NEUROMUSCULAR JUNCTION

BLOCKING AGENTS

Dr Pranav BansalAssociate Professor

BPS GMC, Khanpur kalan, Sonipat

Introduction

What are neuromuscular blocking drugs ?These are agents that act peripherally at neuromuscular junction/muscle fibre itself to block neuromuscular transmission.

Why do we need them ?

In order to facilitate muscle relaxation for surgery & for mechanical ventilation during surgery or in ICU

What are SMRs ?

Definition: SMRs are the drugs that act peripherally at neuromuscular junction or muscle fibre itself or in cerebrospinal axis to reduce muscle tone and /cause muscle paralysis.

HISTORY

HISTORY In 1942 Griffith & Johnson suggested

that d-tubocuranine is a safe drug to use during surgery.

Succinycholine for the first time introduced by Thesleff & by Foldes & colleagues in1952.

In 1962 Baird & reid first administered pancuronium

Vecoronium, a amino steroid & atracurium, a benzylisoquinolinium introduced in 1980 and

Mivacurium introduced in 1990. All modern agents are entirely synthetic

Site of action of neuromuscular blocking agents Two types

Pre junctional recceptor

Post junctional recceptor

Site of action neuromuscular blocking agents

Post junctional receptor

Pentameric structure containing five subunits-2α,β,δ,Є(adult).

Fetal post junctional receptor consists of 2α,β,δ,γ.

Skeletal muscle relaxants

A. Nicotinic (Muscle) receptor blockers – Skeletal muscle relaxants.

B. Nicotinic (Nerve) receptor blockers – Ganglion blockers

Skeletal muscle relaxants Skeletal muscle relaxants block peripherally at the

neuromuscular junction (Nicotinic receptor of Ach – Muscle).

Types of Skeletal muscle relaxants: Competitive (Non-depolarizing) Non-competitive (Depolarizing) Directly acting Muscle relaxants Miscellaneous : Aminoglycosides

Skeletal muscle relaxantsPharmacokinetics : Most peripheral NM blockers are quaternary

compounds – not absorbed orally. Administered intravenously. Do not cross blood brain barrier or placenta No analgesia /loss of consciousness Volatile anes potentiate effect by dec tone of skeletal

muscle and dec sensitivity of post synaptic memb to depolarisation

SCh is metabolized by Pseudocholinesterase. Atracurium is inactivated in plasma by spontaneous

non-enzymatic degradation (Hoffman elimination).

Skeletal muscle relaxants Neuromuscular blockers

Depolarizing blockers : (Non-competitive) Succinylcholine (Suxamethonium)

Non - depolarizing ( competitive ) Long acting : Pancuronium, Pipecuronium,

Intermediate : Vecuronium, Rocuronium, Atracurium

Short acting : Mivacurium

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Mechanism of action (non depolarizing agents)

a) At low doses: These drugs combine with nicotinic receptors and prevent

acetylcholine binding.as they compete with acetycholine for receptor binding they are called competitive blockers

Thus prevent depolarization at end-plate.

Hence inhibit muscle contraction, relaxation of skeletal muscle occurs.

Their action can be overcome by increasing conc. of acetylcholine in the synaptic gap (by ihibition of acetyle choline estrase enzyme) e.g.: Neostigmine ,physostigmine, edrophonium

Anesthetist can apply this strategy to shorten the duration of blockage or over come the overdosage.

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

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

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ACTIONS All the muscles are not equally sensitive to blockade.

Small and rapidly contracting muscles are paralyzed first.

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

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Pharmacokinetics: Administered intravenously

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

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

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

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

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

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

Can also be excreted unchanged in bile.

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

Uses: as adjuvant to anesthesia during surgery. Control of ventilation (Endotracheal intubation) Treatment of convulsion

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Drug interactions

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

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

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Unwanted effects Fall in arterial pressure chiefly a result to ganglion

block , may also be due to histamine release this may give rise to bronchospasm (especially with tubocurarine ,mivacurium ,and atracurium)

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

results in to tachycardia.

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DEPOLARIZING AGENTS DRUGS Suxamethonium ( succinylecholine) Decamethonium Mechanism of action: These drugs act like acetylcholine but persist at the synapse at

high concentration and for longer duration and constantly stimulate the receptor.

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

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

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Therapeutic uses: When rapid endotracheal intubations is required.

Electroconvulsive shock therapy.

Pharmacokinetics: Administered intravenously.

