Chapter 12 Neuromuscular Blocking Drugs

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euromuscular blocking drugs (NMBDs) interrupt transmission of nerve impulses at

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the neuromuscular junction (NMJ) and thereby produce paresis or paralysis of skeletal muscles.

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Two principal clinical uses of NMBDs are to

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produce skeletal muscle relaxation for facilitation of tracheal intubation and to provide optimal surgical working conditions.

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The NMJ consists of a

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prejunctional motor nerve ending separated from the highly folded postjunctional membrane of the skeletal muscle by a synaptic cleft.

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Neuromuscular transmission is initiated by

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arrival of an impulse at the motor nerve terminal with an associated influx of calcium ions and resultant release of the ligand ACh.

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ACh binds to

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nicotinic cholinergic receptors (the ligand-gated channel) on postjunctional membranes and thereby causes a change in membrane permeability to ions, principally potassium and sodium.

his change in permeability and movement of ions causes a decrease in the transmembrane potential from about -90 m V to --45 m V (threshold potential), at which point a propagated action potential spreads over the surfaces of skeletal muscle fibers and leads to muscular contraction.

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ACh is rapidly hydrolyzed

time and by what process

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(within 15 msec) by the enzyme acetylcholinesterase (true

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Acetylcholinesterase is primarily

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located in the folds of the end-plate region, which places it in close proximity to the site of action of ACh.

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ACh is synthesized in the

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motor nerve terminal

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facilitate replenishment of the motor nerve terminal of ACh

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Presynaptic receptors, aided by calcium, facilitate replenishment of the motor nerve terminal, which can be stimulated by SCh and neostigmine and depressed by small doses of noncepolarizing NMBDs.

Front 10

Postjunctional receptors are

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glycoproteins consisting of five subunits

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the subunits of the receptor are arranged such that

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a channel is formed that allows the flow of ions along a concentration gradient across cell membranes.

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____________ are the binding sites for ACh and the sites occupied by NMBDs

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The two a-subunits

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Postjunctional receptors are confined to the area of the end plate precisely opposite the prejunctional receptors, whereas extrajunctional receptors are present

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throughout skeletal muscles.

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Extrajunctional receptor synthesis is normally suppressed by

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neural activity.

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associated with a proliferation of extrajunctional receptors.

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Prolonged inactivity, sepss, and denervarion or trauma (burn injury) to skeletal muscles may be associated with a proliferation of extrajunctional receptors.

When activated, extrajunctional receptors stay open longer and permit more ions to flow, which in part explains the t< exaggerated hyperkale:nic response when SCh is administered to patients with denervation or burn injury. II

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most closely related to ACh structurally.

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Pancuronium is the bisquatemary aminosteroid NMBD most closely related to ACh structurally.

The ACh-like fragments of pancuronium give the steroidal g molecule its high degree of neuromuscular blocking activity.

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subparalyzing dose of a nondepolarizing

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NMBD (pretreatment with 5% to 10% of its 95% effective dose [ED95]) is administered 2 to 4 minutes before injection of SCh to bhlllt fasciculations, the dose of SCh should be increased by about 70%

Front 18

Skeletal muscle paralysis occurs because

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a depolarized postjunctional membrane and inactivated sodium channels cannot respond to subsequent release of ACh

Front 19

Hydrolysis of SCh to inactive metabolites is accomplished by

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plasma cholinesterase (pseudocholinesterase) plasma cholinesterase has an enormous capacity to hydrolyze SCh at a rapid rate (ACh is metabolized even more rapidly) such that only a small fraction of the original intravenous dose reaches the NMJ.

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3ecause plasma cholinesterase is not present at the NM], the neuromuscular blockade produced by SCh is terminated by

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its diffusion away from the NMJ into extracellular fluid.

