Download 1 spasmolytics

Antispastics & Spasmolytic
drugs that act centrally
Objectives
• Antispastics & Spasmolytic drugs that act
centrally:
Diazepam, Baclofen, Tizanidine,
Dantrolene,
Types of skeletal muscle relaxants:
2 groups
•
•
•
•
Neuromuscular blockers
Relax normal muscles
(surgery and assistance of
ventilation)
Interfere with transmission
at the motor end plate
No central nervous system
activity.
Used primarily as a part of
general anesthesia
Spasmolytics
• Reduce spasticity
• Centrally acting (except
dantrolene which act on the
skeletal muscle)
• Used in a variety of
neurologic conditions
Spasmolytic drugs
• Definition of muscle spasm (spasticity):
1. Increased muscle tone
2. together with muscle weakness
It is often associated with cerebral palsy,
multiple sclerosis, and stroke.
Centrally acting spasmolytic drugs
Drug
Mechanism
1- Diazepam
GABA receptor
2- Baclofen
GABA receptors causing hyperpolarization
by increasing potassium conductance
Averse effects: drowsiness and increased
seizure activity
3- Tizanidine
α2 adrenoreceptor agonist
4- Gabapentin
DIAZEPAM
• Benzodiazepines facilitate the action of γ-aminobutyric acid
(GABA) in the central nervous system.
• Diazepam acts at GABAA synapses, and its action in reducing
spasticity is at least partly mediated in the spinal cord
• Although diazepam can be used in patients with muscle spasm of
almost any origin (including local muscle trauma), it produces
sedation at the doses required to reduce muscle tone.
BACLOFEN
• Baclofen (p-chlorophenyl-GABA) was designed to be an
orally active GABA-mimetic agent, its spasmolytic activity at
GABAB receptors, this result in:
– hyperpolarization, probably by increased K+ conductance.
– inhibition of reducing calcium influx
– This will reduce excitation of spinal cords and reduce pain
in patients with spasticity, perhaps by inhibiting the
release of substance P (neurokinin-1) in the spinal cord.
• Baclofen is at least as effective as diazepam in reducing
spasticity while producing less sedation. In addition,
baclofen does not reduce overall muscle strength as much as
dantrolene.
• Adverse effects:
– Drowsiness, tolerant to the sedative effect with
chronic administration.
– Increased seizure activity has been reported in
epileptic patients.
• Therefore, withdrawal from baclofen must be
done very slowly.
TIZANIDINE
• Adverse effects, including drowsiness,
hypotension, dry mouth, and asthenia.
OTHER CENTRALLY ACTING
SPASMOLYTIC DRUGS
• Gabapentin
– It is an antiepileptic drug that has shown considerable promise as a
spasmolytic agent in several studies involving patients with multiple
sclerosis.
• Pregabalin
– is a new analog of gabapentin that may also prove useful. Progabide and
glycine have also been found in preliminary studies to reduce spasticity.
Progabide is a GABAA and GABAB agonist and has active metabolites,
including GABA itself. Glycine is another inhibitory amino acid
neurotransmitter. It appears to possess pharmacologic activity when
given orally and readily passes the blood-brain barrier.
• Idrocilamide and riluzole
– They are newer drugs for the treatment of amyotrophic lateral sclerosis
that appear to have spasm-reducing effects, possibly through inhibition
of glutamatergic transmission in the central nervous system.
Peripheraly acting spasmolytic drugs
Dantrolene:
Mechanism of action:
Dantrolene reduces skeletal muscle strength by interfering
with excitation-contraction coupling in the muscle fibers
Normal contraction involves release of calcium from its stores
in the sarcoplasmic reticulum through a calcium channel
• Dantrolene interferes with the release of calcium through
this sarcoplasmic reticulum calcium channel.
• Cardiac muscle and smooth muscle are depressed only
slightly, perhaps because the release of calcium from their
sarcoplasmic reticulum involves a different process.
Dantrolene:
• Indications:
1- Muscle spasticity
2- Malignant hyperthermia:
o Patients at risk for this condition have a hereditary impairment in
the ability of the sarcoplasmic reticulum to sequester calcium.
o Following administration of one of the triggering agents (general
anesthetics or succinylcholine) there is a sudden and prolonged
release of calcium, with massive muscle contraction, lactic acid
production, and increased body temperature.
Treatment of malignant hyperthermia:
1. control acidosis and body temperature
2. Reduce calcium release with intravenous dantrolene
• Major adverse effects
– are generalized muscle weakness, sedation, and occasionally
hepatitis.