Skeletal muscle relaxants - drdhriti

A power point presentation on "Skeletal Muscle Relaxants" suitable for UG MBBS level students

1. SKELETAL MUSCLE SKELETAL MUSCLE
RELAXANTSRELAXANTS
Dr. D. K. BrahmaDr. D. K. Brahma
Associate ProfessorAssociate Professor
Department of Pharmacology Department of Pharmacology
NEIGRIHMS, ShillongNEIGRIHMS, Shillong

2. Definition: SMRs are the drugs that act
peripherally at neuromuscular junction or
muscle fibre itself or in cerebrospinal axis
to reduce muscle tone and /cause muscle
paralysis.

3. Skeletal Muscle Functions
From Muscle twitch sustained contraction
Muscle twitching refers to small, local, involuntary
muscle contractions (twitching) that may appear like a
shiver under the skin

4. Go Back - Cholinergic
Transmission – Acetylcholine!
Acetylcholine (Ach) is major neurohumoral transmitter at
autonomic, somatic and central nervous system:
1.All preganglionic sites (Both Parasympathetic and sympathetic)
2.All Postganglionic Parasympathetic sites and sympathetic to
sweat gland and some blood vessels
3.Skeletal muscles
4.CNS: Cortex Basal ganglia, spinal chord and others
Parasympathetic Stimulation – Acetylcholine (Ach) release at
neuroeffector junction - biological effects
Sympathetic stimulation – Noradrenaline (NA) at
neuroeffector junction - biological effects
Now, SKELETAL MUSCLES – WHERE ?

5. AT Neuromuscular (NM)
Junction
NM type
Receptors

6. Ultimately - The Skeletal Muscle
Contraction
The complex actin-myosin interaction to cause contraction
(Sliding filament theory)

7. Skeletal Muscle Relaxation, why
clinically ???
In conjunction with GA:
Facilitate intubation of the trachea
Facilitate mechanical ventilation
Optimized surgical working conditions

8. Why Skeletal Muscle Relaxation –
contd.
In Muscle spasm:
It is defined as a sudden involuntary contraction
of one or more muscle groups and is usually an
acute condition associated with muscle strain
(partial tear of a muscle) or sprain
•Musculoskeletal Injury
•Low Back pain or neck pain
•Sports Injury
•Fibromyalgia, tension headaches
Involve afferent nociceptive input from damaged
area
Excitation of alpha motor outflow
Tonic contraction of affected muscle
Build up of pain-mediating metabolites

9. Why Skeletal Muscle Relaxation –
contd.
In Spasticity:
Spastic neurological conditions (Spasticity): It is
a motorneurone disorder characterized by
skeletal muscle rigidity, exaggerated tendon
jerks and paralysis of affected muscles
Associated with Motor neuron conditions
•Cerebral palsy, Stroke, Multiple sclerosis,
Traumatic brain injury, Anoxia and
Neurodegenerative disease
•In many patients with these conditions, spasticity
can be disabling and painful with a marked effect
on functional ability and quality of life

10. Spastic disorders
Danger: Chronic muscle spasm can result in muscle Danger: Chronic muscle spasm can result in muscle
atrophy in the specific muscle or muscle groupatrophy in the specific muscle or muscle group

11. What are SMRs ???
Definition: Skeletal Skeletal
Muscle Relaxants are Muscle Relaxants are
the drugs that actthe drugs that act
1.1.peripherallyperipherally at at
neuromuscular neuromuscular
junction junction
or or muscle fiber muscle fiber itselfitself
1.1.or, or, centrallycentrally in in
cerebrospinal axis to cerebrospinal axis to
reduce muscle tone reduce muscle tone
and /cause muscle and /cause muscle
paralysisparalysis

12. 1. Centrally acting
2. Neuromuscular Junction 3. Directly on muscle

13. Classification: Peripherally acting
SMRs
A.Neuromuscular Blockers:
Nondepolarizing (Competitive) blockers:
Long acting: d-Tubocurarine,
Pancuronium, Doxacurium, Pipecuronium,
Gallamine and Metocurine
Intermediate acting: Vecuronium,
Atracurium, Cisatracurium, Rocuronium,
Rapacuronium
Short acting: Mivacurium
Depolarizing blockers: Succinylcholine
(suxamethonium), Decamethonium
B.Directly acting:Dantrolene and quinine

14. History: From Fun hunting in Jungles to
Operation theatre
Curare: The arrow
poison
Source:
Chondrodendrone
tomentosum and
Strychnos toxifera
 Derived from:
"ourare“ meaning
arrow poison in South
American Indian
Tubocurarine name:
Because of packing in
“hollow bamboo
tubes”

