Viva M1(i)c

This chapter is relevant to Section M (i) of the 2017 CICM Primary Syllabus, which expects the exam candidates to "describe the autonomic nervous system, including anatomy, receptors, subtypes and transmitters (including their synthesis, release and fate)". This section is limited to synthesis, metabolism, mechanisms of neurotransmission and receptor effects of acetylcholine.

How and where is acetylcholine synthesised?

• Acetylcholine is an ester of acetate and choline.
• Made from choline, a quaternary saturated amine, which is an essential water-soluble nutrient usually found complexed with B-vitamins.
• Natural sources are whole eggs and the fatty animal meat
•  In certain neurons, choline is metabolised into acetylcholine; the extra acetyl group is donated by acetyl-CoA (which draws on the inexhaustible supply of acetate anions which are constantly burned in the citric acid cycle).
• The choline acyltransferase enzyme is responsible for catalyzing this process.
• It happens in the body of the neuron, and the finished acetylcholine is transported in vesicles via axoplasmic flow.
• It is taken up into vesicles by the transport protein VAChT

Describe the pathway of cholinergic neurotransmission

• Action potential causes intracellular calcium increase
• Synaptobrevin mediates vesicle fusion
• acetylcholine is released into the synapse
• Immediately broken down by acetylcholinesterase

What are the cholinergic receptors?

• Nicotinic and muscarinic
• Nicotinic are N1 (neuromuscular junction) and N2 (ganglionic)
  • These are ligand gated ion channels
  • Membrane protein with 5 subunits (α₁, α₂, β, γ, δ)
  • Nonspecific cation pore (sodium goes into the cell, potassium comes out)
    • Five functional subunits
    • For the neuromuscular junction receptors, the five subunits are beta, delta epsilon and two alpha-1
    • The two alpha-1 subunits act as the binding sites of acetylcholine as well as the whole lot of neuromuscular blocking agents.
    • For the autonomic ganglia receptors, the five subunits are three beta and two alpha-3
    • The two alpha-3 subunits also act as binding sites for acetylcholine, but they will not bind neuromuscular blocking agents.
• Muscarinic receptors are many:
  • G-protein coupled receptors
  • 5 subtypes
  • Evenly numbered ones (M2, M4) are G_i-coupled, and decrease cAMP

    • Broadly speaking, these receptors are membrane stabilizers.

    • Excitable tissues hyperpolarize, inward rectifying potassium currents start flowing, voltage-gated calcium channels are inhibited.

  • Odd numbered ones (M1, M3, M5) are G_q-coupled, and increase intracellular claim by means of phospholipase C and IP3.
    • In general, the rule of thumb for these receptors is the excitation of excitable tissue, and the activation of various glandular and secretory function.
    • Most glandular cells, posed with a massive influx of diacylglycerol and IP3 will begin to secrete stuff. Similarly, smooth muscle will contract when there is a calcium influx.

What are the effects of muscarinic receptor activation?

M1: 

• Increased cognitive function, eg. memory
• Increased seizure activity

M2:

• Miosis (contraction) of the pupillary sphincter muscle

• Contraction of the ciliary muscle for far vision

• Lacrimal gland secretion

• Significant reduction in heart rate

• Significant reduction in atrial contractility, and shortened action potential duration

• Significant reduction in the conduction velocity of the AV node

• Slight decrease in ventricular contractility

• Increased motility and tone of the stomach

• Relaxation of gastric sphincters

• Stimulation of gastric secretion

• Contraction of the gallbladder

• Relaxation of the intestinal sphincters, and increased intestinal motility

M3

• Miosis (contraction) of the pupillary sphincter muscle

• Contraction of the ciliary muscle for far vision

• Lacrimal gland secretion

• Salivation and dilation of the salivary ducts

• Greatly increased nasal mucus secretion

• Increased production of nitric oxide synthase by the vascular endothelium

• Increased motility and tone of the stomach

• Relaxation of gastric sphincters

• Stimulation of gastric secretion

• Contraction of the gallbladder

• Relaxation of the intestinal sphincters, and increased intestinal motility

• Bladder detrusor muscle contraction, and relaxation of the trigone sphincter

• Erection

• Generalised secretion of the sweat glands (not just sweaty palms, but all over)

• Increased secretion of the pancreatic juice

M4

• Inhibition of neurotransmitter release in the CNS
• Facilitates Dopamine release

M5

• Facilitates Dopamine release

What is the pathway of acetylcholine catabolism?

• Once its job in the synapse is done, synaptic acetylcholinesterase breaks it back down into acetate anions and choline.
• This hydrolysis takes less than a millisecond.
• The acetate goes god knows where (presumably back into Krebs cycle) and the choline is dutifully reabsorbed by its uptake transporters
• (two, one Na⁺ /Cl^- dependent high affinity transporter and another independent transporter of lower affinity).
• This reuptake is the rate-limiting step in acetylcholine synthesis.

Which drugs target the pathway of acetylcholine release, catabolism and reuptake?

• Release
  • Botulinum toxin
  • Ganglionic blockers, eg. guanfacine, older NMJ blockers
• Catabolism:
  • Acetylcholinesterase inhibitors
    • Neostigmine, pyridostigmine, physostigmine
    • Galantamine
    • Donepezil
    • Sarin nerve gas
    • Organophosphates
• Reuptake:
  • Hemicholinium