The document discusses muscle relaxants and the neuromuscular junction. It describes how skeletal muscle relaxants act either peripherally at the neuromuscular junction or centrally in the spinal cord to reduce muscle tone. Neuromuscular blocking agents are used during anesthesia and ventilation to provide muscle relaxation. The document then goes into detail about the motor neuron, acetylcholine synthesis and receptors, and classification of different muscle relaxants.

1. Muscle Relaxants
By Muneeb Khan
Lecturer at Institute of Health Care Management and Development
Peshawar

2. Introduction
 The neuromuscular junction is made up of a motor neuron and a motor endplate with a synaptic cleft
or junctional gap dividing them.
 Skeletal muscle relaxants are drugs that act peripherally at neuromuscular junction / muscle fiber
itself or centrally in the cerebrospinal axis to reduce muscle tone and cause paralysis.
 The neuromuscular blocking agents are used in conjunction with general anesthesia to provide muscle
relaxation e.g. for surgery and in intensive care unit to facilitate ventilation.
 While centrally acting muscle relaxants are used primarily painful muscle spasms and spastic
neurological diseases.

3. The Motor Neuron
Control skeletal muscle activity.
 Originate in the ventral horn of the spinal cord
 Axons are surrounded by a myelin sheath
 Each motor neuron connects to several skeletal muscle fibers
 As the motor neuron enters a muscle, the axon divides into
telodendria, the ends of which, the terminal buttons, synapse
with the motor endplate.
 The junctional gap, release of the neurotransmitter
acetylcholine occurs with consequent binding to the receptors

4.  The surface of motor endplate is is deeply folded with
multiple crests and secondary clefts.
 The nicotinic acetylcholine receptors are located on the crests.
 The clefts of the motor endplate contain acetylcholinesterase peri-junctional zone.
 It is here that the potential developed at the endplate is converted to an action potential.
 The peri-junctional zone has an enhanced ability to produce a wave of depolarization to the muscle
from that produced by the post-synaptic receptors.

6. Acetylcholine synthesis, storage and release
 choline and acetyl-coenzyme A (mitochondria)
 50% of the choline is by a sodium dependent active transport system, the other 50% is from
acetylcholine breakdown.
 Choline acetyltransferase is produced on the ribosomes in the cell
 body of the motor neuron from where it is transported distally by exoplasmic flow to the terminal
button and can be found in high concentrations.
 The activity of choline acetyltransferase is inhibited by acetylcholine and increased by nerve
stimulation.
 Once synthesized the molecules of acetylcholine are stored in vesicles within the terminal button,
each vesicle containing approximately 10,000 molecules of acetylcholine.
 These vesicles are loaded with acetylcholine via a magnesium dependent active transport system in
exchange for a hydrogen ion.
 The vesicles then become part of one of three pools, each varying in their

7.  availability ability for release.
 1% are immediately releasable,
 80% are readily releasable and
 19% the stationary store.

8.  Miniature endplate potentials of 0.5-1mV,
 Muscle action potential, with the arrival of a nerve impulse, P-type calcium channels open, allowing
calcium to enter the cell.
 The combination of depolarization of the presynaptic terminal and influx of calcium triggers 100-300
vesicles to fuse with the presynaptic membrane and release acetylcholine into the synaptic cleft
(exocytosis).
 The depleted vesicles are rapidly replaced with vesicles from the readily releasable store and the
empty vesicles are recycled.

9. The neuromuscular junction

10. Acetylcholine Receptors
 Nicotinic acetylcholine receptors: ~ 50 million acetylcholine receptors
 Five polypeptide subunits surround an ion channel.
 adult receptor has two identical α subunits, one β one δ and one ε subunit.
 In the foetus a γ (gamma) subunit replaces the ε.
 Acetylcholine molecules bind to the α subunits and the ion channel is opened for just 1 msec. This
causes depolarization,
 The cell becomes less negative compared with the extracellular surroundings.
 When a threshold of –50mV is achieved (from a resting potential of –80mV), voltage- gated sodium
channels open, thereby increasing the rate of depolarization and resulting in an end plate potential
(EPP) of 50-100mV.
 This in turn triggers the muscle action potential that results in muscle contraction. By this method
the receptor acts as a powerful amplifier and a switch (acetylcholine receptors are not refractory).

