A. Classification and Prototypes
Skeletal muscle contraction is evoked by a nicotinic cholinergic transmission process. Blockade of transmission at the end plate (the postsynaptic structure bearing the nicotinic receptors) is clinically useful in producing muscle relaxation, a requirement for surgical relaxation, tracheal intubation, and control of ventilation. The neuromuscular blockers are quaternary amines structurally related to acetylcholine (ACh). Most are antagonists (nondepolarizing type), and the prototype is tubocurarine. One neuromuscular blocker used clinically, succinylcholine, is an agonist at the nicotinic end plate receptor (depolarizing type).
B. Nondepolarizing Neuromuscular Blocking Drugs
All agents are given parenterally. They are highly polar drugs and do not cross the blood-brain barrier. Drugs that are metabolized (eg, mivacurium, withdrawn in the USA) or eliminated in the bile (eg, rocuronium) have shorter durations of action (10–20 min) than those eliminated by the kidney (eg, metocurine, pancuronium, pipecuronium, and tubocurarine) which usually have durations of action of 35–60 min. In addition to hepatic metabolism, atracurium clearance involves rapid spontaneous breakdown (Hofmann elimination) to form laudanosine and other products. At high blood levels, laudanosine may cause seizures. Cisatracurium, a stereoisomer of atracurium, is also inactivated spontaneously but forms less laudanosine and currently is one of the most commonly used muscle relaxants in clinical practice.
High Yield Terms to Learn
|Depolarizing blockade ||Neuromuscular paralysis that results from persistent depolarization of the end plate (eg, by succinylcholine) |
|Desensitization ||A phase of blockade by a depolarizing blocker during which the end plate repolarizes but is less than normally responsive to agonists (acetylcholine or succinylcholine) |
|Malignant hyperthermia ||Hyperthermia that results from massive release of calcium from the sarcoplasmic reticulum, leading to uncontrolled contraction and stimulation of metabolism in skeletal muscle |
|Nondepolarizing blockade ||Neuromuscular paralysis that results from pharmacologic antagonism at the acetylcholine receptor of the end plate (eg, by tubocurarine) |
|Spasmolytic ||A drug that reduces abnormally elevated muscle tone (spasm) without paralysis (eg, baclofen, dantrolene) |
|Stabilizing blockade ||Synonym for nonpolarizing blockade |
Nondepolarizing drugs prevent the action of ACh at the skeletal muscle end plate (Figure 27–1). They act as surmountable blockers. (That is, the blockade can be overcome by increasing the amount of agonist [ACh] in the synaptic cleft.) They behave as though they compete with ACh at the receptor, and their effect is reversed by cholinesterase inhibitors. Some drugs in this group may also act directly to plug the ion channel operated by the ACh receptor. Post-tetanic potentiation is preserved in the presence of these agents, but tension during the tetanus fades rapidly. See Table 27–1 for additional details. Larger muscles (eg, abdominal, diaphragm) are more resistant to neuromuscular blockade, but they recover more rapidly than smaller muscles (eg, facial, hand). Of the available nondepolarizing drugs, rocuronium (60–120 s) has the most rapid onset time.
Drug interactions with the acetylcholine (ACh) receptor on the skeletal muscle end plate. Top: ACh, the normal agonist, opens the sodium channel. Bottom left: Nondepolarizing blockers bind to the receptor to prevent opening of the channel. Bottom right: Succinylcholine causes initial depolarization (fasciculation) and then persistent depolarization of the channel, which leads to muscle relaxation. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 27–6.)
TABLE 27–1Comparison of a typical nondepolarizing neuromuscular blocker (rocuronium) and a depolarizing blocker (succinylcholine). ||Download (.pdf) TABLE 27–1 Comparison of a typical nondepolarizing neuromuscular blocker (rocuronium) and a depolarizing blocker (succinylcholine).
