sk. m relaxants (2)

Neuromuscular blocker (Muscle Relaxants) Objectives

1. Physiology of neuromuscular junction

2. Muscle relaxants definition 3. Classification of Muscle Relaxants

4. Role of MR

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3May 3, 2023

Motor unit = Motor neurone Motor axon+ branches+ terminals All muscle fibres to which it connects

One motor neurone has exclusive Control of many muscle fibres

eg 10 oculomotor,1000 biceps

One muscle fibre innervated by one motor nerve terminal

Motor neurone

Motor axon

Skel

etal

mus

cle

fibre

Muscle Relaxants: Definition :

• Neuromuscular blockers (NMB’s) :

Drugs that completely paralyze skeletal muscles (from normal tone to zero) by interfering with acetylcholine at neuromuscular jnx.

• Spasmolytics :

Drugs that used to relieve muscle spasm & bring them from hypertonic state to normal muscle tone.

Drugs that decrease muscle tone

NOT DISCUSSEDantispasmodics, vasodilators, Bronchodilators

IMPORTANT IN SURGERIES6

History : From hunting in Jungles to Operation theatre

• Cuare: The arrow poison• Derived from “Ourare” meaning arrow

poison in south American • Tubocurarine name: Because of packing

in ‘hollow bamboo tubes’:

Role of NMB ‘s in surgery:

NMB’s are co-administrated with anesthetics in the induction phase to induce muscle paralysis (Abdominal wall & lower limbs)

facilitate the surgery, especially intra-abdominal and intra-thoracic surgeries

facilitate endotracheal intubation, endocscopies.Control convulsion Electroshock therapy in psychotic patientRelieve of tetanus and epileptic convulsion• BUT bcz NMB may paralyze muscles required for breathing,

mechanical ventilation should be available to maintain adequate respiration.

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Paralyzed as follow:– Small rapidly contracting muscles of face, eye, Jae,

toes and larynx

– Larger muscles like Limbs, Neck, Trunk,

– Finally Intercostals and lastly diaphragm.Recovery is in reverse.

Sequence of skeletal muscle paralysis

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Skeletal muscle relaxants

A. Nicotinic (Muscle) receptor blockers – Peripherally

B. Centrally acting muscle relaxants

C. Directly acting muscle relaxants

Skeletal muscle relaxants

• Skeletal muscle relaxants block peripherally at the neuromuscular junction (NM receptor of Ach – Muscle).

• Types of Skeletal muscle relaxants:Competitive (Non-depolarizing)Non-competitive (Depolarizing)

A. Non-depolarizing agents (Competitive 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.

Action PotentialCharacteristic series of potential changes due to a conducted stimulus when an axon is stimulated.

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)

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

• Phase –I Block

• Phase –II Block

Advantage of new: minimal NN action, histamine release, short acting reversal easy, rapid acting Sch

Skeletal muscle relaxants

• Neuromuscular blockers – Non - depolarizing ( competitive ) • Long acting : d-TC,Pancuronium, Pipecuronium, Gallamine

(Kidney Excretion) • Intermediate : Vecuronium, Rocuronium, Atracurium

(eliminated by liver)• Short acting : Mivacurium, Ropcacuronium

(Inactivated by plasma cholinesterase)

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

Skeletal muscle relaxants

Pharmacokinetics :• Most peripheral NM blockers are quaternary

compounds N+

• Not absorbed orally.• Administered intravenously.• Primarily metabolized by liver, excreted by kidney• Low volume of distribution • Do not cross blood brain barrier or placenta (Except

Gallamine)• SCh is metabolized by Pseudocholinesterase.

d – Tubocurarine

• More potent• Long duration of action ( 1 - 2 hr. )• Eliminated by kidney 60% - liver 40%.• Histamine releaser

• Bronchospasm • Hypotension

• Blocks autonomic ganglia (Hypotension)

Atracurium

• As potent as curare (1.5)• Has intermediate duration of action (30 min).• Eliminated by non enzymatic chemical

degradation in plasma• used in liver failure & kidney failure, neonate

(drug of choice ).• Liberate histamine (Hypotension ).

