Download Skeletal muscle relaxants

Skeletal Muscle Relaxants
By
S. Bohlooli, PhD
Drugs affecting skeletal muscle function
• Neuromuscular blockers
Used during surgical procedures and ICU
• Spasmolytics
to reduce spacticity in various neurologic
conditions
Neuromuscular blocking drugs
• History
– Raw material in arrow poison called curare
– d-tubucurarine
• Mechanism of blocked
– Depolarinzing agoinst
– Non depolarizing antagonist
• Normal neuromuscular function
Molecular structure of the nicotinic cholinergic receptor.
Basic pharmacology of
neuromuscular blocking drugs
• Chemistry
– Structurally resemble to acetylcholine
– conserving double acetylcholine structure
– Most of them have two quaternary nitrogens
Some chemical and pharmacokinetic properties of neuromuscular blocking drugs
Classification of Neuromuscular Blocking Agents
AGENT
CHEMICAL CLASS
PHARMACOLOGICAL
PROPERTIES
Succinylcholine
(ANECTINE,
others)
Dicholine ester
Ultrashort duration;
depolarizing
d-Tubocurarine
Natural alkaloid (cyclic
benzylisoquinoline)
Atracurium
(TRACRIUM)
TIME OF
ONSET
, min
DURATION,
min
MODE OF ELIMINATION
1-1.5
6-8
Hydrolysis by plasma
cholinesterases
Long duration;
competitive
4-6
80-120
Renal elimination; liver
clearance
Benzylisoquinoline
Intermediate
duration;
competitive
2-4
30-40
Hofmann degradation;
hydrolysis by plasma
cholinesterases
Doxacurium
(NUROMAX)
Benzylisoquinoline
Long duration;
competitive
4-6
90-120
Renal elimination; liver
metabolism and
clearance
Mivacurium
(MIVACRON)
Benzylisoquinoline
Short duration;
competitive
2-4
12-18
Hydrolysis by plasma
cholinesterases
Pancuronium
(PAVULON)
Ammonio steroid
Long duration;
competitive
4-6
120-180
Renal elimination; liver
metabolism and
clearance
Pipecuronium
(ARDUAN)
Ammonio steroid
Long duration;
competitive
2-4
80-100
Renal elimination; liver
metabolism and
clearance
Rocuronium
(ZEMURON)
Ammonio steroid
Intermediate
duration;
competitive
1-2
30-40
Liver metabolism; renal
elimination
Vecuronium
(NORCURON)
Ammonio steroid
Intermediate
duration;
competitive
2-4
30-40
Liver metabolism and
clearance; renal
elimination
Mechanism of action
• Nondepolarizing blocking drugs
– Prototype is tubocurarine
– Surmountable blockade
– Low doses  act at nicotinic receptor site
– High doses  blockade of ion channel pore
Mechanism of action
• Depolarizing blocking drugs
– Phase I block ( depolarizing)
• Depolarization of the end plate
• Causing generalized disorganized contraction of muscle
motor unit
• Finally flaccid paralysis occur
• Augmented by cholinesterase inhibitors
– Phase II block ( desensitizing )
•
•
•
•
•
Membrane become repolarized
Desensitized
Mechanism is unclear  channel blocking is important
Resemble to that of nondepolarizing drugs
Surmountable by acetyl cholinesterase inhibitors
Clinical pharmacology
• Skeletal muscle paralysis
– Nondepolarizing drugs
•
•
•
•
Flaccid paralysis
Larger muscles are more resistant and recover more rapidly
Duration of action
Time to onset of effect
– Depolarizing drugs
• Transient fasciculations followed by flaccid paralysis
• Rapid onset and short duration of action
• Control of ventilation
• Treatment of convulsions
Effect of neuromuscular blocking drugs on other tissues
Drug
Effect on
autonomic
gangelia
Effect on cardiac
muscarinic
receptor
Tendency to cause
histamine releases
Isoquinoline derivatives
Atracurium
None
None
Cisatracurium
None
None
None
Doxacurium
None
None
None
Metocurium
Weak block
None
Slight
Mivacurium
None
None
Slight
Tubocurarine
Weak block
None
Moderate
Steroid derivatives
Pancuronium
None
Moderate block
Pipecuronium
None
None
None
Rapacuronium
None
Very slight block
None
Vecuronium
None
None
None
Other agents
Gallamine
None
Strong block
None
Succinylcholine
Stimulation
Stimulation
slight
slight
None
Effect seen only with depolarizing blockades
•
•
•
•
Hyperkalemia
Increased intraocular pressure
Increased intragastric pressure
Muscle pain
Interaction with other drugs
• Anesthetics
Augmentation of effect with Isoflurane, sevoflurane,
desfulrane, and enflurane > halothane > nitrous
oxide-barbiturate-benzodiazepine-opioid anesthesia
• Antibiotics
Especially aminoglycosides
• Local anesthetics and antiarrhythmic drugs
• Other neuromuscular blocking drugs
Spasmolytic drugs
• What is spasticity?
• Spasticity is characterized by an increase in tonic stretch
reflexes and flexor Muscle spasms together with muscle
weakness. Often associated with cerebral palsy, multiple
sclerosis , and stroke.
• It appear to involve not the stretch reflex arc itself but higher
centers (“ upper motor neuron lesion”)
• Drugs may ameliorate some symptoms by:
 Acting at CNS level
 Acting at stretch reflex arc
 Acting directly with skeletal muscle excitationcontraction coupling
• Diazepam
– Facilitating the action of -aminobutyric acid
(GABA)
– Acts at all GABAA synapses
– Useful in muscle spasms of any origin
• Baclofen
– GABAB agonist
– Induce hyperpolarization  serve as
presynaptic inhibitory function
– Toxicity: drowsiness, seizure activity
– Intrathecal administration effective in sever
spasticity.
• Tizanidine
– It is congener of clonidine
– 2-adrenoceptor agonist
– Reinforces both presynaptic and postsynaptic
inhibition in the cord and inhibition of nociceptive
transmission
– Toxicity: drowsiness, hypotension, dry mouth,
asthenia
– Dose requirement is varies markedly among patient
Postulated
sites of
spasmolytic
action
Other drugs that act in the CNS
•
•
•
•
•
Gabapentin
Progabide
Glycine
Idrocilamide
Riluzole
Dantrolene
• Chemically is a hydantoin derivative
• It reduces skeletal muscle strength by interfering
with excitation-coupling in the muscle fiber.
• In detail, dantrolene bind to ryanodine receptor
and blocks calcium release from sarcoplasmic
reticulum .
• Pharmacokinetics
– Only one-third of an oral dose of dantrolene is
absorbed.
– Half life is about 8 hours
– Major adverse effects are generalized muscle
weakness, sedation, and occasionally
hepatitis
• Special application is in the treatment of
malignant hyperthermia
Other drugs used for local muscle
spasm
•
•
•
•
Botulinum toxin
Carisoprodol
Chlorophenesin
Chlorzoxone
•
•
•
•
Cyclobezaprine
Metaxalone
Methocarbamol
orphenadrine
•Most of them act as sedative or at level of the spinal cord or
brain stem
•The main therapeutic use is in relief of acute temporary
muscle spasm cause by Local trauma or strain