3. Pharmacology
          3.1. Pharmacology principles
              3.1.2. Pharmacodynamics
 3.1.2.3. Dose-response relationship

Dose-response relationship

[RD5:Chp2]

=== Unfinished ===

To be added later:

More detail on therapeutic index, its disadvantages.

Therapeutic ratio

CVS/CNS toxicity ratio (esp in context of LA)

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Terminology

  • Agonist 
    = binds and activates the receptor
    * i.e. Efficacy is 1
  • Antagonist
    = binds to the receptor without causing activation
    * i.e. Efficacy is zero
  • Partial agonist
    = Drugs with intermediate level of efficacy, such that response is submaximal even with 100% receptor occupancy
  • Efficacy
    = The tendency of a drug to activate the receptors once it binds to the receptors
    * i.e. the height of the dose-response curve
  • Affinity
    = The tendency of a drug to bind to the receptors
    * i.e. relates to the slope of the dose-response curve
  • Potency
    = Can be defined as the dose that produce 50% of the maximal response
    = The lower the dose that is required to produce 50% of the maximal response, the more potent the drug is
    * i.e. relates to the horizontal position of the dose-response curve
  • Therapeutic index
    = LD50/ED50

Dose-response curve

Linear vs log scale

When response (% of max) is on y-axis and an agonist drug concentration is on x-axis

  • Graph is a rectangular hyperbola when the x-axis is in linear scale
  • Graph is sigmoid when the x-axis is in log scale

NB:

  • Approximately the log curve is linear between 20% - 80% maximal response
    * MCQ question

Full agonist vs partial agonist

  • Dose-response curve for partial agonists are shorter in height
    * i.e. lower in efficiency
  • Flatter slope and displacement to the right are not essential for the definition, but are common findings
  • A partial agonist may be more potent, as potent, or less potent than a full agonist

Agonist with antagonists

  • With competitive antagonist
    --> Dose-response curve is displaced to the right (same height and slope)
    --> Decreased potency only
  • With non-competitive antagonist
    --> Dose-response curve is displaced to the right
    --> With increasing dose of antagonist, the height is also reduced
    --> Decreased potency
    --> Followed by decreased efficacy with increased dose of non-competitive antagonist

Equations

  • Symbols: 
    * A = agonist
    * R = free receptors
    * AR = agonist-receptor complex
    * TR = total receptors
    * KA = Equilibrium constant
    * P = Proportion of receptor occupied (i.e. occupancy) = AR/(AR+R)
  • A + R <===> AR
  • KA = [A][R]/[AR]
  • Hill-Langmuir equation is:
    --> P = [AR]/[TR] = [A]/(KA+[A])
    * Not in ANZCA syllabus

 



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