Pancuronium

• More potent than curare ( 6 times ).• Excreted by the kidney ( 80 % ).• Long duration of action.• Tachycardia– Antimuscarinic action

Gallamine (Flaxedil)

• Less potent than curare ( 1/5 ).• Metabolized mainly by kidney 100% # in renal failure• Long duration of action.Tachycardia due to :• Atropine like action.• Release of NA from adrenergic nerve endings

Reversal of Blockade (N.D)

• Neostigmine and Pyriodostigmine antagonise• Inc. availability of Ach by Inhibiting AChE • Direct N action at motor end plate

• Use: If longer acting or intermediate acting

• Autonomic ganglia: (NN): some degree blockade, but newer no action

• Histamine release: From mast cells due cataion (-ve) charge, it contribute hypotension

• CVS: fall in BP– Gaglion blockade ( Adr)– Histamine release– Reduced venous return ( paralysis of resp. & limb )

• CNS: no effect don’t cross BBB

Effects

Effects

• Succinylcholine: salivary secretions, bradycardia

• d-Tubocurarine - ganglionic blockade• Pancuronium - vagolysis (M2)

Histamine Release

Histamine release• d.Tubocurarine • Mivacurium • Atracuronium

Skeletal muscle relaxants Duration (mins.)

Pancuronium 40-80

Pipecuronium 50-100

Vecuronium 20-40

Atracurium 20-40

Rocuronium 20-40

Mivacuronium, Rapacuronium

10-20

Succinyl choline 3-6

Synergists & Antagonist

• Anti AChE antagonise• Inhalational G.A stabilize post junctional

membarane Synergetic• Aminoglycoside syner• Ca++ channel blockers Syner

Deploarizing PK

• Quaternary ammonium groups • IV• Doesn’t cross BBB, Palcental B.• Sch 5-10min (ChE)• Stimulates ganglion agonist action on NN

Skeletal muscle relaxants

Depolarizing block (Non-competitive) : Succinylcholine

• It causes muscle pain.• It causes hyperkalemia. (inc. k efflux depolarizing)• Malignant Hyperthermia.• Prolong apnoea• Inc. Intra gastric pressure• CVS arrhythmia

Centrally acting

• Cerebrospinal axis without altering consciousness.

• Mode of action is non specific• Depressants of poly synaptic reflexes (Spinal &

Supra spinal regn of muscle tone)• Mephensin group: Carisoprodol, Chlorozoxazone,

Chlormezanone• Benzodiazepine group: Diazepam & Clonazepam• GABA derivative: Baclofen

Motor unit = Motor neurone Motor axon+ branches+ terminals All muscle fibres to which it connects

One motor neurone has exclusive Control of many muscle fibres

eg 10 oculomotor,1000 biceps

One muscle fibre innervated by one motor nerve terminal

Motor neurone

Motor axon

Skel

etal

mus

cle

fibre

• Chlorzoxazone: Long acting (8-12hr)Slow onset• Carisoprodol: Intermediate action + analgesic,

antipyretic, anti muscarinic action

• BZD• GABA derivative: GABAB – G protein• Inc. K+ conductance, dec. Ca++ conductance

Uses of centrally acting muscle relaxants

• Acute muscle spasm: sprain, tearing of ligament and tendons, fibrosistis, RA disorder causes painful spasm.

• Backache, neralgies, Torticollis• Anxiety and tension: chlormezanone by antianxiety as

well as muscle relaxant• Tetanus: Diazepam • Electroconvlusive therapy• Spastic nerurological disease: descending pathway, inhibitory

influence over stretch reflex

Skeletal muscle relaxants

Directly acting muscle relaxants :Dantrolene :

Depolarization triggered release of calcium from the sarcoplasmic contraction is blocked / reduced (RyR1)

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

• It is the drug of choice – malignant hyperthermia IV 1mg/kg)

Active Zones

• Miscellaneous group: • Quinine: Dec. excitability of motor end plate• Botulinum: Prevents Ca dependent release of

Ach ( Inhibits Ach release)

Consideration for choosing a muscle relaxant include:

* Duration of action required* Route of excretion* Tendency to release histamine* Cardiopulmonary side effects* The ability to reverse the blockage* Contraindication to any specific muscle relaxant.* Cost

Choice of muscle relaxants:

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