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The term cholinergic refers to the effects of the neurotransmitter acetylcholine, as opposed to the adrenergic effects of noradrenaline (norepinephrine). Acetylcholine is synthesized in the nerve terminal by the enzyme cholineacetyltransferase, which catalyzes the reaction between acetylcoenzyme A and choline (Figure 12-1). After its release, acetylcholine is rapidly hydrolyzed by acetylcholinesterase (true cholinesterase) into acetate and choline.
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Acetylcholine is the neurotransmitter for the entire parasympathetic nervous system (parasympathetic ganglions and effector cells), parts of the sympathetic nervous system (sympathetic ganglions, adrenal medulla, and sweat glands), some neurons in the central nervous system, and somatic nerves innervating skeletal muscle (Figure 12-2).
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Cholinergic receptors have been subdivided into two major groups based on their reaction to the alkaloids muscarine and nicotine (Figure 12-3). Nicotine stimulates the autonomic ganglia and skeletal muscle receptors (nicotinic receptors), whereas muscarine activates end-organ effector cells in bronchial smooth muscle, salivary glands, and the sinoatrial node (muscarinic receptors). The central nervous system has both nicotinic and muscarinic receptors. Nicotinic receptors are blocked by muscle relaxants (also called neuromuscular blockers), and muscarinic receptors are blocked by anticholinergic drugs, such as atropine. Although nicotinic and muscarinic receptors differ in their response to some agonists (eg, nicotine, muscarine) and some antagonists (eg, vecuronium vs atropine), they both respond to acetylcholine (Table 12-1). Clinically available cholinergic agonists resist hydrolysis by cholinesterase. Methacholine and bethanechol are primarily muscarinic agonists, whereas carbachol has both muscarinic and nicotinic agonist activities. Methacholine by inhalation has been used as a provocative test in asthma, bethanechol is used for bladder atony, and carbachol may be used topically for wide-angle glaucoma.
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When reversing neuromuscular blockade, the primary goal is to maximize nicotinic transmission with a minimum of muscarinic side effects.
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Normal neuromuscular transmission critically depends on
acetylcholine binding to nicotinic 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 (
spontaneous reversal), often assisted by the administration of specific reversal agents (
pharmacological reversal). Cholinesterase inhibitors
indirectly increase the amount of
acetylcholine available to compete with the nondepolarizing agent, thereby reestablishing normal neuromuscular transmission.
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Cholinesterase inhibitors inactivate acetylcholinesterase by reversibly binding to the enzyme. The stability of the bond influences the duration of action. The electrostatic attraction and hydrogen bonding of edrophonium are short-lived; the covalent bonds of neostigmine and pyridostigmine are longer lasting.
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Organophosphates, a special class of cholinesterase 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 adjustments. Thus, the normally short duration of action of edrophonium can be partially overcome by increasing the dosage. Cholinesterase inhibitors are also used in the diagnosis and treatment of myasthenia gravis.
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Mechanisms of action other than acetylcholinesterase inactivation may contribute to the restoration 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).
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In excessive doses, acetylcholinesterase inhibitors paradoxically potentiate a nondepolarizing neuromuscular blockade. Standard dogma states that
neostigmine in high doses may cause receptor 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 pseudocholinesterase activity.
Neostigmine and to some extent
pyridostigmine display some limited pseudocholinesterase-inhibiting activity, but their effect on acetylcholinesterase is much greater.
Edrophonium has little or no effect on pseudocholinesterase. In large doses,
neostigmine can cause a weak depolarizing neuromuscular blockade.
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Clinical Pharmacology
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General Pharmacological Characteristics
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The increase in acetylcholine caused by cholinesterase inhibitors affects more than the nicotinic receptors of skeletal muscle (Table 12-2). Cholinesterase inhibitors can act at cholinergic receptors of several other organ systems, including the cardiovascular and gastrointestinal systems.
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- Cardiovascular receptors—The predominant muscarinic effect on the heart is bradycardia that can progress to sinus arrest.
- Pulmonary receptors—Muscarinic stimulation can result in bronchospasm (smooth muscle contraction) and increased respiratory tract secretions.
