Skeletal muscle relaxants

Skeletal muscle relaxants

1. Skeletal muscle Skeletal muscle
relaxantsrelaxants
Neuromuscular blocking drugsNeuromuscular blocking drugs
Dr. K. Manimekalai MD,Dr. K. Manimekalai MD,
Professor,Professor,
Department of PharmacologyDepartment of Pharmacology

2. A lot of surgery especially of the abdomen A lot of surgery especially of the abdomen
requires that voluntary muscle tone and reflex requires that voluntary muscle tone and reflex
contraction be inhibited.This can be obtained by contraction be inhibited.This can be obtained by
deep general anaesthesia,regional nerve deep general anaesthesia,regional nerve
blockade or by using neuromuscular blocking blockade or by using neuromuscular blocking
drugs.Deep GA causes CV drugs.Deep GA causes CV
depression,respiratory complications and slow depression,respiratory complications and slow
recovery.But it requires mechanical ventilation recovery.But it requires mechanical ventilation
and technical skill.Neuromuscular blocking drugs and technical skill.Neuromuscular blocking drugs
should be given only after induction of should be given only after induction of
anaesthesia.anaesthesia.

3. Neuromuscular blocking agents-arrow Neuromuscular blocking agents-arrow
poisons.poisons.
Drugs acting at the myoneural junction Drugs acting at the myoneural junction
produce complete paralysis of all voluntary produce complete paralysis of all voluntary
muscle so that movement is impossible muscle so that movement is impossible
and mechanical ventilation is needed.It is and mechanical ventilation is needed.It is
plainly important that a paralysed patient plainly important that a paralysed patient
should be in a state of full analgesia and should be in a state of full analgesia and
unconscious during surgery.unconscious during surgery.

4. MechanismsMechanisms
When an impulse passes down a motor When an impulse passes down a motor
nerve to voluntary muscle it causes nerve to voluntary muscle it causes
release of Ach from the nerve endings into release of Ach from the nerve endings into
the synaptic cleft. This activates receptors the synaptic cleft. This activates receptors
on the membrane of the motor end plate, on the membrane of the motor end plate,
a specialized area on the muscle fibre, a specialized area on the muscle fibre,
opening ion channels for momentary opening ion channels for momentary
passage of sodium which depolarises the passage of sodium which depolarises the
end plate and initiates muscle contraction. end plate and initiates muscle contraction.

5. (Contd…)(Contd…)
Neuromuscular blocking drugs used in Neuromuscular blocking drugs used in
clinical practice interfere with this process. clinical practice interfere with this process.
Natural substances that prevent the Natural substances that prevent the
release of Ach at the nerve ending exist. release of Ach at the nerve ending exist.
Eg. Clostridium botulinum toxin and some Eg. Clostridium botulinum toxin and some
venoms. There are two principal venoms. There are two principal
mechanisms by which drugs used mechanisms by which drugs used
clinically interfere with neuromuscular clinically interfere with neuromuscular
transmission. transmission.

6. By competitionBy competition Ach(Atracurium, Ach(Atracurium,
cisatracurium, mivacurium, pancuronium, cisatracurium, mivacurium, pancuronium,
rocuronium, vecuronium).rocuronium, vecuronium).
These drugs are competitive antagonists of These drugs are competitive antagonists of
Ach.They do not cause depolarisation Ach.They do not cause depolarisation
themselves but protect the endplate from themselves but protect the endplate from
depolarisation by Ach. The result is a flaccid depolarisation by Ach. The result is a flaccid
paralysis.Reversal of this type of neuro muscular paralysis.Reversal of this type of neuro muscular
block can be achieved with anticholinesterase block can be achieved with anticholinesterase
drugs, such as neostigmine which prevent the drugs, such as neostigmine which prevent the
destruction by cholinesterase of Ach released at destruction by cholinesterase of Ach released at
nerve endings, allow the concentration to build nerve endings, allow the concentration to build
up and so reduce the competitive effect of a up and so reduce the competitive effect of a
blocking agent. blocking agent.