|Process ||Rocuronium ||Succinylcholine |
|Phase I ||Phase II |
|Administration of tubocurarine ||Additive ||Antagonistic ||Augmenteda |
|Administration of succinylcholine ||Antagonistic ||Additive ||Augmenteda |
|Effect of neostigmine ||Antagonistic ||Augmenteda ||Antagonistic |
|Initial excitatory effect on skeletal muscle ||None ||Fasciculations ||None |
|Response to tetanic stimulus ||Unsustained (“fade”) ||Sustainedb ||Unsustained |
|Post-tetanic facilitation ||Yes ||No ||Yes |
C. Depolarizing Neuromuscular Blocking Drugs
Succinylcholine is composed of 2 ACh molecules linked end to end. Succinylcholine is metabolized by a cholinesterase (butyrylcholinesterase or pseudocholinesterase) in the liver and plasma. It has a duration of action of only a few minutes if given as a single dose. Blockade may be prolonged in patients with genetic variants of plasma cholinesterase that metabolize succinylcholine very slowly. Such variant cholinesterases are resistant to the inhibitory action of dibucaine. Succinylcholine is not rapidly hydrolyzed by acetylcholinesterase.
Succinylcholine acts like a nicotinic agonist and depolarizes the neuromuscular end plate (Figure 27–1).
The initial depolarization is often accompanied by twitching and fasciculations (prevented by pretreatment with small doses of a nondepolarizing blocker). Because tension cannot be maintained in skeletal muscle without periodic repolarization and depolarization of the end plate, continuous depolarization results in muscle relaxation and paralysis. Succinylcholine may also plug the end plate channels.
When given by continuous infusion, the effect of succinylcholine changes from continuous depolarization (phase I) to gradual repolarization with resistance to depolarization (phase II) (ie, a curare-like block; see Table 27–1).
The action of nondepolarizing blockers is readily reversed by increasing the concentration of normal transmitter at the receptors. This is best accomplished by administration of cholinesterase inhibitors such as neostigmine or pyridostigmine. In contrast, the paralysis produced by the depolarizing blocker succinylcholine is increased by cholinesterase inhibitors during phase I. During phase II, the block produced by succinylcholine is usually reversible by cholinesterase inhibitors. Sugammadex, approved in Europe, is a novel chemical antagonist of rocuronium.
The action of full doses of neuromuscular blockers leads directly to respiratory paralysis. If mechanical ventilation is not provided, the patient will asphyxiate.
2. Autonomic effects and histamine release
Autonomic ganglia are stimulated by succinylcholine and weakly blocked by tubocurarine. Succinylcholine activates cardiac muscarinic receptors, whereas pancuronium is a moderate blocking agent and causes tachycardia. Tubocurarine and mivacurium are the most likely of these agents to cause histamine release, but it may also occur to a slight extent with atracurium and succinylcholine. Vecuronium and several newer nondepolarizing drugs (cisatracurium, doxacurium, pipecuronium, rocuronium) have no significant effects on autonomic functions or histamine release. A summary of the autonomic effects of neuromuscular drugs is shown in Table 27–2.
TABLE 27–2Autonomic effects of neuromuscular drugs. ||Download (.pdf) TABLE 27–2 Autonomic effects of neuromuscular drugs.
|Drug ||Effect on Autonomic Ganglia ||Effect on Cardiac Muscarinic Receptors ||Ability to Release Histamine |
| Atracurium ||None ||None ||Slight |
| Cisatracurium ||None ||None ||None |
| Rocuronium ||None ||Slight block ||None |
| Pancuronium ||None ||Moderate block ||None |
| Tubocurarine ||Weak block ||None ||Moderate |
| Vecuronium ||None ||None ||None |
| Succinylcholine ||Stimulation ||Stimulation ||Slight |
Muscle pain is a common postoperative complaint, and muscle damage may occur. Succinylcholine may cause hyperkalemia, especially in patients with burn or spinal cord injury, peripheral nerve dysfunction, or muscular dystrophy. Increases in intragastric pressure caused by fasciculations may promote regurgitation with possible aspiration of gastric contents.
Inhaled anesthetics, especially isoflurane, strongly potentiate and prolong neuromuscular blockade. A rare interaction of succinylcholine with inhaled anesthetics can result in malignant hyperthermia (see Table 16-2). A very early sign of this potentially life-threatening condition is contraction of the jaw muscles (trismus). Aminoglycoside antibiotics and antiarrhythmic drugs may potentiate and prolong the relaxant action of neuromuscular blockers to a lesser degree.
5. Effects of aging and diseases
Older patients (>75 years) and those with myasthenia gravis are more sensitive to the actions of the nondepolarizing blockers, and doses should be reduced in these patients. Conversely, patients with severe burns or who suffer from upper motor neuron disease are less responsive to these agents, probably as a result of proliferation of extrajunctional nicotinic receptors.