Basic, Basic Sciences
Neuromuscular blocking agents exert their effects at the neuromuscular junction (motor end plate). To understand how they work, it is important to first understand the anatomy of a single motor end plate. A motor end plate is made up of an axon nerve terminal that ends in very close proximity to the sarcolemma of a muscle fiber. The sarcolemma contains many invaginations filled with hundreds of thousands of nicotinic acetylcholine (nACh) receptors. Mature nACh receptors are composed of five protein subunits (2 alpha subunits and 1 beta, delta, and epsilon subunit) and a center channel. Only the two alpha subunits both have two acetylcholine binding sites that are capable of binding to acetylcholine molecules.
During a typical muscle contraction, acetylcholine vesicles containing 5000 to 10,000 acetylcholine molecules are first released from the axon nerve terminal. These vesicles enter the synaptic cleft and travel across the neuromuscular junction to reach the sarcolemma of the muscle fiber. Once here, individual acetylcholine molecules can now bind to the two binding sites on each alpha subunit of the nACh receptor. If both of the binding sites on the alpha subunit nACh receptor are occupied by acetylcholine at the same time, a conformational change occurs resulting in opening of the central channel and ion flux (sodium/calcium in and potassium out). This ion flux generates an end-plate potential and when a large enough end-plate potential is reached, the perijunctional membrane on the muscle cell will depolarize resulting in the opening of perijunctional voltage-gated sodium channels (VGSC) and subsequent calcium release from the sarcoplasmic reticulum and finally muscle contraction.
With this information in mind, neuromuscular blocking agents can be classified into two main categories based on their mechanism of action: depolarizing and nondepolarizing.
- Depolarizing neuromuscular blocking drugs, i.e., succinylcholine, closely resemble acetylcholine molecules and bind directly to the two binding sites on the alpha subunits of the nACh receptor. Once bound, they cause opening of the central channel and ion flux, just like acetylcholine does. Muscle contraction (fasciculation) occurs, however because succinylcholine is not metabolized by acetylcholinesterase (instead butyrylcholinesterase), it stays bound to the acetylcholine receptor causing prolonged depolarization. This ultimately results in the inactivation of the perijunctional VGSCs leading to muscle paralysis. The perijunctional VGSCs stay inactive in a depolarized state until the succinylcholine molecules are no longer bound to the nACh receptors (i.e., phase I block).
- Nondepolarizing neuromuscular blocking agents cause paralysis by means of a different mechanism, hence their different name. Although they too also bind to the binding sites on the alpha subunits of nACh receptors, their binding does not result in the necessary conformational change for channel opening and resultant ion flux. Instead, their binding results in no channel change and simply blocks acetylcholine from binding and all of the subsequent downstream events necessary for muscle contraction as described above. Therefore, nondepolarizing muscle relaxants act as competitive antagonists, whereas depolarizing muscle relaxants act as acetylcholine receptor agonists with prolonged effect.
The structure of nondepolarizing NMBs can be divided into aminosteroids versus benzylisoquinoliniums. They are highly ionized, water-soluble compounds at physiologic pH and are thus minimally lipid soluble. This means they cannot easily cross the blood-brain barrier (BBB), renal tubular epithelium, GI epithelium, or placenta.
o The aminosteroids consist of pancuronium, pipecuronium, vecuronium, and rocuronium. These drugs have a steroid nucleus and depend largely on organ function for metabolism and excretion. Pancuronium is the bisquaternary aminosteroid most similar to ACh in structure. Vecuronium and rocuronium are monoquaternary analogs of pancuronium.
o The benzylisoquinoliniums consist of atracurium, mivacurium, and cisatracurium. These undergo organ-independent metabolism and are more likely than aminosteroids to evoke the release of histamine, possibly due to the presence of a tertiary amine.
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