Neuromuscular Blocking and Reversal Agents

Choice of Neuromuscular Blocking Agent

The choice of NMBA is influenced by its speed of onset, duration of action, route of elimination, and associated adverse effects. The rapid onset and brief duration of skeletal muscle paralysis, characteristic of SCh-induced NMB, are useful when tracheal intubation is the only reason for administering an NMBA. Although SCh could be given intermittently for shorter procedures, doing so is associated with an increased risk of bradycardia, asystolic cardiac arrest, and prolonged duration of NMB. For intubation and maintenance of NMB, administration of short- or intermediate-acting nondepolarizing NMBAs may be appropriate. The choice of long-, intermediate-, or short-acting agent will depend on the duration of NMB that is necessary and the anticipated means of administration of the NMBA (intermittent boluses or an infusion). The choice of specific NMBA in each of these categories will also depend on availability of the NMBA, the presence of patient comorbidities, and plans for antagonism of residual NMB.

Prejunctional Receptors and Release of Acetylcholine

Cholinergic receptors are found presynaptically, at the motor nerve terminal, and at the postsynaptic region of the NMJ. The prejunctional receptors are involved in the modulation of the release of ACh into the NMJ. Prejunctional nicotinic receptors are activated by ACh and are believed to function in a positive-feedback control system that serves to maintain the availability of ACh when demand for it is high. They are involved with the mobilization of ACh, but not the actual process of its release.

Presynaptic receptors, aided by calcium, facilitate replenishment of the motor nerve terminal. In addition to being stimulated by ACh, they are stimulated by SCh and neostigmine and depressed by small doses of nondepolarizing NMBAs. Inhibition of these presynaptic nAChRs explains the fade in response to high-frequency repetitive stimulation such as tetanic or even train-of-four (TOF) stimulation.

Postjunctional Receptors

The postjunctional, mature AChR is an intrinsic membrane glycoprotein with five distinct subunits ( Fig. 11.2 ): two α, one β, one δ, and one ε. The α-subunits contain the major portion of the ACh receptor binding site. Each of the subunits contains four helical domains, M1 to M4, that traverse the cell membrane. The ion channel of each subunit has permeability that is equal to that of Na ⁺ and K ⁺ , allowing for the flow of ions across the cell membrane along their concentration gradients, with Na ⁺ entering and K ⁺ leaving the muscle cell. Calcium contributes ≈2.5% to the total permeability. This flow of ions is the basis of normal neuromuscular transmission. There are two distinct pockets for binding of ACh formed by the N and C termini of the protein. One occurs at the intersection of the α to ε subunits and the other at the intersection of the α to δ subunits. These binding sites have different affinities for different NMBAs. Occupation of one or both α-subunits by a nondepolarizing NMBA causes the ion channel to remain closed, in spite of the release of ACh from the prejunctional neuron so that the ion flow to produce depolarization cannot occur. SCh binds to the AChR binding sites and acts as an agonist, causing the ion channel to remain open (mimicking ACh) and resulting in prolonged depolarization. Its duration of action is longer than that of ACh because it remains in the NMJ available to bind to the AChR until it diffuses away from the NMJ, where it is metabolized by butyrylcholinesterase. SCh is not a metabolite for AChE.

Nondepolarizing NMBAs may, in addition to competitively binding to the AChR, inhibit neuromuscular transmission by occluding the AChR channel preventing the normal flow of ions required for subsequent depolarization. NMB secondary to occlusion of channels is resistant to drug-enhanced antagonism with anticholinesterase drugs. The lipid environment around cholinergic receptors can be altered by volatile anesthetics, which change the properties of the ion channels. This may account in part for the augmentation of NMB by volatile anesthetics.

Extrajunctional Receptors

Extrajunctional receptors are different in structure than the postjunctional nAChRs. They retain the two α-subunits but have γ-unit replacing the ε-subunit. Additionally, whereas postjunctional receptors are confined to the area of the end plate of skeletal muscle that is opposite the prejunctional motor neurons (as a component of the motor end plate), extrajunctional receptors are present throughout skeletal muscles. Extrajunctional receptor synthesis is normally suppressed by neural activity. Prolonged inactivity, sepsis, skeletal muscle denervation, burn injury, or trauma may be associated with a proliferation of extrajunctional receptors. When activated, extrajunctional receptors stay open longer and permit more ions to flow across the muscle cell membrane, which in part explains the exaggerated hyperkalemic response when SCh is administered to patients with denervation or burn injury. Proliferation of these receptors also accounts for the resistance or tolerance to nondepolarizing NMBAs, which can be observed in patients with burns or prolonged immobilization. ^,