15. What is Competitive - Nondepolarizing
Block in Muscles then?
They have affinity but no IA for NM receptors
(Antagonist)
They have N+ atoms and get attracted to the ACh
receptor site – but cannot bring conformational
change like Ach
No EPP generation in nerve endings
However, can only act on closed channels – no
action on already opened channels
But after sometime EPP falls to critical value – no
propagation of AP and thus no contraction
Action can be overcome by increased Ach or
clinically done by Neostigmine
They also block prejunctional Ach receptors on
motor nerve endings – FADE PHENOMENON
Twitches turn to depressed on repetitive stimulation

16. Mechanism of action of non-
depolarizing neuromuscular blockers
Na
Ca
K
ACh
ACh
Normal transmission
1- resting
2- active
Non depolarizing neuromuscular blockadeLow doses:
• competitive
antagonist of Ach
• Action reversed by
Ach esterase inhibitors
Large doses:
• Ion channel is blocked
• More weakness of
neuromuscular
transmission
• Action could not be
reversed by
Ach esterase inhibitors
Other actions:
Can block pre-junctional sodium
channels and interfere with
mobilization of Ach at nerve endings

17. Nondepolarizing Block in Muscles

18. Non-depolarizing - clinically
Intravenous administration of tubocurarine, 0.1–0.4
mg/kg, will initially cause motor weakness, followed by
the skeletal muscles becoming totally flaccid and
unexcitable to electrical stimulation
Larger muscles (eg, abdominal, trunk, paraspinous,
diaphragm) are more resistant to blockade and recover
more rapidly than smaller muscles (e.g. facial, foot,
hand)
Diaphragm is usually the last muscle to be paralyzed
Assuming that ventilation is adequately maintained, no
adverse effects occur
When administration of muscle relaxants is
discontinued, recovery of muscles usually occurs in
reverse order

19. Depolarizing Block –
Succinylcholine
Affinity and sub-maximal intrinsic activity for NM
receptors
Depolarize the muscle end plate by opening Na+
channel (like Ach)
Initially, twitching and fasciculation occur –
partial IA (transient depolarization) and repetitive
excitation (chest and abdomen)
But, unlike ACh do not dissociate rapidly from
end plate region (resistant to AChE) – only to
liver and plasma ChE
Induce prolonged partial depolarization around MEP
Transmembrane potential drops below -50mV -
cause Na+ channel inactivation
No action of ACh to produce MAP – Flaccid
paralysis

20. Succinylcholine –
contd.
Sometimes in some conditions in man - 2 (two) phases
can be describe - Phase I block and Phase II block
Phase I block: Rapid onset, results from persistent
depolarization of muscle end plate - classical depolarizing
block features – short lived – despite of presence of
depolarizing agent, muscles repolarize again as
physiological phenomenon (priming) - But no
neuromuscular transmission – phase II comes …
Phase II block: Slow onset
But cannot generate fresh depolarization
probably due to desensitization of Ach receptors or
Reduced synthesis and mobilization of ACh
Resembles antagonist like action on muscles – like
tubocurarine (non-depolarizing block)
Can partially reversed by AChE
Phase II in man - with fluorinated anaesthetics and with SCh

21. What Anesthetists do ?
Assessment of neuromuscular block by stimulation of
the ulnar nerve
Important for Induction, recovery (reversal drug
amount) from anaethesia and also in ICU patients
Monitored from compound action potentials or muscle
tension developed in the adductor pollicis (thumb)
muscle
Protocols - “train of four” and the “double burst”
Train of four (TOF) – four supramaximal electrical
stimuli are applied at 2Hz and strength of contractions
are recorded
TOF ratio is 1 at recovery
Non-depolarizing agents show – fading phenomenon
Depolarizing agents in phase I shows no fading and
TOF is 1, but in phase II shows fading phenomenon

22. Train-of-four Monitoring

23. Other Actions of NM blockers
Autonomic ganglia:
Partial blockade of ganglia (NN type of receptor)
Results in fall in BP and tachycardia
Histamine release:
Hypotension
Bronchospasm, excess bronchial and salivary
secretion
CVS: Fall in BP due to
Ganglion blockade, histamine release and reduced
venous return
Heart increased – vagal ganglion blockade
(All newer NDP agents have negligible effects on BP
and Heart rate)
 Succinylcholine may cause cardiac arrhythmias
GIT: Paralytic ileus

