Drug Action & Neurotransmission Principles

Principles of Drug Action on Neurotransmission: Aims

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

The Neuron

• The neuron is the basic functional unit.
• NT stands for neurotransmitter.
• A neuron consists of:
  • Cell body
  • Dendrites which receive nerve impulses
  • Axon
  • Nerve terminal

Neuron Connections

• Neurons connect to:
  • Other neurons
  • Muscles
  • Glands
  • Fat tissue
• Local anesthetics inhibit nerve conduction by blocking sodium channels.
• Sympathetic nerves originate from the brain, travel through the spinal cord, synapse at a ganglion, and then extend to tissue.
• Parasympathetic nerves also originate from the brain and spinal cord, synapse at a ganglion, and then extend to tissue.
• Motor nerves extend from the spinal cord to the neuromuscular junction (NMJ) in skeletal muscle.

Neurotransmitters

• Various neurotransmitters are associated with different nerve terminals and locations:
  • Noradrenaline (NA) is found in sympathetic terminals.
  • Acetylcholine (ACh) is present in parasympathetic terminals, ganglia, and NMJ.
  • Dopamine (DA) and Serotonin (5-HT) are located in parts of the central nervous system (CNS).
  • Nitric oxide (NO) is found in various places.

Anatomy of Sympathetic and Parasympathetic Nervous Systems

• The sympathetic nervous system emanates from thoracolumbar segments of the spinal cord.
• Sympathetic ganglia are typically close to the spinal cord in the paravertebral chain.
• The parasympathetic nervous system has a craniosacral outflow.
  • Cranial outflow includes oculomotor, facial, glossopharyngeal, and vagal nerves.
  • Sacral outflow involves nervi erigentes.
• Parasympathetic ganglia are located close to or inside target tissues.

The Neuroeffector Junction

• The neuroeffector junction is the terminal region where neurotransmission occurs.
• The process:
  • An action potential arrives.
  • Depolarization occurs.
  • Voltage-operated calcium channels open, allowing calcium (Ca) to enter the cell.
  • Calcium influx triggers exocytosis, releasing neurotransmitters (NT).
  • Neurotransmitters can bind to postsynaptic receptors or presynaptic autoinhibitory receptors.

Synthesis and Storage of Transmitter

• Synthesis and storage of neurotransmitters can be affected by drugs.
• Inhibitory effects include blocking precursor uptake (e.g., ACh blocked by hemicholinium), inhibiting enzyme cascade (e.g., NA blocked by AMPT), and disrupting storage (e.g., NA blocked by reserpine).
• Stimulatory effects: provides an excess of precursor. (L-DOPA/DA).
• L-DOPA is a major therapeutic drug used to increase dopamine levels in the brains of patients with Parkinson's disease.

Release of Transmitter

• Release of neurotransmitter can be inhibited by:
  • Inhibiting terminal depolarization (e.g., NA blocked by guanethidine).
  • Blocking calcium channels (e.g., conotoxin).
  • Inhibiting vesicle fusion (e.g., ACh blocked by Botulinum).
  • Presynaptic receptors, NA release blocked by clonidine, an a₂ agonist.

Termination of Neurotransmission

• Termination involves diffusion and consideration of the geometry of the synaptic cleft.
• Inhibition of termination will enhance transmission.
• Reuptake can be inhibited, for example, NA by cocaine and 5-HT by fluoxetine.
• Enzymes can be inhibited; neostigmine inhibits ACh.
• Tricyclic antidepressants inhibit NA uptake, and fluoxetine (Prozac) inhibits 5-HT uptake.
• Anticholinesterases reverse muscle relaxation in surgery.

Agonist and Antagonist Action on Receptors

• Agonists have affinity and efficacy, stimulate receptors, and mimic transmitters.
• Antagonists have affinity but no efficacy, block binding sites, and inhibit agonist action.
• Agonists bind to receptors and cause a response in the ion channel or messenger system.

Receptor Agonists and Antagonists

• Salbutamol are examples of receptor agonists that are used for:
  • Asthma (Noradrenaline/2)
  • Decongestant (Noradrenaline/1; phenylephrine)
  • Parkinson's Disease (Dopamine/D2; bromocriptine)
  • Pain relief (Enkephalin/morphine)
  • Anxiety (GABA/A; diazepam)
• Diazepam acts on a site different from the GABA binding site to enhance GABA's effects.
• Prazosin are examples of receptor antagonists that are used for:
  • High blood pressure issues (Noradrenaline/1)
  • High blood pressure issues (Noradrenaline/; propranolol)
  • Muscle relaxants (Acetylcholine/nicotinic; atracurium)
  • Pre-medication (Acetylcholine/muscarinic; atropine)
  • Antipsychotic (Dopamine/D2; trifluoperazine)

Drugs Affecting the Neuroeffector Response

• Benzodiazepine tranquilizers bind to the GABA receptor/Cl ion channel complex to enhance channel opening and potentiate the inhibitory effects of GABA.
• Sildenafil (Viagra) inhibits the breakdown of cyclic GMP produced by nitric oxide in erectile tissue.

Summary: Sites of Drug Action

• The sites of drug action are:
  • Synthesis
  • Storage
  • Release
  • Receptors
  • Cessation of action (reuptake, enzyme degradation & autoinhibition)

Conclusion

• The synapse is an important target for drug action because:
  • It is the site of neurotransmission.
  • Neurotransmitters are synthesized, stored, and released.
  • Receptors act as locations and a target for agonists or antagonists.
  • Receptors offer the chance of producing drugs with selectivity and reduced side effects.