1. Skeletal Muscle Relaxants
Dept. of Pharmacology
Faculty of Medicine & Health Sciences
AIMST

2. Skeletal Muscle Relaxants
Peripherally or centrally acting
(Diazepam, Baclofen)
N.M.Junction Directly (Dantrolene Na)
Nondepolarizing Depolarizing
(-)Release of ACh from vesicle
(Botulinum Toxin-A, B, F)

3. Nondepolarizing & Depolarizing Agents
d-Tubocurarine
Gallamine
Pancuronium
Pipecuronium
Vecuronium
Rocuronium
Atracurium
Mivacurium
Doxacurium
Depolarizing
Succinylcholine
Decamethonium

4. Nondepolarizing & Depolarizing Agents

5. Centrally & Peripherally Acting
↓Muscle tone without ↓voluntary power
(-)polysynaptic reflexes in CNS
CNS depression
Orally/IV
Used in chronic spastic condition/ acute muscle spasm/ tetanus
Muscle paralysis with ↓voluntary movement lost
Block N.M. transmission
No effect on CNS
IV only
Used during surgical operation in short term

6. ACh at the Synapse

7. Cholinergic Nicotinic (NM) Receptors- Neuro Muscular Junction

8. Nondepolarizing (d-Tubocurarine) Mechanism of Action
Acts as an antagonist → compete with ACh for binding to NM receptor at NMJ → flaccid, relaxed paralysis
NMJ block can be reversed by AChE inhibitors

9. Succinylcholine-Mechanism of Action
Depolarizes the postsynaptic membrane in a manner similar to ACh, but dissociates less readily from the receptor than does ACh
Succinylcholine exerts its initial action by opening ion channels in a manner similar to ACh, but persists on the receptor

10. Two Phases of Depolarization Blockers
Phase I
Agonist effect---succinylcholine binds, producing depolarization
Muscle tremor & fasciculation, then flaccid paralysis
Not immediately metabolized, therefore membrane remains depolarized
Effect potentiated by cholinesterase inhibitors

11. Two Phases of Depolarization Blockers (cont.)
Phase II
Blockade--initial depolarization decreases
Membrane becomes repolarized
However, unresponsive to ACh
May be the result of a change in conformation of the receptor
Effect can be reversed by cholinesterase inhibitors

12. Succinylcholine-Mechanism of Action(Summary)
Phase 1 block: acts as an agonist of ACh to bind with NM receptor at NMJ - membrane depolarization-transient fasciculations followed by paralysis
Phase 2 block: desensitization- membrane repolarizes, hyposensitive to ACh

13. PK Properties of NMB Agents
Highly polar, inactive orally, administered IV/IM, low Vd( mL/ kg)
Drugs- Elimination- Duration of action
Tubocurarine- renal >35 min
Doxacurium- renal >35 min
Atracurium- spontaneous min
Mivacurium- plasma ChE min

14. PK Properties of NMB Agents
Drugs Elimination Duration of action
Pancuronium- renal >35min
Pipecuronium- renal & liver- >35min
Vecuronium- liver & renal min
Rocuronium- liver & renal min
S-choline plasma ChE < 8min

15. Pharmacological Actions
Skeletal muscles: Eyes & Fingers→ Hands & Feet→Arm, Legs, Neck, Face → Trunk→Intercostal Muscle→ Diaphragm paralysed (recovery in reverse order)
Autonomic ganglia-block or stimulation
Histamine release-↓BP, flushing, bronchospasm

16. Pharmacological Actions(cont.)
CVS- d-tubocurarine causes ↓BP by ganglion block, histamine release, ↓venous return-Pancuronium & Gallamine causes ↑HR by blocking cardiac M2 receptor -s-choline- ↓HR by stimulation of cardiac M2 receptor & ↑HR by stimulation of ganglia
Other actions by s-choline-↑K+, ↑IOP, muscle pain

17. Therapeutic Uses d-tubocurarine Adjuvants to GA
Treatment of convulsion
For controlled ventilation
Succinylcholine
Brief procedures like endotracheal intubation/ bronchoscopy/ oesophagoscopy/ laryngoscopy
Reduction of fracture
To ↓trauma in ECT

