Hi there,
I can sure understand your concern! After flying seven hours when my son was one, and then four hours with 13 month old twin daughters (them never having their own seat, always sitting with an adult), here's a list of a few things I've found that saved my sanity flying when my kids were that age:
a travel sized etch a sketch - it's little so it doesn't take up much room, and when my children were a year old they enjoyed not only writing on it but also making it disappear.
a roll of scotch tape/post it notes - I stumbled on these by accident during a wait for the plane to taxi down the runway. My kids especially enjoyed sticking them to their faces for a different take on peek-a-boo, and I would stick the tape on the kids and they'd peel it off.
a bottle of bubbles - check with the airline before you board, but I know that most of them allow these on the flights as long as you don't annoy other passengers. We even had the steward blowing them for our twins! These are also really good to use while you wait for the plane - we made quite a few friends!
new toys/books - they don't have to be expensive, just something he's never seen before, your local dollar store should have just what you need.
If your son is "into" finger games (ten little indians, here is the church, etc.), try to find some new ones, maybe an internet search? I think they're also called hand rhymes.
As far as the medicine before flying bit, that has never worked for me, even though Motrin will knock my kids right out at home. Don't know if it was just the excitement of the plane or what.
And don't forget your sense of humor! Even if he flips out the entire flight, which he won't-I'm sure, it's only four hours and what are the chances that you'll ever see anyone on that flight (other than your DH!) again?
Good luck!