- Cerebral receptors—Physostigmine is a cholinesterase inhibitor that crosses the blood-brain barrier and can cause diffuse activation of the electroencephalogram by stimulating muscarinic and nicotinic receptors within the central nervous system. Inactivation of nicotinic acetylcholine receptors in the central nervous system may play a role in the action of general anesthetics. Unlike physostigmine, cholinesterase inhibitors used to reverse neuromuscular blockers do not cross the blood-brain barrier.
- Gastrointestinal receptors—Muscarinic stimulation increases peristaltic activity (esophageal, gastric, and intestinal) and glandular secretions (eg, salivary). Postoperative nausea, vomiting, and fecal incontinence have been attributed to the use of cholinesterase inhibitors.
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Unwanted muscarinic side effects are minimized by prior or concomitant administration of anticholinergic medications, such as atropine sulfate or glycopyrrolate. The duration of action is similar among the cholinesterase inhibitors. Clearance is due to both hepatic metabolism (25% to 50%) and renal excretion (50% to 75%).

Thus, any prolongation of action of a nondepolarizing muscle relaxant from renal or hepatic insufficiency will probably be accompanied by a corresponding increase in the duration of action of a cholinesterase inhibitor.
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As a rule, no amount of cholinesterase inhibitor can immediately reverse a block that is so intense that there is no response to tetanic peripheral nerve stimulation. Moreover, the absence of any palpable single twitches following 5 sec of tetanic stimulation at 50 Hz implies a very intensive blockade that cannot be reversed. Excessive doses of cholinesterase inhibitors may actually prolong recovery. Some evidence of spontaneous recovery (ie, the first twitch of the train-of-four [TOF]) should be present before reversal is attempted. The posttetanic count (the number of palpable twitches after tetanus) generally correlates with the time of return of the first twitch of the TOF and therefore the ability to reverse intense paralysis. For intermediate-acting agents, such as atracurium and vecuronium, a palpable posttetanic twitch appears about 10 min before spontaneous recovery of the first twitch of the TOF. In contrast, for longer-acting agents, such as pancuronium, the first twitch of the TOF appears about 40 min after a palpable posttetanic twitch.
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The time required to fully reverse a nondepolarizing block depends on several factors, including the choice and dose of cholinesterase inhibitor administered, the muscle relaxant being antagonized, and the extent of the blockade before reversal. For example, reversal with
edrophonium is usually faster than with
neostigmine; large doses of
neostigmine lead to faster reversal than small doses; intermediate-acting relaxants reverse sooner than long-acting relaxants; and a shallow block is easier to reverse than a deep block (ie, twitch height >10%). Intermediate-acting muscle relaxants therefore require a lower dose of reversal agent (for the same degree of blockade) than long-acting agents, and concurrent excretion or metabolism provides a proportionally faster reversal of the short- and intermediate-acting agents. These advantages can be lost in conditions associated with severe end-organ disease (eg, the use of
vecuronium in a patient with liver failure) or enzyme deficiencies (eg,
mivacurium in a patient with homozygous atypical pseudocholinesterase). Depending on the dose of muscle relaxant that has been given, spontaneous recovery to a level adequate for pharmacological reversal may take more than 1 hr with long-acting muscle relaxants because of their insignificant metabolism and slow excretion. Factors associated with faster reversal are also associated with a lower incidence of residual paralysis in the recovery room and a lower risk of postoperative respiratory complications.
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A reversal agent should be routinely given to patients who have received nondepolarizing muscle relaxants unless full reversal can be demonstrated or the postoperative plan includes continued intubation and ventilation. In the latter situation, adequate sedation must also be provided.
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A peripheral nerve stimulator should also be used to monitor the progress and confirm the adequacy of reversal. In general, the higher the frequency of stimulation, the greater the sensitivity of the test (100-Hz tetany > 50-Hz tetany or TOF > single-twitch height). Clinical signs of adequate reversal also vary in sensitivity (sustained head lift > inspiratory force > vital capacity > tidal volume).

Therefore, the suggested end points of recovery are sustained tetanus for 5 sec in response to a 100-Hz stimulus in anesthetized patients or sustained head or leg lift in awake patients. Newer quantitative methods for assessing recovery from neuromuscular blockade, such as acceleromyography, may further reduce the incidence of residual postoperative neuromuscular paralysis.