Pharmacology

At the motor nerve ending, the nerve action potential normally causes calcium channels to open, leading to the release of acetylcholine (ACh) from storage vesicles. ACh diffuses across the junctional cleft to react with receptor proteins in the end plate to initiate muscle contraction. Molecules of ACh released from the end plate are quickly (in less than 1 ms) metabolized by acetylcholinesterase molecules that are attached to the end plate outside the cell via stalks of collagen.

Succinylcholine consists of two molecules of ACh linked by methyl groups (Figure 81-1). Succinylcholine attaches to the nicotinic cholinergic receptor and mimics the action of ACh, thus producing depolarization of the postjunctional membrane. Compared with ACh, the hydrolysis of succinylcholine is slow, resulting in a sustained depolarization. Yet, compared with other neuromuscular blocking agents, the duration of action of succinylcholine is brief (3 to 5 min), owing to hydrolysis by butyrylcholinesterase (BChE), also known as plasma cholinesterase or pseudocholinesterase. This rapid breakdown of succinylcholine, to succinylmonocholine and choline, allows only a fraction (approximately 5%-10%) of the administered dose of the drug to reach the neuromuscular junction. The initial metabolite, succinylmonocholine, is 1⁄20 to 1⁄90 as potent as the parent compound. Succinylmonocholine is subsequently hydrolyzed to succinate and choline. There is little or no BChE at the neuromuscular junction, so the action of succinylcholine is terminated by diffusion from the end plate to extracellular fluid. Thus, by controlling the rate at which succinylcholine is hydrolyzed before it reaches, and after it leaves, the neuromuscular junction, BChE influences the onset and duration of action of the drug.

BChE is a serine hydrolyase capable of hydrolyzing esters, including ACh, succinylcholine, mivacurium, trimethaphan, and ester-type local anesthetics. BChE is found in plasma, liver, pancreas, heart, and brain. It is distinct from acetylcholinesterase, which is found in nerve endings and in red blood cells. BChE is an α₂-receptor globulin, weighing 320 kD, that exists in aggregate form, usually as a tetramer. The four subunits are identical, each having an active catalytic site. The enzyme is coded by exons located on chromosome 3q36 and is synthesized by the liver. The serum half-life is 8 to 16 h. The concentration of BChE in plasma is about 5 mg/L. The physiologic role of BChE is obscure, but it may be involved in lipid metabolism, choline homeostasis, or slow nerve conduction. Low levels or even complete absence of BChE are compatible with normal health and development.

Succinylcholine apnea

Clinical interest in BChE abnormalities and pharmacology stemmed from observations that certain patients given succinylcholine develop prolonged apnea. The enzyme present in the plasma of affected individuals differs from normal BChE. Mutations of the gene coding for BChE give rise to a variety of biochemical phenotypes. Most of the variant alleles are the result of single-nucleotide polymorphisms, which have been elucidated by DNA techniques. Clinically significant BChE abnormalities are uncommon, with succinylcholine-induced prolonged apnea occurring in 1 in 2500 patients. Viby-Mogensen studied patients with prolonged apnea after succinylcholine administration and found that 66% had an inherited BChE abnormality. Succinylcholine apnea from the various abnormal BChE phenotypes is usually of shorter duration than the surgical procedure.

Skeletal muscle paralysis of excessive duration caused by succinylcholine requires maintenance of mechanical ventilatory support and continuation of anesthesia or sedation, typically in the postanesthesia care unit or the intensive care unit, until neuromuscular function returns. Some have advocated transfusion of fresh frozen plasma to replace BChE, but the risks of transfusion are far higher than those associated with a few hours of mechanical ventilation. Neostigmine inhibits the degradation of succinylcholine by BChE, and administration is not appropriate in these circumstances.

Measurement of butyrylcholinesterase activity

The activity of BChE refers to the number of succinylcholine molecules hydrolyzed per unit of time, expressed in international units. The BChE proteins produced by genetic variations may differ in enzyme amount (quantitative difference) or in enzyme performance (qualitative difference) when compared with normal BChE. Changes in either quantity or quality of the enzyme will cause alterations in BChE activity. The presence of succinylcholine interferes with both quantitative and qualitative assays; therefore, it is preferable to postpone testing until the day after an episode of prolonged neuromuscular blockade associated with the use of succinylcholine to ensure accurate results. Figure 81-2 illustrates the correlation between the duration of succinylcholine action and BChE activity. There is a wide normal range of BChE activity; prolonged muscle relaxation after administration of succinylcholine is clinically significant only with extreme depression of BChE activity.

Qualitative analysis

Qualitative tests of BChE activity involve assessment of enzyme function in the presence of a variety of inhibitors, including dibucaine, fluoride, and a number of others. Qualitative testing allows identification of a number of BChE variants.

Atypical variants were originally described by Kalow, who identified individuals whose BChE could not metabolize succinylcholine but were only partially inhibited by dibucaine, a local anesthetic. Whereas a normal individual’s hydrolysis of benzoylcholine was inhibited 70% to 80% by dibucaine, affected individuals showed only 20% to 30% inhibition of hydrolysis (Table 81-1). The dibucaine number is defined as the percentage inhibition of BChE in the presence of 40 μmol/L of dibucaine:

Table 81-1

Dibucaine Number and Duration of Succinylcholine or Mivacurium Neuromuscular Blockade

Butyrylcholinesterase Type	Prevalence	Dibucaine No.	Response to Succinylcholine or Mivacurium
Homozygous, typical	Normal	70-80	Normal
Heterozygous, atypical	1/480	50-60	Lengthened by 50-100%
Homozygous, atypical	1/3200	23-30	Prolonged to 4-8 h

Adapted, with permission, from Naguib M, Lien CA. Pharmacology of muscle relaxants and their antagonists. In: Miller RD, Eriksson LI, Fleisher LA, et al, eds. Miller’s Anesthesia. 7th ed. Philadelphia: Churchill Livingstone; 2009: Table 29.1.

< ?xml:namespace prefix = "mml" />Dibucaine number=Total activity–Activity in presence of inhibitorTotal activity×100

Other causes of butyrylcholinesterase abnormalities

A variety of physiologic conditions and drugs can lead to BChE abnormalities (Box 81-1).

Phase I versus phase II block

A phase II neuromuscular blockade can cause prolongation of the action of succinylcholine; it is a risk of using repeated doses or an infusion of the drug. Phase II blockade may occur when the dose (usually >6 mg/kg) or duration (>30 min continuous infusion) of succinylcholine use is excessive. The exact mechanism for the transition from phase I to phase II blockade is not known but is thought to occur when the postjunctional membrane has become repolarized but still does not respond normally to ACh. The onset of phase II block coincides with tachyphylaxis, as more succinylcholine is required for the same effect. Phase II blockade can be avoided if succinylcholine administration is stopped when train-of-four fade becomes evident. Reversal of a phase II blockade is controversial; it should not be attempted until spontaneous recovery of the twitch has occurred. Administration of neostigmine or edrophonium when spontaneous recovery of the twitch response has been observed for 20 to 30 min and has reached a plateau has been suggested to promote return of the train of four to normal. Characteristics of phase I, transition, and phase II neuromuscular blockade during succinylcholine infusion are shown in Table 81-3.