11.  In addition to the post-junctional receptors , there are extrajunctional receptors, and pre-junctional
receptors.
 Denervation injuries and burns are associated with large increases in the number of extra-junctional
receptors.
 The extra junctional receptors have the structure of immature foetal receptors
 Pre-junctional receptors have a positive feedback role. In very active neuromuscular junctions
acetylcholine binds to these receptors and causes an increase in transmitter production via a second
messenger system. These receptors may also play a role in the “fade” seen in non-depolarising muscle
relaxant blockade by inhibiting replenishment of acetylcholine.

12. Acetylcholinesterase
 Hydrolysis of acetylcholine to choline and acetate by acetylcholinesterase (AChE).
 AchE has , an ionic site possessing a glutamate residue and an esteratic site containing a serine
residue. Hydrolysis occurs with transfer of the acetyl group to the serine group resulting in an
acetylated molecule of the enzyme and free choline.
 The acetylated serine group then undergoes rapid, spontaneous hydrolysis to form acetate and
enzyme ready to repeat the process.
 This enzyme is secreted by the muscle cell but remains attached to it by thin collagen threads linking
it to the basement membrane.
 Acetylcholinesterase is found in the junctional gap and the clefts of the postsynaptic folds and breaks
down acetylcholine within 1 m sec of being released.
 Therefore the inward current through the acetylcholine receptor is transient and followed by rapid
repolarization to the resting state.

13. Skeletal Muscle Relaxant Classification
 Centrally acting skeletal muscle Relaxant
E.g. Baclofen Diazepam
 Direct acting skeletal muscle Relaxants
E.g. Dantrolene
Peripherally acting Neuromuscular blockers

14. Peripherally acting
(A) Presynaptic neuromuscular blockers
 Inhibit acetylcholine synthesis
Triecthylacholine – Hemicholinium
 Inhibit acetylcholine release
Mg, Aminoglycosides, Botulinum Toxin,
(B) Postsynaptic Neuromuscular Blockers
 Competitive ( Non Depolarizing Blockers)
d-Tubocurarine
Gallamine
Atracurium
Pancuronium
Vacuronium
 Depolarizing neuromuscular
Succinylcholine ( Suxamethonium)

15. Uses of Neuromuscular Blockers
 Control Convulsion – Electroshock therapy in psychotic patient
 Relieve of tetanus and Epileptic convulsion
 Facilitate endoscopy
 As adjuvant to general anesthesia to induce muscle Relaxant
 Orthopedic Surgery

16. Types of Muscle Relaxants
 Non Competitive ( Depolarizing)
Succinylcholine
Decamethonium (No longer available)
 Competitive ( Non Depolarizing)
Atracurium
Cisaatracurium
Rocuronium
Pancuronium
Vecuronium
Mivacuronium

17. Classification Of Skeletal Muscle Relaxants
A- Neuromuscular blocking agents:
 1. According to their mechanism of action into:
 a) Competitive or Non Competitive
 b) depolarizing neuromuscular blockers.
 2. According to their duration of action into:
 a) Long-acting agents (more than 35 minutes) e.g. d-tubocurarine
 b) Intermediate-acting agents (20-35 minutes) e.g. gallamine, atracurium
 c) Short-acting agents (less than 20 minutes) e.g. succinyl choline, mivacurium
 3. According to their route of elimination from the body into:
 a) Agents eliminated via kidney e.g. gallamine (95%), pancuronium (80%)
 b) Agents eliminated via liver e.g. d-tubocuranine (60- 70%)
 c) Agents eliminated via plasma cholinesterase enzyme, e.g.succinylcholine.
 d) Agents spontaneously broken down (Hofmann elimination) e.g. atracurium.

