Antagonism

• The antagonist reduces the affinity and/or intrinsic efficacy of the agonist
• Antagonists include competitive antagonists, insurmountable antagonists and physiological antagonists
• Competitive Antagonists bind reversibly to the same site as the agonist on a receptor
• The affinity of a competitive antagonist can be determined by its effect on the concentration-response curve of the agonist
• Schild Plots give a straight line
• Dose ratio increases linearly with competitive antagonist concentration
• Each agonist curve at one antagonist concentration gives a point on the Schild plot
• If competitive antagonism:

  • Slope = 1
  • X-axis intercept gives a measure of affinity (KB) and potency (pA2)
• Antagonist affinity is the same as potency since they do not elicit a physiological response
• Characteristics of Competitive Antagonist Dose-Response Curve:

  Parallel, right shifted, attains the same max response
• pA2 must be independent of the agonist because we would expect the same antagonist response from a different agonist
• Insurmountable Antagonism includes irreversible and some forms of allosteric antagonism
• Insurmountable antagonism involves a reduction in the amount of functional receptors available to agonists
• Irreversible antagonism

  • Antagonist binds irreversibly (covalently) or with very slow disassociation
• Insurmountable allosteric antagonism

  • Antagonist binds to a different (allosteric) site from the agonist and reduces receptor activation (intrinsic efficiacy) and agonist binding (affinity)
• Allosteric antagonism

  • Antagonist binds to a different site from the agonist and reduces agonist binding (affinity) without affecting receptor activation (intrinsic efficacy)
• Physiological/functional antagonism

  • Agonists with opposing effects on the same tissue
• Partial antagonism

  • Drug doesn't produce 100% max response even at 100% receptor occupancy
• Chemical antagonism

  • Two substances combine to form an inactive compound