SKELETAL MUSCLE RELAXANTS -1

Speaker : Dr Rachana Menon

Learning Objective

Introduction

History

Physiology of Neuromuscular Junction

Acetylcholine – Synthesis ,Storage , Release

Nicotinic Receptor

Classification of SMR

Depolarizing agents

Directly acting agents

Drugs that act peripherally at neuromuscular junction or

muscle fibre itself or in cerebrospinal axis to reduce

muscle tone and cause muscle paralysis.

INTRODUCTION

HISTORY

The earliest known use of muscle relaxant drugs dates

back to the 16th century.

Natives of the Amazon Basin in South America . The

prey was shot by arrows dipped in curare

Curare, led to some of the earliest scientific studies

in pharmacology.

HISTORY

1935 – d tubocurarine, active

ingredient - Harold King of London,

working in Sir Henry Dale’s laboratory

1943, neuromuscular blocking drugs

became established as muscle

relaxants in the practice of

anaesthesia and surgery

HISTORY

Contd..

1967- Baird and Reid first reported on clinical

administration of the synthetic aminosteroid

pancuronium

1980-Introduction of vecuronium, an aminosteroid, and

atracurium.

• 1990’s Mivacurium, the first short-acting

nondepolarizing neuromuscular blocker was introduced

Neuromuscular Junction

• 1- Motor neuron• 2 -Sarcolemma• 3 -Synaptic vesicle• 4 -nAchR• 5- Mitochondria

NNEUROMUSCULAR JUNCTION

The neuromuscular junction is made up of a

Motor neuron – Originate in the ventral horn of the

spinal cord.

As the axon of a motor neurone enters the structure of

skeletal muscle it forms many branches “Axon

terminals".

Synaptic end bulb – Bulbous swelling at the end of

axon terminal.

Contd..

Each synaptic end bulb contains many synaptic

vesicles, each of which contains ACETLYCHOLINE.

Contd..MOTOR END PLATE - part of

the Sarcolemma of the muscle cell

 that is in closest proximity to the

synaptic end bulb

SYNAPTIC CLEFT - The

area between the axon terminal

and the sarcolemma , release Ach

occurs with consequent binding to

the receptors

Contd..

The surface of motor end plate

deeply folded with MULTIPLE

CREST and secondary clefts

The nAchR are located on the

crests. The clefts contain ACH

ESTERASE

ACETYLCHOLINESTERASE

Acetylcholinesterase ACh

 

Choline Acetate 

Produced on the ribosomes of the motor neuron

Attached - thin collagen threads linking it to the basement

membrane

Found junctional gap clefts of the post-synaptic folds in

high concentrations

Acetylcholinesterase

Transported distally by axoplasmic flow to the terminal button

The cholinergic synapse is rich in AchE

Breaks down Ach within 1 msec of being released.

SKELETAL MUSCLE RELAXANTS -1 ACETYLCHOLINE

SYNTHESIS STORAGE RELEASE

ACETYLCHOLINE STRUCTURE

SYNTHESIS

Acetic acid ester of choline

Synthesised inside the cholinergic nerve fibre

Choline

Acetyl-coenzyme A

Choline acetyltransferase-

1.TRUE AchE2.PLASMA AchE BLACK WIDOW

SPIDER

RATE LIMITING

STEP

Contd…

The events that translate an Action Potential, (a membrane-electrical event) into a mechanical event (contraction)

ACETYLCHOLINE RECEPTORS

NICOTINIC RECEPTOR

•Large extracellular N-terminal domain of ~200 amino acids;  that contributes

to agonist binding site

•Four hydrophobic transmembrane domains (TM1 through TM4)

•A large cytoplasmic loop between TM3 and TM4 with variable AA sequence.

•The M2 transmembrane region is thought to form the ion pore of the nAChR

• Short extracellular C terminus

(Cys-loop) defined by two cysteines (Cys) that in the

mammalian subunits are separated by 13 intervening amino

acids.

Subunits are classified into α- and non-α subunits based

on the presence of a Cys-Cys pair near the entrance to TM1.

Cys-Cys pair

• Required for agonist binding

• Presence designates the subunit as an α-subtype .

STRUCTURE

The N termini of two subunits cooperate to form two distinct binding pockets for Ach , agonist and antagonist

• These pockets occur at the α -γ and the α- δ subunit interface.

• The M2 membrane-spanning domain of each subunit lines the ion

channel.

