Session 6 Drug receptor interactions

• AFFINITY – a measure of the tendency of a drug to bind to a receptor.
• EFFICACY – a measure of the drug, having once bound to a receptor to activate it.
• Lower K(D) = higher affinity

  Higher K(D)= lower affinity
• Affinity + Efficacy = Potency
• AGONIST – a drug whose efficacy is such that it produces a maximal cell/tissue response when less than 100% of receptors are occupied.
• PARTIAL AGONIST – a reduced efficacy which means that even when 100% of receptors are occupied, there is only a sub-maximal response generated.
• Buprenorphine is a partial agonist at opioid receptors.
• Agonist binding site = Orthosteric binding site

  Other molecule binding site = Allosteric binding site
• Types of antagonism?

  • Irreversible
  • Chemical
  • Pharmacokinetic
  • Disruption of receptor-response linkage
  • Physiological
• when the antagonist binds but doesn’t dissociate or dissociates slowly from the receptor - irreversible competitive antagonism
• combination of substances in solution that results in the loss of effect of a drug – almost chelation - Chemical antagonist

  Example: Infliximab –sequesters TNF and is therefore anti-inflammatory.
• interference with absorption, metabolism or excretion by one drug on another - pharmacokinetic antagonist.

  Example: Phenytoin influences metabolism of warfarin.
• DISRUPTION OF RECEPTOR-RESPONSE LINKAGE – downstream inhibition can be described as non-competitive antagonism.Example: Ca2+ channel blockers e.g. nifedipine, non-selectively block smooth muscle contraction induced by all drugs that couple to these channels.
• PHYSIOLOGICAL – vague definition of the actions of two drugs with opposing action in the body

  Example: Histamine promotes H+ release from parietal cells, omeprazole inhibits this by acting as a PPI.
• Tolerance - a reduction in response over hours to weeks. Refractoriness - a loss of therapeutic efficacy.

  Resistance - the loss of efficacy of chemotherapeutic agents.
• Why can't dose-response curves be used to determine the affinity of agonist drug?

  Because responses produced are not always directly proportional to receptor occupancy – maximal response may be produced at <100% occupancy.
• EC50 abbreviates for 'half maximal effective concentration'. In a pharmacological context, this can be the concentration of a drug that is necessary to cause half of the maximum possible effect.
• Significance of partial agonists?

  • they generate a response
  • in the presence of a full agonist, they may reduce the response of that full agonist.