Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 27. Skeletal Muscle Relaxants

Skeletal Muscle Relaxants: Introduction

The drugs in this chapter are divided into 2 dissimilar groups. The neuromuscular blocking drugs, which act at the skeletal myoneural 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 tone caused by neurologic or muscle end plate disease.

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 blockadeSynonym for nonpolarizing blockade

Neuromuscular Blocking Drugs

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).

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, by plasma cholinesterase) or eliminated in the bile (eg, vecuronium) 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 less than 35 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.

Mechanism of Action

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, 11th ed. McGraw-Hill, 2009: Fig. 27-6.)

TABLE 27-1 Comparison of a typical nondepolarizing neuromuscular blocker (tubocurarine) and a depolarizing blocker (succinylcholine).

Succinylcholine Process Tubocurarine 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

aIt is not known whether this interaction is additive or synergistic (superadditive).

bThe amplitude is decreased, but the response is sustained.

Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 9th ed. McGraw-Hill, 2007.

Depolarizing Neuromuscular Blocking Drugs


Succinylcholine is composed of 2 ACh molecules linked end to end. Succinylcholine is metabolized by 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.

Mechanism of Action

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).

Reversal of Blockade

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.


Respiratory Paralysis

The action of full doses of neuromuscular blockers leads directly to respiratory paralysis. If mechanical ventilation is not provided, the patient will asphyxiate.

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 27-2 Autonomic effects of neuromuscular drugs.

Drug Effect on Autonomic Ganglia Effect on Cardiac Muscarinic Receptors Ability to Release Histamine Nondepolarizing Atracurium None None Slight Cisatracurium None None None Doxacurium None None None Mivacurium None None Moderate Pancuronium None Moderate block None Pipecuronium None None None Tubocurarine Weak block None Moderate Vecuronium None None None Depolarizing Succinylcholine Stimulation Stimulation Slight

Modified and reproduced with permission from Katzung BG, editor: Basic & Clinical Pharmacology, 10th ed. McGraw-Hill, 2007.

Specific Effects of Succinylcholine

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.

Drug Interactions

Inhaled anesthetics, especially isoflurane, strongly potentiate and prolong neuromuscular blockade. A rare interaction of succinylcholine (and possibly tubocurarine) with inhaled anesthetics can result in malignant hyperthermia. 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.

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.

Skill Keeper: Autonomic Control of Heart Rate

(See Chapter 6)

Tubocurarine can block bradycardia caused by phenylephrine but has no effect on bradycardia caused by neostigmine. Explain! The Skill Keeper Answer appears at the end of the chapter.

Spasmolytic Drugs

Certain chronic diseases of the CNS (eg, cerebral palsy, multiple sclerosis, stroke) are associated with abnormally high reflex activity in the neuronal pathways that control skeletal muscle; the result is painful spasm. Bladder control and anal sphincter control are also affected in most cases and may require autonomic drugs for management. In other circumstances, acute injury or inflammation of muscle leads to spasm and pain. Such temporary spasm can sometimes be reduced with appropriate drug therapy.

The goal of spasmolytic therapy in both chronic and acute conditions is reduction of excessive skeletal muscle tone without reduction of strength. Reduced spasm results in reduction of pain and improved mobility.

Drugs for Chronic Spasm


The spasmolytic drugs do not resemble ACh in structure or effect. They act in the CNS and in one case in the skeletal muscle cell rather than at the neuromuscular end plate. The spasmolytic drugs used in treatment of the chronic conditions mentioned previously include diazepam, a benzodiazepine (see Chapter 22); baclofen, a -aminobutyric acid (GABA) agonist; tizanidine, a congener of clonidine; and dantrolene, an agent that acts on the sarcoplasmic reticulum of skeletal muscle. These agents are usually administered by the oral route. Refractory cases may respond to chronic intrathecal administration of baclofen. Botulinum toxin injected into selected muscles can reduce pain caused by severe spasm (see Chapter 6) and also has application for ophthalmic purposes and in more generalized spastic disorders (eg, cerebral palsy). Gabapentin and pregabalin, antiseizure drugs, have been shown to be effective spasmolytics in patients with multiple sclerosis.

Mechanisms of Action

The spasmolytic drugs act by several mechanisms. Three of the drugs (baclofen, diazepam, and tizanidine) act in the spinal cord (Figure 27-2).


Sites of spasmolytic action of benzodiazepines (GABA A), baclofen (GABAB), tizanidine (2) in the spinal cord and dantrolene (skeletal muscle). AMPA, amino-hydroxyl-methyl-isosoxazole-proprionic acid, a ligand for a glutamate receptor subtype; Glu, glutamatergic neuron.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 27-11).

Baclofen acts as a GABA B agonist at both presynaptic and postsynaptic receptors, causing membrane hyperpolarization. Presynaptically, baclofen, by reducing calcium influx, decreases the release of the excitatory transmitter glutamic acid; at postsynaptic receptors, baclofen facilitates the inhibitory action of GABA. Diazepam facilitates GABA-mediated inhibition via its interaction with GABAA receptors (see Chapter 22). Tizanidine, an imidazoline related to clonidine with significant 2 agonist activity, reinforces presynaptic inhibition in the spinal cord. All 3 drugs reduce the tonic output of the primary spinal motoneurons.

