After the first hour or so, Zander settles down and just goes to sleep. I keep his leash, water bottle, and treats up front with me. He also gets hot easily, so I blast the air and wear a hoodie. Benedryl does wonders too. I give it half an hour to 45 minutes before we leave, then again before we stop to ease any stress about the hotel room and all the noises and smells. Whenever the car slows or stops for gas, food, or going through towns he still gets a bit antsy. Click/treat for quietly looking out the window and we're golden.
I make a roundtrip 64+ hour drive every 6 months, so we've nearly got the system down pat.