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

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 contraction be inhibited.This can be obtained by deep general anaesthesia,regional nerve by 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 recovery.But it requires mechanical ventilation and technical skill.Neuromuscular ventilation and technical skill.Neuromuscular blocking drugs should be given only after blocking drugs should be given only after induction of anaesthesia.induction of anaesthesia.

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 produce complete paralysis of all voluntary muscle so that movement is voluntary muscle so that movement is impossible and mechanical ventilation impossible and mechanical ventilation is needed.It is plainly important that a is needed.It is plainly important that a paralysed patient should be in a state paralysed patient should be in a state of full analgesia and unconscious of full analgesia and unconscious during surgery.during surgery.

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 release of Ach from the nerve endings into the synaptic cleft. This activates into the synaptic cleft. This activates receptors on the membrane of the motor receptors on the membrane of the motor end plate, a specialized area on the end plate, a specialized area on the muscle fibre, opening ion channels for muscle fibre, opening ion channels for momentary passage of sodium which momentary passage of sodium which depolarises the end plate and initiates depolarises the end plate and initiates muscle contraction. muscle contraction.

(Contd…)(Contd…) Neuromuscular blocking drugs used in Neuromuscular blocking drugs used in

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

By competitionBy competition Ach(Atracurium, Ach(Atracurium, cisatracurium, mivacurium, cisatracurium, mivacurium, pancuronium, rocuronium, pancuronium, rocuronium,

vecuronium).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 paralysis.Reversal of this type of neuro muscular block can be achieved with muscular block can be achieved with anticholinesterase drugs, such as anticholinesterase drugs, such as neostigmine which prevent the destruction neostigmine which prevent the destruction by cholinesterase of Ach released at nerve by cholinesterase of Ach released at nerve endings, allow the concentration to build up endings, allow the concentration to build up and so reduce the competitive effect of a and so reduce the competitive effect of a blocking agent. blocking agent.

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

ACTIONSACTIONS Skeletal muscles: IV injections produces Skeletal muscles: IV injections produces

muscle weakness followed by flaccid paralysis.muscle 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 blockade. Sch may cause ganglionic stimulation by its agonistic action on nicotinic stimulation by its agonistic action on nicotinic receptors 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

(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. paralysis of limb and respiratory muscles. Heart rate may increase due to vagal Heart rate may increase due to vagal ganglionic blockade ganglionic blockade

GIT: Ganglion blocking activity of GIT: Ganglion blocking activity of competitive blockers may enhance post competitive blockers may enhance post operative paralytic ileus after abdominal operative paralytic ileus after abdominal operations operations

CNS: Do not cross BBBCNS: Do not cross BBB

PHARMACOKINETICSPHARMACOKINETICS All neuromuscular blockers are All neuromuscular blockers are

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

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 blockade – muscle paralysis and apnoea lasting hours. Abnormal lasting hours. Abnormal pseudocholinesterase – dibucaine number pseudocholinesterase – dibucaine number

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 circulation, the liver or the kidney (aged, hepatic or renal disease). Very (aged, hepatic or renal disease). Very little effect on CVS but at dose more little effect on CVS but at dose more than 0.5 – 0.6mg/Kg histamine than 0.5 – 0.6mg/Kg histamine release may cause hypotension and release may cause hypotension and bronchospasm bronchospasm

CISATRACURIUMCISATRACURIUM Stereoisomer – less prone to cause Stereoisomer – less prone to cause

histamine release histamine release Vecuronium – synthetic steroid derivative Vecuronium – synthetic steroid derivative

– full neuromuscular blockade about 3mts – full neuromuscular blockade about 3mts after a dose of 0.1mg/kg – duration is 20 – after a dose of 0.1mg/kg – duration is 20 – 30 mts. No cardiovascular side effects and 30 mts. No cardiovascular side effects and does not cause histamine release does not cause histamine release

Rocuronium – steroid derivative – rapid Rocuronium – steroid derivative – rapid onset. 0.6mg/kg. Tracheal intubation – onset. 0.6mg/kg. Tracheal intubation – after 60 seconds. Negligible CV effects and after 60 seconds. Negligible CV effects and similar duration as vecuronium similar duration as vecuronium

MIVACURIUMMIVACURIUM Same chemical family as atracurium. Only Same chemical family as atracurium. Only

non depolarising neuromuscular blocker non depolarising neuromuscular blocker metabolized by plasma cholinesterase. metabolized by plasma cholinesterase. Short acting, can cause some hypotension Short acting, can cause some hypotension because of histamine release.because of histamine release.