Contd…Five polypeptide subunits

Arranged around a pseudo-axis of symmetry to

circumscribe an internally located channel

Adult receptor has two identical α subunits, one β one δ

and one ε subunit in 2:1:1:1 ratio. In the foetus a γ

(gamma) subunit replaces the ε

• The neuronal subtypes are various homomeric or heteromeric

combinations of twelve different nicotinic receptor subunits.

• 7 α-like subunits, termed α2, α3, α4, α5, α6, α7, α9, and α10

• 3 non-α subunits -β2, β3, and β4 cloned from neuronal

tissues. 

BINDING THE CHANNELThe Acetylcholine-binding site

 Opening of the nAChR channel pore

requires the binding of a chemical

messenger

Acetylcholine.

Location - pockets approximately 3.0

nm above the surface membrane at the

α and either γ or δ subunits interface.

OPENING THE CHANNEL

The nAChR is a non-selective cation channel

Binding of 2 Ach molecules to the α-subunits initiates conformational changes that open the channel

  Allows positively charged ions to move across it; in

particular, sodium enters the cell and potassium exits. The net flow of positively-charged ions is inward.

The cell becomes less negative compared with the

extracellular surroundings.

When a threshold of –50mV is achieved (from a resting

potential of –80mV), voltage- gated Na open, thereby

increasing the rate of depolarisation and resulting in an

End plate potential (EPP) of 50-100mV.

Triggers the muscle action potential

Muscle contraction

Neurotoxins

NICOTINIC RECEPTORS

SKELETAL MUSCLE RELAXANTS

PERIHERALLY ACTING CENTRALLY ACTING

SMR - Why Required ?

1. In conjunction with GA

2. Painful muscle conditions

3. Spastic neurological conditions

SKELETAL MUSCLE RELAXANT

PERIPHERALLY ACTING CENTRALLY ACTING

NEURO MUSCULAR ACTING DIRECTLY ACTING

Non- depolarising Agents

• Short Acting

• Intermediate Acting

• Long acting

Depolarising Agents

A) PERIPHERALLY ACTING• Neuromuscular blockers

Non depolarizing agents ( Competitive blockers)Prevent the access of Ach to Nm receptors of motor end plate and prevent depolarisation.

Insoquinoline Derivatives• Tubocurarine• Doxacurium• Atracurium• Metocurine• Mivacurium

Steroid Derivatives• Pancuronuium• Pipecuronium• Rapacuronium• Rocuronium• Vercuronium

Depolarizing agents

• Produce excessive depolarisation which persist for longer duration at NMJ

• Resistant to hydrolysis by true AchE present in synaptic cleft

– Suxamethonium (Succinylcholine)– Decamethonium

B) CENTRALLY ACTING

Benzodiazepine group GABA derivative

Diazepam Baclofen

clonazepam

Central alpha agonist Mephensive group

Tizanidine Chlorxoxazone

Methocarbamol

Chlormezazone

Carisoprodol

DEPOLARISING AGENTS

SUCCINYL CHOLINE

Also known as suxamethonium 

Introduced by Thesleff and by Foldes and colleagues in 1952

Is a nicotinic acetylcholine receptor agonist

STRUCTURE ACTIVITY RELATIONSHIP

Quaternary ammonium compounds

Two molecules of acetylcholine linked back to back through

the acetate methyl groups

Long, thin, flexible molecule.

Enable free bond rotation.

Positive charges at these sites in the molecules mimic

the quaternary nitrogen atom of the transmitter

acetylcholine

MECHANISM OF ACTION

Affinity and sub maximal intrinsic activity for NM receptors

Analouge of Ach

Longer durations at the neuromuscular junction -

resistance to AChE

Do not dissociate from receptors quickly

SCh reacts with Nm receptor – Open Na+ channels

Prolonged persistant depolarisation

Brief period of repetitive excitation

Flaccid paralysis of muscle

Elicit transient and repetitive muscle excitation FASICULATIONS

Neural release of Ach will result in binding of Ach to receptors on a already depolarised plate

• FLACCID PARALYSIS

• This initial depolarization block of

NEUROMUSCULAR TRANSMISSION AND FLACCID

PARALYSIS PHASE l BLOCK

The Na+ receptors at the end-plate and

the perijunctional zone remain

inactivated and junctional transmission

is blocked.

• Recovery from Phase I block occurs as Sch diffuse away

from the NMJ , down a concentration gradient as the

plasma concentration decreases.

Prolonged exposure to succinylcholine, the initial end plate

depolarization decreases membrane becomes repolarized.

