3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.7. Neuromuscular blocking drugs
 3.1.3.7.2. Non-depolarising NMBDs 

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