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

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SUCCINYLCHOLINE• It causes paralysis of skeletal muscle. Sequence of paralysis may be different from that of

non depolarizing drugs but respiratory muscles are paralyzed last

Produces a transient twitching of skeletal muscle before causing block

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

It has shorter duration of action.

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It stimulate ganglion sympathetic and para sympathetic both.

In low dose it produces negative ionotropic and chronotropic effect

In high dose it produces positive ionotropic and chronotropic effect.

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

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

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Unwanted effects: Bradycardia preventable by atropine.

Hyperkalemia in patients with trauma or burns

this may cause dysrhythmia or even cardiac arrest.

Increase intraocular pressure due to contracture of extra ocular muscles .

increase intragastric pressure which may lead to emesis and aspiration of gastric content.

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

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

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

Depolarizing block ( Non-competitive ) : Succinylcholine have affinity and sub maximal intrinsic

activity at NM receptors. They open Na channels which cause initial twitching

and fasciculation. (fasciculation or "muscle twitch", is a small, local, involuntary muscle contraction and relaxation visible under the skin arising from the spontaneous discharge of a bundle of skeletal muscle fibers (muscle fascicle).)

It does not dissociate rapidly from the receptors resulting in prolonged depolarization and inactivation of the Na + channels

A.A. Non-depolarizing agents (Competitive Non-depolarizing agents (Competitive blockers).blockers).

Mechanism of action : • These have an affinity for the Nicotinic (NM) receptors

at the muscle end plates but have no intrinsic activity.• The antagonism is surmountable by increasing the

conc. of Ach.

Neuromuscular blocking agents :

Skeletal muscle relaxants

Duration (mins.)

Pancuronium 40-80

Pipecuronium 50-100

Vecuronium 20-40

Atracurium 20-40

Rocuronium 20-40

Succinyl choline 3-6

Skeletal muscle relaxants

Depolarizing block (Non-competitive) : Succinylcholine

It causes muscle pain. It causes hyperkalemia. Malignant Hyperthermia.

Competitive Non-depolarizing

Non-Competitive Depolarizing

Paralysis Flaccid Fasciculations---› Flaccid

Neostigmine Antagonizes Exaggerate / no effect.

Examples Pancuronium Succinylcholine

Skeletal muscle relaxants

USES OF NEUROMUSCULAR BLOCKERS : Adjuvant in general anesthesia Intubation and endoscopies Brief procedure

Skeletal muscle relaxantsDirectly acting muscle relaxants :Dantrolene :

Depolarization triggered release of calcium from the sarcoplasmic contraction is blocked / reduced.

Dantrolene is used orally/ i.v to reduces spasticity in hemiplegia and cerebral palsy.

It is the drug of choice – malignant hyperthermia

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DANTROLENE It acts directly It reduces skeletal muscle strength by interfering with

excitation-contraction coupling into the muscle fiber, by inhibiting the release of activator calcium from the sarcoplasmic stores.

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

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

Half life of the drug is 8-9 hours.

Classification Two groups

Depolarising or non-competitive type

Non-depolarising or competitive type

Depolarising or non-competitive type Sccinylcholine -consists of two acetylcholine

molecule linked back to back by acetate methyl group.

Mechanism of action-

like acetylcholine it stimulates cholinergic receptor at NMJ & Nicotinic (ganglionic) & muscarinic autonomic sites to open ionic channel leading to depolarisation.

Metabolism of succinylcholine ED950.51-0.63mg/kg.

Onset of action-30-60sec.

Duration of action-9-13 min.

Shortest acting neuromuscular blocking agent.

Metabolised by- butrycholinesterase or - plasma cholinesterase or - pseudocholinesterase

Metabolism of succinylcholine Scuccinycholine on breakdown by

butrycholinesterase produces

1- succinylmonocholine - succinic acid & choline

2-choline.

At neuromuscular junction effect of succinylcholine terminated by diffusion.

Factors affecting metabolism of succinylcholine As succinylcholine enter the circulation, its rapidly

metabolized by pseudocholinesterase.

This process is so efficient that only a fraction of injected dose ever reaches neuromuscular junction.

The duration of action is prolonged by high dose or by abnormal metabolism.

Abnormal metabolism may result from hypothermia, low enzyme levels or genetically aberrant enzyme.

Factors affecting metabolism of succinylcholine Hypothermia decreases rate of hydrolysis. Low levels of pseudocholinesterase accompany

pregnancy, liver dz, renal failure ,neostigmine, perinorm, advanced age, bruns, oral contraceptives.

