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SKELETAL MUSCLE SKELETAL MUSCLE RELAXANTSRELAXANTS

Dr. Abdul Latif MahesarDr. Abdul Latif Mahesar

King Saud UniversityKing Saud University

2204/19/2304/19/23

Classification on basis of site of action Classification on basis of site of action and mechanism of actionand mechanism of action

A)A) PERIPHERALLY ACTINGPERIPHERALLY ACTINGNeuromuscular blockersNeuromuscular blockers Non depolarizing agentsNon depolarizing agents

Isoquinoline derivativesIsoquinoline derivatives steriod derivativessteriod derivatives Tubocurarine Tubocurarine Pancuronu iumPancuronu ium Doxacurium Doxacurium PipecuroniumPipecuronium AtracuriumAtracurium RapacuroniumRapacuronium Metocurine Metocurine RocuroniumRocuronium MivacuriumMivacurium VecuroniumVecuronium

Depolarizing agentsDepolarizing agents Suxamethonium (Succinylcholine)Suxamethonium (Succinylcholine) DecamethoniumDecamethonium

Neuromuscular JunctionNeuromuscular Junction

1: Cholinergic motor neurone,2: 1: Cholinergic motor neurone,2: motor end-plate, 3: vesicles, 4: motor end-plate, 3: vesicles, 4: NNMMR, 5: mitochondrionR, 5: mitochondrion

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Depolarizing agents:Depolarizing agents:Succinyle cholineSuccinyle choline

These drugs are structural analogue pf acetylcholine .These drugs are structural analogue pf acetylcholine .

They either act as antagonists ( non depolarizing) They either act as antagonists ( non depolarizing)

OROR

agonist (depolarizing)agonist (depolarizing)

These drugs are used to increase the safety of general anestheticsThese drugs are used to increase the safety of general anesthetics

These are used parentrallyThese are used parentrally

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B)B) Centrally acting (spasmolytic drugs)Centrally acting (spasmolytic drugs)Diazepam ( act through GABA Diazepam ( act through GABA AA) receptors)) receptors)

Baclofen (GABA Baclofen (GABA B) B) receptorsreceptors

Dantroline ( act directly by interfering release of Dantroline ( act directly by interfering release of calcium from sarcoplasmic reticulum)calcium from sarcoplasmic reticulum)

Note:Note:

these drugs are used to control spastic muscle tone as these drugs are used to control spastic muscle tone as in epilesy ,multiple scelerosis ,cerebral palsy, stroke,in epilesy ,multiple scelerosis ,cerebral palsy, stroke,

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Mechanism of Sk. muscle Mechanism of Sk. muscle contractioncontraction

Initiation of impulseInitiation of impulse

Release of acetylcholineRelease of acetylcholine

Activation of nicotinic receptor at motor end Activation of nicotinic receptor at motor end plateplate

Opening of ion channel, passage of NaOpening of ion channel, passage of Na+ + , , depolarization of end platedepolarization of end plate

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Mechanism cont’dMechanism cont’d

Muscle contraction.Muscle contraction.

Neuromuscular blocking agents used in Neuromuscular blocking agents used in clinical practice interfere with this process.clinical practice interfere with this process.

Drugs, can block neuromuscular transmission/ Drugs, can block neuromuscular transmission/ or muscle contraction by actingor muscle contraction by acting

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Presynaptically:Presynaptically: To inhibit acetylcholine synthesis or release (practically To inhibit acetylcholine synthesis or release (practically not used).not used).

As they may have whole body unspecific nicotinic as well as As they may have whole body unspecific nicotinic as well as muscarinic effectsmuscarinic effects

Postsynaptically:Postsynaptically: To block the receptor activity. To block the receptor activity.

To block ion channel at the end plateTo block ion channel at the end plate

Clinically these drugs are only used as an adjuvant to general anesthesia, Clinically these drugs are only used as an adjuvant to general anesthesia, ((only when artificial respiration is availableonly when artificial respiration is available.).)

They interfere with the post synaptic action of They interfere with the post synaptic action of

acetylcholine.acetylcholine.

