Pharmacology - lecture 6 - Principles of Drug Action on Neurotransmission

Principles of Drug Action on Neurotransmission

  • Focus on how drugs influence neurotransmission.

  • Understanding interference in neurotransmission is critical for developing therapeutic drugs.

Aims of the Lecture

  • Describe neurotransmission and its modification by drugs.

  • By the end of the lecture, students should understand:

    • Why neurotransmission is a therapeutic drug target.

Structure of Neurons

  • Components of a neuron:

    • Dendrites

    • Cell body

    • Axon

    • Nerve terminal

  • Neurotransmission (NT) in different systems:

    • Local anesthetics inhibit nerve conduction by blocking sodium channels.

    • Neurons can interact with muscles, glands, n and fat.

Sympathetic Nervous System (SNS)

  • Anatomy and pathways:

    • Emanates from thoracolumbar segments of the spinal cord.

    • Ganglia typically close to spinal cord within the paravertebral chain.

    • Goes from brain to spinal cord to ganglion to tissue.

Parasympathetic Nervous System (PNS)

  • Anatomy and pathways:

    • Emanates from craniosacral outflow.

      • Cranial nerves involved: Oculomotor, Facial, Glossopharyngeal, Vagal.

      • Sacral nerves: Nervi erigentes.

    • Ganglia located close to or inside target tissues.

    • Also goes from brain to spinal cord to ganglion to tissue.

Neurotransmitters

  • Neurotransmitter: connect nerve terminal to the tissue

  • Key neurotransmitters and their roles:

    • Noradrenaline (NA) - sympathetic terminals

    • Acetylcholine (ACh) - parasympathetic terminals, ganglia, NMJ

    • Dopamine (DA) - central nervous system (CNS)

    • Serotonin (5-HT) - parts of CNS

    • Nitric oxide (NO) - various tissues

Neuroeffector Junction

  • Action potential and neurotransmitter release:

    • Depolarization triggers action potential through voltage-operated calcium channels.

    • Calcium influx leads to neurotransmitter exocytosis.

    • Key processes:

      • Presynaptic autoinhibition

      • Postsynaptic agonism

Synthesis and Storage of Neurotransmitters

  • Neurotransmitter synthesis involves:

    • Precursor uptake (e.g., ACh affected by hemicholinium).

    • Enzyme cascade (e.g., NA affected by AMPT).

    • Storage affected by pharmacological agents (e.g., reserpine).

    • Major therapeutic agent: L-DOPA used to treat Parkinson’s disease by increasing dopamine levels.

Release of Neurotransmitters

  • Mechanisms affecting neurotransmitter release:

    • Inhibition of terminal depolarization through various agents (e.g., guanethidine).

    • Conotoxin inhibiting calcium channels impacting neurotransmitter release.

    • Vesicle fusion inhibited by Botulinum toxin.

    • Displacement agents (e.g., amphetamine) altering neurotransmitter release.

Termination of Neurotransmission

  • Mechanisms:

    • Diffusion and reuptake of neurotransmitters (e.g., NA reuptake inhibited by cocaine).

    • Major therapeutics include:

      • Tricyclic antidepressants (NA uptake inhibitors).

      • Fluoxetine (Prozac) for 5-HT uptake inhibition.

      • Anticholinesterases used to reverse muscle relaxation during surgeries.

Agonist and Antagonist Actions

  • Agonists and antagonists interact with neurotransmitter receptors:

    • Agonists have affinity and efficacy, mimicking neurotransmitters and stimulating receptors.

    • Antagonists have affinity but no efficacy, blocking receptor sites and inhibiting agonist functions.

Clinical Applications of Agonists and Antagonists

  • Therapeutic examples:

    • Agonists:

      • Salbutamol (β2) for asthma.

      • Phenylephrine (α1) as a decongestant.

      • Bromocriptine (D2) for Parkinson’s disease.

      • Morphine (ÎĽ) for pain relief.

      • Diazepam (GABA) for anxiety.

    • Antagonists:

      • Prazosin (α1) to reduce blood pressure.

      • Propranolol (β) to reduce blood pressure.

      • Atracurium (nicotinic ACh) as a muscle relaxant.

      • Trifluoperazine (D2) for antipsychotic needs.

Summary of Sites of Drug Action

  1. Synthesis

  2. Storage

  3. Release of neurotransmitters

  4. Receptor action

  5. Cessation of action (reuptake, enzymatic breakdown)

Conclusion

  • The synapse serves as a major target for drug action because:

    • It is the site of neurotransmission.

    • It encompasses transmitter synthesis, storage, and release.

    • It hosts receptors which are prime targets for drug specificity with a minimized side effect profile.