Despite this repolarization, the membrane desensitized.

Phase II Block (Desensitizing)

Contd…

Unclear mechanism

The channels behave as if they are in a prolonged closed state.Neurotransmission remains blocked through out

1.Presynaptic block reducing the synthesis and

mobilization of ACh

2.Post junctional receptor desensitization

3.Activation of the Na-K ATPase pump by initial

depolarization, which repolarizes it

Contd…

Later in phase II, the blockade identical to those of a nondepolarizing block

Fade of the train-of-four (TOF) twitch response

Tetanic fade Post-tetanic potentiation

Inhalation anaesthetic drugs accelerate the onset of Phase II block. Possible reversal by acetylcholinesterase inhibitor

Threshold for TOF: Need at least 0.9 to minimize risk of post op complicationsAssessment of TOF:  Must use quantitative monitoring

Contd… Phase I:

Initially classical

depolarization block

Repolarization occurs

Neuromuscular

transmission not restored

Cannot reversed by AChE.

Neostigmine potentiates

Phase II:

Slow in onset

Desensitization of

receptors to Ach

Resembles d-TC

Partially reversed by

AChE

PHARMACOKINETICS Rapid onset of effect and ultra short duration of action.

Not absorbed orally

Does not cross BBB, placenta

I.V route - initiation dose 0.5 – 1 mg/kg .tracheal intubation

in adults is 1.0 – 1.5 mg/ kg.

Cheeks,abdomen,neck,limb,face, respiratory paralysis

Apnoea within 1 min.Brief duration of action 6-11 min

Elimination - rapid hydrolysis by plasma cholinesterase in

liver

Succinylcholine

Succinylmonocholine Choline( weaker NM blocking agent)

No butyrylcholinesterase is present at the NMJ

Butyrylcholinesterase has an enormous capacity to hydrolyse

succinylcholine

Butrylcholinesterase

Only 10% of the administered drug reaches the

neuromuscular junction.

Influences the onset and duration of action of Sch by

controlling the rate at which the drug is hydrolyzed before it

reaches and after it leaves the NMJ.

Factors that have been found to lower butyrylcholinesterase activity

Liver disease Advanced age, malnutrition, pregnancy Burns OCPs, MAO inhibitors Ecothiophate, cytotoxic drugs Anticholinesterase drugs Neoplastic disease Tetrahydroaminacrine Hexafluorenium

DIBUCAINE TEST

Patient with abnormal genetic variant of

butyrylcholinesterase ,Sch induced neuromuscular

blockade can be significantly prolonged

Dibucaine inhibits normal butyrylcholinesterase to a far

greater extent than it does the abnormal enzyme.

Contd…

• Under standardized test conditions Dibucaine inhibits

The normal enzyme about 80%

The abnormal enzyme about 20%

Many other genetic variants of butyrylcholinesterase

have been identified, dibucaine-resistant variants are the

most important

DIBUCAINE NUMBER

Measure of the ability of the person to metabolise Sch,

identify at risk patients.

Doesnot measure the concentration of enzyme in plasma

Efficiency of enzyme to hydrolyse the substrate.

THERAPUETIC USES

Adjuvant to General anaesthesia-Rapid-sequence

induction of anaesthesia- (DOC)1.0 mg/kg

succinylcholine facilitate ETintubation at 60 seconds

Assisted ventilation

To prevent trauma during ECT

Before administering the intubating dose of succinylcholine

A small dose of nondepolarizing neuromuscular blocker is

commonly given 2 mins. This defasciculating dose of

attenuate increases in intragastric and intracranial

pressure

minimize the incidence of fasciculations in response to

succinylcholine.

DRUG INTERACTION

Antichloniesterase -Neostigmine / Pyridostigmine.

Sch should not be administered to re establish

neuromuscular blockade - produces relaxation that will

last up to 60 minutes with administration of neostigmine

(5 mg).

Such prolongation can partly be explained by inhibition of

butyrylcholinesterase

• .

Combination of Lithium and succinylcholine resulted in

an additive inhibition.

Verapamil potentiates the neuromuscular block.

Bambuterol, produces marked causes prolongation of

Sch induced blockage.

Esmolol causes only minor prolongation of blockage

ADVERSE REACTIONS

Hyperkalemia Arrhythmias Malignant hyperthermia Master muscle rigidity Increased IOP, ICP Increased IGP Myalgia- lysine acetylsalicylate Succinylcholine apnoea FDA BLACK BOX WARNING IN YOUNG MALES

 [Rosenberg Anesthesiology 77: 1054, 1992]

Succinylcholine apnoea

Occasionally succinylcholine produces prolonged apnoea due

to lack of normal plasma (pseudo) cholinesterase levels.