7. By depolarisation (Sch)By depolarisation (Sch)
By depolarization of the motor end plate By depolarization of the motor end plate
such agonist drugs activate the Ach such agonist drugs activate the Ach
receptor on the motor end plate and at receptor on the motor end plate and at
their first application voluntary muscle their first application voluntary muscle
contracts but as they are not destroyed contracts but as they are not destroyed
immediately, like Ach, the depolarization immediately, like Ach, the depolarization
persists. With prolonged administration persists. With prolonged administration
depolarization block changes to a depolarization block changes to a
competitive block (dual block) – competitive block (dual block) –
desensitization of the receptor to Ach desensitization of the receptor to Ach

8. ACTIONSACTIONS
Skeletal muscles: IV injections produces muscle Skeletal muscles: IV injections produces muscle
weakness followed by flaccid paralysis.weakness followed by flaccid paralysis.
Autonomic ganglia: NAutonomic ganglia: NNN – competitive neuro – competitive neuro
muscular blockers – some degree of ganglionic muscular blockers – some degree of ganglionic
blockade. Sch may cause ganglionic stimulation blockade. Sch may cause ganglionic stimulation
by its agonistic action on nicotinic receptors by its agonistic action on nicotinic receptors
Histamine release: d – Tc release histamine Histamine release: d – Tc release histamine
from mast cells – hypotension by d – Tc, from mast cells – hypotension by d – Tc,
flushing, bronchospasm and increased flushing, bronchospasm and increased
respiratory secretion are other effects respiratory secretion are other effects

9. (Contd…)(Contd…)
CVS: d-Tc – fall in BP due to CVS: d-Tc – fall in BP due to
Ganglionic blockadeGanglionic blockade
Histamine release Histamine release
And reduced venous return – a result of And reduced venous return – a result of
paralysis of limb and respiratory muscles. Heart paralysis of limb and respiratory muscles. Heart
rate may increase due to vagal ganglionic rate may increase due to vagal ganglionic
blockade blockade
GIT: Ganglion blocking activity of competitive GIT: Ganglion blocking activity of competitive
blockers may enhance post operative paralytic blockers may enhance post operative paralytic
ileus after abdominal operations ileus after abdominal operations
CNS: Do not cross BBBCNS: Do not cross BBB

10. PHARMACOKINETICSPHARMACOKINETICS
All neuromuscular blockers are quartenary All neuromuscular blockers are quartenary
compounds – not absorbed orally. compounds – not absorbed orally.
Practically always given IV. Redistribution Practically always given IV. Redistribution
plays significant role in termination of plays significant role in termination of
action of single dose. Do not cross action of single dose. Do not cross
placenta or penetrate brain. Drugs placenta or penetrate brain. Drugs
excreted by the kidney have longer half excreted by the kidney have longer half
life, drugs eliminated by liver – shorter life, drugs eliminated by liver – shorter
duration of action. duration of action.

11. LONG ACTINGLONG ACTING
Doxacurium, metocurine, d-Tc, pancuronium Doxacurium, metocurine, d-Tc, pancuronium
and pipecuroniumand pipecuronium
Sch rapidly hydrolysed by plasma Sch rapidly hydrolysed by plasma
pseudocholinesterase to succinylmonocholine pseudocholinesterase to succinylmonocholine
and then succinic acid + choline. Genetically and then succinic acid + choline. Genetically
determined abnormality or deficiency of determined abnormality or deficiency of
pseudocholinesterase – dominant phase II pseudocholinesterase – dominant phase II
blockade – muscle paralysis and apnoea lasting blockade – muscle paralysis and apnoea lasting
hours. Abnormal pseudocholinesterase – hours. Abnormal pseudocholinesterase –
dibucaine number dibucaine number

12. COMPETITIVE ANTAGONISTS COMPETITIVE ANTAGONISTS
ATRACURIUMATRACURIUM
Inactivation in plasma by spontaneous Inactivation in plasma by spontaneous
nonenzymatic degradation (hoffman nonenzymatic degradation (hoffman
elimination)elimination)
Thus uninfluenced by the state of Thus uninfluenced by the state of
circulation, the liver or the kidney (aged, circulation, the liver or the kidney (aged,
hepatic or renal disease). Very little effect hepatic or renal disease). Very little effect
on CVS but at dose more than 0.5 – on CVS but at dose more than 0.5 –
0.6mg/Kg histamine release may cause 0.6mg/Kg histamine release may cause
hypotension and bronchospasm hypotension and bronchospasm

