Principles of Drug Action on Neurotransmission

Principles of Drug Action on Neurotransmission

Aims

• The aim of these lectures is to describe neurotransmission and how neurotransmission may be modified by drugs.
• By the end of the lecture, students should appreciate why neurotransmission is a target for the development of therapeutic drugs.

The Neuron

• Neurons communicate with each other, as well as with muscles, glands, and fat tissues.
• Communication occurs via neurotransmitters (NT).
• Local anesthetics inhibit nerve conduction by blocking sodium channels.

Neurotransmitters

• Noradrenaline (NA): Sympathetic terminals
• Acetylcholine (ACh): Parasympathetic terminals, ganglia & NMJ (neuromuscular junction)
• Dopamine (DA): Parts of CNS (central nervous system)
• Serotonin (5-HT): Parts of CNS
• Nitric oxide (NO): Odd places

Anatomy of Sympathetic Nervous System

• Emanates from thoracolumbar segments of the spinal cord.
• Ganglia are typically close to the spinal cord in the paravertebral chain.

Anatomy of Parasympathetic Transmission

• Craniosacral outflow:
  • Cranial: oculomotor, facial, glossopharyngeal, vagal
  • Sacral: nervi erigentes
• Ganglia location: Close to or inside target tissues.

The Neuroeffector Junction (Terminal Region)

• The process involves:
  1. Action potential
  2. Depolarization
  3. Voltage-operated calcium channels opening
  4. Calcium influx (Ca)
  5. Exocytosis of neurotransmitter (NT)
  6. NT binding to receptors (R)
  7. Activation or inhibition mediated by the receptor.

Synthesis and Storage of Transmitter

• Process:

  1. Precursor
  2. Enzyme cascade
  3. NT storage

• Inhibitory effects can occur via:

  • Precursor uptake inhibition (ACh inhibited by hemicholinium)
  • Enzyme cascade inhibition (NA inhibited by AMPT)
  • Storage inhibition (NA inhibited by reserpine)

• Stimulatory effects can occur by providing excess precursor (L-DOPA/DA).

• Major Therapeutics: L-DOPA to increase dopamine levels in the brains of patients with Parkinson’s disease

• Choline uptake is inhibited by 4.

Release of Transmitter

• Process:
  1. Depolarization
  2. Calcium influx (Ca)
  3. NT release
• Inhibition:
  • Inhibit terminal depolarization (NA inhibited by guanethidine)
  • Inhibit calcium influx (inhibited by conotoxin)
  • Inhibit vesicle fusion (ACh inhibited by Botulinum)
• Stimulation:
  • Displace NT (NA displaced by amphetamine and guanethidine)
  • Presynaptic receptor (NA release inhibited by clonidine, an α2 agonist)

Termination of Neurotransmission

• Mechanisms:
  • Diffusion
  • Reuptake of NT
  • Enzyme metabolism of NT
• Inhibition of termination enhances transmission.
• Reuptake inhibitors (NA/cocaine; 5-HT/fluoxetine).
  • Major therapeutics: tricyclic antidepressants inhibit NA uptake; fluoxetine (Prozac) inhibits 5-HT uptake.
• Enzyme inhibitors (neostigmine/ACh)
  • Major therapeutics: anticholinesterases to reverse muscle relaxation in surgery.

Agonist and Antagonist Action on Receptors

• Agonist:
  • Affinity and efficacy.
  • Stimulates receptor.
  • Mimics transmitter.
• Antagonist:
  • Affinity but no efficacy.
  • Blocks binding site.
  • Inhibits agonist action.

Receptor Agonists with Major Therapeutic Applications

• Note: diazepam acts on a site different on the receptor from the GABA binding site to enhance the effects of GABA – not strictly an agonist.

Receptor Antagonists with Major Therapeutic Applications

Drugs Affecting the Neuroeffector Response

• Benzodiazepine tranquillisers: Bind to the GABA receptor/Cl ion channel complex to enhance channel opening and potentiate inhibitory effects of GABA.
• Sildenafil (Viagra): Inhibits breakdown of the second messenger substance cyclic GMP produced by nitric oxide in erectile tissue.

Sites of Drug Action - Summary

1. Synthesis
2. Storage
3. Release
4. Receptors
5. Cessation/Autoinhibition

Conclusion

The synapse is an important target for drug action because:

• it is the site of neurotransmission
• it is the site where the transmitter is synthesised, stored and released
• it is a major location for receptors and target for agonists or antagonists
• receptors offer the best chance of producing drugs with a high degree of selectivity and therefore with reduced side effect profile