Treatment:

Artificial respiration until the muscle power returns.

Fresh blood or plasma transfusion to restore

cholinesterase enzyme level.

No specific antidote is available

MALIGNANT HYPERTHERMIA

Rare life-threatening condition

Autosomal dominant disorder

Volatile anaesthetic agents and succinylcholine

Major defects in RYR1, DHPR,  CACNA1S triadin

and FK 506

C/F :sustained muscle contraction and hyperpyrexia

MANAGEMENT

Dantrolene 2mg/kg I.V.

Procainamide - ventricular fibrillation

Rapid cooling

Inhalation of 100% oxygen

Control of acidosis should be considered adjunct

therapy in malignant hyperthermia

DECAMETHONIUM

2 quaternary ammoniums with a 10-carbon chain in

between,

• It's about 2x as potent as succinylcholine

• Derived from decamethylenediamine,

•  Partial agonist of the nicotinic acetylcholine receptor.

contd…

• Persistant depolarisation

• Character of muscle responseto indirect tetanic

stimulation during partial block -Well-sustained

contraction

Does not produce unconsciousness or anesthesia, and

its effects may cause considerable psychological

distress while simultaneously making it impossible for a

patient to communicate

DIRECTLY ACTING AGENTS

SPASMOLYTICS

SPASTICITY

• It is a motor neuron disorder characterized by skeletal muscle rigidity, exaggerated tendon jerks and paralysis of affected muscles.

Causes• Cerebral palsy• Stroke• Multiple sclerosis• Traumatic brain injury• Anoxia• Neurodegenerative disease

DANTROLENE

A hydantoin derivative

Planar

Phenol ring, which is rotated approximately 30°

out of the plane of the furane ring.

Highly lipophilic

Contd..• Phenytoin analouge

• Antispastic action lie outside CNS

• The L-type channel with its T-tubular location serves as the

voltage sensor receiving the depolarizing activation signal.

• Inhibits Ca2+ release from the sarcoplasmic reticulum of skeletal

muscle by limiting the capacity of Ca2+ and calmodulin to

activate RYR-1

PHARMACOKINETICS

Poorly absorbed orally

Penetrates brain and produces sedation

Metabolized in liver into 5-hydroxydantrolene

Excreted in kidney.

T 1/2 9 -12 hrs.

Dose: 25-100 mg 4 times daily

THERAPEUTIC USES

UMN disorders – paraplegia, hemiplegia, cerebral palsy

DOC: Malignant hyperthermia (2.5 – 4 mg/kg)• Prophylactic dantrolene administration before trigger-free

GA for MH-susceptible patients has been recommended

Neuroleptic malignant syndrome: 1 – 2.5 mg/kg

Heat stroke.

ADVERSE EFFECTS

• Sedation- facilitated GABA – depression of brain stem • Malaise• Light headedness• Muscular weakness• Diarrhea • Hepatitis• Neonates are at risk of ‘floppy child syndrome’ –C/s

Drug Interactions

  Diltiazem/ Verapamil 

Severe cardiovascular collapse, arrhythmias, myocardial depressions, and hyperkalemia.

 Vecuronium : Neuromuscular blockade is prolonged.

CNS depressants: Sedative action is potentiated. 

Combined OCPS and HRT  may enhance liver toxicity. 

NEWER AGENT-Azumolene

• Analogue of dantrolene . • 30-fold more watersoluble• The para-nitrophenole group of dantrolene sodium is

replaced by a para-bromo-phenyl group.

• Equipotent to dantrolene in the treatment and prevention

of the clinical manifestations of an MH crisis

Same potency as Dantrolene in

• Inducing relaxation in porcine skeletal muscle in vitro.

• In vivo, even more potent in inhibiting gastronemius

muscle twitches

QUININE Dual action in skeletal muscle:

Acts directly on the muscle fibre increases the tension

response

Increases the refractory period

Decreases the excitability of the motor end-plate

Makes the muscle less susceptible to repetitive neural

stimuli

Less Responsive To Acetylcholine

• The typical adult dosing for nocturnal leg cramps is 260 mg at bedtime.

Adverse events:• Thrombocytopenia• Hypersensitivity reactions • QT prolongation

• FDA Warns of Risks with Unapproved Use of Malaria Drug Qualaquin