Morgan & Mikhail Chap 12(Cholinesterase Inhibitors) Flashcards
Cost of Not Reversing NMBs
Incomplete reversal of neuromuscular blocking agents and residual postprocedure paralysis are associated with morbidity and increased perioperative cost; therefore, careful assessment of neuromuscular blockade and appropriate pharmacological
antagonism are strongly recommended whenever muscle relaxants are administered. The primary clinical use of cholinesterase inhibitors is to reverse nondepolarizing neuromuscular blockers. Some of these agents are also used to diagnose and treat
myasthenia gravis.
Cholinergic Pharmacology
The term cholinergic refers to the effects of the neurotransmitter acetylcholine.
Acetylcholine is the neurotransmitter for the entire parasympathetic nervous system (parasympathetic ganglia and effector cells), parts of the sympathetic nervous system (sympathetic ganglia, adrenal medulla, and sweat glands), some neurons in the
central nervous system, and somatic nerves innervating skeletal muscle
Characteristics of cholinergic receptors
MECHANISM OF ACTION
Normal neuromuscular transmission depends on acetylcholine binding to nicotinic cholinergic receptors on the motor end-plate. Nondepolarizing muscle relaxants compete with acetylcholine for these binding sites, thereby blocking neuromuscular
transmission. Reversal of blockade depends on 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.
The clinical duration of the cholinesterase inhibitors used in anesthesia is probably most influenced by the rate of drug disappearance from the plasma.
Acetylcholinesterase inhibitors prolong the depolarization blockade by succinylcholine.
CLINICAL PHARMACOLOGY
General Pharmacological Characteristics
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 neuromuscular blockade before reversal.
A reversal agent should be routinely given to patients who have received
nondepolarizing muscle relaxants unless full recovery can be demonstrated or the
postoperative plan includes continued intubation and ventilation. In the latter situation, adequate sedation must also be provided.
A peripheral nerve stimulator should also be used to monitor the progress
and confirm the adequacy of reversal
NEOSTIGMINE
Neostigmine consists of a carbamate moiety and a quaternary ammonium group (Figure 12–4). The former provides covalent bonding to acetylcholinesterase. The latter renders the molecule lipid insoluble, so it cannot pass through the blood–brain barrier.
Dosage & Packaging
The maximum recommended dose of neostigmine is 0.08 mg/kg (up to 5 mg in adults),
but smaller amounts often suffice, and larger doses have also been given safely (Table
12–3). Neostigmine is most commonly packaged as 10 mL of a 1 mg/mL solution,
though 0.5 mg/mL and 0.25 mg/mL concentrations are also available.
The effects of neostigmine (0.04 mg/kg) are usually apparent in 5 min, peak at 10 min, and last more than 1 h. In practice, some clinicians use a dose of 0.04 mg/kg (or 2.5 mg) if the preexisting blockade is mild to moderate and a dose of 0.08 mg/kg (or 5 mg) if intense paralysis is being reversed; other clinicians use the “full dose” for all patients.
The duration of action is prolonged in geriatric patients. Muscarinic side effects are minimized by prior or concomitant administration of an anticholinergic agent.
Cholinesterase Inhibitor Dosing
Pyridostigmine
Look at in book
Digital - page 364
Handbook - page 96
Edrophonium
Edrophonium is less than 10% as potent as neostigmine. The recommended dosage is
0.5 to 1 mg/kg.
Edrophonium has the most rapid onset of action (1–2 min) and the shortest duration of effect of any of the cholinesterase inhibitors. Reduced doses should not be used because longer-acting muscle relaxants may outlast the effects of edrophonium.
Higher doses prolong the duration of action to more than 1 h. Edrophonium may not be as effective as
neostigmine at reversing intense neuromuscular blockade.
PHYSOSTIGMINE
Look up in book
Digital - page 365
Handbook - page 97
Other Considerations
SUGAMMADEX
Sugammadex is a novel selective relaxant-binding agent that is rapidly supplanting neostigmine as the preferred agent for reversal of nondepolarizing neuromuscular blockade.
Sugammadex is largely eliminated unchanged via the kidneys and does not require coadministration of an antimuscarinic agent.
Sugammadex has been administered in doses of 4 to 8 mg/kg. With an injection of 8 mg/kg, given 3 min after administration of 0.6 mg/kg of rocuronium, recovery of trainof- four ratio to 0.9 was observed within 2 min. It produces a rapid and effective reversal of both shallow and profound rocuronium-induced neuromuscular blockade in
a consistent manner.
Sugammadex is most effective in the reversal of rocuronium; however, it will bind other steroidal neuromuscular blockers, including vecuronium and pancuronium.
CALABADION
Calabadions prevent muscle relaxant binding to the nicotinic receptor.
Calabadions are
currently under investigation.
L-CYSTEINE
L-cysteine is an endogenous amino acid that is often added to total parenteral
nutrition regimens to enhance calcium and phosphate solubility.
The ultrashort-acting
neuromuscular blocker, gantacurium, and other fumarates rapidly combine with Lcysteine in vitro to form less active degradation products (adducts).
Exogenous administration of L-cysteine (10–50 mg/kg intravenously) given to anesthetized monkeys 1 min after these neuromuscular blocking agents abolished the block within 2 to 3 min; this antagonism was found to be superior to that produced by
anticholinesterases.
This unique method of antagonism by adduct formation and inactivation is still in the investigative stage, especially in terms of its safety and efficacy in humans.
