3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
 3.1.3.7. Neuromuscular blocking drugs 

Neuromuscular blocking drugs (NMBDs)

[CEACCP 2004 Vol 4(1) "Pharmacology of neuromuscular blocking drugs"]

Structure

  • NMBD in use today are quaternary ammonium compounds
  • Structurally related to acetylcholine (ACh)
    * Which contains a quaternary nitrogen group (N+(NH3)3)
  • The positive nitrogen atoms are attracted to the alpha subunits of postsynaptic nicotinic ACh receptor
  • The two quaternary ammonium groups are separated by a bridging structure
    --> The bridging structure is lipophilic and variable in size
    * The bridge is a major determinant in potency

Structure-activity relationships

  • Long and flexible structure of suxamethonium allows binding and activation of cholinergic receptors
  • Bulky and rigid molecules are characteristic of non-depolarising NMBDs which binds, without activating, cholinergic receptors

Acetylcholine

  • Acetylcholine has a positively charged quaternary ammonium group
    --> Attaches to negatively charged cholinergic receptors
  • Acetylcholine (and NMBDs) attaches to ACh receptors, not just at NMJ, but also:
    * Cardiac muscarinic ACh receptors
    * Autonomic ganglia nicotinic ACh receptors
    --> Lack of specificity for the NMJ

Autonomic nAChR and NMJ nAChR

  • Specificity of a drug for autonomic ganglia nAChR vs the NMJ nAChR
    --> Influenced by the length of carbon chain separating two positively charged ammonium groups
  • Maximal autonomic ganglion blockade occurs when the positive charges are separated by 6 carbon atoms
  • NMJ blockade occurs when positive charges are separated by 10 carbon atoms.
  • Thus, a bulky monoquaternary molecule like d-tubocurarine (dTc) is more likely to produce autonomic ganglion blockade than is a bisquaternary drug

Usage

  • Skeletal muscle relaxation
    * Facilitate tracheal intubation
    * Improve surgical working condition during general anaesthesia
  • Tracheal intubation
    --> 2 x the ED95 dose of nondepolarising NMBDs is often recommended
  • Surgical working condition
    --> 90% suppression of single-twitch response is often considered adequate

NB:

  • NMBDs lack analgesic and CNS depressant action
  • Laryngospasm can be treated with suxamethonium dose as low as 0.1mg/kg IV

Classification

Depolarising vs non-depolarising

Depolarising

Only one still in clinical use is suxamethonium (aka succinylcholine)

Non-depolarising

  • Benzylisoquinolinium compounds
  • Aminosteroid 
Benzylisoquinolinium compounds
  • Include:
    * Atracurium
    * Mivacurium
    * Doxacurium
    * Cisatracurium
    * Tubocurarine and other toxiferine derivatives
  • Consists of two quaternary ammonium groups, joined by a thin chain of methyl groups
  • More liable to breakdown in plasma than aminosteroids
  • Lack vagolytic effects
  • More likely to cause histamine release
    * Presumably due to presence of a tertiary amine

NB:

[PHW2:p76]

  • Isoquinolinium is related to papaverine (which is a smooth muscle relaxant)
  • Benzylisoquinolinium has two isoquinolinium structures, linked by a carbon chain containing two ester linkages
Aminosteroid compounds
  • Include:
    * Pancuronium
    * Vecuronium
    * Pipecuronium
    * Rocuronium
    * Rapacuronium
  • Contains an androstane skeleton, with ACh-like moieties at the A ring and D ring
  • Most depend on organs for excretion
  • Tend not to cause histamine release
  • Some undergo deacetylation in liver

Bisquaternary amine vs monoquaternary amine

Bisquaternary amines

  • Two quaternary ammonium cations
  • e.g. succinylcholine, pancuronium, atracurium
  • More potent than monoquaternary amines

Monoquaternary amines

  • One quaternary ammonium cation and a tertiary amine
  • e.g. rocuronium, tubocurarine, and vecuronium
  • At physiological pH, the tertiary amine can become protonated
    --> Increased potency
    --> More potent in acidosis

Pharmacodynamics

NMBDs produce one of the following
* Phase I depolarising blockade
* Phase II depolarising blockade
* Non-depolarising neuromuscular blockade

Muscle relaxation

Onset differences in different muscles

NMBDs affects

  1. Small, rapid moving muscles (e.g. eyes, digits)
    * Onset at larygneal muscle before peripheral muscles (adductor pollicis)
  2. Muscles in trunk and abdomen
  3. Intercostal muscles
  4. Diaphragm