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Sinus bradycardia, junctional rhythm, and even sinus arrest may follow the administration of SCh. These responses reflect the action of SCh at

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cardiac postganglionic muscarinic receptors, where this drug mimics the normal effects of ACh

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MYALGIA

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Postoperative skeletal muscle myalgia, manifested particulady in the muscles of the neck, back, and abdomen, may follow the administration of SCh.

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SCh causes a maximum increase in intraocular pressure

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2 to 4 minutes after its administration.

his increase in intraocular pressure is transient and lasts only 5 to 10 minutes.

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TRISMUS is

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Incomplete jaw relaxation with masseter jaw rigidity after a halothane-SCh sequence is not uncommon in children (occurs in about 4.4% of patients) and is considered a normal response

Because SCh 1S not recommended for use in children, except for emergency airway control, trismus is less of an issue.

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Nondepolarizing NMBDs are classified clinically as long, intermediate, and short acting. These drugs act by

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competing with ACh for a-subunits at the postjunctional nicotinic cholinergic receptors and preventing changes in ion permeability.

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Renal disease markedly alters the pharmacokinetics of

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only the long-acting nondepolarizing NMBDs, such as pancuronium. The intermediate-acting NMBDs are eliminated by the liver (rocuronium), by metabolism by plasma cholinesterase (rnivacurium), by Hofmann elimination (atracuriurr. or cisatracurium), or by a combination of these mechanisms.

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Pancuronium elemination

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80% of a single dose of pancuronium is eliminated . unchanged in urine.

n the presence of renal failure, plasma clearance of pancuronium is decreased 30% to 50%, thus resulting in a prolonged duration of action.

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Pancuronium CARDIOVASCULAR EFFECTS

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Pancuronium typically produces a modest 10% to 15% increase in heart rate, mean arterial pressure, and cardiac output. The increase in heart rate reflects pancuroniuminduced selective blockade of cardiac muscarinic : receptors (atropine-like effect), principally in the sinoatrial node.

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Vecuronium metabolism

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This drug undergoes both hepatic and renal excretion.

he effect of renal failure on the duration of action of vecuronium is small, but repeated or large doses may result in prolonged euromuscular blockade.

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Atracurium Clearance

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this drug is by a chemical mechanism (spontaneous . nonenzymatic degradation at normal body temperature and pH known as Hofmann elimination) and a biologic mechanism (ester hydrolysis by nonspecific plasma esterases).

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Cisatracurium elimination

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This drug principally undergoes degradation by Hofmann elimination to laudanosine.

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muscle is innervated solely by the ulnar nerve, which accounts for the popularity of placing stimulating electrodes from the peripheral nerve stimulator over the ulnar nerve

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adductor pollicis muscle

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Facial nerve stimulation and observation of the

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orbicularis oculi muscle

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correlates with acceptable skeletal muscle relaxation for performance of intra-abdominal surgery in the presence of an adequate concentration of volatile anesthetic.

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Depression of the twitch response greater than 90% or elimination of two to three twitches of the TOF

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TOF concept

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TOF (four electrical stimulations at 2 Hz delivered every 0.5 second) is based on the concept that ACh is depleted by successive stimulations.

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TETANUS

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Tetanus (continuous or tetanic electrical stimulation for 5 seconds at about 50 Hz) is an intense stimulus for the release of ACh at the NMJ.

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· Even if all tests of the adequacy of normal neuromuscular function are normal, ____________ of the receptors at the NMJ may ,till be occupied by an NMBD.

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50%

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Anticholinesterase drugs, such as neostigmine, accelerate the already established pattern of spontaneous recovery at the NMJ by inhibiting the activity of acetyl- · cholinesterase and thereby leading to the

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accumulation of ACh at nicotinic (NMD and muscarinic sites.

ncreased amounts of ACh in the region of the NMJ improve the . chance that two ACh molecules will bind to the (Xsubunits of the nicotinic cholinergic receptors (see Fig. 12-2). This alters the balance of the competition between ACh and a nondepolarizing NMBD in favor of the neuro- , transmitter (ACh) and restores neuromuscular transmission.