Interaction of 2,4-diaminopyridine with cholinesterase inhibitors

The interaction between 2,4 diaminopyridine (2,4-DAP) and neostigmine or edrophonium was studied in vivo in the rat sciatic nerve-tibialis anterior muscle preparation using the constant infusion technique of pancuronium. The ED50 value (dose of drug which produces 50% antagonism) decreased from 17 to 7 micrograms/kg with neostigmine and from 70 to 20 micrograms/kg with edrofonium, when these 2 compounds were co-administered with 40 micrograms/kg 2,4-DAP. The ED50 value of 2,4-DAP decreased from 160 to 90 micrograms/kg when 3.5 micrograms/kg neostigmine was added. From these experiments we conclude that 2,4 DAP acts synergistically with both neostigmine and edrophonium. In experiments using the train of four (T4) stimulation, we compared the antagonistic potencies of the drugs alone and in combination with each other. Neostigmine proved to be the most potent. 2,4-DAP given alone was not able to restore the muscle contraction completely (T4 ratio greater than 70%) up to a dose of 400 micrograms/kg. The doses of neostigmine and edrophonium could be halved, when they were combined with a small amount of 2,4-DAP without apparent lose of antagonistic potency.