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Non depolarizing (majority):Non depolarizing (majority): Act by blocking acetylcholine receptors.Act by blocking acetylcholine receptors.

In some cases (in higher doses), act by blocking ion channels.In some cases (in higher doses), act by blocking ion channels.

DepolarizingDepolarizing::

act as agonists at acetylcholine receptorsact as agonists at acetylcholine receptors

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Mechanism of action Mechanism of action (non depolarizing agents)(non depolarizing agents)

a) a) At low dosesAt low doses::These drugs combine with nicotinic receptors and prevent These drugs combine with nicotinic receptors and prevent acetylcholine binding.as they compete with acetycholine for acetylcholine binding.as they compete with acetycholine for receptor binding they are called competitive blockersreceptor binding they are called competitive blockers

Thus prevent depolarization at end-plate.Thus prevent depolarization at end-plate.

Hence inhibit muscle contraction, relaxation of skeletal Hence inhibit muscle contraction, relaxation of skeletal muscle occurs.muscle occurs.

Their action can be overcome by increasing conc. of Their action can be overcome by increasing conc. of acetylcholine in the synaptic gap(by ihibition of acetylcholine in the synaptic gap(by ihibition of acetyle choline estrase enzyme) acetyle choline estrase enzyme) e.g.: Neostigmine ,physostigmine edrophoniume.g.: Neostigmine ,physostigmine edrophoniumAnesthetist can apply this strategy to shorten the Anesthetist can apply this strategy to shorten the duration of blockage or over come the overdosage.duration of blockage or over come the overdosage.

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At high dosesAt high doses These drugs block ion channels of the end plate.These drugs block ion channels of the end plate.

Leads to further weakening of the transmission and Leads to further weakening of the transmission and reduces the ability of Ach-esterase inhibitors to reduces the ability of Ach-esterase inhibitors to reverse the action.reverse the action.

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ACTIONSACTIONS

All the muscles are not equally sensitive to blockade.All the muscles are not equally sensitive to blockade.

Small and rapidly contracting muscles are paralyzed Small and rapidly contracting muscles are paralyzed first.first.

Respiratory muscles are last to be affected and first to Respiratory muscles are last to be affected and first to recover.recover.

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Pharmacokinetics:Pharmacokinetics:

Administered intravenouslyAdministered intravenously

Cross blood brain barrier poorly (they are poorly lipid Cross blood brain barrier poorly (they are poorly lipid soluble)soluble)

Some are not metabolized in liver, their action is Some are not metabolized in liver, their action is terminated by redistribution, excreted slowly and terminated by redistribution, excreted slowly and excreted in urine unchanged (tubocurarine, excreted in urine unchanged (tubocurarine, mivacurium, metocurine).mivacurium, metocurine).

They have limited volume of distribution as they are They have limited volume of distribution as they are highly ionized.highly ionized.

Atracurium is degraded spontaneously in plasma by Atracurium is degraded spontaneously in plasma by ester hydrolysis ,it releases histamine and can ester hydrolysis ,it releases histamine and can produce a fall in blood pressure ,flushing and produce a fall in blood pressure ,flushing and bronchoconstriction. is metabolized to bronchoconstriction. is metabolized to laudanosine( which can provoke laudanosine( which can provoke seizures),Cisatracurium with similar seizures),Cisatracurium with similar pharmacokinetics is more safer.pharmacokinetics is more safer.

non depolarizers are excreted via kidney ,have long non depolarizers are excreted via kidney ,have long half life and duration of action than those which are half life and duration of action than those which are excreted by liver.excreted by liver.

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Some (vecuronium, rocuronium) are acetylated in liver.( there Some (vecuronium, rocuronium) are acetylated in liver.( there clearance can be prolonged in hepatic impairment)clearance can be prolonged in hepatic impairment)

Can also be excreted unchanged in bile.Can also be excreted unchanged in bile.

They differ in onset, duration and recovery They differ in onset, duration and recovery (see table)(see table)

UsesUses:: as adjuvant to anesthesia during surgery. as adjuvant to anesthesia during surgery.

