Week 10

• Pharmacodynamics


  Understanding what the drug does to the body
• Pharmacodynamics


  • Describes and quantifies the relationship between drug concentration and drug effect
  • Unbound drug concentration in plasma is in equilibrium with unbound drug concentration at the site of action
  • The intensity of therapeutic effect and toxic effects of most drugs is dependant in free drug concentration at the side of action
• Pharmacokinetics


  Describes the relationship between the drug dose and the concentration of drug in the plasma and at drug receptor sites over time
• Pharmacodynamics


  Describes the relationship between drug concentration in the plasma and at drug receptor sites and the drug effect
• Linking pharmacokinetic and pharmacodynamic knowledge


  Allows the prediction of drug effect over time under a given drug dosing regimen
• Targets for drug action


  • Interaction with molecules in the organism
  • Receptors
  • Enzymes
  • Ion channels
  • Carrier molecules
  • Chelation and/or neutralization reaction
  • Physical effects
  • Antimicrobials
• Receptors


  • Protein molecules that have complex three-dimensional structures
  • Have pockets that can be occupied by a ligand
  • Ligands are small molecules that bind to the receptors
  • The ligand may activate or inactivate the receptor
  • Examples of ligands include hormones, neurotransmitters, inflammatory mediators or drugs
  • When the ligand interacts or binds to the receptor it can initiate a chain of intracellular events, called a signal transduction, to produce an effect
• Types of receptors


  • Ligand-gated ion channels
  • G-protein-coupled receptors
  • Kinase-linked and related receptors
  • Intracellular receptors
• Ligand-gated ion channels


  • Rapid action (milliseconds)
  • Extracellular receptors that are associated with an ion channel
  • Binding of a ligand to the receptor modulates the opening and closing or conductance of the ion channel
  • Receptors of this type of control the fastest synaptic events in the nervous system
  • Several drugs act by mimicking or blocking the actions of endogenous ligands that regulate the conductance of ion channels
  • General anaesthetics for example work on ligan-gated ion channels
• 1. protein-coupled receptors


  • G-protein-coupled receptors are membrane receptors that are linked to guanosine triphosphate (GTP) binding protein which is involved in the initiation and transduction of the cell signal
  • Binding of an extracellular ligand to the receptor triggers activation of G protein
  • The activated G protein then changes the activity of an effector element, usually an enzyme or ion channel
  • This leads to activation of cell signalling
  • g-protein coupled receptors have slow signal transduction that takes seconds to minutes
• Kinase-linked and related receptors


  • Kinase-linked receptors have a very slow response that takes minutes to hours
  • Kinase-linked and related receptors are transmembrane receptors
  • Binding of an extracellular ligand causes enzyme activity on the intracellular side
  • Enzyme activity leads to phosphorylation of tyrosine on key signalling molecules
  • This then leads to activation of cell signalling
• Intracellular receptors


  • Intracellular receptors have a very slow response that takes hours
  • Intracellular receptors can be activated by ligands which are sufficiently lipid-soluble to cross the cell membrane
  • The activated receptor is then transported to the nucleus and modulates gene transcription and translation
  • Effects are produced as a result of altered protein synthesis
  • The onset of action od rugs acting on intracellular receptors is delayed but the duration of action may be long
  • Many hormones act at intracellular receptors to produce long-term changes in genetic expression of various proteins in the body
• Drug-receptor interactions


  • Drugs interact with a receptor which has a structural "recognition" with part(s) of the drug molecule. This can activate a second messenger system producing a biochemical/physiological effect
  • The strength of the chemical bonds between the ligand and receptor determines the degree of affinity of ligand to receptor
  • The interaction is normally reversible, meaning the ligand can associate and disassociate with the receptor and compete with other ligands for that site. The interaction may be irreversible is the binding id via covalent bonds
• Properties of receptors


  • Receptors are sensitive - Only a small amount of drug/ligand is required to activate the receptor - as the receptor has a natural signal amplification system
  • Receptors are selective - Only certain drugs/ligands can activate the receptor, only compounds that have the correct molecular size, shape and electric charge to fir the receptor will bind at the binding site
  • Receptors are specific - The response following receptor activation is independent of the drug/ligand involved. Therefore, compounds may activate the same receptor and produce similar therapeutic effects
• Types of receptor ligands


  • Agonists (or full agonists)
  • Partial agonists
  • Antagonists
  • Inverse agonists (full or partial)
• Agonists


  Produce a maximal response comparable to endogenous ligands
• Partial agonists


  Produce a sub-maximal response, a partial agonists can compete with a full agonist, preventing it from producing a maximum response
• Antagonists


  Do not activate secondary messenger systems; they block or reduce the ability of an agonist to activate the receptor
• Inverse agonists


  Produce an opposite response to that of agonists
• Concentration-Effect Relationship


