13: Muscle Relaxants and Monitoring of Relaxant Activity

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CHAPTER 13 Muscle Relaxants and Monitoring of Relaxant Activity

James Duke, MD, MBA

1 Describe the anatomy of the neuromuscular junction

A motor nerve branches near its terminus to contact many muscle cells, losing myelin to branch further and come into closer contact with the junctional area of the muscle surface. Within the most distal aspect of the motor neuron, vesicles containing the neurotransmitter acetylcholine (ACh) can be found. The terminal neuron and muscle surface are loosely approximated with protein filaments, and this intervening space is known as the junctional cleft. Also contained within the cleft is extracellular fluid and acetylcholinesterase, the enzyme responsible for metabolizing ACh. The postjunctional motor membrane is highly specialized and invaginated, and the shoulders of these folds are rich in ACh receptors (Figure 13-1).

image

Figure 13-1 The neuromuscular junction.

(From Kandel ER, Schwartz JH, Jessel TM, editors: Principles of neural science, ed 3, New York, 1991, Elsevier, p 136.)

2 What is the structure of the acetylcholine receptor?

The ACh receptor is contained within the motor cell membrane and consists of five glycoprotein subunits: two alpha and one each of β, δ, and ε. These are arranged in a cylindric fashion; the center of the cylinder is an ion channel. ACh binds to the α-subunits.

3 With regard to neuromuscular transmission, list all locations for acetylcholine receptors

ACh receptors are found in several areas:

image About 5 million ACh receptors per neuromuscular junction (NMJ) are located on the postjunctional motor membrane.
image Prejunctional receptors are present and influence the release of ACh. The prejunctional and postjunctional receptors have different affinities for ACh.
image Extrajunctional receptors are located throughout the skeletal muscle in relatively low numbers owing to suppression of their synthesis by normal neural activity. In cases of traumatized skeletal muscle or denervation injuries, these receptors proliferate.

4 Review the steps involved in normal neuromuscular transmission

image A nerve action potential is transmitted, and the nerve terminal is depolarized.
image ACh is released from storage vesicles at the nerve terminal. Enough ACh is released to bind 500,000 receptors.
image ACh molecules bind to the α-subunits of the ACh receptor on the postjunctional membrane, generating a conformational change and opening receptor channels. Receptors do not open unless both α-receptors are occupied by ACh (a basis for the competitive antagonism of nondepolarizing relaxants).
image Sodium and calcium flow through the open receptor channel generating an end-plate potential.
image When between 5% and 20% of the receptor channels are open and a threshold potential is reached, a muscle action potential (MAP) is generated.
image Propagation of the MAP along the muscle membrane leads to muscle contraction.
image The rapid hydrolysis of ACh by acetylcholinesterase (true cholinesterase) within the synaptic cleft and return of normal ionic gradients return the NMJ to a nondepolarized, resting state, and the ACh receptors are closed.

5 What are the benefits and risks of using muscle relaxants?

By interfering with normal neuromuscular transmission, these drugs paralyze skeletal muscle and can be used to facilitate endotracheal intubation, assist with mechanical ventilation, and optimize surgical conditions. Occasionally they may be used to reduce the metabolic demands of breathing and facilitate the treatment of raised intracranial pressure (ICP). Because they paralyze all respiratory muscles, they are dangerous drugs to use in the unintubated patient unless the caregiver is trained in airway management.

6 How are muscle relaxants classified?

image Depolarizing relaxants: Succinylcholine (SCH) is two molecules of ACh bound together, an agonist at the NMJ, and the only depolarizing relaxant available clinically. As such, SCH binds to the α-subunits of the ACh receptor. After binding, SCH can open the ion channel and depolarize the end plate. Although SCH, like ACh, binds only briefly to the receptor, it is not hydrolyzed in the synaptic cleft by acetylcholinesterase. In fact, SCH molecules may unbind and rebind receptors repeatedly. SCH must diffuse away and be broken down in the plasma by enzymes called plasma- or pseudocholinesterase, and time for clearance from the body is an accurate measure of its duration of effect.
image Nondepolarizing relaxants: These drugs are competitive antagonists to ACh at the postsynaptic membrane. They need only bind to one of the two α-subunits to prevent opening of the ionic pore.

