pharmacology

• Pharmacology

  The study of the action of drugs on the function of living systems
• Drug


  A chemical substance or natural product that affects the function of cells, organs, systems or the whole body (i.e. is bioactive)
• Pharmacokinetics


  What the body does to the drug
• Pharmacodynamics


  What the drug does to the body
• Pharmacology underpins knowledge from inter-related disciplines; e.g. chemistry, physiology, biochemistry, anatomy, microbiology, immunology, etc.
• when Pharmacology emerged as a scientific discipline (materia medica)

  Mid 19th Century
• Principles of experimentation rather than dogma
• Paracelsus, 16th Century: 'All drugs are poisons …it is only the dose which makes a thing poison'
• Sources of drugs

  • Natural products (i.e. plants, animals cannabis)
  • Serendipity (i.e. by accident)
  • Changing the structure of an existing molecule (i.e. structure-activity relationships)
  • Using an existing drug in a new disease (i.e. re-purposing)
  • Computer-aided design
  • Studying disease processes
• Accidental discovery - serendipity


  • Penicillin (Alexander Fleming, Howard Florey, Ernst Chain)
• Drugs from animals


  • Hirudin (leech)
  • Ziconotide (cone snail)
  • Peptide which lowers BP (Bothrops jararaca)
• Drug re-purposing


  • Sildenafil (Viagra)
• Chemical name


  IUPAC name that describes the chemical structure of the drug
• Generic name


  International non-proprietary name given to a molecule
• Proprietary name


  'Trade' name(s) given to an approved drug by the manufacturer
• Drugs in development are also typically given a 'code-name' to disguise their identity
• Pharmacokinetics - "what the body does to the drug"
• Pharmacodynamics - "what the drug does to the body"
• Pharmacokinetics


  • Absorption, distribution, metabolism & excretion
  • Proteins
  • - Drug transporters

  - Metabolising enzymes

  • 
    
  • Cells
  • epithelial, endothelial, hepatocytes
• Routes of drug penetration into cells

  • Diffusion through lipid membrane
  • Diffusion through aqueous channels
  • Carrier-mediated transport
  • Pinocytosis -Transport of insulin into brain​
• Lipinski's rule of 5


  Observation that most orally administered drugs are relatively small and moderately lipophilic molecules
• Physicochemical properties


  • Doxorubicin (mw = 534, H-donors = 7, H-acceptors = 12, Log P = -1.7)
  • Acyclovir (mw = 225, H-donors = 4, H-acceptors = 8, Log P = -1.0)
• Drug metabolism


  • Phase I (oxidation, reduction, hydrolysis)
  • Phase II (glucuronidation, sulphation, acetylation, amino acid conjugation, glutathione conjugation)
  • Excretion
• Oral dosing parameters

  • C_max = maximum concentration
  • T_max = time to achieve C max
  • AUC = area under concentration-time curve
• T max is independent of dose; determined by rate constants for absorption and elimination
• At C max, rate of absorption equals rate of elimination; net concentration change is zero
• AUC is a measure of the total exposure to a drug
• Drug effects


  • At level of the cell
  • At the level of the organ / system
  • At the level of the organism
  • At the level of society
• Many drugs mimic (or block) the action of endogenous molecules (e.g. neurotransmitters, hormones )
• Drugs act at specific sites; receptors, ion channels, enzymes, transporters (all of which are proteins)
• How drugs act

  • Drugs are typically small chemical molecules
  • Drug molecules exert a chemical influence on constituents of cells to produce a pharmacological response
  • Drug molecules must get close enough to cellular constituents in order that they can interact chemically
  • This interaction leads to an alteration in molecular / cellular function
  • Drug molecules must "bind" to particular constituents of cells (known as DRUG TARGETS) in order to produce an effect
• Drug targets

  • Paul Ehrlich - "corpora non agunt nisi fixata" ("A drug will not work unless it is bound")
  • The vast majority of drugs bind directly to cellular constituents; most drug targets are proteins (with some exceptions)
• Why we have receptors

  • Primarily for the purpose of cell-to-cell communication
  • 
    
  • Neurotransmission (e.g. nerve to nerve; nerve to muscle )​
  • Effects of chemical mediators in bloodstream (e.g. adrenaline on heart )​
  • Hormone and growth factor signalling (e.g. action of insulin on muscle )  ​
• What is a receptor


  • A recognition molecule for a chemical mediator through which a response is transduced
  • Often a protein or complex of two or more proteins and often expressed on the surface of cells (with some exceptions)
• Lock and key concept - basic

  • Receptor is the lock, drug is the key
  • Some keys fit into the lock (i.e. Drug A) but others do not (i.e. Drug B)
  • Depends on chemical structure
  • Most locks (i.e. receptors) have a master key (an endogenous ligand)
• Basic receptor structure


  • Extracellular domain (contains ligand binding sites)
  • Transmembrane domain (anchors protein in membrane)
  • Intracellular domain (interacts with effector mechanisms)
• Signal transduction (basic)

  • Signal: ligand arrives at receptor
  • Reception: ligand binds to receptor
  • Transduction: ligand-bound receptor changes conformation (i.e. shape change)
  • Response: change in conformation leads to some form of intracellular response
• Receptors - basic terminology

  • Ligand: any chemical that binds to a receptor
  • Agonist: a drug that binds to a specific site on a receptor, mimics the effect of the endogenous ligand for that site
  • Antagonist: a drug that binds to a specific site on a receptor, blocks the effect of the endogenous ligand (same or different binding site as ligand)
• Lock and key concept - more advanced

  • Agonist: fits into the lock, mimics the action of the key, can be used to pick the lock and activate the receptor
  • Antagonist: also fits into the lock, gets stuck and prevents opening of the lock (i.e. activation of the receptor) by either endogenous ligand or agonist
• What do agonists do?

  • Agonists bind to receptors and activate them
  • Agonists possess both affinity and efficacy