18. Adverse Effects
Respiratory paralysis & prolonged apnoea (scoline apnoea)
Flushing
↓BP & CVS collapse
Cardiac arrhythmias & arrest
Can precipitate asthma
Post operative muscle soreness
Malignant hyperthermia

19. Prolonged Apnea with Succinylcholine
Genetically atypical pseudocholinesterase
Autosomal recessive trait characterized by low affinity of butyrylcholinesterase for the substrate
Detected using Dibucaine, a local anesthetic which inhibits esterase activity

20. Malignant Hyperthermia
Any volatile anesthetic, but especially halothane
Succinylcholine
Mutation in the Ca++ release mechanism of the SR/Ryanodine receptor
Excessive release of Ca++ occurs
Widespread muscle rigidity
Reverse effects with Dantrolene-Na
Increased body temperature

21. Malignant Hyperthermia-Treatment
Administer oxygen 100% - with hyperventilation
Dantrolene-Na
Correct acidosis- bicarbonate
Control hyperkalemia
Cooling/pack in ice

22. Important Drug Interactions
Antagonism with anticholinesterase (Neostigmine)
Potentiation with General Anesthetics, Antibiotics (Aminoglycosides),Ca2+ channel blockers, etc.

23. Botulinum Toxin–Type A
Produced by Clostridium botulinum
(-)release of ACh from cholinergic vesicles
Uses:
Spasmodic torticollis
Hemifacial spasm
Blepharospasm
Laryngospasm

24. Dantrolene Na–Oral/IV
Compete with ryanodine for binding with Ca2+ channel→ (-)release of Ca2+ from S.R. Ca2+ channel
Uses
UMN disorder/Hemiplegia/Paraplegia/Cerebral Palsy/Multiple Sclerosis/Malignant Hyperthermia/ Neuroleptic Malignant Syndrome
Adverse Effects
Muscular weakness/Sedation/Malaise/Diarrhoea/ Liver Toxicity

25. Diazepam
Facilitates the action of GABA in CNS→influx of Cl- ion→ hyperpolarization of membrane→ Sk.muscle relaxation
Use in muscle spasm of any origin like spinal injury/tetanus/local muscle trauma
Adverse effects like sedation/ dependence/amnesia,etc.

26. Baclofen–Oral/Intrathecal
GABA agonist at GABAB receptor→↑K+ conductance→ hyperpolarization of membrane→Sk.mus.relaxation
Also(-)release of Substance P
Use in severe spasticity & pain like multiple sclerosis/ALS(amyotropic lateral sclerosis)/spinal injuries
Adverse effects like drowsiness/confusion/ seizure/respiratory depression/coma

27. Others
Mephenesin/Chlorzoxazone/Carisoprodol/ Chlormezanone/Methocarbamol/ Orphenadrine/Cyclobenzaprine
Sedation/(-)polysynaptic reflexes in CNS
Use in acute muscle spasm due to trauma or strain
Adverse effects like gastric irritation/ sedation

28. Skeletal Muscle Relaxants- Lecture Summary
Classification with examples
Peripheral vs. centrally acting agents
Mechanism of action of Nondepolarizing & Depolarizing agents

29. Skeletal Muscle Relaxants- Lecture Summary (contd.)
PK Properties of NMB Agents
Pharmacological actions
Therapeutic uses
Adverse effects
Important drug interactions
Botulinum toxin

30. Skeletal Muscle Relaxants- Lecture Summary (contd.)
Centrally acting agents-
Dantrolene(MOA/ Uses/Adverse Effects)
Diazepam(MOA/Uses/Adverse Effects)
Baclofen(MOA/Uses/Adverse Effects)
Others

31. For Further Reading..!
Goodman & Gilman’s The Pharmacologic Basis of Therapeutics (10th Edition) (Chapter 9)
Basic & Clinical Pharmacology by Bertram G. Katzung (9th Edition) (Chapter 27)
Clinical Pharmacology by D. R. Laurence, P. N. Bennett & M. J. Brown (8th Edition)(Chapter 21)