Neuromuscular Neuromuscular Blocking AgentsBlocking AgentsNeuromuscular Neuromuscular Blocking AgentsBlocking Agents

Pawitra PulbutrPawitra PulbutrM.Sc. In Pharm (Pharmacology)M.Sc. In Pharm (Pharmacology)

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epolarizing blocking agents และ De polarizing blocking agents

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- Non depolarizing blocking agentsและ Depolarizing blocking agents

Muscle relaxing Muscle relaxing drugsdrugs

Muscle relaxing Muscle relaxing drugsdrugs

• Neuromuscular blocking agentsNeuromuscular blocking agents– Neuromuscular blocker Neuromuscular blocker – Acting on NMJActing on NMJ– Use in surgeryUse in surgery– Focus here !Focus here !

• Centrally acting muscle relaxantsCentrally acting muscle relaxants– Spasmolytic agentSpasmolytic agent– Diazepam, BaclofenDiazepam, Baclofen– CNS drugCNS drug

• DantroleneDantrolene– Direct acting at skeletal muscleDirect acting at skeletal muscle

Neuromuscular junction Neuromuscular junction (NMJ)(NMJ)

• Junction b/w motor nerve terminal (somatic nerve) and skeletal muscle

• NTs = Acetylcholine Acetylcholine (ACh)(ACh)

• Motor end plate contain Nicotinic Nicotinic ReceptorReceptor & & AChEAChE

NMJ

Motor nerve

How to block end How to block end plate function ?plate function ?

How to block end How to block end plate function ?plate function ?

• Antagonist drugsAntagonist drugs– Interfere ACh binding to nicotinic nicotinic

RCRC at end plate– ““Non-depolarizing blocking Non-depolarizing blocking

agents”agents”– Prototype = TubocurarinePrototype = Tubocurarine

• Depolarizing blockDepolarizing block– Excess depolarizing agonist– ““Depolarizing blocking agents”Depolarizing blocking agents”– SuccinylcholineSuccinylcholine

Mechanism of actionMechanism of action• Non-depolarizing blocking agents

– All are this type (except succinylcholine)

– Prototype = “Tubocurarine”“Tubocurarine”– Competitive binding with ACh to

Nicotinic ACh RC at motor end plate– ““Competitive antagonist”Competitive antagonist”– May block in ion channel of RC

(Pore blocking)– Also block at prejunctional receptor

… Interfere ACh mobilization in nerve

Characteristic of Non-Characteristic of Non-depolarizing blockersdepolarizing blockers

No muscle fasciculationTetanic fadingPost tetanic potentiation

Competitive binding with ACh

Antagonism with “AChE inhibitor” … increased ACh

Depolarizing blocking Depolarizing blocking agentsagents

Decamethonium & Suxamethonium (succinylcholine)SuccinylcholineSuccinylcholine … Only one leftFast onset & short durationPhase I block Phase I block

depolarizing block

Phase II blockPhase II blockdesensitizationnon-depolarizing block

Phase I block Phase I block

• Depolarizing blockDepolarizing block• Bind to Nicotinic RC … depolarizationBind to Nicotinic RC … depolarization• Prolong ion conductance & Prolong ion conductance &

depolarizationdepolarization• No repolarizationNo repolarization• No excitation-contraction couplingNo excitation-contraction coupling• No muscle contractionNo muscle contraction• Flaccid paralysisFlaccid paralysis• Potentiation by AChE inhibitor Potentiation by AChE inhibitor

Characteristic of Phase I Characteristic of Phase I BlockBlock

Characteristic of Phase I Characteristic of Phase I BlockBlock

Muscle fasciculation before relaxationNo tetanic fading … Just lower responseNo post tetanic potentiationPotentiation by AChE inhibitorsAntagonism by Non-depolarizing blocker

Phase II blockPhase II block

Desensitization blockDesensitization block

Prolonged succinylcholineProlonged succinylcholine

DesensitizationDesensitization of nicotinic RC of nicotinic RC

Channel blockChannel block

No responseNo response

Non-depolarizing blocking like Non-depolarizing blocking like effecteffect

Antagonism by AChE inhibitorAntagonism by AChE inhibitor

• A = Non-depolarizing blockade … Fading

• B = Depolarizing blockade … No fading

• A = Post tetanic potentiation … Non-depolarizing blockade

• B = No post tetanic potentiation … Depolarizing blockade

Clinical Pharmacology Clinical Pharmacology of Neuromuscular of Neuromuscular

blockersblockers

Muscle relaxation in surgery & endotracheal tube insertionIn the past … use deep anesthesia … Danger !... CNS depressionNeuromuscular blocker

No CNS depressant effect

Effects seen only with Effects seen only with depolarizing blockade depolarizing blockade

(succinylcholine)(succinylcholine)

HyperkalemiaHyperkalemia

Increased ocular pressureIncreased ocular pressure

Increased intragastric Increased intragastric pressurepressure

Muscle painMuscle pain

Malignant hyperthermiaMalignant hyperthermia

Drug InteractionDrug Interaction

Depolarizing agent VSVS Non-depolarizing agentAntagonismNon-depolarizing agent can prevent fasciculation from depolarizing agentIncrease dose of succinylcholine ~ 50-90%

Factors considered Factors considered before NMB selectionbefore NMB selection

Duration of actionCVS effectsElimination pathwaysADRs

Make yourself Make yourself GOOD LUCK for GOOD LUCK for Mid-Term ExamMid-Term Exam