1. Skeletal Muscle RelaxantsBy
S. Bohlooli, PhD
Functional circuitry between the cortex, basal ganglia, and thalamus. The major neurotransmitters are indicated. In Parkinson's disease, there is degeneration of the pars compacta of the substantia nigra, leading to overactivity in the indirect pathway (red) and increased glutamatergic activity by the subthalamic nucleus.

2. Drugs affecting skeletal muscle function
Neuromuscular blockers
Used during surgical procedures and ICU
Spasmolytics
to reduce spacticity in various neurologic conditions

3. Neuromuscular blocking drugs
History
Raw material in arrow poison called curare
d-tubucurarine
Mechanism of blocked
Depolarinzing agoinst
Non depolarizing antagonist
Normal neuromuscular function

5. Molecular structure of the nicotinic cholinergic receptor.

6. Basic pharmacology of neuromuscular blocking drugs
Chemistry
Structurally resemble to acetylcholine
conserving double acetylcholine structure
Most of them have two quaternary nitrogens

9. PHARMACOLOGICAL PROPERTIES
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)
90-120
Renal elimination; liver metabolism and clearance
Mivacurium (MIVACRON)
Short duration; competitive
12-18
Pancuronium (PAVULON)
Ammonio steroid
Pipecuronium (ARDUAN)
80-100
Rocuronium (ZEMURON)
1-2
Liver metabolism; renal elimination
Vecuronium (NORCURON)
Liver metabolism and clearance; renal elimination

10. 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

11. 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

12. 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

13. Effect of neuromuscular blocking drugs on other tissues
Effect on autonomic gangelia
Effect on cardiac muscarinic receptor
Tendency to cause histamine releases
Isoquinoline derivatives
Atracurium
None
slight
Cisatracurium
Doxacurium
Metocurium
Weak block
Slight
Mivacurium
Tubocurarine
Moderate
Steroid derivatives
Pancuronium
Moderate block
Pipecuronium
Rapacuronium
Very slight block
Vecuronium
Other agents
Gallamine
Strong block
Succinylcholine
Stimulation

14. Effect seen only with depolarizing blockades
Hyperkalemia
Increased intraocular pressure
Increased intragastric pressure
Muscle pain

15. 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

16. 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

17. 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.

18. 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

19. Postulated sites of spasmolytic action
Postulated sites of spasmolytic action of tizanidine (2), benzodiazepines (GABAA), and baclofen (GABAB) in the spinal cord. Tizanidine may also have a postsynaptic inhibitory effect. Dantrolene acts on the sarcoplasmic reticulum in skeletal muscle. Glu, glutamatergic neuron.

20. Other drugs that act in the CNS
Gabapentin
Progabide
Glycine
Idrocilamide
Riluzole

21. 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 .

22. Special application is in the treatment of malignant hyperthermia
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

23. 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