Muscle relaxant and reversal agents

For Undergraduate and Postgraduate Medical Teaching

1. Skeletal Muscle Relaxants and Skeletal 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-atracuriumGallamine
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
NeostigmineAntagonizes 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 DoseOnsetDurationElim/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 (ANTI CHOLINESTERASE 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 cmH
2
O, able to swallow and maintain a patent airway

Other crude tests : tongue protrusion, arm lift, hand grip
strength