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 AGENTCHEMICAL CLASSPHARMACOLOGICAL PROPERTIES TIME OF ONSET, min DURATION, min MODE OF ELIMINATION Succinylcholine (ANECTINE, others) Dicholine esterUltrashort duration; depolarizing Hydrolysis by plasma cholinesterases d-TubocurarineNatural alkaloid (cyclic benzylisoquinoline) Long duration; competitive Renal elimination; liver clearance Atracurium (TRACRIUM) BenzylisoquinolineIntermediate duration; competitive Hofmann degradation; hydrolysis by plasma cholinesterases Doxacurium (NUROMAX) BenzylisoquinolineLong duration; competitive Renal elimination; liver metabolism and clearance Mivacurium (MIVACRON) BenzylisoquinolineShort duration; competitive Hydrolysis by plasma cholinesterases Pancuronium (PAVULON) Ammonio steroidLong duration; competitive Renal elimination; liver metabolism and clearance Pipecuronium (ARDUAN) Ammonio steroidLong duration; competitive Renal elimination; liver metabolism and clearance Rocuronium (ZEMURON) Ammonio steroidIntermediate duration; competitive Liver metabolism; renal elimination Vecuronium (NORCURON) Ammonio steroidIntermediate duration; competitive 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

DrugEffect on autonomic gangelia Effect on cardiac muscarinic receptor Tendency to cause histamine releases Isoquinoline derivatives Atracurium None slight CisatracuriumNone DoxacuriumNone MetocuriumWeak blockNoneSlight MivacuriumNone Slight TubocurarineWeak blockNoneModerate Steroid derivatives Pancuronium NoneModerate block None PipecuroniumNone RapacuroniumNoneVery slight blockNone VecuroniumNone Other agents Gallamine NoneStrong blockNone SuccinylcholineStimulation 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 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 excitation- contraction coupling

Diazepam –Facilitating the action of  -aminobutyric acid (GABA) –Acts at all GABA A synapses –Useful in muscle spasms of any origin Baclofen –GABA B 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