Neuromuscular Blocking Agents

2. Propagation of the action potential initiates release of calcium from the sarcoplasmic reticulum, where activation of myosin adenosine triphosphate leads to excitation–contraction coupling of the myofilaments.

3. ACh is hydrolyzed (within milliseconds to prevent prolonged depolarization) by acetylcholinesterase (true cholinesterase) to choline, which is reused for synthesis of new ACh, and acetate.

E. Presynaptic Events

1. The release of ACh normally decreases during high-frequency stimulation under physiologic conditions because the pool of readily releasable ACh becomes depleted faster than it can be replenished. In the presence of nondepolarizing NMBDs, this decreased release of ACh produces a progressive decrease in skeletal muscle response and a characteristic TOF and tetanic fade.

2. Succinylcholine (SCh) has virtually no effect on presynaptic receptors, explaining the lack of fade observed with this drug.

II. NEUROMUSCULAR BLOCKING AGENTS. NMBDs interact with the ACh receptor either by depolarizing the end plate (depolarizing agents) or by competing with ACh for binding sites (nondepolarizing agents) (Table 20-1). The only depolarizing agent in clinical use is SCh.

TABLE 20-1 DEFINITION OF NEUROMUSCULAR BLOCKING DRUGS ACCORDING TO THE ONSET AND DURATION OF BLOCK AT THE ADDUCTOR POLLICIS

A. Pharmacologic Characteristics of Neuromuscular Blocking Agents. The effect of NMBDs is measured as the depression of adductor muscle contraction (twitch) after electrical stimulation of the ulnar nerve.

1. Potency is determined by constructing the dose-response curves, which describe the relationship between twitch depression and dose. The effective dose 95 (ED₉₅) is a clinically relevant value that corresponds to 95% block of single twitch (half of patients will reach 95% block, and half will reach a lower percentage) (Fig. 20-2).

2. Onset time or time to maximum blockade can be shortened if the dose is increased (2 × ED₉₅).

3. Duration of action is the time from injection of the NMBD to return of 25% twitch height (comparisons are usually made at 2 × ED₉₅). Categories of NMBDs may be based on their durations of action.

4. Recovery index is the time interval between 25% and 75% twitch height (this reflects speed of recovery after return of twitch is manifest). The adductor pollicis is the most commonly monitored muscle for determining the onset and duration of action of NMBDs.

FIGURE 20-2. Example of a dose–response relationship. The ED₅₀ is the dose corresponding to 50% blockade, and ED₉₅ is the dose corresponding to 95% blockade.

III. DEPOLARIZING BLOCKING DRUGS: SUCCINYLCHOLINE. Succinylcholine (SCh) remains a useful muscle relaxant because of its ultra-rapid onset and short-duration neuromuscular blocking properties, which cannot be duplicated by any of the available nondepolarizing muscle relaxants.

A. Neuromuscular Effects. SCh binds to postsynaptic nicotinic receptors, where it exhibits ACh-like activity. SCh also binds to extrajunctional receptors and presynaptic receptors.

1. The net effect of SCh-induced depolarization is uncoordinated skeletal muscle activity that manifests clinically as fasciculations.

2. SCh predictably increases masseter muscle tone (this may be responsible for poor intubating conditions), and masseter muscle spasm may be associated with malignant hyperthermia. It is likely that increased masseter muscle tone is mediated by ACh receptors because it is blocked by nondepolarizing drugs.

TABLE 20-2 CHARACTERISTICS OF PHASE I DEPOLARIZING BLOCKADE

Decreased twitch amplitude

Absence of fade with continuous (tetanic) stimulation

Similar decreases in the amplitude of all twitches in the train-of-four ratio (>0.7)

Absence of posttetanic potentiation

Antagonism by nondepolarizing muscle relaxants

Augmentation by anticholinesterase drugs

3. Nonparalyzing doses of nondepolarizing drugs (pretreatment) block visible evidence of SCh-induced depolarization, suggesting that presynaptic receptors are principally involved in the production of fasciculations.

4. The blocking effect of SCh at the NMJ is probably attributable to desensitization (prolonged exposure to an agonist leads to a state characterized by a lack of responsiveness of the receptors).

B. Characteristics of Depolarizing Blockade

1. SCh initially produces features characterized as phase I block (Table 20-2).

2. Phase II block develops after prolonged exposure to SCh or high doses of SCh and has characteristics of a nondepolarizing neuromuscular blockade (Table 20-3). The onset of phase II block coincides with the appearance of tachyphylaxis to the effects of SCh.