Characteristics of Blockade

SCh mimics the action of ACh and produces a sustained depolarization of the postjunctional membrane. Skeletal muscle paralysis occurs because a depolarized postjunctional membrane and inactivated sodium channels cannot respond to subsequent release of ACh. Depolarizing NMB is also referred to as phase I blockade . Phase II blockade is present when the postjunctional membrane has become repolarized but still does not respond normally to ACh (desensitization NMB). The mechanism of phase II blockade is unknown but may reflect the development of nonexcitable areas around the end plates that become repolarized but unable to promote the spread of impulses initiated by ACh. With the initial dose of SCh, subtle signs of a phase II blockade begin to appear (fade to tetanic stimulation). Phase II blockade, which resembles the blockade produced by nondepolarizing NMBAs, predominates when the intravenous dose of SCh exceeds 3 to 5 mg/kg.

Pharmacodynamics

SCh is the only depolarizing NMBA used clinically. Its mechanism of action and its relatively rapid metabolism ( Fig. 11.4 ) are responsible for its unique pharmacodynamic properties, which include both a rapid onset and an ultrashort duration of action. Typically, doses of 0.5 to 1.5 mg/kg are administered intravenously to produce a rapid onset of skeletal muscle paralysis (30 to 60 seconds) that lasts 5 to 10 minutes. These pharmacodynamic characteristics are useful in a compound that is administered to facilitate tracheal intubation. SCh has been used clinically for more than 60 years, and despite consistent industrial efforts, no NMBA has been developed that has these pharmacodynamic properties. Although an intravenous dose of 0.5 mg/kg may be adequate, larger doses are commonly administered to facilitate tracheal intubation. If a subparalyzing dose of a nondepolarizing NMBA (pretreatment with 5% to 10% ED95—the dose that, on average, will cause 95% suppression of muscle response to neural stimulation) is administered 2 to 4 minutes before administration of SCh to blunt fasciculations, the dose of SCh should be increased by about 70%. It is important to remember that the administration of even small, precurarizing or defasciculating doses of NMBAs can cause symptomatic muscle weakness and put patients at risk of difficulty breathing or swallowing.

The sustained depolarization produced by the initial administration of SCh is initially manifested as transient generalized skeletal muscle contractions known as fasciculations . The sustained opening of sodium channels produced by SCh is associated with leakage of potassium from the interior of cells sufficient to increase plasma concentrations of potassium by about 0.1 to 0.4 mEq/L in a healthy patient. In patients with denervation, burns, or trauma, where there is likely to be proliferation of extrajunctional nAChRs and damaged muscle membranes, many more channels will leak potassium, causing hyperkalemia.

Metabolism

Hydrolysis of SCh to inactive metabolites is accomplished by plasma cholinesterase (pseudocholinesterase, butyrylcholinesterase), which is produced in the liver. Plasma cholinesterase has an enormous capacity to hydrolyze SCh at a rate rapid enough that only a small fraction of the original intravenous dose of SCh reaches the NMJ. Because plasma cholinesterase is not present at the NMJ, the NMB produced by SCh is terminated by its diffusion from the NMJ into plasma. Therefore plasma cholinesterase influences the duration of action of SCh by controlling the amount of SCh that is hydrolyzed before it reaches the NMJ. Liver disease must be severe before decreases in the synthesis of plasma cholinesterase are sufficient to prolong the effects of SCh. Anticholinesterases, as used in the treatment of myasthenia gravis, and certain chemotherapeutic drugs (nitrogen mustard, cyclophosphamide) may decrease plasma cholinesterase activity enough that prolonged skeletal muscle paralysis follows the administration of SCh.

Adverse Side Effects

In spite of its utility in facilitating tracheal intubation, SCh has many adverse effects ( Box 11.1 ). Adverse side effects after the administration of SCh are numerous and may limit or even contraindicate the use of this NMBA in certain patients. SCh should not be given to patients more than 24 hours after major burns, trauma, and extensive denervation of skeletal muscles because it may cause acute hyperkalemia and cardiac arrest. When administered to boys with unrecognized muscular dystrophy, SCh has resulted in acute hyperkalemia and cardiac arrest. Because of this, the U.S. Food and Drug Administration (FDA) issued a warning against the use of SCh in children, except for emergency control of the airway. When administered with volatile anesthetics in susceptible patients it can trigger malignant hyperthermia.