Pharmacodynamics of injected drugs

[Ref: SH4:p19]

 

Pathways of drug actions

Drugs invoke cellular changes by

• Acting on transmembrane protein receptors
• Acting on cytoplasmic (intracellular) receptors
• Stimulation or inhibition of enzyme system

Other mode of actions include

• Formation of strong bonds with metallic cations (chelating drugs)
• Direct neutralisation of gastric acid (antacids)

 

3 mechanisms of signal transduction at surface receptors

• Ligand-gated ion channels
• G protein-coupled receptors
• Receptor-linked enzymes

 

Excitable transmembrane proteins

• Voltage-sensitive ion channels
• Ligand-gated ion channels
  * aka ionotropic receptors
• Transmembrane receptors
  * aka G-protein coupled receptors

Voltage-sensitive ion channels

Depolarisation of membrane
--> Conformational changes
--> Ion channels opens

Ligand-gated ion channels

• Binding of ligand to the receptor
  --> Associated ion channels open (without invovlement of a second messenger)
• Pentameric receptors (??? 5 subunits)
  * Each subunit has 4 transmembrane segments
  * [SH:p36]

Two families

1. Specific neurotransmitters

• Excitatory, cation-selelctive
  * Nicotinic acetylcholine receptor (nAch)
  * Serotonin receptor (5HT3)
• Inhibitory, anion-selective
  * Gamma-aminobutyric acid receptor (GABAa)
  * Glycine receptors

2. Ligand-gated glutamate receptors

• N-methyl-D-aspartate (NMDA)
• Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)
• Kainate

Glutamate vs GABA

Glutamate
... is the principle excitatory neurotransmitter in CNS
* Cannot cross BBB --> Must originate from local metabolism

GABA
... is the primary inhibitory neurotransmitter in CNS
* Responsible for most fast synaptic inhibition of neurons
* 1/3 of all synapses in CNS respond to GABA
* Cannot cross BBB --> Can't be administered systemically

Examples of ligand-gated ion channels

• Neuromuscular blocking drugs act on nAch receptor
• Barbiturates and benzodiazepines act on GABAa receptor
• Ketamine acts on NMDA receptor

Transmembrane receptors

• Can bind to hydrophilic ligands in the ECF
• Involves G protein
• Monomeric receptor consisting of 7 transmembrane segments
  * [SH4:p36]