Which acetylcholinesterase inhibitor crosses the blood-brain barrier?

• A. Pyrodostigmine
• B. Neostigmine
• C. Physostigmine
• D. Edrophonium

Answer: (C)

The key concept is how acetylcholinesterase inhibitors reach the central nervous system. The blood-brain barrier blocks most charged, polar compounds, so lipophilicity and lack of permanent charge determine CNS entry. Inhibitors that are quaternary ammonium compounds carry a permanent positive charge and are highly polar, so they stay outside the brain and act mainly at peripheral sites. Physostigmine, however, is a tertiary amine and more lipophilic, allowing it to cross the blood-brain barrier and inhibit acetylcholinesterase in the CNS as well as peripherally. This is why physostigmine can reverse central anticholinergic toxicity and has CNS effects, whereas the others listed (pyridostigmine, neostigmine, and edrophonium) do not cross into the CNS and exert effects only at peripheral neuromuscular junctions.