Neuromuscular Blocking Drugs

Skeletal muscles are innervated by somatic motor nerves, which originate in the spinal cord, terminate at muscle cells, and release ACh as their neurotransmitter (see Chapters 9 10). Upon arrival of an action potential, ACh is released from synaptic vesicles by exocytosis, crosses the synapse, and interacts with skeletal muscle nicotinic cholinergic receptors to depolarize the postsynaptic membrane (see Chapter 1). When the membrane reaches threshold, a muscle action potential is generated and propagates along the fiber to initiate excitation-contraction coupling. The action of ACh is terminated very rapidly by hydrolysis by acetylcholinesterase (AChE) located in the synaptic junction. Neuromuscular transmission is depicted in Figure 12-1.

FIGURE 12–1 Neuromuscular transmission and sites of drug action. (1) The action potential is conducted down the motor nerve axon and can be blocked by Na⁺ channel blockers, such as local anesthetics or tetrodotoxin. (2) When the action potential reaches the nerve terminal, Ca⁺⁺-mediated vesicular acetylcholine (ACh) release occurs by exocytosis, a process blocked by botulinum toxin or hemicholinium. (3) After release, ACh diffuses across the synaptic cleft and binds to nicotinic receptors in the motor endplate. The binding can be blocked competitively by nondepolarizing neuromuscular blockers such as curare or noncompetitively by depolarizing neuromuscular blockers, such as succinylcholine. (4) ACh is very rapidly hydrolyzed by acetylcholinesterase (AChE), which can be inhibited by cholinesterase inhibitors, such as neostigmine. (5) ACh-activated nicotinic receptors in the motor endplate generate a muscle action potential, which leads to Ca⁺⁺ release mediated by ryanodine receptors, initiating excitation-contraction coupling and muscle contraction; this Ca⁺⁺ release can be blocked by the antispasticity drug dantrolene.

Neuromuscular blocking agents interfere with neurotransmission by either: (1) occupying and activating the nicotinic receptor for a prolonged period of time, leading to blockade, which occurs with the depolarizing agents; or (2) competitively antagonizing the actions of ACh at nicotinic acetylcholine receptors, which occurs with the nondepolarizing agents. Not surprisingly, the structures of the depolarizing agents resemble that of ACh, whereas the nondepolarizing agents are bulky, rigid molecules. A comparison of the structure of ACh with prototypical depolarizing (succinylcholine) and nondepolarizing (tubocurarine and pancuronium) neuromuscular blockers is shown in Figure 12-2.

FIGURE 12–2 Structures of acetylcholine, a depolarizing neuromuscular blocker (succinylcholine), and several chemical types of nondepolarizing (competitive) neuromuscular blocking agents.

As mentioned, the nondepolarizing blockers are competitive antagonists at nicotinic receptors. They have little or no agonist activity but competitively occupy the receptor binding site. The first compound, d-tubocurarine, was extracted from plants by native South Americans to coat their darts and rapidly paralyze their prey. This led to the development of synthetic compounds including the benzylisoquinolines such as atracurium and the aminosteroids such as pancuronium.

Nondepolarizing neuromuscular blocking drugs decrease the ability of ACh to open the ligand-gated cation channels in skeletal muscle, producing flaccid paralysis. Muscle contraction is partially impaired when 75% to 80% of receptors are occupied and inhibited totally when 90% to 95% are occupied. Required concentrations vary with the drug, the muscle and its location, and the patient.

Because nondepolarizing blockers compete with ACh, the blockade can be reversed by increasing the concentration of ACh. This is done by inhibiting AChE, which hydrolyzes ACh (Chapter 9 10). Neostigmine, edrophonium, and pyridostigmine are AChE inhibitors used clinically to reverse neuromuscular block caused by nondepolarizing blockers. However, if the concentration of the competitive blocking agent is greater than that needed for blockade of 95% of the receptors, AChE inhibitors will be unable to increase ACh sufficiently to reverse the block.

There is only one depolarizing agent currently in clinical use, succinylcholine (see Fig. 12-2). This compound binds to and activates muscle nicotinic receptors in the same manner as ACh. However, succinylcholine is not metabolized by AChE, resulting in receptor occupation for a prolonged period. Succinylcholine is hydrolyzed primarily by butyrylcholinesterase, which is present in the plasma but not in high concentrations at the neuromuscular junction, resulting in continuing muscle depolarization. The neuromuscular block resulting from succinylcholine is characterized by two phases. The first, termed phase I block, is a consequence of prolonged depolarization, rendering the membrane unresponsive to further stimuli. It is characterized by initial muscle fasciculations followed by a flaccid paralysis that is not reversed, but intensified, by administration of AChE inhibitors. With continued exposure to succinylcholine, phase II block occurs, during which the membrane repolarizes but is still unresponsive, reflecting a desensitized state of the nicotinic cholinergic receptor. This phase progresses to a state in which the block appears similar to that produced by nondepolarizing agents, that is, it becomes responsive to high concentrations of ACh and can be reversed by AChE inhibitors.

Spasmolytics

Antispasticity Drugs

The antispasticity agents include baclofen, which is a structural analog of γ-aminobutyric acid (GABA). Baclofen decreases spasticity by binding to GABA_B receptors on presynaptic terminals of spinal interneurons (Fig. 12-3). Binding to presynaptic GABA_B receptors results in hyperpolarization of the membrane, which reduces Ca⁺⁺ influx and decreases the release of the excitatory neurotransmitters, glutamate, and aspartate. Postsynaptic interactions with sensory afferent terminals cause membrane hyperpolarization via a G-protein-coupled receptor that leads to increases in K⁺ conductance, enhancing inhibition. Baclofen may also inhibit γ-motor neuron activity and reduce muscle spindle sensitivity, leading to inhibition of monosynaptic and polysynaptic spinal reflexes.

FIGURE 12–3 Sites of spasmolytic drug action on the spinal cord and muscle. Baclofen acts presynaptically at GABA_B receptors in the spinal cord to reduce transmitter release. Tizanidine also acts presynaptically at α₂ adrenergic receptors to inhibit spinal motorneurons. Diazepam enhances the action of GABA at GABA_A receptors to enhance inhibition at presynaptic and postsynaptic sites in the spinal cord; it also acts in the brain (not shown). Botulinum toxin produces a long-lasting paralysis of “spastic” muscles by preventing ACh release. Dantrolene reduces spasticity by reducing Ca⁺⁺-mediated excitation-contraction coupling through block of ryanodine receptor channels.

Benzodiazepines such as diazepam have an antispasticity effect by acting on GABA_A receptors to increase their affinity for GABA in the brain and in the spinal cord (see Chapter 31 and Fig. 12-3).

Tizanidine is a clonidine derivative with short-acting presynaptic α₂ adrenergic receptor agonist actions. The ability of tizanidine to affect spinal motor neurons via presynaptic inhibition is believed to mediate its antispasticity effects.

Dantrolene has direct effects on skeletal muscle to inhibit ryanodine receptor Ca⁺⁺ release channels on the sarcoplasmic reticulum of skeletal muscle, thereby uncoupling motor nerve excitation and muscle contraction (see Fig. 12-3). Dantrolene may also have actions on the CNS that contribute to its antispasticity effects, although the cellular mechanisms have not been elucidated.

Neuromuscular Blocking Drugs

The neuromuscular blocking drugs differ considerably in their pharmacokinetic properties, and the choice of a particular compound is determined in part by the duration of action of the agent needed for the particular procedure (Table 12-1