Drugs that relax skeletal muscle are divided into two dissimilar groups. The neuromuscular blocking drugs (NM blockers), which act at the skeletal neuromuscular junction, are used to produce muscle paralysis to facilitate surgery or assisted ventilation. The spasmolytic drugs, most of which act in the CNS, are used to reduce abnormally elevated muscle tone caused by neurologic or muscle end plate disease.
NEUROMUSCULAR BLOCKING DRUGS
A. Classification and Prototypes
Skeletal muscle contraction is evoked by motor neurons that release acetylcholine (ACh), which binds nicotinic cholinoceptors. 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 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). Neuromuscular blocking drugs do not enter the CNS and have no effect on cognition, memory, or sensory input, including perception of pain.
B. Nondepolarizing Neuromuscular Blocking Drugs
All NM blockers 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 Drugs that are metabolized (eg, mivacurium, withdrawn in the USA) or eliminated in the bile (eg, rocuronium) have shorter durations of action (10–20 min) than those eliminated by the kidney (eg, metocurine,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, thus atracurium is rarely used. Cisatracurium, a stereoisomer of atracurium, is also inactivated spontaneously but forms less laudanosine and currently is one of the muscle relaxants most commonly used in clinical practice.
Table Graphic Jump Location
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 nondepolarizing blockade |
2. Mechanism of action
Nondepolarizing drugs prevent the action of ACh at the skeletal muscle end plate (Figure 27–1). They act as surmountable blockers. (Thus, the ...