Acetylcholine Receptors

Understanding of the pharmacology of anticholinesterase drugs.

Describe the adverse effects of anticholinesterase agents.

This covers the pharmacology of acetylcholine receptors and the production and metabolism of ACh. Detailed information on specific agents is in the pharmacopeia.

Acetylcholine is a neurotransmitter vital for normal function of:

• CNS
• ANS
• Muscle contraction

Synthesis, Release, and Metabolism

ACh is produced is the nerve cytoplasm by acetyltransferase from:

• Choline
  From diet and recycled ACh.
• Acetyl-coenzyme A
  Produced in the inner mitochondrial matrix.

Once synthesised, ACh is then packaged into vesicles (each containing ~10,000 ACh molecules), which are released in response to calcium influx occurring at the culmination of an action potential.

Acetylcholine is metabolised by acetylcholinesterase on the post-junctional membrane. AChE:

• Has two binding sites:
  • Anionic binding site
    Binds the positively charged quaternary ammonium moiety.
  • Esteratic binding site
    Binds the ester group of ACh.
• Once bound, ACh is acetylated
• Acetylated-ACh is then hydrolysed to produce acetic acid

ACh Receptor Subtypes

There are two types of ACh receptor:

• Nicotinic ACh receptors
  • Inotropic
    Linked to an ion channel.
    • Non-specific - may allow Na⁺, K⁺, or Ca²⁺ to cross
  • Consists of five subunits:
    • Two α
      Bind ACh.
    • One β
    • One δ
    • One γ
  • Located in:
    • Post-synaptic NMJ
    • Preganglionic autonomic nervous system
      Antagonism causes ganglion blockade.
    • Brain
  • Known as nicotinic because nicotine agonises this receptor
  • Activation:
    • 2 ACh molecules must bind to activate the receptor
    • Once bound, receptor undergoes a conformational change which opens the central ion pore
      Permeability to Na⁺ (and to a lesser extent, K⁺ and Ca²⁺) increases, leading to depolarisation

• Muscarinic ACh receptors
  • Metabotropic
    G-protein coupled.
  • Known as muscarinic because muscarine also agonises this receptor
  • Subdivided into:
    • M₁ (Gq)
      Secretory glands and CNS.
    • M₂ (Gi)
      Heart.
    • M₃ Gq
      Bronchial and arteriolar smooth muscle.
    • M₄ (Gi) and M₅ (Gq)
      CNS.

References

1. Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.