7 What are the indications for using succinylcholine?

SCH provides the most rapid onset and termination of effect of any neuromuscular blocker (NMB) currently available. Its onset is 60 to 90 seconds, and the duration of effect is only 5 to 10 minutes. When the patient has a full stomach and is at risk for pulmonary aspiration of gastric contents, rapid paralysis and airway control are priorities, and SCH is often the drug indicated. (Rocuronium when given in large doses also has a SCH-like onset of action, although a prolonged duration of effect would contraindicate its use in patients likely to be difficult to ventilate or intubate.) Patients at risk for full stomachs include those with diabetes mellitus, hiatal hernia, obesity, pregnancy, severe pain, bowel obstructions, and trauma.

8 If succinylcholine works so rapidly and predictably, why not use it all the time?

SCH has numerous side effects:

image SCH stimulates both nicotinic and muscarinic cholinergic receptors. Stimulation of muscarinic receptors within the sinus node results in numerous bradyarrhythmias, including sinus bradycardia, junctional rhythms, ventricular escape and asystole.
image SCH is a trigger for malignant hyperthermia.
image Prolonged exposure of the receptors to SCH results in persistent open receptor channel and ionic fluxes through the ion pore, known as phase II or desensitization blockade. Normal depolarization/repolarization is not possible until SCH is metabolized.
image In patients ambulatory soon after surgery, random generalized muscle contractions (fasciculations) have been associated with painful myalgias. Whether pretreating with a subparalyzing dose of a nondepolarizing relaxant before SCH is effective in reducing myalgias continues to be a matter of debate.
image SCH increases ICP. The etiology is not completely understood, but it is known that a subparalyzing dose of a nondepolarizing relaxant before SCH administration reduces the increase in ICP; thus perhaps fasciculations are the cause of the increase in ICP.
image In the presence of immature extrajunctional receptors, administration of SCH may result in severe hyperkalemia and malignant ventricular arrhythmias. Extrajunctional receptors are normally suppressed by activity. Any condition that decreases motor-nerve activity results in a proliferation of these receptors. Examples include spinal cord and other denervation injuries, upper and lower motor neuron disease, closed head injuries, burns, neuromuscular diseases, and even prolonged immobility.
image SCH increases intraocular pressure (IOP). There is a theoretic risk for the use of SCH in patients with open eye injury (i.e., extrusion of extraocular contents). However, the increases in IOP are modest, and from a clinical perspective extrusion of ocular contents has not been observed. Certainly if a nondepolarizing agent is administered instead of SCH and the patient is intubated before optimal intubating conditions, coughing on the endotracheal tube (called “bucking”) increases IOP significantly and puts the patient at risk for extruding ocular contents.

9 How do mature and immature acetylcholine receptors differ?

Mature ACh receptors are also known as innervated or ε-containing receptors (because of the ε-subunit within the ACh receptor. They are tightly clustered at the NMJ and are responsible for normal neuromuscular activation. Immature receptors, also known as fetal, extrajunctional, or γ-receptors, differ from the mature receptors in that they are present during fetal development and suppressed by normal activity, are dispersed across the muscular membrane rather than localized at the NMJ, and have a γ-, not an ε-subunit as part of the receptor. The half-life of mature receptors is about 2 weeks, whereas the half-life of immature receptors is less than 24 hours. The immature receptors depolarize more easily in the presence of ACh or SCH and thus are more prone to release potassium. Also, once depolarized, immature receptors tend to stay open longer. Immature receptors are up-regulated in the presence of denervation injuries, burns, and the like. This also exaggerates the potential for hyperkalemia when SCH is administered.

10 Differentiate between qualitative and quantitative deficiencies in pseudocholinesterase

Pseudocholinesterase is produced in the liver and circulates in the plasma. Quantitative deficiencies of pseudocholinesterase are observed in liver disease, pregnancy, malignancies, malnutrition, collagen vascular disease, and hypothyroidism; they slightly prolong the duration of blockade with SCH. However, from a practical standpoint the increase in duration of SCH is probably not clinically important.

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