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SOE 106: Affinity, Efficacy & Potency

Introduction

Regarding the interaction between a drug and a receptor…

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Question No. 2

Q: What is the law of mass action and how can you represent it graphically for a drug-receptor complex?

Answer No. 2

  • Drug-receptor interaction is explained by the 'law of mass action':
    • Proposes that the rate of binding is directly proportional to the product of the concentrations of the reactants
  • Can be demonstrated by the equation:
  •  

[D] + [R] \underset{K_{on}}{\stackrel{K_{off}}{\rightleftharpoons}} [DR]

[D] is drug
[R] is receptor
[D-R] is drug–receptor complex
Kon is rate of forward reaction (assocation rate constant)
Koff is rate of backward reaction (dissociation rate constant)

Question No. 3

Q: How do you define affinity and how is it described?

Answer No. 3

Term
Definition
Description
Affinity
A measure of quantity of drug needed to bind to receptors (how avidly a drug binds)
  • Drugs of high affinity bind to a critical number of receptors at low concentration compared with rugs of low affinity which require a high concentration to bind to a critical number of receptors
  • Affinity of a drug is described by it's KD

Question No. 4

Q: How is the KD defined?

Answer No. 4

  • KD is the uquilibrium dissociation constant describing the relationship between association and dissociation rates
  • It can also be described as:
    The drug concentration at which 50% of the maximum receptor population is occupied, usually expressed in units of mmol/L

Question No. 5

Q: What is the KD used for?

Answer No. 5

  • The KD is a physiochemical constant - it the same for a given receptor and drug combination in any tissue, in any species
  • It can therefore be used:
    • To quantitatively compare the affinity of different drugs on the same receptor
    • To identify an unknown receptor

Question No. 6

Q: What is efficacy and how is it described?

Answer No. 6

Term
Definition
Description
Efficacy
(Intrinsic Activity)
A measure of the magnitude of the effect that a drug-receptor system produces
  • Can be described using graded or quantal responses
  • Graded response
    • Value between 0 - 100% given depending on the effect on a particular system
    • The value of 100% represents maximal effect of a drug-receptor complex (Emax) irrespective of drug concentration
  • Quantal response:
    • Value between 0 - 100% is given depending on the proportion of a specific population in which effect is produced
    • Efficacy forms the y-axis in a dose-response curve (efficacy vs dose)

Question No. 7

Q: When discussing efficacy and potency what are graded and quantal responses?

Answer No. 7

Can be measured by assessing graded or quantum response:

  •  
Graded Response
  • Measures the efficacy of a receptor-effector in a particular system (e.g. tissue, animal or patient)
  • Measures effect on a continuous scale
  • