This document discusses skeletal muscle relaxants and their reversal. It begins by defining neuromuscular blocking drugs as those that act at the neuromuscular junction to block neuromuscular transmission, in order to facilitate muscle relaxation for surgery. It then covers the history, classification, and mechanisms of action of both depolarizing drugs like succinylcholine and non-depolarizing drugs. It discusses the pharmacology, clinical uses, and side effects of various muscle relaxants. It concludes by addressing the reversal of neuromuscular blockade using anticholinesterase drugs like neostigmine and strategies to minimize their muscarinic side effects.

1. Skeletal Muscle Relaxants andSkeletal Muscle Relaxants and
Reversal AgentsReversal Agents
Dr Pranav Bansal
Professor & HeaD
DePartment of anaestHesiology
BPs gmC, KHanPur Kalan, soniPat

2. Learning Objectives
 PY3.4 Describe the structure of neuro-muscular junction and
transmission of impulses
 PY3.5 Discuss the action of neuro-muscular blocking agents
 PH1.15 Describe mechanism/s of action, types, doses, side
effects, indications and contraindications of skeletal muscle
relaxants
 AS4.1 Describe and discuss the pharmacology of drugs used in
induction and maintenance of general anaesthesia (including
depolarising and non-depolarising muscle relaxants,
anticholinesterases. Part 2/2)

3. Introduction
What are neuromuscular blocking drugs ?
These are agents that act peripherally at
neuromuscular junction/muscle fibre itself to block
neuromuscular transmission.
Why do we need them ?
In order to facilitate muscle relaxation for surgery,
Optimize surgical working conditions & for mechanical
ventilation during surgery or in ICU

4. HISTORY

5. How skeletal muscle
relaxation can be achieved
Intra-operatively?
 High doses of volatile anesthetics
 Regional anesthesia
 Administration of neuromuscular blocking
agents

6. Muscle Relaxants
 How do they work?
 Neuromuscular junction

Nerve terminal

Motor endplate of a muscle

Synaptic cleft
 Nerve stimulation
 Release of Acetylcholine (Ach)
 Postsynaptic events

7. Neuromuscular Junction
(NMJ)

8. Skeletal Muscle Relaxants
 Drugs that act peripherally at the neuromuscular
junction (Nicotinic receptor of Ach – Muscle).
 Types of Skeletal muscle relaxants:

Competitive (Non-depolarizing)

Non-competitive (Depolarizing)

Miscellaneous : Aminoglycosides

9. Muscle Relaxants
 Depolarizing muscle relaxant
 Succinylcholine, Decamethonium
 Nondepolarizing muscle relaxants
 Ultrashort acting
 Short acting
 Intermediate acting
 Long acting

10. Depolarizing Muscle
Relaxant
 Succinylcholine
 What is the mechanism of action?
 Physically resemble Ach
 Act as acetylcholine receptor agonist
 Not metabolized locally at NMJ
 Metabolized by pseudocholinesterase in plasma
 Depolarizing action persists > Ach
 Continuous end-plate depolarization causes muscle
relaxation

11. SUCCINYLCHOLINE
It causes paralysis of skeletal muscle.
 Sequence of paralysis may be different from that of
non depolarizing drugs but respiratory muscles are
paralyzed last
 Produces a transient twitching of skeletal muscle
before causing block
 It causes maintained depolarization at the end plate,
which leads to a loss of electrical excitability.
 It has shorter duration of action.

12. 12
DEPOLARIZING AGENTS
 Mechanism of action:
 These drugs act like acetylcholine but persist at the synapse
at high concentration and for longer duration and constantly
stimulate the receptor.
 First, opening of the Na+ channel occurs resulting in
depolarization, this leads to transient twitching of the muscle,
continued binding of drugs make the receptor incapable to
transmit the impulses, paralysis occurs.
 The continued depolarization makes the receptor incapable
of transmitting further impulses.

