NON-DEPOLARISING SKELETAL MUSCLE RELAXANTS

1. Separated into two distinct groups – isoquinoline and steroid derivatives:
   • Isoquinoline – Atracurium, cisatracurium, mivacurium and tubocurarine
   • Steroid – Rocuronium, Vecuronium and Pancuronium

1. Mechanism of action
   • Both groups mainly act by competitive antagonism of ACh at the nicotinic receptor.
   • Note that of all the non-depolarising agents, rocuronium is the least potent, having the fastest onset and fastest offset.
   • Larger doses will actually allow the drug to enter the pore of the channel, producing a stronger blockade. This reduces the ability of acetylcholinesterase inhibitors to antagonize the effects. Larger doses may also interfere with pre-junctional release of ACh.
2. Specific organ effects
   • Rocuronium, vecuronium and cisatracurium are the most cardiac stable, with little, if any, CVS side effects.
   • Tubocurarine and atracurium may cause brief hypotension due to histamine release.
   • Pancuronium is associated with tachycardia due to a vagolytic response. It increases cardiac output but does not change systemic vascular resistance.

1. IV only – it is inactive orally for all agents.

1. All agents are highly polar/ionized, and therefore not strongly bound in peripheral tissues.
2. All agents have very small Vd.

1. The duration of neuromuscular blockade is strongly correlated with elimination half-life. The agents all have different mechanisms of metabolism:
   • Atracurium, in addition to hepatic metabolism, is inactivated by spontaneous breakdown (Hoffmann elimination). The main breakdown product is laudanosine. Laudanosine is slowly metabolized by the liver, has long elimination T ½ (150 minutes) and crosses the BBB. At high levels, it will cause seizures and increase the volatile anesthetic requirement.
   • Cisatracurium is metabolized via Hoffmann elimination as well, but depends less on hepatic metabolism, produces less laudanosine and has less chance of releasing histamine. These features make it overall a better drug than atracurium.
   • The steroid drugs, rocuronium and vecuronium undergo hepatic metabolism and biliary excretion. This means their duration of action is shorter (25-30 minutes). They are metabolized to 3-hydroxy, 17-hydroxy or 3, 17-dihydroxy compounds. The 3-hydroxy compounds have longer half-lives and are active metabolites. They may accumulate and cause prolonged paralysis.
   • Pancuronium is mainly dependent on renal excretion (80% excreted renally). This means it has the longest duration of action (>35 minutes)

[One application of the above is that cisatracurium is used for prolonged paralysis in ICU, and rocuronium and vecuronium are not]

1. Rocuronium/vecuronium – hepatic/biliary excretion
2. Pancuronium – renal

1. Facilitate endotracheal intubation
   • Note that rocuronium may be used in modified RSI setting by giving a large dose – 0.9mg/kg, which will have an onset time of 60-120s.
2. Maintenance of paralysis to aid ventilation/transport of patient.
3. In penetrating eye injuries where suxemethonium is contraindicated,
4. May be used in ICU setting to prevent shivering when therapeutic hypothermia protocol is being used.

1. Previous hypersensitivity reaction
2. Unmonitored/non-resuscitation settings
3. Inadequate personnel
4. Known difficult intubation/ventilation

1. Need monitored setting/experienced clinicians to use
2. Dose according to lean muscle mass in obese patients
3. Specific disease conditions:
   • Advanced age and myasthenia gravis will prolong action of drug
   • Burns will decrease action of drug

1. Aminoglycosides (e.g. Gentamicin) will enhance NM blockade

1. As stated above, in pharmacodynamic section

1. Rocuronium
   • 0.6mg/kg as induction
   • 0.1-0.2mg/kg every 20-30 minutes for maintenance
   • 0.9mg/kg for modified RSI

1. Block may be reversed by cholinesterase inhibitors, e.g. neostigmine or erdrophonium.
2. Rocuronium has a pharmacological antagonist – sugammadex