I'm a moderate Independent, so nothing really hurts, but I think if I were a Conservative, the constant political jabs would start to annoy me. When it's too hamfisted, it does have an effect.
I love Battlestar Galactica, but recently they were really laying on analogies to Iraq etc so thickly that at times it sort of took me out of the show. I didn't piss me off, it just made my mind kind of ponder the politics of the real world for a moment, instead of paying attention to the show. I imagine some of Weeds political jabs could have the same effect on many people.
It's fine when it subtle, not so good when it's silly; like having the school kids launch into a political diatribe that's beyond their years.