13. Depolarizing Muscle
Relaxant
 Succinylcholine
 What is the clinical use of
succinylcholine?
 Most often used to facilitate intubation
 What is intubating dose of
succinylcholine?
 1-1.5 mg/kg
 Onset 30-60 seconds, duration 5-10
minutes

14. Depolarizing Muscle
Relaxant
 Succinylcholine
 What is phase I neuromuscular
blockade?
 What is phase II neuromuscular
blockade?

Resemble blockade produced by
nondepolarizing muscle relaxant

Succinylcholine infusion or dose >5-7 mg/kg

15. Succinylcholine Side effects:

Cardiovascular

Fasciculation

Muscle pain

Increase intraocular pressure

Increase intragastric pressure

Increase intracranial pressure

Hyperkalemia
 Prolonged Paralysis: Succinylcholine-induced neuromuscular
blockade can be significantly prolonged if a patient has an abnormal
genetic variant of butyrylcholinesterase (Atypical
Pseudocholinesterase).

Malignant hyperthermia

16.  Prolonged paralysis: due to factors which reduce the activity of
plasma cholinesterase:

genetic variants as abnormal cholinesterase, its severe
deficiency.

anti -cholinesterase drugs

liver disease
 Malignant hyperthermia: rare inherited condition probably
caused by a mutation of Ca++
release channel of sarcoplasmic
reticulum, which results muscle spasm and dramatic rise in body
temperature. (This is treated by cooling the body and
administration of Dantrolene)

17. Signs of MH
 Specific
 Muscle rigidity
 Increased CO2
production
 Rhabdomyolysis
 Marked temperature
elevation
 Non-specific
 Tachycardia
 Tachypnea
 Acidosis
 Hyperkalemia

18. Immediate Therapy of MH
 Discontinue triggering agents
 Hyperventilate with oxygen
 Get help
 Dantrolene 2.5 mg/kg push. Must dilute 20 mg bottle with
60 ml DW. Continue for 24-48 hours
 Cooling the patient
 Do not give calcium channel blockers
 Labs as necessary for K+, myoglobin

19. 19
Succinylcholine
 Therapeutic uses:
 When rapid endotracheal intubations is required.
 Electroconvulsive shock therapy.
Pharmacokinetics:
 Administered intravenously.
 Metabolised to succinyl-monocholine and choline. Succinyl-
monocholine is metabolized much more slowly to succinic acid
and choline. The elimination half-life of succinylcholine is
estimated to be 47 seconds.

20. Non depolarising neuromuscular blocking
drugs classification (on basis of chemical
strucure)
Benzylisoquinolinium
D-tubocurare
Metocurine
Doxacurium
Atracurium
Cisatracurium
Mivacurium
Aminosteroid
Pancuronium
Vecuronium
Rocuronium
Rapacuronium
Asymmetri
c mixed-
onium
fumarates
Gantacurium

21. Classification of Non-Depolarising Muscle
Relaxants according to Duration of Action
Ultra short Short Intermediate Long
Gantacurium
Rapacuronium Mivacurium Vecuronium Pancuronium
GW 280430 Atracurium d-Tubocurare
Cis-atracurium Gallamine
Rocuronium Metocurine
Doxacurium
Pipecuronium

22. Nondepolarizing Muscle
Relaxants
 What is the mechanism of action?
 Compete with Ach at the binding sites
 Do not depolarize the motor endplate
 Act as competitive antagonist
 Excessive concentration causing channel
blockade
 Act at presynaptic sites, prevent movement of
Ach to release sites

23. Competitive
Non-depolarizing
Non-Competitive
Depolarizing
Paralysis Flaccid Fasciculations---›
Flaccid
Neostigmine Antagonizes Exaggerate /
no effect.
Examples Pancuronium Succinylcholine

