What is the mechanism of action of neostigmine?

From the Guidelines

Neostigmine acts as an acetylcholinesterase inhibitor that prevents the breakdown of acetylcholine at synaptic junctions, allowing acetylcholine to accumulate and prolong its effects on both muscarinic and nicotinic receptors. By inhibiting the enzyme acetylcholinesterase, neostigmine enables the accumulation of acetylcholine in the synaptic cleft, which is crucial for enhancing muscle contraction by promoting effective binding to nicotinic receptors on skeletal muscle 1. This mechanism is particularly significant at the neuromuscular junction. Neostigmine is commonly used to reverse non-depolarizing neuromuscular blockade after surgery, typically administered at doses of 0.03-0.07 mg/kg IV along with an anticholinergic agent like glycopyrrolate to counteract muscarinic side effects 1. It's also used to treat myasthenia gravis. The drug's effects are limited to the peripheral nervous system due to its water-solubility and quaternary ammonium group, which prevents it from crossing the blood-brain barrier.

Key Points:

• Neostigmine inhibits acetylcholinesterase, increasing acetylcholine levels in the synaptic cleft.
• It enhances muscle contraction by promoting binding to nicotinic receptors on skeletal muscle.
• Commonly used to reverse non-depolarizing neuromuscular blockade and treat myasthenia gravis.
• Typically administered with an anticholinergic agent to counteract muscarinic side effects.
• Effects are limited to the peripheral nervous system due to its chemical properties.

Clinical Use:

Neostigmine's role in clinical practice, especially in anesthesia and neurology, is well-established for its ability to reverse neuromuscular blockade and manage myasthenia gravis. Its use must be carefully considered, taking into account the patient's overall clinical status and potential for side effects. Monitoring and dose adjustment are crucial for optimal outcomes. According to recent guidelines, quantitative monitoring of neuromuscular blockade after neostigmine administration is recommended until a TOF ratio of 0.9 is achieved 1.

Mechanism and Effects:

The mechanism of action of neostigmine involves the inhibition of acetylcholinesterase, leading to an increase in acetylcholine concentration in the synaptic cleft. This increase in acetylcholine levels competes with non-depolarizing muscle relaxants at the nicotinic receptor, thereby antagonizing their action and reversing neuromuscular blockade 1. The dose of neostigmine required for effective reversal can vary based on the depth of neuromuscular blockade, with studies suggesting doses in the range of 40 to 50 mg/kg may be effective under certain conditions 1.

Safety and Side Effects:

While neostigmine is effective, its use is not without potential side effects, including muscarinic effects that can be mitigated with anticholinergic agents. The choice of anticholinergic agent and the dose of neostigmine must be carefully considered to minimize adverse effects. In the context of chronic intestinal failure, neostigmine may be considered as part of the management strategy to enhance intestinal motility, though its use in this setting is less common and should be guided by clinical judgment and patient response 1.

From the FDA Drug Label

Neostigmine methylsulfate is a competitive cholinesterase inhibitor. By reducing the breakdown of acetylcholine, neostigmine methylsulfate induces an increase in acetylcholine in the synaptic cleft which competes for the same binding site as non-depolarizing neuromuscular blocking agents, and reverses the neuromuscular blockade.

Mechanism of Action: Neostigmine works by inhibiting the enzyme cholinesterase, which breaks down acetylcholine. This leads to an increase in acetylcholine levels in the synaptic cleft, allowing it to compete with non-depolarizing neuromuscular blocking agents and reverse neuromuscular blockade. The key effects of neostigmine include:

• Increase in acetylcholine levels
• Competition with non-depolarizing neuromuscular blocking agents
• Reversal of neuromuscular blockade 2 2

From the Research

Mechanism of Action of Neostigmine

• Neostigmine is a parasympathomimetic drug that acts as a reversible acetylcholinesterase inhibitor 3, 4.
• It enhances excitatory parasympathetic activity by competing with acetylcholine for attachment to acetylcholinesterase at sites of cholinergic transmission and enhancing cholinergic action 4.
• Neostigmine increases postoperative colonic motility in patients undergoing colorectal surgery by increasing the colonic motility index and colonic tone 5.
• It can be used to stimulate colonic motility after colorectal surgery and has a similar effect postoperatively as in healthy volunteers 5.
• Neostigmine appears to be useful in reversing ileus caused by anticholinergic drug overdose by enhancing gastrointestinal motility 6.

Effects of Neostigmine on the Endplate Acetylcholine Receptor Channel Complex

• The effects of neostigmine are concentration dependent, with low concentrations increasing miniature endplate current (MEPC) amplitude and the time constant of MEPC decay 7.
• Concentrations greater than 5 X 10(-5) M decrease MEPC amplitude and split the decay of MEPCs into two components, one faster and one slower than the control rate 7.
• Neostigmine exhibits direct effects on the endplate receptor channel complex which are unrelated to acetylcholinesterase inhibition, including a prolongation of the gating kinetics of the endplate receptor channel complex and a direct action to block the acetylcholine receptor 7.