Recovery occurs in reverse order
* i.e. Diaphragm recovers first

Different order listed in Miller

[RDM6:p503-504]

  • Onset of NMJ blockade in laryngeal adductors, diaphragm, and masseter are
    * Faster
    * Laster a shorter time
    * Recover faster
    (than adductor pollicis)
  • The difference is probably mostly due to differences in regional blood flow
    * High blood flow in diagphram and larynx allows exposure to a higher peak plasma concentration
  • NMJ blockade by non-depolarising NMBDs at larynx
    * Onset occurs 1-2 minutes earlier than at adductor pollicis
    * Pattern of blockade (onset, depth, and speed of recovery) is similar to orbicularis oculi
Muscle types
  • Muscles involved in glottis closure (thyroarytenoid muscles)
    * Fast muscle fibre
    * Greater density of ACh receptors
    --> More receptors need to be occupied to block a fast muscle
  • Adductor pollicis
    * Slow fibre
Vocal cord
  • Rapid action at vocal cord
    --> Due to faster equilibration time between the plasma concentration and the concentration at the airway muscles
  • With short and intermediate acting NMBDs, the period of laryngeal paralysis
    * Brief
    * May be dissipating before maximal effect is reached at the adductor pollicis
Diaphragm
  • Diaphragm requires about twice the dose as that required to achieve the same degree of paralysis at adductor pollicis muscle
Adductor pollicis
  • Adductor pollicis is a poor indication of laryngeal relaxation (cricothyroid muscle)
  • Facial nerve stimulation (and orbicularis oculi muscle contraction) reflects the onset of neuromuscular blockade at the diaphragm
    --> Orbicularis oculi may be a better indicator of laryngeal muscle blockade
Orbicularis oculi

[SH4:p242]

  • Loss of function at orbicularis oculi
    * Correlates with maximal paralysis of laryngeal adductor muscles and diaphragm
    * Better than adductor pollicis

Pharmacokinetics

  • Equal potency between NMBDs is determined by measuring the dose needed to produce 95% suppression of the single-twitch response (ED95)

Distribution

  • NMBDs are NOT highly bound to plasma proteins
    * <50%
    * Changes in protein binding is unlikely to affect renal excretion of NMBDs
  • Quaternary ammonium groups
    --> Highly ionised
    * Water soluble at physiological pH
    * Limited lipid solubility

Thus,

  • Vd is limited and close to ECF (20%)
  • NMBDs do not cross lipid membranes easily (BBB, renal tubuar epithelium, GIT epithelium, placenta)
    * No CNS effects
    * Minimal renal tubular reabsorption
    * Ineffective oral absorption
    * Maternal administration does not affect foetus

Elimination

Clearance, Vd, and elimination half-time are influenced by

  • Age
  • Volatile anaesthetic agents
  • Hepatic or renal disease
    * Renal disease can greatly influence the pharmacokinetics of long-acting nondepolarising NMBDs

Action profile

  • Plasma level of a long-acting NMBDs decreases in two phases
    * Rapid decline due to redistribution
    * Slower decline due to clearance
  • Elimination half-time of NMBD are poorly correlated with the duration of action

Clinical

Interaction

Inhaled anaesthetic agents

  • Volatile anaesthetics greatly decreases the ED95 of NMBDs
  • Inhaled anaesthetic agents do NOT affect pharmacokinetics
  • Inhaled anaesthetic agents affect pharmacodynamics of NMBDs
    * Lower plasma concentration is needed to achieve the same degree of blockade

Choice of drugs

  • Rapid onset and brief duration:
    * Suxamethonium
    * Mivacurium (to some extent)
  • Rocuronium also provide rapid onset of action
    * Fast enough to mimic suxamethonium
    * But prolonged duration of action
  • Atracurium or mivacurium
    --> Significant decrease in BP due to histamine release
  • Pancuronium
    --> Increase in HR
  • Devoid of circulatory effects
    * Vecuronium, rocuronium, cisatracurium, doxacurium, pipecuronium

Trivia

History

  • Purified fractions of d-tubocurarine (dTc)
    * First used to control tetanus muscle spasm in 1932
    * In 1942, first used in surgery (appendicecetomy) by Griffith and Johnson
  • Suxamethonium is first researched in 1906 for its parasympathomimetic effects
    * Muscle relaxation property recognised in 1949
  • Pancuronium introduced in 1960
  • 1980, atracurium and benzylisoquinoline introduced
  • 1995, cisatracurium introduced
  • ??? 1996, rocuronium
  • 1997, mivacurium introduced