Basic Pharmacology of Neuromuscular Blocking Drugs

BASIC PHARMACOLOGY OF NEUROMUSCULAR BLOCKING DRUGS

Chemistry

All of the available neuromuscular blocking drugs bear a structural resemblance to acetylcholine. For example, succinylcholine is two acetylcholine molecules linked end-to-end (Figure 27–3).

In contrast to the single linear structure of succinylcholine and other depolarizing drugs, the nondepolarizing agents (eg, pancuronium) conceal the “double-acetylcholine” structure in one of two types of bulky, semi-rigid ring systems (Figure 27–3). Examples of the two major families of nondepolarizing blocking drugs—the isoquinoline and steroid derivatives—are shown in Figures 27–4 and 27–5. Another feature common to all currently used neuromuscular blockers is the presence of one or two quaternary nitrogens, which makes them poorly lipid soluble and limits entry into the CNS.

Pharmacokinetics of Neuromuscular Blocking Drugs

All of the neuromuscular blocking drugs are highly polar com-pounds and inactive orally; they must be administered parenterally.

A. Nondepolarizing Relaxant Drugs

The rate of disappearance of a nondepolarizing neuromuscular blocking drug from the blood is characterized by a rapid initial distribution phase followed by a slower elimination phase. Neuromuscular blocking drugs are highly ionized, do not readily cross cell membranes, and are not strongly bound in peripheral tissues. Therefore, their volume of distribution (80–140 mL/kg) is only slightly larger than the blood volume.

The duration of neuromuscular blockade produced by nonde-polarizing relaxants is strongly correlated with the elimination half-life. Drugs that are excreted by the kidney typically have lon-ger half-lives, leading to longer durations of action (> 35 minutes). Drugs eliminated by the liver tend to have shorter half-lives and durations of action (Table 27–1). All steroidal muscle relaxants are metabolized to their 3-hydroxy, 17-hydroxy, or 3,17-dihydroxy products in the liver. The 3-hydroxy metabolites are usually 40–80% as potent as the parent drug. Under normal circum-stances, metabolites are not formed in sufficient quantities to produce a significant degree of neuromuscular blockade during or after anesthesia. However, if the parent compound is administered for several days in the ICU setting, the 3-hydroxy metabolite may accumulate and cause prolonged paralysis because it has a longer half-life than the parent compound. The remaining metabolites possess minimal neuromuscular blocking properties.

The intermediate-acting steroid muscle relaxants (eg, vecuro-nium and rocuronium) tend to be more dependent on biliaryexcretion or hepatic metabolism for their elimination. These muscle relaxants are more commonly used clinically than the long-acting steroid-based drugs (eg, pancuronium).

Atracurium (Figure 27–4) is an intermediate-acting isoquino-line nondepolarizing muscle relaxant. In addition to hepatic metabolism, atracurium is inactivated by a form of spontaneous breakdown known as Hofmann elimination. The main breakdown products are laudanosine and a related quaternary acid, neither of which possesses neuromuscular blocking properties. Laudanosine is slowly metabolized by the liver and has a longer elimination half-life (ie, 150 minutes). It readily crosses the blood-brain barrier, and high blood concentrations may cause seizures and an increase in the volatile anesthetic requirement. During surgical anesthesia, blood levels of laudanosine typically range from 0.2 to 1 mcg/mL; however, with prolonged infusions of atracurium in the ICU, laudanosine blood levels may exceed 5 mcg/mL.

Atracurium has several stereoisomers, and the potent isomer cisatracurium has become one of the most commonly usedmuscle relaxants in clinical practice. Although cisatracurium resembles atracurium, it has less dependence on hepatic inactiva-tion, produces less laudanosine, and is less likely to release hista-mine. From the clinical perspective, cisatracurium has all the advantages of atracurium with fewer side effects. Therefore, cisa-tracurium has largely replaced atracurium in clinical practice.

Mivacurium, another isoquinoline compound, has the shortestduration of action of all nondepolarizing muscle relaxants (Table 27–1). However, its onset of action is significantly slower than that of succinylcholine. In addition, the use of a larger dose to speed the onset can be associated with profound histamine release leading to hypotension, flushing, and bronchospasm. Clearance of mivacu-rium by plasma cholinesterase is rapid and independent of the liver or kidney (Table 27–1). However, because patients with renal fail-ure often have decreased levels of plasma cholinesterase, the short duration of action of mivacurium may be prolonged in patients with impaired renal function. Although mivacurium is no longer in widespread clinical use, an investigational ultra-short-acting isoquinoline nondepolarizing muscle relaxant, gantacurium, is cur-rently in phase 3 clinical testing.

Gantacurium represents a new class of nondepolarizing neuro-muscular blockers, called asymmetric mixed-onium chlorofumar-ates. It is degraded nonenzymatically by adduction of the aminoacid cysteine and ester bond hydrolysis. Preclinical and clinical data indicate gantacurium has a rapid onset of effect and predict-able duration of action (very short, similar to succinylcholine) that can be reversed with edrophonium or administration of cysteine. At doses above three times the ED₉₅, cardiovascular adverse effects have occurred, probably due to histamine release. No broncho-spasm or pulmonary vasoconstriction has been reported at these higher doses.

