pharmacodynamics-2

• Pharmacodynamics


  The study of the biochemical and physiological effects of drugs and their mechanisms of action
• Stimulus


  The ability of a drug to initiate a response from a receptor
• Efficacy


  The capacity of a drug to initiate a stimulus from one receptor, and thus relates the number of receptors bound to produce a response
• Spare receptors

  The extra receptors that need not be occupied to produce a maximal response
• Receptor reserve

  The increased sensitivity to ligands due to the presence of spare receptors
• Intrinsic efficacy


  A measure of the ability of a drug to stabilise the receptor active state and provide stimulus
• Full agonist


  A drug that produces the maximal response of the system, with an intrinsic activity of 1
• Partial agonist


  A drug that produces a submaximal response of the system, with an intrinsic activity >0 but <1
• Inverse agonist


  A drug that decreases the elevated basal activity of a system, with an intrinsic activity less than 0
• Antagonist


  A drug with an intrinsic activity of 0 that opposes the effects of agonists
• Conformational selection


  The molecular mechanism underlying efficacy, where a ligand binds to and stabilises a particular receptor conformation
• Efficacy (e) and stimulus (S)


  1. Agonist occupies receptor

  2. Provides stimulus (S)

  3. Stimulus is related to tissue response

  4. Efficacy (e) is the ability to provide stimulus once receptors are occupied
• Efficacy (e)


  Can have a positive value (agonist), zero (antagonist), or negative value (inverse agonist)
• Efficacy (e) and EC50


  • When e is low (partial agonist), EC50 can be approximated by Kd (affinity) alone
  • As e increases, maximal possible response increases until maximum is attained
  • If e is very high, EC50 < Kd, shifting the concentration-response curve to the left
• Receptor upregulation and downregulation

  Increase or decrease in receptor numbers in response to various stimuli, affecting drug responsiveness
• Efficacy is dependent on both the nature of the drug and the nature of the tissue
• Intrinsic efficacy

  A measure of the ability of a drug to provide stimulus that is independent of receptor number
• Rate theory


  Stimulus is provided by the initial event of occupation, but does not continue with further occupation
• Desensitisation


  Decreased stimulus over time due to decreased rate of receptor occupation as receptors become occupied
• Tachyphylaxis


  Decreased stimulus over time due to decreased rate of receptor occupation as receptors become occupied
• Rate Theory vs Occupation Theory

  1. Occupation theory: stimulus generated throughout receptor occupancy

  2. Rate theory: stimulus only from initial occupation event

  3. High efficacy agonists have slow off-rate constants (occupation theory) or high off-rate constants (rate theory)
• Types of antagonism


  • Chemical
  • Physiological
  • Pharmacokinetic
  • Pharmacological
• Pharmacological antagonists


  Bind to receptors without eliciting a response, competing with agonists for the same receptor
• Antagonist potency


  Depends on the affinity of the antagonist for the target protein, measured as the equilibrium dissociation constant
• Allosteric antagonism


  Agonist and antagonist bind at separate sites, interaction through conformational change
• Orthosteric antagonism


  Antagonist binds at the same site as the agonist, precluding agonist binding
• Competitive antagonism


  Effects are surmountable, increasing agonist concentration can overcome antagonism
• Non-competitive antagonism


  Effects are insurmountable, antagonist decreases the total number of available receptors