13. CISATRACURIUMCISATRACURIUM
Stereoisomer – less prone to cause histamine Stereoisomer – less prone to cause histamine
release release
Vecuronium – synthetic steroid derivative – full Vecuronium – synthetic steroid derivative – full
neuromuscular blockade about 3mts after a neuromuscular blockade about 3mts after a
dose of 0.1mg/kg – duration is 20 – 30 mts. No dose of 0.1mg/kg – duration is 20 – 30 mts. No
cardiovascular side effects and does not cause cardiovascular side effects and does not cause
histamine release histamine release
Rocuronium – steroid derivative – rapid onset. Rocuronium – steroid derivative – rapid onset.
0.6mg/kg. Tracheal intubation – after 60 0.6mg/kg. Tracheal intubation – after 60
seconds. Negligible CV effects and similar seconds. Negligible CV effects and similar
duration as vecuronium duration as vecuronium

14. MIVACURIUMMIVACURIUM
Same chemical family as atracurium. Only non Same chemical family as atracurium. Only non
depolarising neuromuscular blocker metabolized depolarising neuromuscular blocker metabolized
by plasma cholinesterase. Short acting, can by plasma cholinesterase. Short acting, can
cause some hypotension because of histamine cause some hypotension because of histamine
release.release.
Pancuronium – First steroid derivative – longer Pancuronium – First steroid derivative – longer
acting - slight tachycardiaacting - slight tachycardia
d-Tc – obsolete. Potent antagonist at autonomic d-Tc – obsolete. Potent antagonist at autonomic
ganglia and causes significant hypotension ganglia and causes significant hypotension

15. ANTAGONISM OF COMPETITIVE ANTAGONISM OF COMPETITIVE
NEURO MUSCULAR BLOCKER NEURO MUSCULAR BLOCKER
Neostigmine – which allow accumulation Neostigmine – which allow accumulation
of Ach. Neostigmine given IV with of Ach. Neostigmine given IV with
glycopyronium to prevent bradycardia glycopyronium to prevent bradycardia
caused by the parasympathetic autonomic caused by the parasympathetic autonomic
effects of the neostigmine effects of the neostigmine

16. DEPOLARISING NEURO DEPOLARISING NEURO
MUSCULAR BLOCKER - SChMUSCULAR BLOCKER - SCh
Paralysis is preceded by muscular fasciculation Paralysis is preceded by muscular fasciculation
and this may be the cause of muscle pain after and this may be the cause of muscle pain after
its use. Pain can be minimized by preceding with its use. Pain can be minimized by preceding with
a small dose of competitive neuromuscular a small dose of competitive neuromuscular
blocking agent. Most rapid onset and shortest blocking agent. Most rapid onset and shortest
durtion of action.Tracheal intubation in less than durtion of action.Tracheal intubation in less than
60 seconds and total paralysis lasts upto 60 seconds and total paralysis lasts upto
4mts,with 50% recovery in about 10mts-4mts,with 50% recovery in about 10mts-
indicated for rapid sequence induction of indicated for rapid sequence induction of
anaesthesia in patients who are at risk of anaesthesia in patients who are at risk of
aspiration – the ability to secure the airway aspiration – the ability to secure the airway
rapidly with a tracheal tube is of utmost rapidly with a tracheal tube is of utmost
importance importance

17. KINETICSKINETICS
Destroyed by plasma pseudocholinesterase and Destroyed by plasma pseudocholinesterase and
so its persistence in the body is increased by so its persistence in the body is increased by
neostigmine which inactivates that enzyme and neostigmine which inactivates that enzyme and
in patients with hepatic disease or severe in patients with hepatic disease or severe
malnutrition whose plasma enzyme malnutrition whose plasma enzyme
concentrations are lower than normalconcentrations are lower than normal
Abnormal enzyme – paralysis then last for hours Abnormal enzyme – paralysis then last for hours
and individual requires ventilatory support and and individual requires ventilatory support and
sedation until spontaneous recovery. sedation until spontaneous recovery.