Dantrolene acts in the skeletal muscle cell to reduce the release of activator calcium from the sarcoplasmic reticulum via interaction with the ryanodine receptor (RyR1) channel. Cardiac muscle and smooth muscle are minimally depressed. Dantrolene is also effective in the treatment of malignant hyperthermia, a disorder characterized by massive calcium release from the sarcoplasmic reticulum of skeletal muscle. Though rare, malignant hyperthermia can be triggered by general anesthesia protocols that include succinylcholine or tubocurarine (see Chapter 25). In this emergency condition, dantrolene is given intravenously to block calcium release.


The sedation produced by diazepam is significant but milder than that produced by other sedative-hypnotic drugs at doses that induce equivalent muscle relaxation. Baclofen causes somewhat less sedation than diazepam, and tolerance occurs with chronic use—withdrawal should be accomplished slowly. Tizanidine may cause asthenia, drowsiness, dry mouth, and hypotension. Dantrolene causes significant muscle weakness but less sedation than either diazepam or baclofen.

Drugs for Acute Muscle Spasm

Many drugs (eg, cyclobenzaprine, methocarbamol, orphenadrine) are promoted for the treatment of acute spasm resulting from muscle injury. Most of these drugs are sedatives or act in the brain stem. Cyclobenzaprine, a typical member of this group, is believed to act in the brain stem, possibly by interfering with polysynaptic reflexes that maintain skeletal muscle tone. The drug is active by the oral route and has marked sedative and antimuscarinic actions. Cyclobenzaprine may cause confusion and visual hallucinations in some patients. None of these drugs used for acute spasm is effective in muscle spasm resulting from cerebral palsy or spinal cord injury.

Patients with renal failure often have decreased levels of plasma cholinesterase, thus prolonging the duration of action of mivacurium or succinylcholine.

Skill Keeper Answer: Autonomic Control of Heart Rate

(See Chapter 6)

Reflex changes in heart rate involve ganglionic transmission. Activation of 1 receptors on blood vessels by phenylephrine elicits a reflex bradycardia because mean blood pressure is increased. One of the characteristic effects of tubocurarine is its block of autonomic ganglia; this action can interfere with reflex changes in heart rate. Tubocurarine would not prevent bradycardia resulting from neostigmine (an inhibitor of acetylcholinesterase) because this occurs via stimulation by ACh of cardiac muscarinic receptors.


When you complete this chapter you should be able to:

Describe the transmission process at the skeletal neuromuscular end plate and the points at which drugs can modify this process.

Identify the major nondepolarizing neuromuscular blockers and 1 depolarizing neuromuscular blocker; compare their pharmacokinetics.

Describe the differences between depolarizing and nondepolarizing blockers from the standpoint of tetanic and post-tetanic twitch strength.

 Describe the method of reversal of nondepolarizing blockade.

 List drugs for treatment of skeletal muscle spasticity and identify their sites of action and their adverse effects.

Drug Summary Table: Skeletal Muscle Relaxants

Subclass Mechanism of Action Receptor Interactions Pharmacokinetics Adverse Effects Depolarizing Succinylcholine Agonist at ACh-N receptors causing initial twitch then persistent depolarization Stimulates ANS ganglia and M receptors Parenteral: short action, inactivated by plasma esterases Muscle pain, hyperkalemia, increased intragastric and intraocular pressure Nondepolarizing d-Tubocurarine Cistracurium Mivacurium Rocuronium Vecuronium Competitive antagonists at skeletal muscle ACh-N receptors ANS ganglion block (tubocurarine) Cardiac M block (pancuronium) Parenteral use, variable disposition Spontaneous inactivation (atracurium, cisatracurium) Plasma ChE (mivacurium) Hepatic metabolism (rocuronium, vecuronium) Renal elimination (doxacurium, pancuronium, tubocurarine) Histamine release (mivacurium, tubocurarine) Laudanosine formation (atracurium) Muscle relaxation is potentiated by inhaled anesthetics, aminoglycosides and possibly quinidine Centrally acting Baclofen Facilitates spinal inhibition of motor neurons GABA B receptor activation: pre- and postsynaptic

Oral and intrathecal for severe spasticity Sedation, muscle weakness Cyclobenzaprine (many others; see text) Inhibition of spinal stretch reflex Mechanism unknown Oral for acute muscle spasm due to injury or inflammation M block, sedation, confusion, and ocular effects Diazepam Facilitates GABA-ergic transmission in CNS GABAA receptor activation—postsynaptic

Oral and parenteral for acute and chronic spasms Sedation, additive with other CNS depressants; abuse potential Tizanidine Pre- and postsynaptic inhibition 2 Agonist in spinal cord

Oral for acute and chronic spasms Muscle weakness, sedation, hypotension Direct-acting Dantrolene Weakens muscle contraction by reducing myosin-actin interaction Blocks RyR1 Ca2+ channels in skeletal muscle

Oral for acute and chronic spasms; IV for malignant hyperthermia Muscle weakness

ACh, acetylcholine; ANS, autonomic nervous system; ChE, choninesterase.

If you find an error or have any questions, please email us at admin@doctorlib.info. Thank you!