18. B- Antispasticity agents
 Which are used to decrease painful muscle spasms. According to their
site of action, they are divided into
 1- Central muscle relaxants:
Their site of action is the spinal cord and subcortical areas of the brain. They
do not directly relax spastic muscles. They include benzodiazepine
 2- Direct muscle relaxants:
They do not act on central synapses or neuromuscular junction. They act
directly on skeletal muscles e.g. dantrolene

19. A.NEUROMUSCULAR BLOCKING AGENTS
 All of the neuromuscular blocking drugs has a chemical structural resemblance to acetylcholine.
 They are :
 a) poorly soluble in lipid
 b) They do not enter into the CNS.
 c) They do not affect consciousness.
 d) All are highly polar and inactive when given by mouth
 e) Intravenously.

20. ATRACURIUM (TRACIUM):
 1- potent as tubocurarine
 2- It has a shorter duration of action (~30 min).
 3- It is spontaneously broken down in the plasma by a
 non-enzymatic chemical process “Hofmann’s degradation”.
 Thus it is non-cumulative. It could be used in patients with
 either liver and/or kidney disease.
 4- It is the relaxant of choice in fragile patients and in renal
 failure.
 5- It is a weak histamine releaser, but has no effect on
 autonomic ganglia or on cardiac muscarinic receptor
 6- Dose: 0.5 mg/kg

21.  Drug Interactions
Synergists:
 a) inhalational anesthetics e.g. ether, halothane, isoflurane, act synergistically with competitive
blockers. Consequently their doses should be reduced..
 b) Some antibiotics, e.g. aminoglycosides as streptomycin, neomycin inhibit acetylcholine release
from cholinergic nerves by competing with calcium ions. The paralysis could be reversed by
administration of calcium ions.
 c) Local anesthetics e.g. procaine may block neuromuscular transmission through a stabilizing effect
on the nicotinic receptor ion channels.

22. Competitive Neuromuscular blocker
 Mechanism of Action
 Competitive Antagonist – Compete with Acetylcholine at the Nicotinic Receptor of NMJ.
 No Depolarization of the post junction membrane.
 Cholinesterase inhibitor can reverse blockade (Neostigmine).

23. Pharmacokinetics
 They are polar comp
 Inactive orally and taken parentally.
 No cross placenta and CNS
 Metabolism depend upon kidney and liver Except Atracurium- Mivacurium

24. Pharmacological Action
 Skeletal Muscle Relaxant
 CVS
Hypotension ( Histamine Release)
d-tubocurarine
Mivacurium
Atracurium
Heart Rate Increase
Gallamine
Pancurium

25. Gallamine
 Less potent than curare (1/5)
 Metabolized mainly by kidney 100%
 Long duration of Action
 Tachycardia due to
atropine like action
Release of NA from Adrenergic nerve endings.

26. D-tubocurarine
 More potent than Gallamine
 Long duration of Action ( 1-2 hrs)
 Eliminated by 60 % by Kidney and 40 % by liver.
 Histamine Releaser
Bronchospasm
Hypotension
 Block autonomic ganglia ( Hypotension)

27. Mivacurium
 Chemically Related to Atracurium.
 Metabolized by Pseudo Cholinesterase's.
 Fast Onset of Action
 Short duration of Action (15 min)
 Transient Hypotension ( Histamine Release)
 Longer duration in patients with liver diseases or Genetic cholinesterases deficiency.

