Skeletal muscle relaxants

1. Skeletal muscleSkeletal 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 abdomenA lot of surgery especially of the abdomen
requires that voluntary muscle tone and reflexrequires that voluntary muscle tone and reflex
contraction be inhibited.This can be obtained bycontraction be inhibited.This can be obtained by
deep general anaesthesia,regional nervedeep general anaesthesia,regional nerve
blockade or by using neuromuscular blockingblockade or by using neuromuscular blocking
drugs.Deep GA causes CVdrugs.Deep GA causes CV
depression,respiratory complications and slowdepression,respiratory complications and slow
recovery.But it requires mechanical ventilationrecovery.But it requires mechanical ventilation
and technical skill.Neuromuscular blocking drugsand technical skill.Neuromuscular blocking drugs
should be given only after induction ofshould be given only after induction of
anaesthesia.anaesthesia.

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

4. MechanismsMechanisms
 When an impulse passes down a motorWhen an impulse passes down a motor
nerve to voluntary muscle it causesnerve to voluntary muscle it causes
release of Ach from the nerve endings intorelease of Ach from the nerve endings into
the synaptic cleft. This activates receptorsthe 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 momentaryopening ion channels for momentary
passage of sodium which depolarises thepassage of sodium which depolarises the
end plate and initiates muscle contraction.end plate and initiates muscle contraction.

5. (Contd…)(Contd…)
 Neuromuscular blocking drugs used inNeuromuscular blocking drugs used in
clinical practice interfere with this process.clinical practice interfere with this process.
Natural substances that prevent theNatural 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 someEg. Clostridium botulinum toxin and some
venoms. There are two principalvenoms. There are two principal
mechanisms by which drugs usedmechanisms by which drugs used
clinically interfere with neuromuscularclinically 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 ofThese drugs are competitive antagonists of
Ach.They do not cause depolarisationAch.They do not cause depolarisation
themselves but protect the endplate fromthemselves but protect the endplate from
depolarisation by Ach. The result is a flacciddepolarisation by Ach. The result is a flaccid
paralysis.Reversal of this type of neuro muscularparalysis.Reversal of this type of neuro muscular
block can be achieved with anticholinesteraseblock can be achieved with anticholinesterase
drugs, such as neostigmine which prevent thedrugs, such as neostigmine which prevent the
destruction by cholinesterase of Ach released atdestruction by cholinesterase of Ach released at
nerve endings, allow the concentration to buildnerve endings, allow the concentration to build
up and so reduce the competitive effect of aup 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 plateBy depolarization of the motor end plate
such agonist drugs activate the Achsuch agonist drugs activate the Ach
receptor on the motor end plate and atreceptor on the motor end plate and at
their first application voluntary muscletheir first application voluntary muscle
contracts but as they are not destroyedcontracts but as they are not destroyed
immediately, like Ach, the depolarizationimmediately, like Ach, the depolarization
persists. With prolonged administrationpersists. With prolonged administration
depolarization block changes to adepolarization block changes to a
competitive block (dual block) –competitive block (dual block) –
desensitization of the receptor to Achdesensitization of the receptor to Ach

8. ACTIONSACTIONS
 Skeletal muscles: IV injections produces muscleSkeletal 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 ganglionicmuscular blockers – some degree of ganglionic
blockade. Sch may cause ganglionic stimulationblockade. Sch may cause ganglionic stimulation
by its agonistic action on nicotinic receptorsby its agonistic action on nicotinic receptors
 Histamine release: d – Tc release histamineHistamine release: d – Tc release histamine
from mast cells – hypotension by d – Tc,from mast cells – hypotension by d – Tc,
flushing, bronchospasm and increasedflushing, bronchospasm and increased
respiratory secretion are other effectsrespiratory secretion are other effects

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

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

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

12. COMPETITIVE ANTAGONISTSCOMPETITIVE ANTAGONISTS
ATRACURIUMATRACURIUM
 Inactivation in plasma by spontaneousInactivation in plasma by spontaneous
nonenzymatic degradation (hoffmannonenzymatic degradation (hoffman
elimination)elimination)
 Thus uninfluenced by the state ofThus 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 effecthepatic 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 cause0.6mg/Kg histamine release may cause
hypotension and bronchospasmhypotension and bronchospasm

13. CISATRACURIUMCISATRACURIUM
 Stereoisomer – less prone to cause histamineStereoisomer – less prone to cause histamine
releaserelease
 Vecuronium – synthetic steroid derivative – fullVecuronium – synthetic steroid derivative – full
neuromuscular blockade about 3mts after aneuromuscular blockade about 3mts after a
dose of 0.1mg/kg – duration is 20 – 30 mts. Nodose of 0.1mg/kg – duration is 20 – 30 mts. No
cardiovascular side effects and does not causecardiovascular side effects and does not cause
histamine releasehistamine release
 Rocuronium – steroid derivative – rapid onset.Rocuronium – steroid derivative – rapid onset.
0.6mg/kg. Tracheal intubation – after 600.6mg/kg. Tracheal intubation – after 60
seconds. Negligible CV effects and similarseconds. Negligible CV effects and similar
duration as vecuroniumduration as vecuronium