Obese and m. gravis resistant to s.choline 1 in 50 pts has one normal & abnormal gene, resulting in

a slightly prolonged block(20-30 min). 1 in 3000 pts have 2 abnormal genes (homozygus

atypical) which will have a very long blockade (eg 6-8 h). Prolonged paralysis caused by atypical cholinesterase

should be treated with cont mechanical ventilation until muscle function returns to normal.

Qualitative analysis of Butrycholinesterase

Dibucain number- it is a amide based local anesthetic that inhibits

normal butrycholinesterase by 80%. Abnormal enzyme by 20%.

Flouride number

Side effects

1. Cardiovascular: can increase or decrease blood pressure and

heart rate (due to stimulation at parasympathetic and sympathetic ganglia)

Bradycardia- dt stimulation at SA node by

succinylmonocholine.More common in; Unatropinised children Digitalised and beta-blocked patient

Side effects

2. Hyperkalemia normal short lasting rise in K+ (0.5-1.0 mmol/L).

Life threatening K+ elevation possible in burn injury,massive trauma,neurologic or muscular disorder.

Side effects3. Fasciculation4. Muscle pains5. Intragastric pressure elevation6. Intraocular pressure elevation7. Malignant hyperthermia

-potent trigerring agent in patient susceptible to MH.8. Prolonged paralysis

Side effects9. Intracranial pressure

-slight increase in cerebral blood flow and intracranial pressure in some patients.-can be prevented by pretreating with NDMR and IV Lignocaine (1.5-2mg/kg) 2-3 minutes prior intubation.

Indication of use of succinylcholine- rapid sequence induction.

SuccinylcholineRecommendations for use:

use Peripheral Nerve Stimulator

maximal dose 1-1.5 mg/kg

look for recovery before admin of NDMR’s

Do not treat with anti AChE unless:proper N-M monitoring is availablespont. recovery of TOF is documented orChE is administered first

Non depolarising neuromuscular blocking drugs classification (on basis of chemical strucure)

BenzylisoquinoliniumD-tubocurareMetocurineDoxacuriumAtracuriumCisatracuriummivacurium

Aminosteroid PancuroniumVecuroniumRocuroniumRapacuronium

Classification of Non-Depolarising Muscle Relaxants

Ultra short Short Intermediate Long

Rapacuronium Mivacurium Vecuronium PancuroniumGW 280430 Atracurium d-Tubocurare

Cis-atracurium GallamineRocuronium Metocurine

DoxacuriumPipecuronium

Pancuronium Bis-quaternary Aminosteroid NMJ blocking agent. ED95 B-70µg/kg Onset of action-3-5min / Duration-60-90 min. Dosage-intubation-0.08-0.12mg/kg

maintenance-0.04mg/kg

Long acting No or slight increase on blood pressure, HR (Vagolytic) Hepatic metabolism & Renal clearance ( dose reduction in failure) Histamine release

Vecuronium aminosteriod ED95 B-50µg/kg Onset of action-3-5min/Duration-20-35min Dosage-intubation-0.08-0.12mg/kg maintenance-0.04mg/kg infusion-1-2µg/kg/min Depends primarily on biliary excretion and secondarily on renal

excretion (no dose reduction required) Intermediate acting Active metabolites- 3 cis vecuronium responsible for prolonged

effect Prolonged effect in old age, obesity, renal failure, AIDS, obesity

Atracurium Benzoisoquinoline derivative Non-organ dependent elimination

Non specific estererase: 60% of elimination Hofmann elimination : spontaneous nonenzymatic chemical breakdown occurs at physiologic pH and T.

Histamine release at higher clinical dose in 30% of patients(Hypotension,tachycardia,Bronchospasm)

Laudanosine toxicity-breakdown product from Hofmann elimination, assoc. with central nervous system excitation resulting in elevation of MAC and precipitation of seizures.

Temperature and pH sensitivity-action markedly prolonged in hypo- thermic or acidotic patients.

Cis-atracurium

Benzoisoquinoline derivative

3x more potent than atracurium.

No ester hydrolysis.

dosage: 0.1-0.15mg/kg (within 2 min) 1.0-2.0 mcg/kg/min (infusion rate)

Minimal histamine release.