Pancuronium – First steroid derivative – Pancuronium – First steroid derivative – longer acting - slight tachycardialonger acting - slight tachycardia

d-Tc – obsolete. Potent antagonist at d-Tc – obsolete. Potent antagonist at autonomic ganglia and causes significant autonomic ganglia and causes significant hypotension hypotension

ANTAGONISM OF COMPETITIVE ANTAGONISM OF COMPETITIVE NEURO MUSCULAR BLOCKER NEURO MUSCULAR BLOCKER

Neostigmine – which allow Neostigmine – which allow accumulation of Ach. Neostigmine accumulation of Ach. Neostigmine given IV with glycopyronium to given IV with glycopyronium to prevent bradycardia caused by the prevent bradycardia caused by the parasympathetic autonomic effects parasympathetic autonomic effects of the neostigmine of the neostigmine

DEPOLARISING NEURO DEPOLARISING NEURO MUSCULAR BLOCKER - SChMUSCULAR BLOCKER - SCh

Paralysis is preceded by muscular Paralysis is preceded by muscular fasciculation and this may be the cause of fasciculation and this may be the cause of muscle pain after its use. Pain can be muscle pain after its use. Pain can be minimized by preceding with a small dose of minimized by preceding with a small dose of competitive neuromuscular blocking agent. competitive neuromuscular blocking agent. Most rapid onset and shortest durtion of Most rapid onset and shortest durtion of action.Tracheal intubation in less than 60 action.Tracheal intubation in less than 60 seconds and total paralysis lasts upto 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

KINETICSKINETICS Destroyed by plasma pseudocholinesterase Destroyed by plasma pseudocholinesterase

and so its persistence in the body is increased and so its persistence in the body is increased by neostigmine which inactivates that enzyme by neostigmine which inactivates that enzyme and in patients with hepatic disease or severe and 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 Abnormal enzyme – paralysis then last for hours and individual requires ventilatory hours and individual requires ventilatory support and sedation until spontaneous support and sedation until spontaneous recovery. recovery.

(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 probably due to cholinoceptor activation in the heart and are prevented by atropine.the 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

USESUSES Only those who can under take Only those who can under take

tracheal intubation and ventilation of tracheal intubation and ventilation of the patients lungs should use these the patients lungs should use these drugs.drugs.

Used to provide muscular relaxation Used to provide muscular relaxation during surgery and occasionally to during surgery and occasionally to assist mechanical ventilation in ITU.assist mechanical ventilation in ITU.

Used during ECT to prevent injury to Used during ECT to prevent injury to the patient due to excessive muscular the patient due to excessive muscular contraction. contraction.

OTHER MUSCLE RELAXANTS - OTHER MUSCLE RELAXANTS - SPASMOLYTICSSPASMOLYTICS

There is a place for drugs that reduce There is a place for drugs that reduce the spasm of the voluntary muscles the spasm of the voluntary muscles without impairing voluntary without impairing voluntary movement. movement.

Can be useful in spastic states, Can be useful in spastic states, lowback syndrome and rheumatism lowback syndrome and rheumatism with muscle spasm. with muscle spasm.

BACLOFENBACLOFEN Structurally related to GABA – an inhibitory CNS Structurally related to GABA – an inhibitory CNS

transmitter – it inhibits reflex activity mainly in transmitter – it inhibits reflex activity mainly in the spinal cord. Reduces spasticity and flexor the 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

DIAZEPAM DIAZEPAM Acts at all GABAActs at all GABAAA synapses – synapses –

sedation limits use sedation limits use Tizanidine – Alpha2 adrenoceptor Tizanidine – Alpha2 adrenoceptor

agonist reinforces both pre and post agonist reinforces both pre and post synaptic inhibition in the cord also synaptic inhibition in the cord also inhibits nociceptive transmission in inhibits nociceptive transmission in the spinal dorsal horn the spinal dorsal horn

ADR: Drowsiness, hypotension, dry ADR: Drowsiness, hypotension, dry mouth and astheniamouth and asthenia

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, disorders, hemiplegia, paraplegia, cerebral palsy and multiple sclerosis.cerebral palsy and multiple sclerosis.

ADR: generalised muscle weakness, ADR: generalised muscle weakness, sedation and occasionally hepatitis.sedation and occasionally hepatitis.

