The NMJ consists of the motor nerve terminus, acetylcholine (ACh), and the muscle end-plate. In response to neuronal action potentials, ACh is released from presynaptic axonal storage vesicles into the synapse of the NMJ. Both the presynaptic membrane and postsynaptic end-plate contain specialized nicotinic ACh receptors (nAChRs). The chemical signal is converted into an electrical signal by binding of two ACh molecules to the receptor, causing a transient influx of sodium and calcium, and efflux of potassium from muscle cells. This depolarization propagates an action potential that results in a muscle contraction. Unbound ACh is quickly hydrolyzed in the synapse by the enzyme acetylcholinesterase to acetic acid and choline, thus effectively controlling the duration of receptor activation. A repolarization of the motor end-plate and muscle fiber then occurs.

The nAChR is built of five subunit proteins forming an ion channel. This ionic channel mediates neurotransmission at the NMJ, autonomic ganglia, spinal cord, and the brain. During early development, differentiation and maturation of the NMJ and transformation of the nAChR takes place: Fetal nAChRs gradually disappear with a rise of new, functionally distinct, mature nAChRs.

These mature nAChRs (also termed adult, innervated, σ-containing) have a subunit composition of α2βσδ in the synaptic muscle membrane. The only structural difference from the fetal nAChR is in substitution of the γ for the σ subunit, although functional, pharmacologic, and metabolic characteristics are quite distinct. Mature nAChRs have a shorter burst duration and a higher conductance to Na+, K+, and Ca²+ and are metabolically stable with a half-life averaging about 2 weeks. The 2 α, β, δ, and σ/γ subunits interact to form a channel and an extracellular binding site for ACh and other mediators as well. As mentioned previously, simultaneous binding of two ACh molecules to αδ and ασ subunits of a nAChR initiates opening of the channel and a flow of cations down their electrochemical gradient. In the absence of ACh or other mediators, the stable closed state (a major function of σ and γ subunits) normally precludes channel opening [6].

Adult skeletal muscle retains the ability to synthesize not only adult, but also fetal (often called immature or extrajunctional) type nAChRs. The synthesis of fetal nAChRs might be triggered in response to altered neuronal input such as loss of nerve function or prolonged immobility, or in the presence of certain disease states. The major differences between fetal and adult type of nAChRs is that fetal receptors migrate across the entire membrane surface and adult ones are mostly confined to the muscle end-plate. Secondly, these fetal nAChRs have much shorter half-life and are more ionically active with prolonged open channel time that exaggerates the K+ efflux. Lastly, these receptors are much more sensitive to depolarizing agents such as succinylcholine and resistant to nondepolarizing neuromuscular blockers.

The functional difference between depolarizing and nondepolarizing neuromuscular blockers lies in their interaction with AChRs. Depolarizing neuromuscular blockers are structurally similar to ACh and bind to and activate AChRs. Nondepolarizing neuromuscular blockers are competitive antagonists. There is emerging evidence pointing to yet another variant nAChR subunit (α7 acetylcholine receptors [α7nAChRs]), recently described to be expressed in muscle also [7]. These receptors not only bind ACh and succinylcholine, but also agonists such as choline and nicotine, as well as antagonists such as pancuronium, cobra toxin, and α-bungarotoxin [8].

Succinylcholine is the only depolarizing neuromuscular blocker in clinical use. Its use is limited to facilitating rapid-sequence intubation in the emergency setting. Succinylcholine mimics the effects of ACh by binding to the ACh receptor and inducing a persistent depolarization of the muscle fiber. Muscle contraction remains inhibited until succinylcholine diffuses away from the motor end-plate and is metabolized by serum (pseudo-) cholinesterase [9]. The clinical effect of succinylcholine is a brief excitatory period, with muscular fasciculations followed by neuromuscular blockade and flaccid paralysis. The intravenous dose of succinylcholine is 1 to 1.5 mg per kg and offers the most rapid onset of action (60 to 90 seconds) of the NMBAs. Recovery to 90% muscle strength after an intravenous dose of 1 mg per kg takes from 9 to 13 minutes [10]. Succinylcholine is also suitable for intramuscular administration; however, there are several limitations. Firstly, the required dose is higher (4 mg per kg) and time to maximum twitch depression is significantly longer (approximately 4 minutes). Secondly, the duration of action of succinylcholine after intramuscular injection is prolonged. It should be noted that the most frequent indication for intramuscular succinylcholine is for the treatment of laryngospasm in pediatric patients without intravenous access; however, the dose range listed here has also been verified in the adult population [11, 12].

Potential adverse drug events associated with succinylcholine include hypertension, arrhythmias, increased intracranial and intraocular pressure, hyperkalemia, malignant hyperthermia, myalgias, and prolonged paralysis [13]. Neuromuscular blockade can persist for hours in patients with genetic variants of pseudocholinesterase isoenzymes [14]. Contraindications to succinylcholine use include major thermal burns, significant crush injuries, spinal cord transection, malignant hyperthermia, and upper or lower motor neuron lesions. Caution is also advised in patients with open globe injuries, renal failure, serious infections, and near-drowning victims [15].

Nondepolarizing NMBAs function as competitive antagonists and inhibit ACh binding to postsynaptic nAChRs on the motor end-plate. They are categorized on the basis of chemical structure into two classes: benzylisoquinoliniums and amino- steroids. Within each of these classes, the therapeutic agents may further be categorized as short-acting, intermediate-acting, or long-acting agents. The benzylisoquinolinium agents commonly used in the critical care setting include mivacurium, atracurium, cisatracurium, and doxacurium, whereas the aminosteroid agents include vecuronium, rocuronium, pancuronium, and pipecuronium.

The nondepolarizing NMBAs are administered by the intravenous route and have volumes of distribution (V_ds) ranging from 0.2 to 0.3 L per kg in adults.

A clinical relationship exists between the time to onset of paralysis and neuromuscular blocker dosing, drug distribution, and ACh-receptor sensitivity. An important factor to consider is V_d, which may change as a result of disease processes. Cirrhotic liver disease and chronic renal failure often result in an increased V_d and decreased plasma concentration for a given dose of water-soluble drugs. However, drugs dependent on renal or hepatic excretion may have prolonged clinical effect. Therefore, a larger initial dose but smaller maintenance dose may be appropriate.

Alterations in V_d affect both peak neuromuscular blocker serum concentrations and time to paralysis. The pharmacokinetic and pharmacodynamic principles of commonly used NMBAs are summarized in Table 24-1.