Autonomic Medications - Adrenergic Transmission

Study Notes

Synthesis of Noradrenaline (NA)
- Occurs in the axon of noradrenergic neurons.
- Tyrosine is converted to DOPA by tyrosine hydroxylase.
- DOPA is converted to dopamine by DOPA decarboxylase.
- Dopamine is converted to noradrenaline by dopamine hydroxylase.
- In the adrenal medulla, NA is converted to adrenaline by phenylethanolamine N-methyl transferase enzyme.

NA is stored with ATP in vesicles.
Two main release mechanisms:
- Exocytosis: Calcium influx into the presynaptic neuron triggers the release of NA into the synaptic cleft by exocytosis.
- Non-exocytosis: Certain drugs, such as amphetamines, can displace and release NA from the vesicles.

Auto-inhibitory feedback mechanism:
- Released NA stimulates α2 receptors on the presynaptic neuron, inhibiting the release of further NA.

Catecholamines (NA, adrenaline, isoprenaline) are eliminated by re-uptake and/or metabolic degradation.
Re-uptake:
- Uptake 1 (presynaptic): NA is taken back into the presynaptic neuron.
- Uptake 2 (extraneuronal): NA is taken up by effector organs, such as the heart and smooth muscle, and is more selective for adrenaline.
Metabolism:
- Monoamine oxidase (MAO): An enzyme found in mitochondria, particularly abundant in neurons.
- Catechol-O-methyl transferase (COMT): Found in various neuronal and non-neuronal tissues.

Two main classes:
- α receptors (α1 and α2)
- β receptors (β1, β2, and β3)

α1 receptors:
- Found in smooth muscle of various organs.
- Actions:
  - Vasoconstriction : Constriction of blood vessels.
  - Gastrointestinal (GI) relaxation: Relaxation of GI smooth muscle.
  - Sphincter contraction: Contraction of all sphincters (GI and urinary).
  - Mydriasis: Pupillary dilation due to contraction of the dilator pupillae muscle.
α2 receptors:
- Found in presynaptic neurons, CNS, and blood vessels.
- Actions:
  - Inhibition of transmitter release: Inhibit release of neurotransmitters.
  - Platelet aggregation: Promote platelet clumping.
  - If found postsynaptically, they can function similarly to α1 receptors.
β1 receptors:
- Primarily found in the heart.
- Actions:
  - Increased contractility: Strengthening of heart contractions.
  - Increased heart rate: Faster heartbeat..
β2 receptors:
- Found in smooth muscle.
- Actions:
  - Bronchodilation: Relaxation of the bronchioles, widening airways.
  - Peripheral vasodilation: Relaxation of blood vessels in the periphery.
  - Visceral smooth muscle relaxation: Relaxation of smooth muscle in internal organs.
  - Skeletal muscle tremor: Muscle tremors.
  - Increased aqueous humor secretion: Increased fluid production in the eye.
  - Increased liver glycogenolysis: Breakdown of glycogen in the liver.
β3 receptors:

Adrenaline, noradrenaline, and isoprenaline all activate both α and β receptors, but have different potencies.
Noradrenaline: More potent at stimulating α receptors, less potent at stimulating β receptors.
Isoprenaline: More potent at stimulating β receptors, less potent at stimulating α receptors.

Choline transport: Choline is transported from the extracellular fluid into the cholinergic neuron's cytoplasm using an energy-dependent carrier system.
Choline acetyl-transferase: This enzyme combines choline with acetyl coenzyme A (CoA) to form ACh.
Choline properties: Choline is a quaternary amine with a permanent positive charge, preventing it from diffusing through the membrane.

Action potential arrival: An action potential reaching the nerve terminal opens voltage-gated calcium channels.
Calcium influx: Increased intracellular calcium concentration triggers the fusion of vesicles with the cell membrane, releasing ACh into the synaptic space.
Botulinum toxin: Blocks the release of ACh.

Rapid signal termination: ACh is quickly broken down into choline and acetate in the synaptic cleft by acetylcholinesterase.
Choline recycling: Choline is recaptured by a high-affinity uptake system, transporting it back into the neuron for the synthesis of new ACh.