C. Pharmacology of Succinylcholine

1. SCh is rapidly hydrolyzed (the elimination half-life of <1 minute) by plasma cholinesterase (pseudocholinesterase).

TABLE 20-3 CHARACTERISTICS OF THE NONDEPOLARIZING NEUROMUSCULAR BLOCKADE

Decreased twitch amplitude

Fade with continuous (tetanic) stimulation

Train-of-four ratio <0.7

Posttetanic potentiation

Absence of fasciculations

Antagonism by anticholinesterase drugs

Augmentation by other nondepolarizing muscle relaxants

FIGURE 20-3. Duration of action of neuromuscular blockade with 1 mg/kg of succinylcholine (Sux) and 1.2 mg/kg of rocuronium followed 3 minutes later by 16 mg/kg of sugammadex (Roc-sug).

2. The dose producing 95% blockade (ED₉₅) at the adductor pollicis is 0.3 to 0.5 mg/kg.

3. The time until full recovery at the adductor pollicis muscle is dose dependent and reaches 10 to 12 minutes after a dose of 1 mg/kg (Fig. 20-3).

D. Side Effects (Table 20-4)

E. Clinical Uses

1. The principal indication for SCh is to facilitate tracheal intubation (1 mg/kg intravenous [IV] is the usual dose, which is increased to 1.5–2.0 mg/kg IV if pretreatment is used).

2. SCh is especially indicated for “rapid sequence induction” when a patient presents with a full stomach and the possibility of aspiration of gastric contents (fast onset and brief duration allowing return of spontaneous breathing).

3. SCh (4 mg/kg intramuscular) is the only effective NMBD in children with difficult intravenous access and provides adequate intubating conditions in about 4 minutes.

IV. NONDEPOLARIZING DRUGS. Nondepolarizing NMBDs bind to postsynaptic to postsynaptic receptors (they must bind to one of the α subunits) in a competitive fashion to produce neuromuscular blockade.

A. Characteristics of Nondepolarizing Blockade (see Table 20-3). The fade observed in response to high-frequency stimulation is characteristic of nondepolarizing blockade.

TABLE 20-4 SIDE EFFECTS OF SUCCINYLCHOLINE

Bradycardia (especially in children; more likely in adults with second dose)

Allergic reactions

Fasciculations

Muscle pains (relationship to fasciculations not conclusively established)

Increased intragastric pressure (offset by even greater increase in lower esophageal sphincter pressure)

Increased intraocular pressure (caused by the cycloplegic action of succinylcholine and not reliably blunted by pretreatment)

Increased intracranial pressure (small effect and of questionable clinical significance)

Transient increase in plasma potassium concentration (a normal increase of 0.5–1.0 mEq/L is enhanced by denervation injuries, burns, extensive trauma, or unrecognized muscular dystrophy in boys)

Trigger for malignant hyperthermia (masseter muscle spasm may be an early sign)

Prolonged response in the presence of atypical cholinesterase or drug-induced inhibition of plasma cholinesterase activity (neostigmine but not edrophonium)

B. Pharmacokinetics (Table 20-5)

1. The pharmacokinetic variables derived from measurements of plasma concentrations of nondepolarizing muscle relaxants depend on the dose administered, the sampling schedule used, and the accuracy of the assay.

2. All nondepolarizing muscle relaxants have a volume of distribution that is approximately equal to extracellular fluid volume.

C. Onset and Duration of Action (Table 20-6)

1. Although peak plasma concentrations of nondepolarizing NMBDs occur within 1 minute of injection, the onset of maximum blockade is reached only after 2 to 7 minutes, reflecting the time required for drug transfer between plasma and NMJ.

2. The duration of action of nondepolarizing NMBDs is determined by the time required for drug concentration at site of action to decrease below a certain level, usually corresponding to 25% first-twitch blockade

D. Individual Nondepolarizing Relaxants (Tables 20-5 to 20-8)

1. Atracurium is an intermediate-acting benzylisoquinolinium-type nondepolarizing NMDB. Metabolism is by nonspecific ester hydrolysis (group of tissue esterases that are distinct from plasma or acetyl cholinesterases with the same tissue esterases that are responsible for degradation of esmolol and remifentanil) and the Hofmann reaction (nonenzymatic degradation at body temperature and pH). Subjects with abnormal plasma cholinesterase have a normal response to atracurium. An end product of degradation of atracurium is laudanosine. (High doses in animals cause seizures, but no deleterious effect has been conclusively documented in humans.)

TABLE 20-5 TYPICAL PHARMACOKINETIC DATA FOR NONDEPOLARIZING MUSCLE RELAXANTS