B. Depolarizing Relaxant Drugs

The extremely short duration of action of succinylcholine (5–10 minutes) is due to its rapid hydrolysis by butyrylcholinesterase and pseudocholinesterase in the liver and plasma, respectively. Plasma cholinesterase metabolism is the predominant pathway for succinylcholine elimination. Since succinylcholine is more rapidly metabolized than mivacurium, its duration of action is shorter than that of mivacurium (Table 27–1). The primary metabolite of succi-nylcholine, succinylmonocholine, is rapidly broken down to succinic acid and choline. Because plasma cholinesterase has an enormous capacity to hydrolyze succinylcholine, only a small percentage of the original intravenous dose ever reaches the neuromuscular junction. In addition, because there is little if any plasma cholinesterase at the motor end plate, a succinylcholine-induced blockade is terminated by its diffusion away from the end plate into extracellular fluid. Therefore, the circulating levels of plasma cholinesterase influence the duration of action of succinylcholine by determining the amount of the drug that reaches the motor end plate.

Neuromuscular blockade produced by succinylcholine and mivacurium can be prolonged in patients with an abnormal genetic variant of plasma cholinesterase. The dibucaine number is a measure of the ability of a patient to metabolize succinylcholine and can be used to identify at-risk patients. Under standardized test conditions, dibucaine inhibits the normal enzyme by 80% and the abnormal enzyme by only 20%. Many genetic variants of plasma cholines-terase have been identified, although the dibucaine-related variants are the most important. Given the rarity of these genetic variants, plasma cholinesterase testing is not a routine clinical procedure.

Mechanism of Action

The interactions of drugs with the acetylcholine receptor-end plate channel have been described at the molecular level. Several modes of action of drugs on the receptor are illustrated in Figure 27–6.

A. Nondepolarizing Relaxant Drugs

All the neuromuscular blocking drugs in current use in the USA except succinylcholine are classified as nondepolarizing agents. Although it is no longer in widespread clinical use, d-tubocurarine is considered the prototype neuromuscular blocker. When small doses of nondepolarizing muscle relaxants are administered, they act predominantly at the nicotinic receptor site by competing with acetylcholine. The least potent nondepolarizing relaxants (eg, rocuronium) have the fastest onset and the shortest duration of action. In larger doses, nondepolarizing drugs can enter the pore of the ion channel (Figure 27–1) to produce a more intense motor blockade. This action further weakens neuromuscular transmission and diminishes the ability of the acetylcholinesterase inhibitors (eg, neostigmine, edrophonium, pyridostigmine) to antagonize the effect of nondepolarizing muscle relaxants.

Nondepolarizing relaxants can also block prejunctional sodium channels. As a result of this action, muscle relaxants interfere with the mobilization of acetylcholine at the nerve ending and cause fade (Figure 27-7). One consequence of the surmountable nature of the postsynaptic blockade produced by nondepolarizing muscle relaxants is the fact that tetanic stimulation, by releasing a large quantity of acetylcholine, is followed by transient posttetanic facilitation of the twitch strength (ie, relief of blockade). An important clinical consequence of this principle is the reversal of residual blockade by cholinesterase inhibitors. The characteristics of a nondepolarizing neuromuscular blockade are summarized in Table 27–2 and Figure 27–7.

B. Depolarizing Relaxant Drugs

1. Phase I block (depolarizing)—Succinylcholine is the onl clinically useful depolarizing blocking drug. Its neuromuscular

effects are like those of acetylcholine except that succinylcholine produces a longer effect at the myoneural junction. Succinylcholine

reacts with the nicotinic receptor to open the channel and causedepolarization of the motor end plate, and this in turn spreads to the adjacent membranes, causing contractions of muscle motor units. Data from single-channel recordings indicate that depolarizing blockers can enter the channel to produce a prolonged“flickering” of the ion conductance (Figure 27–8). Because succinylcholine is not metabolized effectively at the synapse, thedepolarized membranes remain depolarized and unresponsive tosubsequent impulses(ie,a state of depolarizingblockade).Furthermore,  because  excitation-contraction  coupling  requires end plate repolarization (“repriming”) and repetitive firing to maintain muscle tension, a flaccid paralysis results. In contrast to the nondepolarizing drugs, this so-called phase I (depolarizing) block is augmented, not reversed, by cholinesterase inhibitors. The characteristics of a depolarizing neuromuscular blockade are summarized in Table 27–2 and Figure 27–7.

2. Phase II block (desensitizing)—With prolonged exposureto succinylcholine, the initial end plate depolarization decreases and the membrane becomes repolarized. Despite this repolariza-tion, the membrane cannot easily be depolarized again because it is desensitized. The mechanism for this desensitizing phase is unclear, but some evidence indicates that channel block may become more important than agonist action at the receptor in phase II of succinylcholine’s neuromuscular blocking action. Regardless of the mechanism, the channels behave as if they are in a prolonged closed state (Figure 27–7). Later in phase II, the char-acteristics of the blockade are nearly identical to those of a nonde-polarizing block (ie, a nonsustained twitch response to a tetanic stimulus) (Figure 27–7), with possible reversal by acetylcholines-terase inhibitors.