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Co-morbidities—meaning the presence of other diseases in the patient—raise the risk of adverse reactions to preoperative medications because they alter how drugs are processed and how the body responds. When organs such as the liver or kidneys are not functioning perfectly, drug clearance is reduced, causing drugs to stay in the body longer and potentially reach higher levels that increase side effects or toxicity. Co-existing heart or lung conditions can change how drugs distribute in the body and how sensitive the body is to their effects. In addition, having multiple conditions often means taking several medicines (polypharmacy), which increases the chance of drug–drug interactions that can amplify adverse reactions. So, the combination of impaired organ function and multiple medications makes adverse reactions more likely.

Young age, excellent health, or high tolerance to anesthesia do not inherently carry the same elevated risk from preoperative medications. Younger or healthier patients typically have better organ function and fewer interactions, and high tolerance to anesthesia doesn't reliably predict safety from other drug effects and can mask early problems.