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