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

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)

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

Nondepolarizing & Depolarizing Agents

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

ACh at the Synapse

Cholinergic Nicotinic (NM) Receptors- Neuro Muscular Junction

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

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

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

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

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

PK Properties of NMB Agents Highly polar, inactive orally, administered IV/IM, low Vd(80-140 mL/ kg) Drugs- Elimination- Duration of action Tubocurarine- renal - >35 min Doxacurium- renal - >35 min Atracurium- spontaneous- 20-35min Mivacurium- plasma ChE- 10-20min

PK Properties of NMB Agents Drugs Elimination Duration of action Pancuronium- renal- >35min Pipecuronium- renal & liver- >35min Vecuronium- liver & renal- 20-35min Rocuronium- liver & renal- 20-35min S-choline- plasma ChE- < 8min

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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)