Sundowns were undone by goals either side of the break from Akwa and Aforu at Sekondi Stadium.
The Brazilians, who won the first leg 3-1, were hampered by the 65th minute dismissal of goalkeeper Denis Onyango.
Downs came under pressure early into the contest, with Onyango being forced into a number of saves.
The hosts eventually struck in the 36th minute via Akwa's successful penalty following a foul in the box by Thabo Nthethe.
Aforu then made it 2-0 in the 64th minute.
The visitors suffered a further setback moments later with the sending off of Onyango for a kick on Mohammed Abass, prompting Pitso Mosimane to bring on keeper Kennedy Mweene for Bangaly Soumahoro.
Mosimane's men pressed but were unable to find a way back as Medeama earned a spot in the group stages draw, taking place in Cairo, Egypt on May 24.
Sundowns: Onyango, Mphahlele, Nthethe, Arendse, Langerman (T Zwane 58'), S Zwane, Kekana, Soumahoro (Mweene 65'), Modise (Malajila 46'), Dolly, Billiat.