Pharmacodynamics

• Drugs can be naturally occurring or synthetic.
• Drugs often mimic or block the action of our own signalling molecules
• Ligand gated ion channels

  • require ligand binding
  • typically pentameric
• G-protein coupled receptors

  • largest family
  • 7-TM domains
• Kinase-linked receptors

  • single membrane spanning domain
  • dimerisation
• Nuclear receptors

  • nuclear or cytosolic
  • ligands lipid soluble
  • act as transcription factors
• Drug specificity

  • drugs bind selectively to particular receptor types
  • no drug is 100% specific (only selective)
• Agonist drugs activate receptors
• Antagonist drugs block receptors and often inhibit endogenous agonist action
• Agonist drug action

  • drug binding (affinity)
  • receptor activation (efficacy)
• Drug effect is proportional to drug concentration. Agonist and antagonist drugs elicit observable effects.
• Relatively small change in drug concentration leads to big effect
• Full agonists elicit 100% effect of the endogenous agonist
• Partial agonists elicit < 100% effect
• Super agonists elicit > 100% endogenous effect
• Inverse agonists reduce basal receptor activity
• Drug activity

  A) full agonist

  B) partial agonist

  C) inverse agonist

  
• Agonist drug potency involves affinity + efficacy
• Relative drug potency is determined by drugs affinity and efficacy. Equipotent molar ration
• Antagonist potency only involves affinity
• Antagonist drugs inhibit receptor or downstream signalling pathway
• Often, not all receptors need to be occupied for maximum effect to be achieved (i.e. spare or reserve receptors)
• Usually because of amplication of signal, EC50 is much smaller than Kd
• Pharmacogenomics = genetic variability in the way drugs behave in the body.

  • pharmacokinetic - enzyme polymorphism
  • pharmacodynamic - receptor variants
• Desensitisation - a drug's effectiveness may decrease rapidly when given repeatedly or continuously
• Tolerance - decrease in a drug's effectiveness over days or weeks
• Resistance - adaptive changes, less effective
• Even when adjusted for age, weight, gender, disease etc. unpredictability still occurs in both pharmacokinetic and pharmacodynamic response
• Patient-controlled analgesia: Patient regulates dosing and if excessive becomes too drowsy to administer more drug. Dose size and lockout interval set to ensure time allowed for dose to work e.g. morphine 1mg bolus/ 5 minute lockout
• Whenever possible, administer drugs according to a measurable response and not a dosing schedule
• Easily measured clinical drug outcomes

  • terminating status epilepticus with lorazepam
  • providing analgesia with morphine
• Easily measured investigation drug outcomes

  • warfarin - INR
  • insulin - blood glucose
• Drug outcome may not be easily measured

  • long delay in seeing result
  • multi-factorial condition
  • examples
  • immunising against disease
  • preventing ischaemic heart disease
• • select correct drug
  • choose suitable route
  • start with appropriate dose schedule
  • monitor effect and adjust accordingly
  • be alert for unwanted effects