Cholinergic Pharmacology: Mechanism of Action

MECHANISM OF ACTION

Normal neuromuscular transmission criti-cally depends on acetylcholine binding tonicotinic cholinergic receptors on the motor end-plate. Nondepolarizing muscle relaxants act by competing with acetylcholine for these binding sites, thereby blocking neuromuscular transmission. Reversal of blockade depends on gradual diffusion, redistribution, metabolism, and excretion from the body of the nondepolarizing relaxant (spontaneousreversal), often assisted by the administration ofspecific reversal agents ( pharmacological reversal). Cholinesterase inhibitors indirectly increase the amount of acetylcholine available to compete with the nondepolarizing agent, thereby reestablishing normal neuromuscular transmission.

Cholinesterase inhibitors inactivate acetylcho-linesterase by reversibly binding to the enzyme. The stability of the bond influences the duration of action. The electrostatic attraction and hydro-gen bonding of edrophonium are short-lived; the covalent bonds of neostigmine and pyridostigmine are longer lasting.

Organophosphates, a special class of cholines-terase inhibitors, form very stable, irreversible bonds to the enzyme. They are used in ophthalmology and more commonly as pesticides. The clinical duration of the cholinesterase inhibitors used in anesthesia, however, is probably most influenced by the rate of drug disappearance from the plasma. Differences in duration of action can be overcome by dosage adjust-ments. Thus, the normally short duration of action of edrophonium can be partially overcome by increas-ing the dosage. Cholinesterase inhibitors are also used in the diagnosis and treatment of myasthenia gravis.

Mechanisms of action other than acetylcholin-esterase inactivation may contribute to the restora-tion of neuromuscular function. Edrophonium seems to have prejunctional effects that enhance the release of acetylcholine. Neostigmine has a direct (but weak) agonist effect on nicotinic receptors. Acetylcholine mobilization and release by the nerve may also be enhanced (a presynaptic mechanism).In excessive doses, acetylcholinesterase inhibi-tors paradoxically potentiate a nondepolarizing neuromuscular blockade. Standard dogma states that neostigmine in high doses may cause recep-tor channel blockade; however, clinical evidence of this is lacking. In addition, these drugs prolong the depolarization blockade of succinylcholine. Two mechanisms may explain this latter effect: an increase in acetylcholine (which increases motor end-plate depolarization) and inhibition of pseu-docholinesterase activity. Neostigmine and to some extent pyridostigmine display some limited pseudo-cholinesterase-inhibiting activity, but their effect on acetylcholinesterase is much greater. Edrophonium has little or no ef fect on pseudocholinesterase. In large doses, neostigmine can cause a weak depolar-izing neuromuscular blockade.