Control of ventilation (Endotracheal intubation)Control of ventilation (Endotracheal intubation) Treatment of convulsionTreatment of convulsion

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Drug interactionsDrug interactions

Choline esterase inhibitors such as neostigmine, Choline esterase inhibitors such as neostigmine, pyridostimine and edrophonium reduces or overcome pyridostimine and edrophonium reduces or overcome their activity but with high doses they can cause their activity but with high doses they can cause depolarizing block due to elevated acetylcholine depolarizing block due to elevated acetylcholine concentration at the end plate.concentration at the end plate.

Halogenated Halogenated hydrocarbons ,aminoglycosides ,calcium channel hydrocarbons ,aminoglycosides ,calcium channel blockers synergize their effect.blockers synergize their effect.

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Unwanted effectsUnwanted effectsFall in arterial pressure Fall in arterial pressure chiefly a result to ganglion chiefly a result to ganglion block , may also be due to histamine release this may block , may also be due to histamine release this may give rise to bronchospasm (especially with give rise to bronchospasm (especially with tubocurarine ,mivacurium ,and atracurium)tubocurarine ,mivacurium ,and atracurium)

Gallamine and pancuronium block, muscarinic Gallamine and pancuronium block, muscarinic receptors also, particularly in heart which may receptors also, particularly in heart which may

results in to tachycardia.results in to tachycardia.

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DEPOLARIZING AGENTSDEPOLARIZING AGENTS

DRUGS DRUGS Suxamethonium ( succinylecholineSuxamethonium ( succinylecholine))DecamethoniumDecamethonium

Mechanism of action:Mechanism of action:These drugs act like acetylcholine but persist at the synapse at These drugs act like acetylcholine but persist at the synapse at high concentration and for longer duration and constantly high concentration and for longer duration and constantly stimulate the receptor.stimulate the receptor.

First, opening of the Na+ channel occurs resulting in First, opening of the Na+ channel occurs resulting in depolarization, this leads to transient twitching of the muscle, depolarization, this leads to transient twitching of the muscle, continued binding of drugs make the receptor incapable to continued binding of drugs make the receptor incapable to transmit the impulses, paralysis occurs.transmit the impulses, paralysis occurs.

The continued depolarization makes the receptor incapable of The continued depolarization makes the receptor incapable of transmitting further impulses.transmitting further impulses.

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Therapeutic uses:Therapeutic uses:When rapid endotracheal intubations is required.When rapid endotracheal intubations is required.

Electroconvulsive shock therapy.Electroconvulsive shock therapy.

PharmacokineticsPharmacokinetics::Administered intravenously.Administered intravenously.

Due to rapid inactivation by plasma cholinestrase, Due to rapid inactivation by plasma cholinestrase, given by continued infusion.given by continued infusion.

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SUCCINYLCHOLINESUCCINYLCHOLINE• It causes paralysis of skeletal muscle.It causes paralysis of skeletal muscle.

Sequence of paralysis may be different from that of Sequence of paralysis may be different from that of non depolarizing drugs but respiratory muscles are non depolarizing drugs but respiratory muscles are paralyzed lastparalyzed last

Produces a transient twitching of skeletal muscle Produces a transient twitching of skeletal muscle before causing blockbefore causing block

It causes maintained depolarization at the end plate, It causes maintained depolarization at the end plate, which leads to a loss of electrical excitability.which leads to a loss of electrical excitability. It has shorter duration of action.It has shorter duration of action.

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It stimulate ganglion sympathetic and para It stimulate ganglion sympathetic and para sympathetic both.sympathetic both.

In low dose it produces negative ionotropic In low dose it produces negative ionotropic and chronotropic effectand chronotropic effect

In high dose it produces positive ionotropic In high dose it produces positive ionotropic and chronotropic effect.and chronotropic effect.

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It act like acetylcholine but diffuse slowly to It act like acetylcholine but diffuse slowly to the end plate and remain there for long enough the end plate and remain there for long enough that the depolarization causes loss of electrical that the depolarization causes loss of electrical excitabilityexcitability

If cholinestrase is inhibited ,it is possible for If cholinestrase is inhibited ,it is possible for circulating acetylcholine to reach a level circulating acetylcholine to reach a level sufficient to cause depolarization block.sufficient to cause depolarization block.