Mivacurium Bisquaternary benzylisoquinoline potency, 1/3 that of atracurium

slow onset 1.5 min with 0.25 mg/kg

short duration 12-18 min with 0.25 mg/kg

histamine release with doses 3-4X ED95

hydrolyzed by pChE, recovery may be prolonged in some populations (e.g. atypical pChE)

Rocuronium

Mono-quaternary aminosteroid potency, approx 1/6 that of Vecuronium fast onset (< I min with 0.8 mg/kg) intermediate duration (44 min with 0.8 mg/kg) minimal CV side effects onset and duration prolonged in elderly slight decrease in elimination in RF

Rapacuronium monoquaternary aminosteroid, analogue of

Vecuronium low potency, fast onset, short to intermediate duration 1.5-2.0 mg/kg doses give good intubating conditions at 60

sec duration of action, dependent on dosage and age of patient 20 % decrease in aBP observed with 2-3 mg/kg doses principle route of elimination may be liver as 22% is renal

excretion. introduced in 2000 in US and removed from market 19

mos. later, after paediatric deaths (bronchospasm), never available in Canada)

Comparative Pharmacology of Muscle Relaxants

Agent ED95 Int Dose Onset DurationElim/Met(mg/kg) (mg/kg) (min) (min)

Succinylcholine 0.3 1-1.5 < 1 12 pChERapacuronium (1.0) 1.3 1.5 9 nonenzym./Hep.

Rocuronium 0.3 0.6 1 60 Hep./Renal

Mivacurium 0.08 0.2 2 25 PChEAtracurium 0.2 0.6 2-3 60 Hoff/hydrol.Cis-atracurium 0.05 0.15 3-4 60 Hoff/hydrol.Vecuronium 0.05 0.10 2-3 60 Hep./RenalPancuronium 0.07 0.10 3-5 100 Renal/HepaticPipecuronium 0.05 0.15 2-5 190 RenalDoxacurium 0.025 0.08 3-5 200 Renal/ChE

Percent of Dose Dependant on Renal Elimination

> 90% 60-90% 40-60% <25%

Gallamine (97) Pancuronium (80) d-TC (45) SuccinylcholinePipecuronium (70) Vecuronium (20)Doxacurium (70) Atracurium (NS)Metocurine (60) Mivacurium (NS)

Rocuronium

POSTOPERATIVE RESIDUAL CURARIZATION PORC)

common after NDMRs

long acting > intermediate > short acting

Assoc with respir. morbidity

not observed in children

monitoring decreases incidence

CHOLINESTERASE INHIBITORS (ANTI CHOLINESTERASE INHIBITORS (ANTI CHOLINESTERASE)CHOLINESTERASE)

Primary clinical use is to reverse nondepolarising muscle blockade

Neuromuscular transmission is blocked when NDMR compete with Ach to bind to nicotinic cholinergic receptors.

The cholinesterase inhibitors indirectly increase amount of Ach available to compete with NDMR, thereby re-establish NM transmission.

Cholinesterase inhibitors

In excessive doses, Achse inhibitors can paradoxically potentiate a nondepolarizing NM blockade.

It also prolong the depolarization blockade of succinylcholine.

ANTICHOLINESTERASE AGENTS

1. Neostigmine

2. Pyridostigmine

3. Edrophonium

4. Physostigmine

Neostigmine

Quaternary ammonium group Dosage : 0.04-0.08 mg/kg Effects apparent in 5-10 min and last more than

1 hour. Muscarinic side effects are minimized by prior or

concomitant administration of anticholinergic agent.

Also used to treat myasthaenia gravis, urinary bladder atonyand paralytic ileus.

Pyridostigmine

Dosage : 0.1-0.4 mg/kg Onset slower (10-15 min) and duration slightly

longer (>2 hours) Equivalent dose of anticholinergic are required

to prevent bradycardia.

Edrophonium

Dosage : 0.5-1.0mg/kg Less potent Most rapid onset (1-2 min ) Shortest duration of action Higher dose prolong duration of action to > than

1 hour. More effective at reversing mivacurium

blockade.

Difficulty reversing block Right dose? Intensity of block to be reversed? Choice of relaxant? Age of patient? Acid-base and electrolyte status? Temperature? Other drugs?

Atropine Tertiary amine Dosage : 0.01-0.02 mg/kg up to usual adult

dose of 0.4-0.6 mg. Potent effects on heart and brochial smooth

muscle.

ScopolamineScopolamine Dose is same as atropine and usually given

intramuscularly. More potent antisialagogue than atropine and

cause greater central nervous system effects. Can cause drowsiness and amnesia. Prevent motion sickness Avoided in patient with close-angle glaucoma

Glycopyrrolate Dosage : 0.005-0.01 mg/kg up to 0.2-0.3 mg in

adults. Cannot cross blood-brain barrier and almost

always devoid of central nervous system and ophthalmic activity.

Potent inhibition of salivary gland and respiratory tract secretions.

Longer duration than atropine (2-4 hours)