No problem, road are much pleasant and faster now.
Better to break your journey in Sukkur, its throughout motorway from Islamabad till there. If you will stay in Multan then you have to take drive of 13-15 hours till karachi, out of which approx 7.5 - 9 hours on National highway, which is an unpleasant experience at night specifically.
Isb-Sukkur= Total Motorway, pleasant and smooth ride.
Sukkur - Khi = Good during the day time. Leave early and you'll be in khi by Maghrib.