Every time Billy/Dr. Horrible displays a facial tic, take a sip.
Hard Mode: Take a drink or shot on the same condition. (WARNING: When his eye starts twitching, drink one time, not once for each twitch. We almost lost a few people that way.)
Take a shot every time someone sings over someone else.
Hard: Count the duets, too.
Take a sip when light shines off Dr. Horribles' goggles.
Do a shot whenever Billy/Doc Horrible gets injured.
Another shot for every time Billy is horribly awkward.