Skeletal Muscle Relaxants

Classes of muscle relaxant

1. Centrally acting muscle relaxants: diazepam, baclofen, tizanidine,
clonidine, cyclobenzaprine
2. Peripherally acting muscle relaxants:
(i) botulinum toxin
(ii) neuromuscular-blocking agents
-Depolarizing agents: succinylcholine, suxamethonium
-Nondepolarizing or competitive blocking
agents: tubocurarine, pancuronium, atracurium, vecuronium.
(iii) Direct-acting muscle relaxants: dantrolene
Centrally acting muscle relaxants: Diazepam
Benzodiazepines
Mechanism of action: act by binding to a specific regulatory site on the GABAA
receptor, and increase the frequency of channel opening produced by GABA;
thus, enhancing the inhibitory effect of GABA.

From Katzung: Basic and Clinical Pharmacology, 11th edition,

2009.
 GABAA receptor

Flumazenil is a GABAA-receptor
antagonist that can rapidly reverse the
effects of benzodiazepines.
 GABAB receptor

Brodys Human Pharmacology, 5th edition, 2010

Benzodiazepines-mediated potentiation of GABA response

Harvry RA and Champe PC, Pharmacology, 4th edition, 2009

Pharmacological effects of benzodiazepine
1. Reduction of anxiety (by inhibiting synapses in the limbic system, a
CNS region associated with the control of emotional behavior)

2. Sedation and induction of sleep (facilitating sleep onset and

increasing the overall duration of sleep)

3. Reduce skeletal muscle spasticity by increasing the activation of

inhibitory GABAergic interneurons in the spinal cord.

4. Antiepileptic effect stem from their ability to augment GABA-

mediated membrane hyperpolarization and, thus, to decrease the
neuronal excitability that contributes to seizure onset.
Therapeutic uses of benzodiazepine
Chronic, severe anxiety, and the anxiety associated with some
forms of depression and schizophrenia.

Muscular disorders:diazepam is useful in the treatment of

skeletal muscle spasms such as occur in muscle strain, and in
treating spasticity from degenerative disorders, such as multiple
sclerosis and cerebral palsy.

Seizures

Sleep disorders

Adjunct for anaesthesia (reduce preoperative anxiety); IV

general anesthetic.
Side effects of benzodiazepines

Drowsiness and confusion: the most common side effects

Ataxia
Cognitive impairment (learning and memory)
Tolerance
Dependence (psychological and physical dependence) can develop
if high doses of the drugs are given over a prolonged period.
 Toxicity of bezodiazepines
High doses of benzodiazepines rarely cause death unless administered
with other drugs, such as ethanol, CNS depressants, opioid analgesics, or
tricyclic antidepressants.

One possible cause of the enhanced CNS depression seen with

concomitant ethanol and benzodiazepine use is the ethanol-mediated
inhibition of hepatic microsomal enzymes. This effect is thought to
decrease benzodiazepine clearance and, thus, lead to increased CNS
depression.
 Pharmacokinetics of bezodiazepine
Rapid and complete absorption after oral administration and
distribute throughout the body (due to their lipophilic nature)
Metabolized by hepatic microsomal enzymes and excreted in the urine.
Because benzodiazepine metabolism can generate active metabolites
with longer half-lives than that of the original drug, the
pharmacodynamic effects may extend beyond the expected duration
of action.
Duration of action: The half-lives of the benzodiazepines are very
important clinically, because the duration of action may determine the
therapeutic usefulness.
1. Half-lives
2. Receptor dissociation rates
3. Redistribution
Harvry RA and Champe PC, Pharmacology, 4th edition, 2009
 Centrally acting muscle relaxant: baclofen
Mechanism of action: inhibiting the afferent
input to the a motor neurons via interaction
with presynaptic GABAB receptors on the
afferent nerve terminals, thus less
neurotransmitter (glutamate) is released for
activating the a motor neurons. Activation of
GABAB receptors in the brain as well as in the
spinal cord results in hyperpolarization,
probably by increased K+ conductance. This
causes presynaptic inhibition by reducing
Ca2+ influx and reduces the release of
neurotransmitters.

It is usually given orally and it is rapidly and

completely absorbed from the gut and has a
plasma half-life of 3-4 hours.

It is effective for spasticity due to spinal cord From Katzung: Basic and Clinical
Pharmacology, 11th edition, 2009.
lesions. It may also reduce pain in patients
with spasticity, perhaps by inhibiting the
release of substance P in the spinal cord.
 Centrally acting muscle relaxant: Tizanidine
and clonidine
a2-adrenoceptor agonist
Reduce muscle spasm, probaly through
peripheral and central effects.
Side effects: drowsiness, hypotension, dry
mouth

Harvry RA and Champe PC, Pharmacology, 4th edition, 2009

From Katzung: Basic and Clinical Pharmacology, 11th edition, 2009.
Peripherally acting muscle relaxants

From Katzung: Basic and Clinical Pharmacology, 11th edition, 2009.

