Neuromuscular Blocking Agents

Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)

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วัตถุประสงค ์เชิงพฤติกรรม

นิสิตมีความรู้ความเข้าใจถึงเภสัชวิทยา กลไกการออกฤทธิ์ เภสัชจลนศาสตร ์ การ ใช้ประโยชน์ทางคลินิก อาการไม่พึง ประสงค ์ และปฏิกิริยาระหว่างยา ของยา หย่อนกล้ามเนื้อชนิด Non-depolarizing blocking agents และ Depolarizing blocking agents นิสิตมีความเข้าใจถึงความแตกต่างของ การตอบสนองของกล้ามเนื้อต่อ ยาหย่อน กล้ามเนื้อชนิด Non-depolarizing blocking agents และ Depolarizing blocking agents

Muscle relaxing drugs

• Neuromuscular blocking agents – Neuromuscular blocker – Acting on NMJ – Use in surgery – Focus here ! • Centrally acting muscle relaxants – Spasmolytic agent – Diazepam, Baclofen – CNS drug • Dantrolene – Direct acting at skeletal muscle

Neuromuscular junction (NMJ)

Motor nerve NMJ

• Junction b/w motor

nerve terminal (somatic nerve) and skeletal muscle

• NTs =

Acetylcholine (ACh)

• Motor end plate

contain Nicotinic Receptor & AChE

How to block end plate function ?

• Antagonist drugs – Interfere ACh binding to

nicotinic RC

–

at end plate “ Non-depolarizing blocking agents ”

– Prototype = Tubocurarine • Depolarizing block – Excess depolarizing agonist –

“ Depolarizing blocking agents ”

– Succinylcholine

Mechanism of action

• Non-depolarizing blocking agents – All are this type (except succinylcholine) – Prototype =

“ Tubocurarine ”

– Competitive binding with ACh to

Nicotinic ACh RC at motor end plate

–

“ Competitive antagonist

– May block in ion channel of RC

(Pore blocking) ”

– Also block at prejunctional receptor

… Interfere ACh mobilization in nerve

Characteristic of Non depolarizing blockers No muscle fasciculation Tetanic fading Post tetanic potentiation Competitive binding with ACh Antagonism with “ AChE inhibitor ” … increased ACh

Depolarizing blocking agents

Decamethonium & Suxamethonium

(succinylcholine) Succinylcholine Phase I block Phase II block desensitization

…

depolarizing block

Only one left Fast onset & short duration

non-depolarizing block

Phase I block

• Depolarizing block • Bind to Nicotinic RC • No repolarization • Flaccid paralysis

…

• Prolong ion conductance & depolarization • No excitation-contraction coupling • No muscle contraction

depolarization

• Potentiation by AChE inhibitor

Characteristic of Phase I Block

Muscle fasciculation before relaxation No tetanic fading … Just lower response No post tetanic potentiation Potentiation by AChE inhibitors Antagonism by Non-depolarizing blocker

Phase II block

Desensitization block Prolonged succinylcholine Desensitization of nicotinic RC Channel block No response

Non-depolarizing blocking like effect

Antagonism 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 of Neuromuscular blockers

Muscle relaxation in surgery & endotracheal tube insertion In the past … use deep anesthesia … Danger !... CNS depression Neuromuscular blocker No CNS depressant effect

Effects seen only with depolarizing blockade (succinylcholine) Hyperkalemia Increased ocular pressure Increased intragastric pressure Muscle pain Malignant hyperthermia

Drug Interaction

Depolarizing agent VS Non-depolarizing agent Antagonism Non-depolarizing agent can prevent fasciculation from depolarizing agent Increase dose of succinylcholine ~ 50 90%

Factors considered before NMB selection

Duration of action CVS effects Elimination pathways ADRs

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