If I'm sending, say 50 XRP, first time to an exchange or wallet, will 20 XRP be locked forever and become unusable? Since 20 xrp are required to activate that account.
If it's a native wallet on the ledger, then 20 XRP will not be transferrable, though you can use it to pay transaction fees. Exchanges typically have you pay into their account, so there's no reserve that you need to pay. For reasons that nobody has ever figured out, Poloniex does make you pay the 20 XRP reserve.