Non-depolarising NMBDs

[SH4:p222-p228; CEACCP 2004 Vol 4(1) "Pharmacology of neuromuscular blocking drugs"]

Pharmacodynamics

Mechanism of action

Nondepolarising NMBDs act by

• Bind to the alpha subunits in junctional nAChRs without causing any activation
  --> Thus preventing ACh from binding to alpha subunits
• Compete with acetylcholine
• At high doses
  --> May also act by physically blocking the ion receptor channels (without binding to the alpha subunits)

Nondepolarising NMBDs also act on prejunctional nAChRs
--> Blocks prejunctional nAChRs
--> Inhibition of ACh release (??? what about mobilisation and synethsis)

Actions on prejunctional nAChR

• Normally ACh also act on prejunctional nAChRs
  --> Increase its own release during high frequency stimulation (>2Hz)
  * i.e. positive-feedback
• Non-depolarising NMBDs blocks prejunctional nAChRs
  --> ACh not sufficiently mobilised (in prejunctional terminal) to keep up with the the demands of high-frequency stimulation
  --> Manifest as tetanic fade and TOF fade
• Overall, actions on postjunctional nAChRs are more important

Margin of safety

• There is a wide safety margin of NMJ transmission.
• When 70% of the nAChRs are occupied by non-depolarising NMBDs
  --> No evidence of NMJ blockade (using twitch response to a single electical stimulus
• When 80-90% of the nAChRs are blocked
  --> NMJ transmission fails (twitch height rapidly drops)
• Complete blockade requires at least 92% of receptors are blocked
  * [CEACCP]

Desensitisation block

• Non-depolarising NMBDs bind tightly to desensitised receptors
  --> Trapping these receptors in these states
  * This is a non-competitive block
  * [CEACCP]

Causes of altered response to nondepolarising NMBDs

[SH4:p224]

Drugs that may enhance the effects of nondepolarising NMBDs

• Volatile anaesthetic agents
• Aminoglycoside antibiotics
• Local anaesthetics
• Cardiac antidysrhythmic drugs
• Diuretics
• Magnesium and lithium
• Others
  * Cyclosporin
  * Dantrolene [RDM6:p518]
  * Antiestrogenic drugs such as tamoxifen [RDM6:p518]

 

Drugs that may antagonise the effects of nondepolarising NMBDs

• Calcium [RDM6:p517]
• Corticosteroids
• Azathioprine
• Anticonvulsant

 

Other factors that may influence the effects of nondepolarising NMBDs

• Hypothermia
• Acid-base alterations
• Changes in serum potassium concentration
• Adrenocortical dysfunction
• Thermal (burn) injury
• Allergic reactions

Drugs that enhance the effects of NMBDs

Volatile anaesthetics

[SH4:p224; RDM6:p515]

• Volatile anaesthetic agents produce dose-dependent enhancement of the magnitude and duration of NMJ blockade
  * Greatest with enflurane, isoflurane, desflurane, and (esp) sevoflurane
  * Least with nitrous oxide
  * Order of potentiation: Des > Sevo > Iso > Hal > N2O [RDM6:p515]
• This enhancement is more marked with long-acting non-depolarising NMBDs
  * Less enhancement with intermediate-acting NMBDs
• Enhancement is due to changes in pharmacodynamics rather than pharmacokinetics
• Mechanism:
  * Depression of CNS --> Decrease of muscle tone
  * Volatile anaesthetics may decrease the sensitivity of postjunctional membrane to depolarisation
  * (In isoflurane only) Increased muscle blood flow --> More drugs delivered to NMJ
• Mechanism is NOT by effects on ACh release, nor on nAChR configuration

NB:

[RDM6:p515]

• Proposed mechanisms of potentiation include:
  * A central effect on alpha-motor neurons and interneuron synapses
  * Inhibition of the postsynaptic nAChRs
  * Augmentation of the antagonist affinity at the receptor site

Antibiotics

• Some types of antibiotics enhanced NMJ blockade by nondepolarising NMBDs
  * Especially aminoglycoside antibiotics
• Penicillin and cephalosporins have NO effect on the NMJ blockade
• Tetracycline enhance blockade by actions on postjunctional membrane
  * [RDM6:p516]

 

Mechanism (variable and unpredictable) by which aminoglycoside enhance NMJ blockade:

