TYPES OF NEUROMUSCULAR BLOCKADE AND

FACTORS AFFECTING IT
NEUROMUSCULAR TRANSMISSION

Action potential reaches the presynaptic terminal

Opening of Voltage gated calcium channels

Exocytosis of Ach into synaptic cleft

NEUROMUSCULAR TRANSMISSION

Ach binds to recognition sites of both alpha subunits

Conformation change

Opening of the central channels

Flow of ions along concentration gradient

 Sodium and Calcium flow from the outside of the cell to inside
 Potassium flows from inside to outside
 Depolarisation of the motor end plate

 Voltage gated Sodium channels sense membrane depolarization

 Excitation contraction coupling

VOLTAGE GATED SODIUM CHANNELS

 Cylindrical transmembrane protein

 Two gates- Voltage dependent and Time dependent
 Both gates must be open for the movement of sodium ions
 These 2 gates acts sequentially
 Posses three functional states
TYPES OF NEUROMUSCULAR BLOCKADE

 Classical
 Non depolarising
 Depolarising

 Non classical
 Desensitization block
 Channel block
 Phase II block

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NON-DEPOLARISING BLOCK

 Competitive antagonism-competes with the agonist Ach for the binding sites on the post synaptic receptors.
 Neuromuscular block depends on their respective conc.& affinity to receptors.
 Recovery from the block-achieved by lowering the conc.of the drug in the synaptic cleft or by ↑ing the conc of
Ach by inhibiting the enzyme acetylcholineesterase.

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NON DEPOLARISING BLOCK

 Competition b/w drug & Ach

 Blocking drug has to bind only one α-subunit of the receptor to block it.
 This explains why it is difficult or even impossible to reverse an intense Nm blockade with an injection of
anticholinesterase drug.
 Channel block also plays a role in it.

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NON DEPOLARISING BLOCKADE

 Competitive antagonism at Ach receptor

 Prevent binding of Ach to receptor
 Incapable of producing conformational change in receptor

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NON DEPOLARISING BLOCKADE

 Drug repeatedly associate & dissociate with receptor

 Outcome depends on

1. Relative concentration of drug

2. Competitive affinity of receptor

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NON-DEPOLARIZING BLOCK

 Slow onset to maximal effect 5-12 min

 Central muscles (diaphragm, larynx) affected than peripheral (adductor pollicis)
 Failure to maintain muscle tension in response to repeated stimulation fade
 Block can be reversed by anticholinesterase

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DEPOLARIZATION BLOCK

 Depolarizing drugs are agonists at Ach receptors

 Example- Succinylchoine, Decamethonium
 Succinylcholine is the only depolarizing NMB in clinical use- Two ACh molecules joined through acetate methyl
group
 Depolarizing relaxants have biphasic action on muscle

Initial contraction Relaxation ( minutes to hours)

 2 Quaternary ammonium radicals bind to two alpha subunits of nicotic recptor
 Activation of Ach recepors
 Depolarization of motor end plate
 Voltage gated sodium channels open
 Muscle Contraction
PHASES OF BLOCK IN DEPOLARIZING NMBA

 PHASE 1 BLOCK

 Perijunctional sodium channel cannot reopen until motor end plate repolarizes
 The end plate cannot repolarize as long as the depolarizing muscle rel;axant continues to bind to Ach receptors

 PHASE II BLOCK
 Occurs after repeated bolus or prolong infusion of Depolarizing NMBA
 Characterised by fade of TOF, tetanic fade and post tetanic potentiation
PHASE 1 BLOCK

 Depolarization block/ Accommodation block

 Preceded by muscle fasciculation

MECHANISM

 Depolarizing muscle relaxants are not rapidly hydrolysed

 Not eliminated from the junctional cleft until they are eliminated from the plasma
 Repeatedly react with receptors
 After separating from one receptor immediately reattach with another receptor
 Repeat depolarization of motor end plate
 Motor end plate continues to be depolarized
 Voltage dependent gates of Sodium channels remain open and time dependent gates stay closed
 No Sodium influx
 Not able to depolarize perijunctional muscle membrane
 Channels beyond perijunctional membranes are freed of depolarizing influence
 ACCOMODATION- Burst of Acetylcholine from the nerve cannot overcome the inactivated sodium channels in
the perijunctional zone and neuromuscular transmission is blocked

 During accommodation,synapse is inexcitable through the nerve but direct electrical stimulation of muscle can
cause muscle contraction
DEPOLARISATION BLOCK

