjust dosing and shorten wake-up times, it must be interpreted cautiously and validated further, especially in vulnerable patients.
Overall, the scientific evidence indicates that the response to anesthesia is the result of a complex, multifactorial interaction among pharmacokinetics, pharmacodynamics, genetics, neurologic state, inflammation, and comorbidities, among other factors. In response to this reality, anesthesiology is moving toward increasingly personalized clinical practice models supported by biomarkers, advanced monitoring, and analysis of large data sets. This approach aims to optimize anesthetic efficacy and safety while recognizing and managing each patient’s biological uniqueness.