LEC 2

• Drug action is the mechanism by which a drug produces an effect
• Drug action = It is how the effect is produced
• Drug effect is the biological response after drug administration
• Drug Effect = It is what the drug produced in the animal
• Drug effects can be subtherapeutic, therapeutic/beneficial, or harmful (toxic or lethal)
• Drug actions can be receptor-mediated or non-receptor mediated
• Example: Ibuprofen action involves cyclooxygenase inhibition
• Ibuprofen effect includes analgesia (pain relief), anti-pyrexia (fever relief), and inflammation reduction
• Receptor-mediated drug action involves receptors that are specialized macromolecules binding with ligands for cell signaling
• Receptors can be proteins or glycoproteins
• Endogenous ligands are neurotransmitters, hormones, etc., while exogenous ligands are drugs, synthetic hormone preparations, etc.
• Receptor classes according to location include cell-surface receptors and intracellular/cytoplasmic receptors
• Cell-surface receptors can be enzyme-linked, G-protein-coupled, or ion channel receptors
• Intracellular receptors include transcription factor receptors
• Chemical bonds in drug-receptor interaction can be ionic, hydrogen, van der Waals forces, or covalent bonds
• Ionic bonds occur between ions of opposite charge; i.e. electrostatic
• Hydrogen bonds involve the ability of a proton to accept an electron pair
• Van der Waals forces form weak bonds between dipoles or induced dipoles
• Covalent bonds are tight and irreversible, requiring more energy to break
• Cell signaling involves cell communication and intracellular responses to drugs and endogenous ligands
• Stages in cell signaling include reception, transduction, and response
• Response can vary from activating a gene/enzyme to rearranging the cytoskeleton
• Non-receptor-mediated drug action includes neutralization reactions, nonspecific perturbation of cell membrane, and chelation (binding with small molecules and ions)
• Neutralization reactions involve acid-base neutralization
• Nonspecific perturbation of cell membrane can be seen with osmotic diuretics like Mannitol
• Chelation, for example, EDTA chelating lead (Pb+)
• Covalent bonds are rare and is present only in toxic situations
• Enzyme-linked receptors are kinase domain that forms a dimer when ligands bind
• G-protein-coupled receptor is the largest receptor family with three sub-units: alpha, beta, & gamma
• G-protein is guanine nucleotide-binding protein
• Ion channel receptors modulates ions and hydrophilic molecule passages thru ligand-gated and voltage-gated receptors
• Ligand-gated receptor opens in response to chemical signal/ligand
• Voltage-gated receptor opens in response to voltage depolarizing the membrane
• Examples of ligand-gated receptors:

  • Nicotinic acetylcholine (Ach) receptor
  • Type A gamma-aminobutyric acid (GABA) receptor
• Examples of voltage-gated channels:

  • Calcium channel
  • Sodium channel
  • Potassium channel
• Transcription factor receptor for fat-soluble signaling molecules found in the cytosol and migrates to the nucleus after ligand-binding
• Example of transcription factor receptor = Steroid hormone
• First 3 types of bonds are the principal bond forces, involved in drug action, and easily reversible (20° - 40°C or approx. 5kcal/mol)
• Reception is the chemical message/ligand that binds to cell surface receptor (e.g., hormone, drug)
• Transduction is the cascade of reactions that elicit cellular response