 Extra ocular muscles

1. small tonic muscles

2. Multiple innervation
3. Chemically excitable
4. Numerous end plates
5. contain mature & fetal receptors.

 No accommodation  Persistent contraction  increase in IOP

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PHASE II BLOCK

 Complex phenomenon associated with typical fade in muscle during continuous exposure to depolarizing drugs
 Causes

I. Presynaptic block reducing the synthesis and mobilization of Ach

II. Repeated opening of channels continuous efflux of potassium and influx of Sodium ionsAbnormal
electrolyte balance Distorts function of junctional membrane
III. Calcium entering the muscle through the opened channels can cause disruption of receptors
FACTORS INFLUENCING DURATION OF PHASE II BLOCK

 Duration of exposure to drug

 Concentration of drug
 Type of muscle- fast or slow
 Interaction with Anesthetic agents
 Reversal response of a phase II block produced by depolarizing muscle relaxant to the cholinesterase inhibitors is
difficult to predict
 NON CLASSIC AND NON COMPETITIVE ACTIONS OF
NEUROMUSCULAR DRUGS

 Some drugs can react with neuromuscular receptor to change its function and impair transmission
 These reaction cause drug induced changes in the dynamics of the receptor
 Modified channels are sluggish- Open more slowly and stay open longer or Close slowly
 Eg: Procaine, ketamine, inhaled anesthetics or other drugs that dissolve in membrane lipid may change opening or
closing characteristics of the channel
 These drugs can be involved in two clinically important reactions:

I. DESENSITIZATION BLOCK
II. CHANNEL BLOCK
DESENSITIZATION BLOCK

 Neuromuscular block due to decrease in receptor sensitivity.

 Under normal conditions a receptor on the end plate exists in 3 physiological states:

1. Resting state—ion channel closed.

2. Active state-ion channel is open.
3. Desensitised state-ion channel is closed.

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DESENSITIZATION BLOCK

 Desensitization occurs when Ach receptors are insensitive to the channel opening effect of agonist
 Receptors are in constant state of transition between resting and desensitized state , regardless of whether agonists
are present
 Agonist do promote transition to a desensitized state or trap receptors in that state ,as receptors have a high
affinity for them
 Normally Ach is hydrolysed so rapidly that it has no potential for causing desensitization
 Desensitization block may be a safety mechanism that prevents overexcitation of the neuromuscular junction
DESENSITIZATION BLOCK

 POSTULATED CHANGES IN THE RECEPTOR

 Change in receptor polypeptide macromolecular structure
 Lipid-protein interphase alteration
 Phosphorylation of tyrosine units

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 Several factors promote desensitisation:

1. Local anaesthetics: lidocaine, dibucaine, prilocaine

2. Volatile agents: halothane, isoflurane
3. Intravenous anaesthetics: Barbiturates
4. Calcium channel blockers, ACE inhibitors
5. Antibiotics polymyxin b
6. Alcohol ethanol, butanol
7. ↑ed conc. of agonists & antagonists.

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CHANNEL BLOCK

 Some drugs block the flow of ions through the Ach receptor
 Two types- Closed Channel block

Open Channel block

Closed Channel block- Drug molecules occupy the mouth of the receptors and prevent ions from passing through the
channel to depolarize the end plate
It has been proposed as the mechanism of action of Tricyclic antidepressents , naltrexone and naloxone in potentiating
neuromuscular block
 Open Channel Block- Molecules enter the open ion channel and occlude it

Use dependent- Molecules can enter the channel only when it is opened by an agonist

 With channels blocked, influx of sodium ions is obstructed

 Prevents depolarization and results in weaker or complete block of neutotransmission
 High concentration of NMDR causes open channel block- So difficult to antagonize profound neuromuscular
block
 Drugs causing Open channel Block- NMDR, Steroids, local anesthetics, antibiotics, Calcium channel blockers and
inhalational anesthetics
DEPOLARISING BLOCK NON DEPOLARISING
Fasciculation No fasciculation
Fast onset and fast recovery Slow onset

No post tetanic potentiation, fade Post tetanic facilitation, fade

Anti cholinesterase increase block Decreases block

Reversed by ACE
Fast dissociation constant Slow dissociation constant
Potentiation by depolarisers Antagonism by other depolarisers

May develop phaseII block No change in block

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 FACTORS AFFECTING NEUROMUSCULAR
BLOCKADE

 Pharmacokinetic & dynamic factors

1. Perfusion
2. Clearance
3. Potency
4. Dose
5. Priming
6. Protein binding

 Physiological factors

1. Age
2. Obesity
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3. Gender
4. Temperature
PERFUSION

 Higher blood flow – faster onset of action eg:

 Infants hyperdynamic circulation

CLEARANCE
 If metabolism /redistribution is rapid onset time is reduced
 Eg- Sch, mivacurium