• Act on prejunctional membrane (similar to the effect of magnesium)
  --> Decreased ACh release
  * Could be due to competition of antibiotics with calcium
• Stabilise postjunctional membrane

Local anaesthetics

• Ester local anaesthetics competes with other drugs (including suxamethonium) for plasma cholinesterase
• Depending on the dose, local anaesthetics can
  * Interfere with prejunctional release of ACh
  * Stabilise postjunctional membranes
  * Directly depress skeletal muscle fibres

Cardiac antidysrhythmic drugs

• Lignocaine IV used to treat cardiac dysrhythmias
  --> Could increase the preexisting NMJ blockade
• Quinidine also potentiate NMJ blockade by non-depolarising NMBDs
  * Presumably by intefering with the prejunctional release of ACh

Diuretics

• Frusemide (1mg/kg IV)
  --> Inhibition of cAMP production
  --> Decreased prejunctional ACh release
  --> Enhancement of NMJ blockade by NMBDs
• However, large doses of frusemide may
  --> Inhibit phosphodiesterease
  --> More cAMP available
  --> Antagonism of NMJ blockade by NMBDs
• Mannitol
  --> No effect on NMJ blockade by non-depolarising NMBDs
• Chronic hypokalaemia due to diuretics
  --> Increase effect of pancuronium
  --> Smaller dose required for pancuronium
  --> Greater dose of neostigmine required to reverse NMJ blockade

Magnesium

• Enhance NMJ blockade by BOTH depolarising and non-depolarising NMBDs
  --> Significance in pregnant women receiving magnesium infusion
• Magnesium enhances the NMJ blockade by non-depolarising NMBDs (like aminoglycoside antibiotics)
  * Also somewhat enhances the NMJ blockade by suxamethonium
• Mechanisms
  * Decreased prejunctional release of ACh
  * Decreased sensitivity to ACh (due to stabilisation of postjunctional membrane)
• Mechanism for enhancement of suxamethonium is not clear
  * May be due to earlier onset of phase II blockade

Lithium

• Also enhance the NMJ blockade by NMBDs (depolarising and non-depolarising)

Cyclosporine

• Cyclosporine prolong the duration of NMJ blockade by non-depolarising NMBDs

Dantrolene

[RDM6:p518]

• Used to treat MH
• Prevents Ca2+ release from sarcoplasmic reticulum
  --> Blocks excitation-contraction coupling
• Does NOT block NMJ transmission
• Mechanical response of the muscles are still depressed
  --> Enhancement of NMJ blockade by non-depolarising NMBDs

Drugs that may antagonise the effects of nondepolarising NMBDs

Calcium

[RDM6:p517]

• Ca2+
  * Triggers ACh release from motor nerve terminal
  * Enhance excitation-contraction coupling in muscles
• Increase Ca2+ concentration
  --> Decreased sensitivity to dTc and pancuronium
• Hypercalcaemia secondary to hyperparathyroidism is associated with
  * Decreased sensitivity to atracurium
  * Shortened NMJ blockade

Corticosteroids

• Cortisol and adrenocorticotrophic hormone
  --> Improve NMJ function in myasthenia gravis
• Corticosteroids do NOT alter NMJ blockade produced by non-depolarising NMBDs [SH4:p226]

But

• Steroid antagonise the effects of non-depolarising NMBD [RDM6:p518]

Anticonvulsants

• Chronic treatment of anticonvulsants (phenytoin, carbamazepine)
  * Resistance to some non-depolarising NMBDs (pancuronium, vecuronium, rocuronium, cisatracurium)
  * But not to others (mivacurium, atracurium)
• Resistance is due to pharmacodynamic mechanism
  * Resistance to vecuronium in children (due to phenytoin and carbamazepine usage) is due to pharmacokinetic changes
• Acute administration of phenytoin
  --> Augmentation of NMJ blockade by rocuronium

Azathioprine

• An immunosuppressant drug which interferes with purine synthesis
• Azathioprine
  --> Inhibits phosphodiesterase
  --> Antagonism of NMJ blockade by non-depolarising NMBD, but enhancement of blockade by suxamethonium

Aminopyridine

• Blocks voltage-gated K+ channels [RD5:p61]
  --> Prolong the action potential in the presynaptic nerve terminal [RD5:p160]
  --> Antagonism of NMJ blockade [RD5:p160, RDM6:p516, MCQ:Q126]

 

Other factors that may influence the effects of nondepolarising NMBDs

Hypothermia

• Mild hypothermia doubles the duration of NMJ blockade by vecuronium
  * Due to decreased clearance of vecuronium and slower rate of effect-site equilibration
  * Tissue sensitivity is NOT affected
• Hypothermia also increases the NMJ blockade by atracurium
  * Due to decreased degradation by Hofmann elimination and decreased metabolism by ester hydrolysis
• Hyperthermia does not seem to affect blockade [???]

