Week 2 Pharmacology

Muscle relaxants

  • Skeletal muscle relaxants are either neuromuscular blockers (peripheral)  used as adjuncts in GA or spasmolytics used in chronic situations (these are centrally acting)
  • Normal NMJ: action potential –> Ca 2+ release –> acetylcholine release from nerve end –> bind to nicotinic receptor on muscle –>action potential initiated and propagated in muscle –>  muscle contraction
  • All the NMJ blocking drugs look similar to acetylcholine
  • Poorly lipid soluble – limiting entry to CNS
  • Highly polar
  • Inactive orally, must be administered parenterally



Non-depolarising muscle relaxants

  • Have a rapid distribution leading to drop in blood concentration
  • Then a slower elimination phase
  • Vd approx 80-140mL/kg – only slightly more than blood volume
  • Renally excreted ones have longer half lives = approx 60mins
  • Steroid muscle relaxants are all b/d in liver – in ICU setting if used for days the active metabolite accumulates in significant amount to act as well
  • At low dose it competes with Ach, at higher dose it enters the ion channel to produce a more intense blockade
  • Can be reversed with Acetylcholinesterase inhibitors (neostigmine, edrophonium, pyridostigmine).
  • Side effects: very little cardiovasc effects, prolonged apnoea if toxic.
  • Contraindications: hypersensitivity/anaphylaxis
  • Pancuronium/Pipercuronium (Long acting steroid based)
  • Vecuronium/Rocuronium (intermediate acting steroid muscle relaxant). Biliary excretion/hepatic metabolism
  • Atracurium (Intermediate acting isoquinoline nondepolarizing muscle relaxant.)
    • Hepatic metabolism and spontaneous breakdown
    • One of the breakdown products laudanosine can accumulate if pt on infusion for days –increase seizure risk.
  • Cisatracurium – an stereoisomer which produces less laudanosine so is now much more commonly used


Depolarising muscle relaxants:

  • Extremely short duration of action(5-10mins)
  • Rapid hydrolysis in liver and plasma
  • Only a small part of original dose reaches NMJ
  • No break down at the plate – Effect terminated by succinylcholine diffusing away from the end plate
  • The effect is prolonged in patients with genetic variant of plasma cholinesterase
  • Suxamethonium- IMPORTANT drug.
    • Reacts with nicotinic receptor –> open channel–> depolarisation of motor end plate–> spreads to adjacent membrane too –> widespread muscle contraction–> depolarised membrane stays depolarised and is unresponsive to further stimulation.
    • Flaccid paralysis occurs (cos contraction requires ongoing firing to maintain muscle tension).
    • This is the phase 1 block (depolarising) – this is augmented by acetylcholinesterase inhibitors.
    • Phase II block.
      Prolonged exposure to sux –> initial depolarisation decreases –> membrane repolarises but still it cannot easily depolarise cos it is desensitised.
    • Channels behave like they’re in prolonged closed state. Just like nondepolarising blockade so can be reversed with acetylcholinesterase inhibiters.
  • Side effects: arrhythmias, high K, transient increase in intra-abdominal and intra-ocular pressure, post op muscle pain.
  • Contraindications:
    • muscular dystrophy or other skeletal myopathies (including critical illness myopathy)
    • personal or family history of malignant hyperthermia
    • hypersensitivity to suxamethonium
    • acute phase of injury following major burns, extensive denervation of skeletal muscle, or upper motor neuron injury
    • [The risk of hyperkalemia in these patients increases over time and usually peaks at 7-10 days after the injury. The risk is dependent on the extent and location of the injury. The precise time of onset and the duration of the risk period are not known.
    • Pseudocholinesterase deficiency.



Malignant Hyperthermia.

  • Autosomal dominant
  • Ryanodine receptor gene issue
  • Sux triggers uncontrolled oxidative metabolism in skeletal muscle –> overwhelms body –> cannot supply enough O2 and remove CO2 and heat –> circulatory collapse
  • Dantrolene. – a spasmolytic used to treat malignant hyperthermia. Not centrally acting (unlike other spasmolytics)

Viva questions:

Contrast the actions of nondepolarising and depolarising muscle relaxants.

Compare Suxamethonium and Rocuronium

Tell me about Suxamethonium.

What is Phase II block ?

Tell me about the NMDR’s

Tell me about local anaesthetics