24. Nondepolarizing Muscle
Relaxants
 Pancuronium
 Aminosteroid compound
 Onset 3-5 minutes, duration 60-90 minutes
 Intubating dose 0.08-0.12 mg/kg
 Elimination mainly by kidney (85%), liver
(15%)
 Side effects : hypertension, tachycrdia,
dysrhythmia

25. Nondepolarizing Muscle
Relaxants
 Vecuronium
 Analogue of pancuronium
 much less vagolytic effect and shorter duration
than pancuronium
 Onset 3-5 minutes duration 20-35 minutes
 Intubating dose 0.08-0.12 mg/kg
 Elimination 40% by kidney, 60% by liver

26. Atracurium
 Non-organ dependent elimination
 Non specific estererase: 60% of elimination
 Hofmann elimination : spontaneous nonenzymatic
chemical breakdown occurs at physiologic pH and Temp.
 Onset 3-5 minutes, duration 25-35 minutes
 Intubating dose 0.5 mg/kg
 Side effects : histamine release causing hypotension, tachycardia,
bronchospasm
 Laudanosine toxicity-breakdown product from Hofmann elimination,
assoc. with central nervous system excitation resulting in elevation of
MAC and precipitation of seizures.
 Temperature and pH sensitivity-action markedly prolonged in hypo-
thermic or acidotic patients.

27. Nondepolarizing Muscle
Relaxants
 Cisatracurium
 Isomer of atracurium
 Metabolized by Hofmann elimination
 Onset 3-5 minutes, duration 20-35 minutes
 Intubating dose 0.1-0.2 mg/kg
 Minimal cardiovascular side effects
 Much less laudanosine produced

28. Mivacurium
 Bisquaternary benzylisoquinoline
 Potency, 1/3 that of atracurium
 slow onset 1.5 min with 0.25 mg/kg
 short duration 12-18 min with 0.25 mg/kg
 histamine release with doses 3-4 X ED95
 hydrolyzed by AChE, recovery may be prolonged in
some populations (e.g. atypical AChE)

29. Nondepolarizing Muscle
Relaxants
 Rocuronium
 Analogue of vecuronium
 Rapid onset 1-2 minutes, duration 20-35
minutes
 Onset of action similar to that of
succinylcholine
 Intubating dose 0.6 mg/kg
 Elimination primarily by liver, slightly by kidney

30. Comparative Pharmacology of Muscle
Relaxants
Agent ED95 Int Dose Onset Duration Elim/Met
(mg/kg) (mg/kg) (min) (min)
Succinylcholine 0.3 1-1.5 < 1 12 pChE
Rapacuronium (1.0) 1.3 1.5 9 nonenzym./Hep.
Rocuronium 0.3 0.6 1 60 Hep./Renal
Mivacurium 0.08 0.2 2 25 PChE
Atracurium 0.2 0.6 2-3 60 Hoff/hydrol.
Cis-atracurium 0.05 0.15 3-4 60 Hoff/hydrol.
Vecuronium 0.05 0.10 2-3 60 Hep./Renal
Pancuronium 0.07 0.10 3-5 100 Renal/Hepatic
Pipecuronium 0.05 0.15 2-5 190 Renal
Doxacurium 0.025 0.08 3-5 200 Renal/ChE

31. Percent of Dose Dependant
on Renal Elimination
> 90% 60-90% 40-60% <25%
Gallamine (97) Pancuronium (80) d-TC (45) Succinylcholine
Pipecuronium (70) Vecuronium (20)
Doxacurium (70) Atracurium (NS)
Metocurine (60) Mivacurium (NS)
Rocuronium

32. Alteration of responses
 Temperature
 Acid-base balance
 Electrolyte abnormality
 Age
 Concurrent diseases
 Drug interactions

33. Alteration of responses
 Concurrent diseases
 Neurologic diseases
 Muscular diseases

Myasthenia gravis

Myasthenic syndrome (Eaton-Lambert synrome)
 Liver diseases
 Kidney diseases

34. Alteration of responses
 Drug interactions
 Inhalation agents
 Intravenous anesthetics
 Local anesthetics
 Antibiotics
 Anticonvulsants
 Magnesium