18. (Contd…)(Contd…)
Repeated injections of Sch can cause Repeated injections of Sch can cause
bradycardia, extrasystole, and even arrest – bradycardia, extrasystole, and even arrest –
probably due to cholinoceptor activation in the probably due to cholinoceptor activation in the
heart and are prevented by atropine.heart and are prevented by atropine.
Does not cross placenta Does not cross placenta
Succinyl choline depolarisation causes release Succinyl choline depolarisation causes release
of potassium from muscle – problem only if of potassium from muscle – problem only if
patients plasma K was already high. Eg. ARFpatients plasma K was already high. Eg. ARF
In patients with spinal cord injuries and with In patients with spinal cord injuries and with
major burns Sch cause exaggerated release of major burns Sch cause exaggerated release of
K from muscle sufficient to cause arrest K from muscle sufficient to cause arrest

19. USESUSES
Only those who can under take tracheal Only those who can under take tracheal
intubation and ventilation of the patients intubation and ventilation of the patients
lungs should use these drugs.lungs should use these drugs.
Used to provide muscular relaxation Used to provide muscular relaxation
during surgery and occasionally to assist during surgery and occasionally to assist
mechanical ventilation in ITU.mechanical ventilation in ITU.
Used during ECT to prevent injury to the Used during ECT to prevent injury to the
patient due to excessive muscular patient due to excessive muscular
contraction. contraction.

20. OTHER MUSCLE RELAXANTS - OTHER MUSCLE RELAXANTS -
SPASMOLYTICSSPASMOLYTICS
There is a place for drugs that reduce the There is a place for drugs that reduce the
spasm of the voluntary muscles without spasm of the voluntary muscles without
impairing voluntary movement. impairing voluntary movement.
Can be useful in spastic states, lowback Can be useful in spastic states, lowback
syndrome and rheumatism with muscle syndrome and rheumatism with muscle
spasm. spasm.

21. BACLOFENBACLOFEN
Structurally related to GABA – an inhibitory CNS Structurally related to GABA – an inhibitory CNS
transmitter – it inhibits reflex activity mainly in the transmitter – it inhibits reflex activity mainly in the
spinal cord. Reduces spasticity and flexor spinal cord. Reduces spasticity and flexor
spasms – function is commonly not improved. spasms – function is commonly not improved.
Ambulant patients may need their leg spasticity Ambulant patients may need their leg spasticity
to provide support and reduction of spasticity to provide support and reduction of spasticity
may expose the weakness of the limb.may expose the weakness of the limb.
It benefits some cases of trigeminal neuralgia – It benefits some cases of trigeminal neuralgia –
orally orally

22. DIAZEPAM DIAZEPAM
Acts at all GABAActs at all GABAAA synapses – sedation synapses – sedation
limits use limits use
Tizanidine – Alpha2 adrenoceptor agonist Tizanidine – Alpha2 adrenoceptor agonist
reinforces both pre and post synaptic reinforces both pre and post synaptic
inhibition in the cord also inhibits inhibition in the cord also inhibits
nociceptive transmission in the spinal nociceptive transmission in the spinal
dorsal horn dorsal horn
ADR: Drowsiness, hypotension, dry mouth ADR: Drowsiness, hypotension, dry mouth
and astheniaand asthenia

23. DANTROLENEDANTROLENE
Prevents the calcium release from the Prevents the calcium release from the
sarcoplasmic reticulum through the sarcoplasmic reticulum through the
ryanodine receptors (RyR1) channel.ryanodine receptors (RyR1) channel.
Used orally reduces spasticity in UMN Used orally reduces spasticity in UMN
disorders, hemiplegia, paraplegia, cerebral disorders, hemiplegia, paraplegia, cerebral
palsy and multiple sclerosis.palsy and multiple sclerosis.
ADR: generalised muscle weakness, ADR: generalised muscle weakness,
sedation and occasionally hepatitis.sedation and occasionally hepatitis.

24. MALIGNANT HYPERTHERMIAMALIGNANT HYPERTHERMIA
Triggered by volatile GAs and Sch-sudden Triggered by volatile GAs and Sch-sudden
and prolonged release of calcium with and prolonged release of calcium with
massive muscle contraction, lactic acid massive muscle contraction, lactic acid
production and increased body production and increased body
temperature. Prompt treatment is essential temperature. Prompt treatment is essential
to control acidosis and body temperature to control acidosis and body temperature
and to reduce calcium release-later is and to reduce calcium release-later is
accomplished by IV dantrolene accomplished by IV dantrolene

25. BOTULINUM TOXINBOTULINUM TOXIN
Local injection – for the treatment of Local injection – for the treatment of
generalized spastic disorders (cerebral generalized spastic disorders (cerebral
palsy) we utilise type A but type B is also palsy) we utilise type A but type B is also
available available
Local muscle spasm: carisoprodol, Local muscle spasm: carisoprodol,
methocarbamol. methocarbamol.