Acetylcholine release
inhibitor: Botulinum toxin

Botulinum toxin degrades synaptobrevin and, thus,

prevents synaptic vesicle fusion with the axon
terminal membrane. It is currently used in the
treatment of several diseases associated with
increased muscle tone, such as cerebral palsy. It is
also approved for cosmetic treatment of ficial lines
or wrinkles.

Brodys Human Pharmacology, 5th edition, 2010

Neuromuscular-blocking agents
-Depolarizing agents: succinylcholine,suxamethonium
-Non-depolarizing or competitive blocking
agents:tubocurarine,pancuronium,atracurium,vecuronium.
 Dantrolene sodium
Mechanism of action: inhibition of skeletal muscle excitation-contraction
coupling by decreasing calcium release from the sarcoplasmic reticulum, so
relieves spasticity by a direct action on skeletal muscle.

Not only relieves spasticity but also produce muscle weakness, which
reduces its clinical usefulness.

A special application of dantrolene is in the treatment of malignant

hyperthermia, a rare heritable disorder that can be triggered by a variety
of stimuli, including general anesthetic and neuromuscular blocking drugs
(eg, succinylcholine). Patients have a hereditary impairment in the ability of
the sarcoplasmic reticulum to sequester calcium. Following adminstration
of one of the triggering agents, there is a sudden and prolonged release of
calcium, with massive muscle contraction, lactic acid production, and
increased body temperature.
 Dantrolene sodium
It is ususlly given orally, but it is not completely absorbed.

Side effects: muscle weakness, seadation and hepatotoxicity.

This drug is contraindicated in patients with either respiratory

muscle weakness or liver disease.

Regular liver function test is recommended when this drug is used

therapeutically.
 Skeletal muscle relaxants
Diazepam, baclofen,tizanidine, clonidine, cyclobenzaprine
Brain

Botulium toxin

Neuromuscular blocking drugs

Therapeutic uses of muscle relaxants
Facilitate endotracheal intubation
Relieve laryngeal spasm
Provide relaxation during surgical procedures
Reduce muscular spasticity in neurological disorders
Reduce the muscular spasm and pain resulting from
sprains, arthritis, myositis and fibrositis
 Anxiolytics
Benzodiazepines-diazepam
Nonbenzodiazepine- buspirone
tricyclic antidepressants
(TCA)
selective serotonin
reuptake inhibitors
(SSRIs)
monoamine oxidase
inhibitors (MAOIs)
 Barbiturates
Mechanism of action: Interaction with GABAA receptors,
which enhances GABA action on chloride entry into the
neuron by prolonging the duration of the chloride channel
openings.

Actions:
1. Depression of CNS: Degree of depression of the CNS
depends on the dose. At low doses, they produce sedation.
At higher doses, the drugs cause hypnosis, followed by
anesthesia, and finally, coma and death. The drugs have no
analgesic properties. Chronic use leads to tolerance.
2. Respiratory depression: suppress the chemoreceptor response
to CO2 and overdosage is followed by respiratory depression
and death.
3. Enzyme induction: induce p450 microsomal enzymes in the
liver.
 Barbiturates
Therapeutic uses:
1. Anesthesia: Ultrashort-acting barbiturates, such as thiopental, are used
intravenously to induce anesthesia.
2. Anticonvulsant: Phenobarbital
3. Anxiety
Pharmacokinetics: Cross the blood-brain barrier. Absorbed orally and
distributed widely throughout the body. Redistribution is important in
causing the short duration of action of drugs (thiopental). Hepatic
metabolism.
Poisoning: Cause death resulting from drug
overdoses, which severely suppress
respiration and central cardiovescular center.
Treatment includes artificial respiration,
purging the stomach of its contents,
hemodialysis and alkalinization of the urine.

Barbiturates have been largely replaced by

the benzodiazepines, primarily because
barbiturates (1) induce tolerance, drug-
metabolizing enzymes, physical dependence,
and are associated with very severe
withdrawal symptoms;(2) cause coma in
toxic dose.

Harvry RA and Champe PC, Pharmacology, 4th edition, 2009

 Buspirone
Dose not interact directly with GABAergic system
5-HT1A receptor agonist
Relieve anxiety without causing marked sedative or
hypnotic effects
Has no anticonvulsant or muscle relaxant properties
Anxiolytic effects take days or weeks to develop
It causes less coordination impairment than
benzodiazepines. The drug does not potentiate effects
of conventional sedative-hypnotic drugs, ethanol.
Principles of Pharmacology, 2nd, 2008