  • Generally, a higher drug concentration at a receptor site leads to a greater drug effect
  • There will be a concentration at which the maximum number of receptors are occupied and increasing the drug concentration beyond this point has no additional effect
  • Very high concentrations of drug may actually force interactions with other, off-target, receptors, which could lead to unwanted side effects
• Concentration-effect relationships


  • The interaction of a drug with a receptor involves it binding to the receptor in the same structurally specific way that a substrate binds to the active site of an enzyme
  • The concentration-effect relationship of a drug can be described by the same equation and similar parameters as those used in the Michaelis-Menten model of enzyme kinetics
• Michaelis-Menten model of enzyme kinetics


  V = (Vmax x C)/(Km + C)
• Concentration effects


  1. E = (Emax x C)/(EC50 + C)

  2. Drug effect (E ) can increase with increasing drug concentration (C )

  3. At higher drug concentrations the number of receptors available to interact with drug molecules starts to become saturated, and the effect starts to approach a maximum effect (Emax)

  4. At Emax it does not matter how many more drug molecules are present the effect will no longer increase, it plateaus out

  5. EC50 is the drug concentration associated with half the maximum effect
• Concentration-effect: Emax model


  • With increasing drug concentration the effect increases, up to a maximum effect
  • At low drug concentrations, increasing the concentration results in a rapid rise in effect
  • At higher drug concentrations most receptors are nor occupied and the effect no longer increases at such a rapid pate, it starts to plateau and head to an Emax value
  • Emax is the theoretical maximum effect
• Parameters of the Emax model


  • E = E0 + [(Emax x C)/(EC50 +C)]
  • E is the effect or the clinical response to a drug
  • E0 is the effect at baseline, where there is no drug
  • Emax is the maximum possible effect
  • EC50 is the drug concentration at 50% of Emax
  • C is the drug concentration
  • Enet = E - E0
  • E0 does not need to be included in the Emax model equation, as the disease process being treated does not have a baseline effect associated with it
  • Including E0 allows consideration of the fact that there may already be an effect within the system prior to commencing the drug
• EC50 properties and Potency


  • EC50 is a concentration term, it is the concentration at half of the maximum effect
  • The higher the EC50 the more molecules are needed to elicit 50% of the maximum effect
  • EC50 is a measure of the affinity of a drug for a given receptor
  • Potency is the concentration (EC50) or dose (ED) of a drug required to produce 50% of that drugs maximal effect
  • The lower the EC50, the more potent a drug
  • The higher the EC50 the less potent a drug
• Emax properties and Efficacy


  • Emax is a measure of capacity of a drug for a given receptor
  • Drug does not by default produce one standard unit of response. When a drug occupies a receptor it may produce a complete response, or no response, or some partial response
  • Emax is the maximum effect which can be expected from a drug when all receptors are occupied, meaning that once this magnitude of effect is achieved, giving an increasingly higher dose of the drug will not produce an increase in the magnitude of effect
  • Emax cannot be directly observed as it occurs when drug concentration is infinite
  • Efficacy is the maximum effect which can be expected from a drug, when this magnitude is reached, increasing the dose will not produce a greater magnitude of effect
• Concentration-effect curve (potency)


  Measure of the potency of a drug's effect
• Drugs with different potency

  • Higher potency means you need less of the drug to achieve the same response as a drug with a lower potency
• Concentration-effect curve (efficacy)


  Measure of the magnitude of a drug's effect
• Full agonist


  Has better efficacy than a partial agonist
• Partial agonist


  Has lesser efficacy than a full agonist
• Sigmoid Emax model


  Some drugs have a steeper relationship between drug concentration and effect than described by the Emax model
• Sigmoid Emax model


  • Steeper relationships can be described by the sigmoid Emax model
  • The sigmoid Emax model has similar parameterisation as the Emax model but it has a new parameter called the Hill coefficient
  • The Hill coefficient (gamma) describes the steepness of the concentration-response curve
  • This steepness is function of the drug molecule and the particular receptor system it is activating
• Sigmoid Emax model


  1. E = E0 + [(Emax x C^y)/(EC50^y + C^y)]

  2. E is the effect

  3. E0 os the effect at baseline

  4. Emax is the maximum possible effect

  5. EC50 is the drug concentration causing 50% of Emax

  6. C is the drug concentration

  7. Y is the shape or steepness factor - the Hill coefficient
• Note that the Emax model = Sigmoid Emax model when y = 1
• Hill coefficient (gamma)


  • Addition of a gamma value allows for an empirically description of the rate at which a pharmacological effect changes as a function of drug concentration
  • The Hill coefficient (gamma) is a power function that has been put in the concentration terms, but not the effect terms
• Changing the gamma value


  Provides new models to describe the shape of the concentration-effect relationship of a drug
• In theory, an "all or nothing" concentration-effect relationship may be observed when the Hill coefficient is very large. Where you go from having no drug effect to full drug effect with only a negligible increase in drug concentration
• PK-PD relationship


  Relationship between pharmacokinetics (drug concentration) and pharmacodynamics (drug effect)