Drug 6

• endogenous agonists produce unwanted effects in many clinical conditions
• chemical antagonists 


  bind soluble agonists, decrease agonist binding to receptor and receptor activation = inhibit agonist induced effects
• 2 types of chemical antagonists

  1. monoclonal antibody - bind endogenous agonists
  2. soluble receptor - prevents agonist interaction with receptor
• monoclonal antibody example


  adalimumab (binds TNF)
• soluble receptor example


  etanercept - binds TNF
• monoclonal antibodies inhibit agonist-receptor interaction. Some bind to agonist and other bind to receptor
• monoclonal antibodies drug suffix

  -mab
• what is ritonavir 


  a CYP3A4 enhancer, so if a drug is given with it know it is metabolised by these enzymes
• competitive receptor antagonist


  compete with endogenous agonist for same binding site on the receptor, prevents receptor activation
• antagonist binding is reversible
• adrenaline


  released by exercise or stress, activates the B1 receptor on heart to increase HR and force of contraction (an agonist)
• metoprolol 


  a competitive receptor antagonist at B1 adrenoreceptor on heart, inhibit activity so doesn't get activitated by adrenaline and relief heart work to treat angina
• angina 


  insufficient blood supply to the heart due to narrowing of coronary arteries
• irreversible receptor antagonists 


  share a binding site on receptor with agonist and involves formation of a bond that is reversible or slowly reversible (covalent)
• effect of irreversible receptor antagonists

  less functional receptors that can be agonist bound and activated, decreased max effect of agonist
• name 2 irreversible receptor antagonists

  phenoxybenzamine and tiotropium
• phenoxybenzamine 


  irreversibly binds A1 adrenoreceptors forming covalent bond, is not used clinically
• tiotropium 


  slowly reversible antagonist at muscarinic Ach receptor, long duration of action is used to treat asthma and COPD
• allosteric antagonist 


  bind site on receptor that is not agonist binding site and produce conformational change in the receptor that changes agonist affinity for receptor
• NAM


  negative antagonist, decrease affinity or efficacy of agonist for receptor
• PAM


  drug binding increase affinity of receptor for agonist
• allosteric antagonist graph 


  as conc antagonist increases shifts right (need more agonist), max effect doesn't change but will stop shifting once all binding site saturated and have max effect
• maraviroc


  a NAM, decrease affinity of CCR5 on T cell surface for HIV1 viral particle by binding CCR5 receptor and changing shape. prevents interaction and entry of genetic material into host cell
• gefitinib 


  tyrosine kinase inhibitor used to treat non small advanced lung cancer
• how gefitinib works 


  binding to the ATP binding site, ATP binding is required for tyrosine phosphorylation which initiates intracellular signalling so it stops cell growth and proliferation
• functional/physiological antagonists 


  agonists that active different receptors to produce opposing effects within the same cell
• example of functional antagonism

  histamine and adrenaline
• histamine in anaphylactic reaction

  mast cells release, binds H1 receptors on airway smooth muscle = contraction and airway narrowing
• adrenaline from epipen function

  bind B2 adrenoreceptors on airway smooth muscle, muscle relaxation and airway opening