Skeletal Muscle Relaxants

Published on 28/02/2015 by admin

Filed under Basic Science

Last modified 28/02/2015

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 2795 times

Chapter 12 Skeletal Muscle Relaxants

ACh Acetylcholine
AChE Acetylcholinesterase
CNS Central nervous system
GABA γ-Aminobutyric acid

Therapeutic Overview

Drugs that relax skeletal muscle are classified according to their use and mechanisms of action. These agents include the neuromuscular blocking agents, which produce muscle paralysis required for surgical procedures, and the spasmolytics, which are used to treat muscle hyperactivity.

The introduction of the neuromuscular blockers in the early 1940s marked a new era in anesthetic and surgical practice. Today, many surgical procedures are performed more safely and rapidly with the aid of drugs that produce skeletal muscle paralysis. These drugs interrupt transmission at the skeletal neuromuscular junction and are classified according to their action as either depolarizing or nondepolarizing.

The spasmolytics include antispasticity drugs, the antispasm drugs, and the motor nerve blocking drug botulinum toxin. The antispasticity drugs include agents such as baclofen that act via the spinal cord, and dantrolene, which has a direct action on skeletal muscle and is often referred to as a directly acting skeletal muscle relaxant. These agents alleviate skeletal muscle hyperactivity, cramping, and tightness caused by specific neurological disorders such as multiple sclerosis, cerebral palsy, stroke, or spinal injury. Although these drugs are not curative, their ability to relieve symptoms enables patients to successfully pursue other treatments, such as physical therapy.

The antispasm drugs, formerly known as centrally active muscle relaxants, include agents such as cyclobenzaprine, metaxalone, and methocarbamol and are used to treat use-related muscle spasms. These compounds relax skeletal muscle by acting on the central nervous system (CNS) and perhaps spinal reflexes.

The motor nerve blocker botulinum toxin is used for muscle disorders of the eye (blepharospasm and strabismus), certain forms of spasticity (e.g., cerebral palsy), and elective cosmetic purposes. Botulinum toxin produces

long-lasting muscle paralysis by blocking the release of acetylcholine (ACh) from motor nerves.

Clinical uses of these compounds are listed in the Therapeutic Overview Box.

Therapeutic Overview
Neuromuscular blocking drugs
Endotracheal intubation
Reduce muscle contractility and depth of anesthesia required for surgery
In the intensive care unit to prevent high airway pressures, decrease O2 consumption, and abolish muscle rigidity in patients on mechanical ventilation
Prevent bone fractures during electroconvulsive therapy
Antispasticity drugs
Reduce muscle cramping and tightness in neurological disorders and spinal cord injury and disease
Antispasm drugs
Prevent use-related minor muscle spasms
Motor nerve blocker (Botulinum toxin)
Blepharospasm and strabismus
Elective cosmetic purposes

Mechanisms of Action

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.

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.

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.


Antispasticity Drugs

The antispasticity agents include baclofen, which is a structural analog of γ-aminobutyric acid (GABA). Baclofen decreases spasticity by binding to GABAB receptors on presynaptic terminals of spinal interneurons (Fig. 12-3). Binding to presynaptic GABAB 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.

Benzodiazepines such as diazepam have an antispasticity effect by acting on GABAA 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.