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