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
TIME OF ONSET
, min
DURATION, min
MODE OF ELIMINATION
Succinylcholine (ANECTINE, others)
Dicholine ester Ultrashort duration; depolarizing
1-1.5 6-8 Hydrolysis by plasma cholinesterases
d-Tubocurarine Natural alkaloid (cyclic benzylisoquinoline)
Long duration; competitive
4-6 80-120 Renal elimination; liver clearance
Atracurium (TRACRIUM)
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
• 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
Mechanism of action
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
Drug Effect on autonomic gangelia
Effect on cardiac muscarinic
receptor
Tendency to cause histamine releases
Isoquinoline derivativesAtracurium
None Noneslight
Cisatracurium None None None
Doxacurium None None None
Metocurium Weak block None Slight
Mivacurium None None Slight
Tubocurarine Weak block None Moderate
Steroid derivativesPancuronium
None Moderate blockNone
Pipecuronium None None None
Rapacuronium None Very slight block None
Vecuronium None None None
Other agentsGallamine
None Strong block None
Succinylcholine Stimulation Stimulation slight
Effect of neuromuscular blocking drugs on other tissues
Effect seen only with depolarizing blockades
• Hyperkalemia
• Increased intraocular pressure
• Increased intragastric pressure
• Muscle pain
Interaction with other drugs
• AnestheticsAugmentation of effect with Isoflurane, sevoflurane,
desfulrane, and enflurane > halothane > nitrous oxide-barbiturate-benzodiazepine-opioid anesthesia
• AntibioticsEspecially 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 levelActing at stretch reflex arcActing directly with skeletal muscle excitation-
contraction 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