pharmacodynamics - receptor theory 1

• Pharmacokinetics


  The study of the movement of drugs within the body
• Receptor Theory


  The study of how drugs interact with receptors in the body
• Concept of receptors originated by John Langley in 1887
• Term "receptor" coined by Ehrlich in 1900
• Occupation theory


  Proposed by Clark in 1926, allows prediction of the relationship between drug concentration and response
• Agonist


  Any ligand, which when bound to its receptor, elicits an observable response (may be endogenous or exogenous)
• Antagonist


  Any ligand, that itself may not produce any response, which interferes with the response to an agonist
• Agonist Concentration-Response Relationships


  • There will be a graded response with an increase in drug concentration (or dose)
  • Can be plotted as a dose/concentration curve to show the relationship between doses (in vivo) or concentrations (in vitro) of a drug and pharmacologic effect
• Agonist Concentration-Response - example

  • Epinephrine (8 µg to 150 µg)
• Agonist Concentration-Response - example

  • Expressing the dosage on a semi-logarithmic scale allows a wide range of doses to be shown concisely and the maximum more easily observed
  • The responses are now characteristically sigmoidal in shape
  • Can now apply mathematical models to fully define the relationship
• In vivo it is assumed that the dosage of drug used provides a known concentration of drug at the target receptor, but this is not necessarily true, leading to the study of pharmacokinetics
• In vitro experimentation in which tissues are incubated in media mimicking true physiology in chambers of constant volume will remove variance in drug concentration and accurately link concentration to drug activity
• Potency


  The concentration of the drug needed to produce a defined response or effect
• EC50


  The concentration of agonist producing half of the maximal response to the same agonist
• pD2


  The negative logarithm of the molar concentration of the drug that produces half the maximal response to the drug (the EC50)
• Efficacy


  • The change in state of the drug target upon bind of the drug
  • Describes the way in which agonists vary in the response they produce even when they occupy the same number of receptors
• Intrinsic activity


  • The maximal response of the drug being studied may or may not equal the system maximal response
  • FULL AGONIST - drug produces the maximal response of the system, has an intrinsic activity of 1
  • PARTIAL AGONIST - drug produces submaximal response of the system, has an intrinsic activity >0 but <1
  • INVERSE AGONIST - some systems have elevated basal activity which can be decreased through drug action, intrinsic activity less than 0
  • ANTAGONIST - intrinsic activity of 0
• Drug targets are coupled to cell via biochemical reactions or signals

  • The reactions that link cell surface signalling to cytosolic responses are saturable
  • Low levels of stimulus cause the most change (amplification)
  • At high levels of stimulus, the system is maximally engaged and no further response can be elicited
  • The nature, capacity and sensitivity of the biochemical reactions linking stimulus and response vary from cell to cell, tissue to tissue (efficiency of coupling)
• Agonist effects result from the interplay of four factors


  • Two related to the drug: Affinity - the propensity of a drug molecule to associate closely with a target, Efficacy - the property of the drug that causes the target to change its behaviour once the drug is bound
  • Two related to the system: Target density, Target coupling efficiency
• Relative Potency


  When using drugs that bind to the same receptor in the same tissue, we can compare the potency of drugs directly as it depends only on the two drug factors: affinity and efficacy
• Affinity and Efficacy are unique properties of the drug-target interaction and are true for that target in all tissues in which it is expressed
• Agonist selectivity


  • An agonist may activate the specific biological target (solid arrows) or activate non-specific (off target) (dashed arrows)
  • Two methods to determine selectivity of agonism: Pharmacologic Selectivity Test - use of a specific antagonist for the target, Recombinant Selectivity Test - agonist effects in presence and absence of target
• Occupation Theory


  • There is a bimolecular, reversible interaction between drug (D) and receptor (R) leading to generation of drug-receptor complex (DR) in which binding of drug to receptor is an independent event
  • Response size (E) is related to the amount of drug-receptor complex (DR)
• Occupation theory remains the foundation of modern pharmacodynamics, but many ligand-receptor interactions are not bimolecular, not always reversible, not always independent, and response size is usually not linearly related to the proportion of occupied receptors
• Reversibility of drug-target interactions

  • Most ligand-receptor interactions involve the formation of a few (~3) low energy bonds (e.g. hydrogen bonds)
  • The energy of binding is low (~50-100 kJ/mol)
  • It is because of this low energy that these interactions are described as reversible or competitive
  • Some compounds bind to their receptors covalently in a much more energetic reaction, these are irreversible or non-competitive ligands (e.g. alkylating agents used as antineoplastic agents)
• Cooperativity of drug-target interactions

  • Many ligands interact with their receptors to form tri-molecular complexes
  • Ligand binding to a receptor and the ensuing biological response is often influenced by other receptors or the presence of ligand on the receptor
  • If the presence of ligand enhances further ligand binding, there is positive cooperativity (e.g. insulin receptor)
  • If the presence of ligand decreases further ligand binding, there is negative cooperativity (e.g. nAChR)
• Langmuir Adsorption Isotherm


  • A simple model of ligand binding originally designed to describe binding of chemicals to metal surfaces
  • The amount of chemical bound to surface is the product of: 1) Concentration of drug (µ), 2) Rate of binding (α), 3) Fraction of surface left for binding (1-ϴµ)
  • The amount of drug diffusing away is a product of: Amount already bound (ϴµ) multiplied by rate of dissociation (V1)
• Applying Langmuir Adsorption Isotherm to drug receptor interactions

  • Drug receptor interaction is generally reversible and obeys the law of mass action
  • The "rate of association" of the drug with the target (k+1) is driven by energy changes such that it is energetically favourable for the drug to bind (DR)
  • The drug also has a "rate of dissociation" from the receptor (K-1) which described the energy change when the molecule diffuses away from the receptor
  • Leads to an equilibrium whereby the rate of drug leaving will equal the rate of drug approaching and entering the binding pocket
• Equilibrium dissociation constant (Kd)

  • The ratio of k-1/k+1 determines the amount of drug bound to the receptor at any one time and becomes a measure of how well the drug binds to the receptor
  • The reciprocal of Kd is the affinity constant (affinity of drug for the target)
  • The smaller the Kd - the higher the affinity of the drug for its receptors
• Langmuir's isotherm


  • E = D / (D + Kd)
  • When the concentration of drug equals Kd, then the drug occupies 50 % of the receptor population
  • Kd is the concentration of ligand [D] required to occupy 50 % of receptors at equilibrium
  • The magnitude of Kd is inversely proportional to the affinity of the drug for the receptor
• Affinity - Example


  • Drug with Kd = 10-9 M occupies 50 % of receptors at a concentration 1/100 of that required by a drug with Kd = 10-7 M
  • The drug with Kd of 10-9 M has a higher affinity for the receptor than the drug with a Kd of 10-7 M
• EC50 of partial agonists


  • Can be used to estimate Kd, as when half of the receptors are occupied, [D] = Kd, and half of the maximal response is produced
  • Low EC50 indicates high affinity of binding
• Using a full agonist, maximal tissue response cannot be reliably equated with 100 % receptor occupation, and changes in cellular sensitivity to full agonists result in variation of EC50
• pD2


  • The negative logarithm of the molar concentration of the drug that produces half the maximal response to the drug (the EC50)
  • High values of pD2 indicate high affinity of binding