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

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

16. DEPOLARISING NEURODEPOLARISING NEURO
MUSCULAR BLOCKER - SChMUSCULAR BLOCKER - SCh
 Paralysis is preceded by muscular fasciculationParalysis is preceded by muscular fasciculation
and this may be the cause of muscle pain afterand this may be the cause of muscle pain after
its use. Pain can be minimized by preceding withits use. Pain can be minimized by preceding with
a small dose of competitive neuromusculara small dose of competitive neuromuscular
blocking agent. Most rapid onset and shortestblocking agent. Most rapid onset and shortest
durtion of action.Tracheal intubation in less thandurtion of action.Tracheal intubation in less than
60 seconds and total paralysis lasts upto60 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 ofindicated for rapid sequence induction of
anaesthesia in patients who are at risk ofanaesthesia in patients who are at risk of
aspiration – the ability to secure the airwayaspiration – the ability to secure the airway
rapidly with a tracheal tube is of utmostrapidly with a tracheal tube is of utmost
importanceimportance

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

18. (Contd…)(Contd…)
 Repeated injections of Sch can causeRepeated injections of Sch can cause
bradycardia, extrasystole, and even arrest –bradycardia, extrasystole, and even arrest –
probably due to cholinoceptor activation in theprobably due to cholinoceptor activation in the
heart and are prevented by atropine.heart and are prevented by atropine.
 Does not cross placentaDoes not cross placenta
 Succinyl choline depolarisation causes releaseSuccinyl choline depolarisation causes release
of potassium from muscle – problem only ifof 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 withIn patients with spinal cord injuries and with
major burns Sch cause exaggerated release ofmajor burns Sch cause exaggerated release of
K from muscle sufficient to cause arrestK from muscle sufficient to cause arrest

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

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

21. BACLOFENBACLOFEN
 Structurally related to GABA – an inhibitory CNSStructurally related to GABA – an inhibitory CNS
transmitter – it inhibits reflex activity mainly in thetransmitter – it inhibits reflex activity mainly in the
spinal cord. Reduces spasticity and flexorspinal cord. Reduces spasticity and flexor
spasms – function is commonly not improved.spasms – function is commonly not improved.
 Ambulant patients may need their leg spasticityAmbulant patients may need their leg spasticity
to provide support and reduction of spasticityto 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 –
orallyorally

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

23. DANTROLENEDANTROLENE
 Prevents the calcium release from thePrevents the calcium release from the
sarcoplasmic reticulum through thesarcoplasmic reticulum through the
ryanodine receptors (RyR1) channel.ryanodine receptors (RyR1) channel.
 Used orally reduces spasticity in UMNUsed orally reduces spasticity in UMN
disorders, hemiplegia, paraplegia, cerebraldisorders, 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-suddenTriggered by volatile GAs and Sch-sudden
and prolonged release of calcium withand prolonged release of calcium with
massive muscle contraction, lactic acidmassive muscle contraction, lactic acid
production and increased bodyproduction and increased body
temperature. Prompt treatment is essentialtemperature. Prompt treatment is essential
to control acidosis and body temperatureto control acidosis and body temperature
and to reduce calcium release-later isand to reduce calcium release-later is
accomplished by IV dantroleneaccomplished by IV dantrolene

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

26.  Other centrally acting spasmolytics: GabapentinOther 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 GABABB agonist and has active metabolitesagonist and has active metabolites
including GABA itselfincluding GABA itself
 Glycine – inhibitory aminoacid neurotransmitterGlycine – inhibitory aminoacid neurotransmitter
posses activity when given orally and readilyposses activity when given orally and readily
cross the BBBcross the BBB

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

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

30. GANGLIONIC STIMULANTSGANGLIONIC STIMULANTS
Selective nicotinicSelective nicotinic
agonistsagonists
Non selective/muscarinicNon selective/muscarinic
agonistsagonists
Nicotine (small dose)Nicotine (small dose) AcetylcholineAcetylcholine
LobelineLobeline CarbacholCarbachol
Diemethyl phenylDiemethyl phenyl
piperazinium iodidepiperazinium iodide
(DMPP)(DMPP)
PilocarpinePilocarpine
Tetramethyl ammoniumTetramethyl ammonium
(TMA)(TMA)
AnticholinesterasesAnticholinesterases

31. GANGLIONIC BLOCKERSGANGLIONIC BLOCKERS
 Competitive blockers – Quartenary ammoniumCompetitive blockers – Quartenary ammonium
compounds: Hexamethonium, pentoliniumcompounds: Hexamethonium, pentolinium
 Amines – (secondary/ tertiary): mecamylamine,Amines – (secondary/ tertiary): mecamylamine,
pempidinepempidine
 Monosulfonium compound: trimethaphan,Monosulfonium compound: trimethaphan,
camphor sulfonatecamphor sulfonate
 Persisting depolarizing blockers: Nicotine (largePersisting 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 forReplaced by more selective drugs for
treatment of hypertension. They may betreatment of hypertension. They may be
some times employed forsome times employed for
 1. Hypertensive emergency: Pentolinium1. 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 are60 – 600mg until maximum effects are
producedproduced

33.  2. induced hypotension: to produce2. induced hypotension: to produce
controlled hypotension in order to reducecontrolled hypotension in order to reduce
bleeding in the field of operation in neurobleeding in the field of operation in neuro
surgery or orthopaedic surgery.surgery or orthopaedic surgery.
Trimethaphan is used, short duration ofTrimethaphan is used, short duration of
action and produces vasodilatation byaction and produces vasodilatation by
ganglionic blockade, direct effect on bloodganglionic blockade, direct effect on blood
vessels and by liberation of histaminevessels and by liberation of histamine