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Unwanted effects:Unwanted effects:Bradycardia preventable by atropine.Bradycardia preventable by atropine.

Hyperkalemia in patients with trauma or burnsHyperkalemia in patients with trauma or burns

this may cause dysrhythmia or even cardiac arrest.this may cause dysrhythmia or even cardiac arrest.

Increase intraocular pressure due to contracture of Increase intraocular pressure due to contracture of extra ocular muscles .extra ocular muscles . increase intragastric pressure which may lead to increase intragastric pressure which may lead to emesis and aspiration of gastric content.emesis and aspiration of gastric content.

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Malignant hyperthermia:Malignant hyperthermia: rare inherited condition rare inherited condition probably caused by a mutation of Caprobably caused by a mutation of Ca++ ++ release channel release channel of sarcoplasmic reticulum, which results muscle of sarcoplasmic reticulum, which results muscle spasm and dramatic rise in body temperature. (spasm and dramatic rise in body temperature. (ThisThis is is treated by cooling the body and administration of Dantrolene)treated by cooling the body and administration of Dantrolene)

Prolonged paralysisProlonged paralysis:: due to factors which reduce the due to factors which reduce the activity of plasma cholinesteraseactivity of plasma cholinesterase

genetic variants as abnormal cholinesterase, its severe deficiency. genetic variants as abnormal cholinesterase, its severe deficiency. anti -cholinesterase drugs anti -cholinesterase drugs neonatesneonates liver disease liver disease

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Characteristics of neuromuscular-blocking drugsCharacteristics of neuromuscular-blocking drugs

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Some properties of neuromuscular blockersSome properties of neuromuscular blockers

DrugDrug EliminationElimination Approximate potency Approximate potency relative to Tubocurarinerelative to Tubocurarine

AtracuriumAtracurium spontaneousspontaneous 1.51.5

DoxacuriumDoxacurium kidneykidney 66

MivacuriumMivacurium Plasma cholinesterasePlasma cholinesterase 44

MetocurineMetocurine Kidney 40%Kidney 40% 44

TubocurarineTubocurarine Kidney 40%Kidney 40% 11

Panacurium Panacurium Kidney 80%Kidney 80% 66

RocuroniumRocuronium Liver 70-80%,kidneyLiver 70-80%,kidney 0.80.8

vecuroniumvecuronium Liver 75-90%,kidneyLiver 75-90%,kidney 66

pipecuroniumpipecuronium Kidney ,liverKidney ,liver 66

RapacuroniumRapacuronium liverliver 0.40.4

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DANTROLENE DANTROLENE It acts directlyIt acts directlyIt reduces skeletal muscle strength by interfering with It reduces skeletal muscle strength by interfering with excitation-contraction coupling into the muscle fiber, by excitation-contraction coupling into the muscle fiber, by inhibiting the release of activator calcium from the inhibiting the release of activator calcium from the sarcoplasmic stores.sarcoplasmic stores.

It is very useful in the treatment of malignant hyperthermia It is very useful in the treatment of malignant hyperthermia caused by depolarizing relaxants.caused by depolarizing relaxants.

This drug can be administered orally as well as intravenously. This drug can be administered orally as well as intravenously. Oral absorption is only one third.Oral absorption is only one third.

Half life of the drug is 8-9 hoursHalf life of the drug is 8-9 hours..

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BaclofenBaclofen It acts through GABA B receptorsIt acts through GABA B receptors

It causes hyper polarization by increased K+ conductance reducing calcium influx It causes hyper polarization by increased K+ conductance reducing calcium influx and reduces excitatory transmitter in brain as well as spinal cord and reduces excitatory transmitter in brain as well as spinal cord

It also reduces pain by inhibitory substance P. in spinal cord It also reduces pain by inhibitory substance P. in spinal cord

It is less sedativeIt is less sedative

It is rapidly and completely absorbed orallyIt is rapidly and completely absorbed orally

It has a half life of 3- 4 hours It has a half life of 3- 4 hours

It may increases seizures in epileptics It may increases seizures in epileptics

It is also useful to prevent migraine.It is also useful to prevent migraine.