35. Muscle Relaxants
 Muscle relaxants must not be given without
adequate dosage of analgesic and hypnotic
drugs
 Inappropriately given : a patient is
paralyzed but not anesthetized

36. Skeletal muscle relaxants
Pharmacokinetics :
 Most peripheral NM blockers are quaternary
compounds – not absorbed orally.
 Administered intravenously.
 Do not cross blood brain barrier or placenta
 No analgesia /loss of consciousness
 Volatile anes potentiate effect by dec tone of skeletal
muscle and dec sensitivity of post synaptic memb to
depolarisation
 SCh is metabolized by Pseudocholinesterase.
 Atracurium is inactivated in plasma by spontaneous
non-enzymatic degradation (Hoffman elimination).

37. Reversal of
Neuromuscular Blockade
 Goal : re-establishment of spontaneous
respiration and the ability to protect
airway from aspiration

38. CHOLINESTERASE INHIBITORS (ANTICHOLINESTERASE INHIBITORS (ANTI
CHOLINESTERASE)CHOLINESTERASE)
 Primary clinical use is to reverse non-depolarising
muscle blockade
 Neuromuscular transmission is blocked when NDMR
compete with Ach to bind to nicotinic cholinergic
receptors.
 The cholinesterase inhibitors indirectly increase
amount of Ach available to compete with NDMR,
thereby re-establish NM transmission.

39. Antagonism of
Neuromuscular Blockade
 What is the mechanism of action?
 Inhibiting activity of acetylcholineesterase
 More Ach available at NMJ, compete for sites
on nicotinic cholinergic receptors
 Action at muscarinic cholinergic receptor

Bradycardia

Hypersecretion

Increased intestinal tone

40. Antagonism of
Neuromuscular Blockade
Effectiveness of anticholinesterases depends on the
degree of recovery present when they are
administered
 Anticholinesterases
 Neostigmine

Onset 3-5 minutes, elimination half life 77 minutes

Dose 0.04-0.07 mg/kg
 Pyridostigmine
 Edrophonium

41. Antagonism of
Neuromuscular Blockade
 Muscarinic side effects are minimized
by anticholinergic agents
 Atropine

Dose 0.01-0.02 mg/kg
 Scopolamine
 Glycopyrrolate

42. Neostigmine
 Quaternary ammonium group
 Dosage : 0.04-0.08 mg/kg
 Effects apparent in 5-10 min and last more than 1
hour.
 Muscarinic side effects are minimized by prior or
concomitant administration of anticholinergic
agent.
 Also used to treat urinary bladder atony and
paralytic ileus.

43. Glycopyrrolate
 Dosage : 0.005-0.01 mg/kg up to 0.2-0.3 mg in adults.
 Cannot cross blood-brain barrier and almost always
devoid of central nervous system and ophthalmic
activity.
 Potent inhibition of salivary gland and respiratory tract
secretions.
 Longer duration than atropine (2-4 hours)

44. Postoperative Residual Curarization
(PORC)
 Common after NDMRs
 Long acting > intermediate > short acting
 Associated with respiratory morbidity
 Not observed in children
 Monitoring decreases incidence

45. Monitoring
Neuromuscular Function
 What are the purposes of
monitoring?
 Administer additional relaxant as
indicated
 Demonstrate recovery

46. Monitoring Neuromuscular Function
How to monitor?
 Clinical signs
 Use of nerve stimulator

47. Monitoring
Neuromuscular Function
 Clinical signs
 Signs of adequate recovery

Sustained head lift for 5 seconds

Lift the leg (child)

Ability to generate negative inspiratory pressure at least
25 cmH2O, able to swallow and maintain a patent airway

Other crude tests : tongue protrusion, arm lift, hand grip
strength