24. Pharmacokinetic of NPharmacokinetic of NMM blockers blockers
Polar quaternary compounds - Not absorbed orally, do not cross
cell membranes, low Vd and do not cross BBB or placental barrier
– always given IV or rarely IM
Muscles with high blood flow affected earlier
Redistribution to non-muscular tissues occur and action may
persist longer than half life
Drugs metabolized in plasma/liver – short half-life (Vecuronium,
atracuronium, rocuronium etc.) – 20-40 min.
Drugs excreted in urine – longer half-life (dTC and pancuronium)
– 60-120 min.
Succinylcholine succinylmonocholine succinic
acid + choline (plasma cholinesterase): 3-5 min.
In some – genetically determined abnormality and deficient
pseudocholinesterase paralysis & apnoea

25. Individual compounds - Succinylcholine
Advantages:
•Most commonly used SMR for ET intubation
•Good intubation conditions – relax jaw, separated vocal chords with
immobility, no diaphargmatic movements
•Quick onset of action (1 – 2 min)
•Used as continuous infusion occasionally
Disadvantages:
Cardiovascular: unpredictable BP, HR and arrhythmias
Fasciculation
Muscle pain
Increased intraocular pressure
Increased intragastric pressure
Increased intracranial pressure
Hyperkalemia: K+ efflux from muscles, life threatening in CHF,
patient with diuretics etc.
Not indicated below 8 years of age
Malignant hyperthermia

26. What is Malignant hyperthermia
Rare genetically determined reaction to
susceptible persons having abnormal RyR
receptor Ca+ channel
Caused by Halothane and manifests as high
temperature due to persistent muscle contraction
– increased intracellular Ca+
Succinylcholine accentuates this condition
Treatment:
Rapid external cooling – ice pack
Bicarbonate infusion
100% oxygen inhalation
Injection of dantrolene: Direct acting muscle
relaxant

27. What is succinylcholine
apnoea?
A condition where muscles paralyzed for an increased length
of time and cannot breath adequately at the end of an
anaesthetic
Can be – inherited or spontaneous in a person with no family
history
In inherited – reduced level of plasma cholinesterase
In acquired – normal level but reduced enzyme activity
(Pregnancy, Hypothyroidism, Liver disease, Renal disease ,
Carcinomatosis)
Management:
Anaesthetize the patient and ventilate
Monitor the NM transmission (TOF)
patient should remain ventilated and anaesthetized until breathing
spontaneously
Family members should be tested by blood test and tagged if
positive

28. Individual Compounds – contd.
Pancuronium:Pancuronium:
Steroidal compound 5 times more potent than dTC
No cardiac or respiratory toxicity (little ganglion blockade)
Low histamine release – no bronchospasm or flushing
Long duration of action – reversal required
Preferred only in long surgeries
Vecuronium:Vecuronium:
Congener of Pancuronium
Slow onset but prolonged action
CVS stability – no histamine release
Spontaneous and Quick recovery
Mostly commonly used

29. Individual Compounds – contd.
Atracurium:
Competitive blocker and less potent than
pancuronium
Reversal not required
Non-enzymatic spontaneous degradation in addition
to cholinesterase
Preferred in elderly and neonates
Rocuronium: Non-depolarizing agent
Rapid and immediate action
Alternative to SCh for tracheal intubation
Also acts as maintenance relaxant and no reversal
required
Rapid intubation condition 60 – 90 seconds
Also used in ICU for mechanical ventilation

30. Neuro-muscular blockers - InteractionsNeuro-muscular blockers - Interactions
1.Thiopentone Sodium – same syringe
2.General anaesthetics – potentiate blockers
3.Anticholinesterases – Neostigmine
4.Antibiotics – Aminoglycosides
5.Calcium Channel blockers: potentiate
blockers (Verapamil) – both competitive
and non-competitive
6.Diuretics – hypokalemia: enhances
competitive block

31. Neuro muscular blockers - usesNeuro muscular blockers - uses
1.Adjuvant to General anaesthesia
2.Assisted ventilation
3.Convulsion and trauma from
electroconvulsive therapy
4.Status epilepticus
Vocal cord