26. Other centrally acting spasmolytics: Gabapentin Other centrally acting spasmolytics: Gabapentin
– antiepileptic drug spasmolytic in several – antiepileptic drug spasmolytic in several
studies – with multiple sclerosisstudies – with multiple sclerosis
Progabide and glycine – Progabide is a GABAProgabide and glycine – Progabide is a GABAAA
and GABAand GABAB B agonist and has active metabolites agonist and has active metabolites
including GABA itselfincluding GABA itself
Glycine – inhibitory aminoacid neurotransmitter Glycine – inhibitory aminoacid neurotransmitter
posses activity when given orally and readily posses activity when given orally and readily
cross the BBB cross the BBB

27. Idrocilamide and Riluzole – newer drugs – Idrocilamide and Riluzole – newer drugs –
amyotrophic lateral sclerosis – through amyotrophic lateral sclerosis – through
inhibition of glutamatergic transmission in inhibition of glutamatergic transmission in
the CNSthe CNS
Thiocolchicoside 4mg – GABAThiocolchicoside 4mg – GABAAA receptor receptor
antagonist – myorelaxant effects could be antagonist – myorelaxant effects could be
exerted at the supraspinal level – painful exerted at the supraspinal level – painful
spasm spasm

29. GANGLIONIC STIMULANTS & GANGLIONIC STIMULANTS &
BLOCKERSBLOCKERS
Ach is the primary excitatory Ach is the primary excitatory
neurotransmitter in both sympathetic and neurotransmitter in both sympathetic and
parasympathetic ganglia.parasympathetic ganglia.
Dominant receptor – NDominant receptor – NNN subsidiary subsidiary
receptors are M1, M2, adrenergic, receptors are M1, M2, adrenergic,
dopaminergic and peptidergic receptors dopaminergic and peptidergic receptors

30. GANGLIONIC STIMULANTS GANGLIONIC STIMULANTS
Selective nicotinic Selective nicotinic
agonists agonists
Non selective/muscarinic Non selective/muscarinic
agonists agonists
Nicotine (small dose)Nicotine (small dose)Acetylcholine Acetylcholine
LobelineLobeline CarbacholCarbachol
Diemethyl phenyl Diemethyl phenyl
piperazinium iodide piperazinium iodide
(DMPP)(DMPP)
Pilocarpine Pilocarpine
Tetramethyl ammonium Tetramethyl ammonium
(TMA)(TMA)
Anticholinesterases Anticholinesterases

31. GANGLIONIC BLOCKERS GANGLIONIC BLOCKERS
Competitive blockers – Quartenary ammonium Competitive blockers – Quartenary ammonium
compounds: Hexamethonium, pentolinium compounds: Hexamethonium, pentolinium
Amines – (secondary/ tertiary): mecamylamine, Amines – (secondary/ tertiary): mecamylamine,
pempidinepempidine
Monosulfonium compound: trimethaphan, Monosulfonium compound: trimethaphan,
camphor sulfonate camphor sulfonate
Persisting depolarizing blockers: Nicotine (large Persisting depolarizing blockers: Nicotine (large
dose), Anticholinesterase (large dose)dose), Anticholinesterase (large dose)

32. USESUSES
Non-selective –wide range of effects. Non-selective –wide range of effects.
Replaced by more selective drugs for Replaced by more selective drugs for
treatment of hypertension. They may be treatment of hypertension. They may be
some times employed for some times employed for
1. Hypertensive emergency: Pentolinium 1. Hypertensive emergency: Pentolinium
2.5mg SC increased by 0.5 – 1mg 6hrly – 2.5mg SC increased by 0.5 – 1mg 6hrly –
60 – 600mg until maximum effects are 60 – 600mg until maximum effects are
produced produced

33. 2. induced hypotension: to produce 2. induced hypotension: to produce
controlled hypotension in order to reduce controlled hypotension in order to reduce
bleeding in the field of operation in neuro bleeding in the field of operation in neuro
surgery or orthopaedic surgery. surgery or orthopaedic surgery.
Trimethaphan is used, short duration of Trimethaphan is used, short duration of
action and produces vasodilatation by action and produces vasodilatation by
ganglionic blockade, direct effect on blood ganglionic blockade, direct effect on blood
vessels and by liberation of histamine vessels and by liberation of histamine