Serum potassium concentration

• Hypokalaemia
  --> An acute decrease in ECF K+
  --> Increase membrane potential
  --> Hyperpolarisation of cell membranes

Thus,

• Resistance to depolarising NMBDs
• Sensitivity to nondepolarising NMBDs

 

Hyperkalaemia has opposite effect

• Sensitivity to depolarising NMBDs
• Resistance to nondepolarising NMBDs

Burns

• Burns injury
  --> Resistance to nondepolarising NMBDs (receptor-mediated)
  * Start about 10 days after injury
  * Peak about 40 days
  * Declines after 60 days
• > 30% of body must be burned to produce resistance
• Mechanism is pharmacodynamics
  * Due to altered affinity of nAChRs for non-depolarising NMBDs
  * NOT due to increases in extrajunctional nAChRs
• Burns also decrease plasma cholinesterase activity [SH4:p244]

Paresis or hemiplegia

• Both the paretic side and the normal side shows resistance to the NMJ blockade effect of NMBDs
  * Paretic side shows greater resistance
• Peripheral nerve stimulator may underestimate the level of NMJ blockade at the diaphragm
• Mechanism is likely to be the proliferation of extrajunctional nAChRs

Suxamethonium followed by non-depolarising NMBDs

• Subsequent administration of non-depolarising NMBD
  --> Greater effect even when suxamethonium has worn off
• Mechanism is due to desensitised postjunctional membrane by suxamethonium
• But duration of atracurium and vecuronium (after suxamethonium) is not increased despite initial enhancement

Gender

• Women are more sensitive to vecuronium than men
  * Men has larger Vd --> lower plasma concentration of vecuronium
• Women are also more sensitive to rocuronium
  * Reason is unclear
  * Probably due to greater muslce mass in men, thus greater Vd

Side effects

CVS effect

Some non-depolarising NMBDs may have CVS effect due to"

• Drug-induced release of histamine or other vasoactive substances (e.g. prostacyclin from mast cells)
• Action at cardiac muscarinic receptors
• Effects on nAChRs at autonomic ganglia

--> Rarely do these CVS effects have much clinical significance

Autonomic margin of safety

• Autonomic margin of safety
  = the difference between the dose of NMBD that produce NMJ blockade and the dose that produce CVS effect

For example,

• Pancuronium has a narrow autonomic margin of safety
  --> ED95 dose that produce NMJ blockade also likely to produce CVS changes
• Vecuronium, rocuronium, and cisatracurium have wide margin of safety
  --> The ED95 dose that produce NMJ blockade is less than the dose required to evoke CVS changes

Critical illness myopathy

[SH4:p223]

• Some patients who has been on mechanical ventilation for prolonged periods of time (usually >6 days) develops skeletal muscle weakness on recovery
  * Moderate to severe quadriparesis with or without areflexia
  * Usually retain normal sensory function
• Risk may be increased by administration of glucocorticoids (including nondepolarising NMBDs)

Mechanism of critical illness myopathy

• Mechanism unknown
• Possible mechanisms include:
  * Prolonged NMBD action due to decreased clearance or active metabolites
  * Metabolic disorder
  * Polypharmacy
• The number of steroid receptors in skeletal muscles increases with denervation
  --> Possible increased susceptibility to myopathic effects of systemically administered steroids

Nondepolarising NMBDs administered to an awake person

• First difficulty in focusing and weakness in mandibular muscles
  --> ptosis, diplopia, and dysphagia
• Consciousness and sensorium are maintained at all times
• Relaxation of small muscles in middle ear --> Hearing acuity improved

 

Clinical

Special considerations

Obesity

In obese patients (weighing >30% more than ideal body weight)
--> Dosage should be based on ideal body weight

Allergic reactions

• Cross-sensitivity between all NMBDs
• Quaternary ammonium group is a common antigenic component
  * Present in cosmetics or soaps
• True anaphylaxis can occur on first exposure due to prior sensitisation by cosmetics or soaps