Question 2

College Answer

For a good answer candidates were expected to mention that an agonist is a drug that elicits a maximal response on binding to a receptor. A partial agonist has intrinsic affinity with only partial efficacy and hence is unable to elicit a maximal response. A competitive drug acts at the same binding site of a receptor as an endogenous ligand (e.g. acetylcholine at the neuromuscular junction) and its action therefore is surmountable with increasing concentrations of drug and how this conceptrelatesto suxemethonium. For the remainder of the question, Candidates were expected to mention the advantages and disadvantages of suxamethonium within Intensive Care practice. Good answers included a systematic approach and use of tables and/or well organised lists.

Discussion

Non-competitive partial agonist:

• Non-competitive:
  • A non-competitive antagonist can prevent the action of an agonist without any effect on the binding of the agonist to the receptor.
  • The antagonist, while still opposing the action of the agonist, does so without competing with it for the binding site.
  • Once a receptor is bound by such a drug, agonists cannot surmount the inhibitory effect irrespective of their concentration
• Partial agonist:
  • A partial agonist does not reach the maximal response capability of the system even at full receptor occupancy.
  • A partial agonist acts as an antagonist in the presence of a full agonist (if they compete for the same receptors)

Advantages:

• Rapid onset (fastest acting NMJB agent)
• Rapid offset, an advantage for:
  • electroconvulsive therapy
  • cardioversion
  • short ENT procedures
  • for the reduction of fractures.
• Organ-independent metabolism:  suxamethonium is metabolised by plasm pseudocholinesterase
• Safety in pregnancy and in neonates is mentioned as an advantage, though it also must be pointed out that many other NMJ blockers are also considered safe in pregnancy, and basically all of them are considered safer than an unprotected airway for a pregnant patient
• Cost is an advantage. Suxamethonium is among the cheapest NMJ blockers available.
• Pre-mixed should be listed as an advantage, mainly to increase the length of the list

Disadvantages:

• Pharmacokinetic:
  • Pseudocholinesterase may be deficient in the critically ill (eg. liver failure)
• Pharmacodynamic:
  • ​​​​​​​Unsuitable for sustained NMJ blockade; tachyphylaxis, Phase II block and self-antagonism with sustained use
• Adverse effects
  • ​​​​​​​Masseter spasm
  • Autonomic side effects: bradycardia OR tachycardia
  • Increased intraocular pressure
  • Increased intragastric pressure
  • Increased intracranial pressure
  • Fasciculations
  • Myalgia
  • Hyperkalemia
• Contraindications
  • Spinal injury
  • Stroke
  • Burns
  • Denervation
  • Prolonged immobility
  • Critical illness (ICU-associated weakness)

Lee, Chingmuh. "Suxamethonium in its fifth decade." Baillière's clinical anaesthesiology 8.2 (1994): 417-440.

Lee, C. "Goodbye suxamethonium!." Anaesthesia 64 (2009): 73-81.

Gibb, David B. "Suxamethonium—A Review: Part I.—Physico-Chemical Properties and Fate in the Body." Anaesthesia and Intensive Care 1.2 (1972): 109-118.

Gibb, David B. "Suxamethonium—A Review: Part II—Neuromuscular Blocking Properties." Anaesthesia and Intensive Care 1.3 (1973): 183-201.

Gibb, David B. "Suxamethonium-A Review: Part III—Pharmacological Actions of Suxamethonium Apart from Its Neuromuscular Blocking Effect." Anaesthesia and Intensive Care 2.1 (1974): 9-26.

Torda, T. A., et al. "Pharmacokinetics and pharmacodynamics of suxamethonium." Anaesthesia and intensive care 25.3 (1997): 272-278.