28. Pancuronium
 More potent than Curare (6 times)
 Excreted by Kidney 80%
 Tachycardia
 Antimuscarinic action
 Increase Norepinephrine Release from adrenergic nerve ending

29. Vecuronium
 More potent than tubocururine ( 6 times)
 Metabolized mainly by liver
 Intermediate duration of action
 Has Few side Effect
No Histamine Release
No Ganglion block
No Antimuscarinic Action

30. Depolarizing Neuromuscular Blocker
Mechanism of Action
Phase I (Depolarizing)
Combine with nicotinic receptors Depolarization of motor end plate
Muscle twitching Persistent depolarization Paralysis.
Phase I block is augmented not reverse by Anticholinesterases.
Phase II ( Desensitization Block )
Continuous Exposure to succinylcholine depolarizing become decrease and the membrane become repolarized
But the membrane by Acetylcholine as long as succinylcholine present Desensitization of the membrane
This phase is reverse by Anticholinesterase.

31. Succinylcholine ( Suxamethonium)
Pharmacological Actions
 Skeletal Muscle Fasciculation Spastic Paralysis.
 Hyperkalemia Cardiac Arrest
 Eye Intraocular Pressure
 GIT Intragastric Pressure Regurgitation of gastric Content into the Esophagus
 CVS Arrhythmias

32. Pharmacokinetics
 Short onset of action ( 1 min)
 Short Duration of action ( 5 – 10 min)
 Destroyed by Pseudocholinesterase.

33. Mechanism of Action
Depolarization block
 Succinylcholine has a similar effect to acetylcholine on the motor end plate receptors (open the
sodium channel and cause depolarization of the motor end plate) but instead of producing transient
depolarization, it produces prolonged depolarization which is associated with transmission failure.
Thus it produces initial stimulation of the muscle which is manifested as fasciculation of the muscle
followed by muscle paralysis
 Succinylcholine stimulates the nicotinic receptors in sympathetic and parasympathetic ganglia (NN)
and the muscarinic receptors (M2) in the SA node of the heart.
 Histamine release, particularly in larger doses.

34. Side Effects:
1- Succinylcholine apnea:
 Occasionally succinylcholine produces prolonged apnoea due to lack of
 normal plasma (pseudo) cholinesterase levels.
 This may be the result of:
 a) Genetic abnormality in the enzyme:
 i- Its activity may be lower than normal or
 ii- Abnormal variant of pseudocholinesterase (atypical form of the
 enzyme) that may be totally unable to split succinylcholine.
 b) Acquired low level of pseudocholinesterase activity occurs in:
 i- Severe liver disease.
 ii- Malnutrition.
 iii- Exposure to insecticides.
 iv- Cancer patients
Treatment
 a) Artificial respiration until the muscle power returns.
 b) Fresh blood or plasma transfusion to restore cholinesterase
 enzyme level.
 c) No specific antidote is available.

35. Side Effects
 Hyperkalemia
 CVS arrhythmia ( Bradycardia Extrasystole and Cardiac Arrest )
 IOP Glaucoma
 Malignant Hyperthermia
 Succinylcholine Apnea due to :
I. Liver Diseases (Neonate Elderly )
II. Malnutrition
III. Organophosphorus poisoning.

36. Drugs Duration Side Effect Notes
Tubocurarine Long 1 Hrs Hypotension Renal Excretion
Renal Failure
Gallamine Long Tachycardia
Muscarinic Antagonist
Renal Failure
Pancuroniun Long Tachycardia
Muscarinic Antagonist
Renal Failure
Vecuronium Long Few Side Effect Liver Failure
Atracurium Short Transient Hypotension
Histamine Release
Spontaneous degradation
Used in liver and kidney failure
Cisatracurium Less Histamine Release
Mivacurium Short Similar to Cisatracurium
Metabolized by plasma
Cholinesterase
Suxamethonium Short Hyperkalemia
Arrhythmias
Increase IOP
CVS Disease
Glaucoma
Liver Disease

39. B. Spasmolytic
 Baclofen
Centrally acting ( GABA agonist )
 Diazepam
Centrally acting agent facilitate GABA action on CNS
 Dantrolene
Directly acting on Skeletal muscle
Uses of spasmolytics
Reduce muscle spasm in
I. Spinal cord injury
II. Stroke
III. Cerebral palsy