Muscle relaxation caused by a muscle relaxant drug can be terminated spontaneously by diffusion, redistribution, metabolism, and excretion or via pharmacological antagonism using specific reversal agents known as cholinesterase inhibitors. Acetylcholinesterase is an enzyme found at the motor end plate. It functions by breaking down and reducing the amount of acetylcholine (ACh) at the nerve terminal. By inhibiting acetylcholinesterase, cholinesterase inhibitors indirectly increase the amount of ACh molecules that are available to compete with the nondepolarizing muscle relaxant for the binding sites of the ACh receptors.
Drugs within the class of cholinesterase inhibitors are neostigmine, pyridostigmine, physostigmine, and edrophonium (Table 60-1). Neostigmine and edrophonium are most commonly used clinically. The use of physostigmine as a reversal agent is limited because it crosses the blood–brain barrier (BBB).
TABLE 60-1Cholinesterase Inhibitors and Anticholinergics ||Download (.pdf) TABLE 60-1 Cholinesterase Inhibitors and Anticholinergics
|Cholinesterase Inhibitor ||Usual Dose of Cholinesterase Inhibitor ||Recommended Anticholinergic ||Usual Dose of Anticholinergic per mg of Cholinesterase Inhibitor |
|Neostigmine ||0.04–0.08 mg/kg ||Glycopyrrolate ||0.2 mg |
|Pyridostigmine ||0.1–0.25 mg/kg ||Glycopyrrolate ||0.05 mg |
|Edrophonium ||0.5–1 mg/kg ||Atropine ||0.014 mg |
|Physostigmine1 ||0.01–0.03 mg/kg ||Usually not necessary ||NA |
Cholinesterase inhibitors will increase acetylcholinesterase not just at the neuromuscular junction of skeletal muscles, but at all sites of acetylcholinesterase action. These locations include autonomic ganglia and muscarinic receptors of the cardiovascular, gastrointestinal, genitourinary, and respiratory systems. The use of these reversal agents can, therefore, lead to numerous side effects, including some potentially lethal ones (Table 60-2).
TABLE 60-2Side Effects of Acetylcholinesterase Inhibitors ||Download (.pdf) TABLE 60-2 Side Effects of Acetylcholinesterase Inhibitors
|Organ System ||Muscarinic Side Effects |
|Cardiovascular ||Decreased heart rate, bradyarrhythmias |
|Pulmonary ||Bronchospasm, bronchial secretions |
|Cerebral ||Diffuse excitation1 |
|Gastrointestinal ||Intestinal spasm, increased salivation |
|Genitourinary ||Increased bladder tone |
|Ophthalmological ||Pupillary constriction |
The effect on the cardiac conduction system is particularly concerning. Unopposed muscarinic activity at the sinoatrial node can lead to bradycardia and even asystole. To avoid this (and other) effects, cholinesterase inhibitors are administered simultaneously with muscarinic anticholinergics, such as glycopyrrolate and atropine. The pharmacodynamics and pharmacokinetic profiles of each drug will determine the specific pairings. For example, neostigmine is usually paired with glycopyrrolate, whereas edrophonium is usually paired with atropine.
The dose of acetylcholinesterase inhibitor administered should be altered based on the degree of block. An overdose can lead to too much ACh in the neuromuscular junction. This can lead to an antagonistic effect where it may act ...