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