Often, the meds are either interacting directly with the body systems as a substitute for missing/tiny titers of the natural active component, or act as an antagonist for the same, so metering/shutting down the target system. This isn't quite the same as other systems that can develop tolerances (thereby requiring higher doses for the same perceived effect). Honestly, we'd have to take this on a case-by-case basis as no blanket statement is correct. Nor does this function in a natural selection format like antibiotics with bacteria that either evolve of die, where plasmids xfered via sex confer resistance for survivors.

There are plenty of other metabolic considerations. Some drugs are useless in their taken form, and only modifications/metabolism in the gut biome or liver or elsewhere generate the active physiological daughter products.