I started drawing my comic at the exact size I would upload it and at 72 dpi. It was a terrible mistake. It looks nice online, but I had to print a copy for my table at my country's Comic-Con a couple of years ago and it was a nightmare. If I ever want to publish it for some reason I will have to redraw a lot of it and cry. Of course, I stopped working like this once I realized the comic had gained a certain amount of readers and people started asking about printed copies, but the damage was done. Now I work with a much larger canvas and at 300 dpi.
So, basically there's nothing wrong with drawing with the final file size if you want, but it might give you troubles later. It's better to play safe and just work in a larger canvas and a better resolution.