32. Directly acting relaxants - Dantrolene
•Different from neuromuscular blockers, no action on Different from neuromuscular blockers, no action on
NM transmission NM transmission
•MOA – Ryanodine receptors (RyR) calcium channels – MOA – Ryanodine receptors (RyR) calcium channels –
prevents depolarization – no intracellular release of prevents depolarization – no intracellular release of
Ca++Ca++
•Absorbed orally, penetrates brain and produces Absorbed orally, penetrates brain and produces
sedation, metabolized in liver, excreted in kidney. T1/2 sedation, metabolized in liver, excreted in kidney. T1/2
8-12 hrs.8-12 hrs.
•Dose: 25-100 mg 4 times dailyDose: 25-100 mg 4 times daily
•Uses: UMN disorders – paraplegia, hemiplegia, cerebral Uses: UMN disorders – paraplegia, hemiplegia, cerebral
palsy and malignant hyperthermia (drug of choice 2.5 – palsy and malignant hyperthermia (drug of choice 2.5 –
4 mg/kg))4 mg/kg))
•Adverse effects – Sedation, malaise, light headedness, Adverse effects – Sedation, malaise, light headedness,
muscular weakness, diarrhoea and hepatotoxicitymuscular weakness, diarrhoea and hepatotoxicity

33. Centrally acting Muscle relaxantsCentrally acting Muscle relaxants
Classification:Classification:
1.Mephenesin congeners –
Mephenesin, Carisoprodol,
Chlorzoxazone, Methocarbamol
and Chlormezanone
2.Benzodiazepines – Diazepam,
lorazepam, Clonazepam and others
3.GABA derivative – Baclofen
4.Central α-2 agonist - Tizanidine

34. Centrally acting Muscle relaxantsCentrally acting Muscle relaxants
Drugs that reduce skeletal muscle tone by
selective action on cerebrospinal axis
Depress the spinal and supraspinal
reflexes of muscle tone
Also depresses polysynaptic reflexes of
ascending reticular formation –
wakefulness disturbed (sedation)
No effect on NM junction but reduce UMN
spasticity and hyperreflexia

35. Centrally acting Vs Peripherally Centrally acting Vs Peripherally
actingacting
Centrally actingCentrally acting
Decrease muscle tone
but no reduction in
power
Polysynaptic reflexes in
CNS
CNS depression
Orally and parenterally
Spastic conditions,
muscle spasm
Peripherally Peripherally
actingacting
Cause muscle paralysis
Block NM transmission
No CNS effect
Given IV
Short term surgical
procedures

36. Centrally acting Muscle relaxants – Centrally acting Muscle relaxants –
contd.contd.
Mephenesin (Relaxyl/medicreme)
Modulation of reflexes in spinal internuncial
neurone
Cannot be used systemically
Irritant rather than relaxant – topical
preparations
Carisoprodol, Chlorzoxazone (Mobizox),
Methocarbamol (Robinax/Robiflam) and
Chlormezanone – similar but can be used
orally

37. Benzodiazepines as muscle relaxant
Very potent centrally acting muscle
relaxant – supraspinal
Mechanism of action is via “GABAA
receptor Cl- complex” enhancement
– inhibitory in nature
Diazepam and Clonazepam are the
most potent ones
Diazepam is the prototype of BZDs

38. GABAA-Benzodiazepine receptor-
chloride channel complex

39. BaclofenBaclofen (β-parachlorophenyl (β-parachlorophenyl
GABA)GABA)
Mechanism of action: GABA B agonist
- hyperpolariztion of neurones by increasing K+
conductance and alteration of Ca++ flux
- Does not affect to Cl- conductance
Site of action: spinal chord – depresses polysynaptic
and monosynaptic reflexes
Clinical effects: decreased hyperreflexia; reduced
painful spasms; reduced anxiety
Dose: orally 5 mg three times daily, gradually increase
to 20 mg four times daily or higher
intrathecally initially 50 mcg/day increase to 300-
800 mcg/day

40. Individual Compounds - Individual Compounds - TizanidineTizanidine
Mechanism of action: alpha-2 receptor
agonist – inhibits the release of excitatory
amino acids in spinal interneurones
Clinical effects: reduced tone, spasm
frequency, and hyperreflexia
Doses: tizanidine initial 4 mg three times
daily increase to 36 mg/day; clonidine
initial 0.1 mg twice daily increase to 2.4
mg/day

41. Uses of Centrally acting relaxants
1.1.Acute muscle spasmsAcute muscle spasms
2.2.Backache and neuralgiasBackache and neuralgias
3.3.Anxiety and tensionAnxiety and tension
4.4.Spastic neurological disordersSpastic neurological disorders
5.5.TetanusTetanus
6.6.Electroconvulsive therapyElectroconvulsive therapy
7.7.Orthopaedic manipulationsOrthopaedic manipulations

42. What to Remember !!
Skeletal Muscle Relaxants -
Classification
Mechanism of non-depolarizing
Mechanism of Depolarizing – Phase 1
and phase 2
Succinylcholine apnoea and
malignant hyperthermia
Few Drug Interactions of SMRs
Centrally acting Muscle relaxants –
names

43. Thank you