MALIGNANT HYPERTHERMIAMALIGNANT HYPERTHERMIA Triggered by volatile GAs and Sch-Triggered by volatile GAs and Sch-

sudden and prolonged release of sudden and prolonged release of calcium with massive muscle calcium with massive muscle contraction, lactic acid production and contraction, lactic acid production and increased body temperature. Prompt increased body temperature. Prompt treatment is essential to control treatment is essential to control acidosis and body temperature and to acidosis and body temperature and to reduce calcium release-later is reduce calcium release-later is accomplished by IV dantrolene accomplished by IV dantrolene

BOTULINUM TOXINBOTULINUM TOXIN Local injection – for the treatment of Local injection – for the treatment of

generalized spastic disorders generalized spastic disorders (cerebral palsy) we utilise type A but (cerebral palsy) we utilise type A but type B is also available type B is also available

Local muscle spasm: carisoprodol, Local muscle spasm: carisoprodol, methocarbamol. methocarbamol.

Other centrally acting spasmolytics: Other centrally acting spasmolytics: Gabapentin – antiepileptic drug Gabapentin – antiepileptic drug spasmolytic in several studies – with spasmolytic in several studies – with multiple sclerosismultiple sclerosis

Progabide and glycine – Progabide is a Progabide and glycine – Progabide is a GABAGABAAA and GABA and GABAB B agonist and has active agonist and has active metabolites including GABA itselfmetabolites including GABA itself

Glycine – inhibitory aminoacid Glycine – inhibitory aminoacid neurotransmitter posses activity when neurotransmitter posses activity when given orally and readily cross the BBB given orally and readily cross the BBB

Idrocilamide and Riluzole – newer Idrocilamide and Riluzole – newer drugs – amyotrophic lateral sclerosis drugs – amyotrophic lateral sclerosis – through inhibition of glutamatergic – through inhibition of glutamatergic transmission in the CNStransmission in the CNS

Thiocolchicoside 4mg – GABAThiocolchicoside 4mg – GABAAA receptor antagonist – myorelaxant receptor antagonist – myorelaxant effects could be exerted at the effects could be exerted at the supraspinal level – painful spasm supraspinal level – painful spasm

GANGLIONIC STIMULANTS & GANGLIONIC STIMULANTS & BLOCKERSBLOCKERS

Ach is the primary excitatory Ach is the primary excitatory neurotransmitter in both sympathetic neurotransmitter in both sympathetic and parasympathetic ganglia.and parasympathetic ganglia.

Dominant receptor – NDominant receptor – NNN subsidiary subsidiary receptors are M1, M2, adrenergic, receptors are M1, M2, adrenergic, dopaminergic and peptidergic dopaminergic and peptidergic receptors receptors

GANGLIONIC STIMULANTS GANGLIONIC STIMULANTS Selective nicotinic Selective nicotinic agonists agonists

Non Non selective/muscarinic selective/muscarinic agonists agonists

Nicotine (small dose)Nicotine (small dose) Acetylcholine Acetylcholine LobelineLobeline CarbacholCarbacholDiemethyl phenyl Diemethyl phenyl piperazinium iodide piperazinium iodide (DMPP)(DMPP)

Pilocarpine Pilocarpine

Tetramethyl Tetramethyl ammonium ammonium (TMA)(TMA)

Anticholinesterases Anticholinesterases

GANGLIONIC BLOCKERS GANGLIONIC BLOCKERS Competitive blockers – Quartenary ammonium Competitive blockers – Quartenary ammonium

compounds: Hexamethonium, pentolinium compounds: Hexamethonium, pentolinium Amines – (secondary/ tertiary): Amines – (secondary/ tertiary):

mecamylamine, pempidinemecamylamine, pempidine Monosulfonium compound: trimethaphan, Monosulfonium compound: trimethaphan,

camphor sulfonate camphor sulfonate Persisting depolarizing blockers: Nicotine Persisting depolarizing blockers: Nicotine

(large dose), Anticholinesterase (large dose)(large dose), Anticholinesterase (large dose)

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 treatment of hypertension. They may be some times employed for be some times employed for

1. Hypertensive emergency: 1. Hypertensive emergency: Pentolinium 2.5mg SC increased by Pentolinium 2.5mg SC increased by 0.5 – 1mg 6hrly – 60 – 600mg until 0.5 – 1mg 6hrly – 60 – 600mg until maximum effects are produced maximum effects are produced

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