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POTENCY
 Less potent- rapid onset eg: rocuronium.
 More potent – slower onset, long duration eg:pancuronium

DOSE
 Large dose – rapid onset

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PRIMING

 10% intubating dose of NDMR 2-4 mts before the large dose
 Faster onset of action

 But increase the risk of pulmonary aspiration

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PROTEIN BINDING
 Increased binding -  free fraction of drug, less renal
elimination.
 dTC to globulin & others to albumin

AGE
 Pediatric
 increased sensitivity to NDMR  increased action
 large volume of distribution
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 Initial large dose , subsequent doses according to response.
 GERIATRICS

1. Distance between axon & motor end plate.

2. Flattening of folds of motor end plate.
3. Decreased concentration of Ach recptors at motor end plate.
4. Decrease in Ach in each vesicle.
5. Decrease release of Ach

6. Decreased TBW
7. Increased total body fat
8. decreased hepatic and renal blood flow.
9. Decreased cardiac reserve
10. Decreased hepatic function
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 prolonged block
OBESITY

 Elimination decreased
 Dose –20% more than lean body mass than actual body
weight

GENDER
 FEMALES dose 20-30% less
 Due to less muscle mass
 Difference in sensitivity to drugs

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HYPOTHERMIA ON NMJ

 ↓ in temp-

1. ↓in conduction along the nerve

2. ↑release of Ach from the motor nerve terminal
3. ↓in acetylcholinesterase
4. ↑postsynaptic receptor sensitivity

 Increase/decrease the effect of d-tubocurare

 Increase/no effect on pancuronium
 Increase the paralysis of Sch
 Prolongs the effect of vecuronium & atracurium
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ACID BASE IMBALANCES

  in pH –potentiates block, by changes in ionisation.- ing affinity & specificity for receptors.(vecuronium, dTc)
 Metabolic & Respiratory acidosis augment NDM block

 Sch -potentiate action in alkalosis

 -antagonism in acidosis

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ELECTROLYTE IMBALANCE

 POTASSIUM
 Hypokalemia increase in transmembrane potential  hyperpolarisation & enhance NDMR blockade.

 Hyperkalemia  RMP causing resistance to action of NDMR & sensitive to DMR

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ELECTROLYTES

SODIUM
 Hyponatremia potentiates depolarising blockade
 Hypernatremia potentiate NDMR

MAGNESIUM
Prolongs NDMR block
1.  amount of Ach released from motor nerve terminal.
2. Excitability of muscle fibres.
3.  amplitude of end plate potential.
4.  sensitivity of post junctional membrane.
5. Inhibit plasma cholinesterases
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6. depolarising action of Ach on post jn membrane
DRUG INTERACTIONS

 INHALED ANAESTHETICS

 Cause  in NM transmission.
 Prolonged duration of action.
 Potentiate NM blocking of NDMR.
 Desflurane >sevo >iso >halothane >N2O

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DRUG INTERACTIONS

ANTIBIOTICS
 Amino glycosides , Polymyxins, Lincomycin, Clindamycin
 Inhibit presynaptic release of Ach
 Depress postsynaptic receptor sensitivity to Ach

 Tetracyclines  Exibit postjunctional activity.

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DRUG INTERACTIONS

 LITHIUM

 Activation of K Channels.
 Pre & post synaptic inhibition of NM transmission.
 Prolong DMR & NDMR action.

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DRUG INTERACTIONS

 LOCAL ANAESTHETICS

 Large dose Potentiate NDMR & DMR

 Small dose enhance NM Transmission
 PROCAINE Inhibit butyrylcholinesterase
 Verapamil potentiate NM blockade

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 DRUG INTERACTIONS

ANTI EPILEPTICS

 Resistance to NDMR
 Increased clearance
 Increased binding of Alpha 1 acid glycoproteins
 Upregulation of neuromuscular Ach receptorsw

DIURETICS

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 Frusemide :  Ach Release


PATHOLOGICAL CONDITIONS

 RENAL DISEASE

  Elimination of drug.
  activity of Butyryl cholinesterase.
 atracurium is safe in renal disease
 Gallamine exclusively excreted by kidney.

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PATHOLOGICAL CONDITIONS

 LIVER DISEASE
  Volume of distribution-initial large dose,recovery slower.
 Decreased synthesis of plasmacholinesterase
 prolonged action of NDMR due to decreased plasma clearance.eg:Pancuronium and Vecuronium.

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REFERENCES

 Miller’s Anesthesia, ninth edition

 Stoelting’s Pharmacology and Physiology in Anesthetic Practice, sixth edition
THANK YOU