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Skeletal muscle relaxants - drdhriti
1. SKELETAL MUSCLESKELETAL MUSCLE
RELAXANTSRELAXANTS
Dr. D. K. BrahmaDr. D. K. Brahma
Associate ProfessorAssociate Professor
Department of PharmacologyDepartment 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 ?
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 muscleDanger: 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: SkeletalSkeletal
Muscle Relaxants areMuscle Relaxants are
the drugs that actthe drugs that act
1.1. peripherallyperipherally atat
neuromuscularneuromuscular
junctionjunction
oror muscle fibermuscle fiber itselfitself
1.1. or,or, centrallycentrally inin
cerebrospinal axis tocerebrospinal axis to
reduce muscle tonereduce muscle tone
and /cause muscleand /cause muscle
paralysisparalysis
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
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
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 blockersblockers
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
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 PeripherallyCentrally 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
PeripherallyPeripherally
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
39. BaclofenBaclofen (β-parachlorophenyl(β-parachlorophenyl
GABA)GABA)
Mechanism of action: GABAB 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
Sketch of the sodium channel. The bars v and t represent parts of the molecule that act as gates. Gate v is voltage-dependent, and gate t is time-dependent. (a) Resting state: v is closed while t is open. (b) Active state: v opens when the surrounding membrane is depolarized to allow ion flow; t closes soon afterwards to inactivate the channel. (c) Inactive state: v remains open while t is closed. This state is maintained as long as the surrounding membrane is depolarized. The channel reverts to the resting state (a) when the membrane repolarizes. (B) Several states of nicotinic acetylcholine receptors. Upper (left to right): resting; resting with agonist bound to recognition sites but channel not yet opened; and active with open channel allowing ion flow. Lower (left to right): desensitized without agonist; desensitized with agonist bound to recognition site. Both are non-conducting. All conformations are in dynamic equilibrium. (Reproduced, with permission of Elsevier, from Standaert FG. Neuromuscular physiology and pharmacology. In: Miller RD (ed) Anesthesia, 4th edn. New York: Churchill Livingstone, 1994; 731–54).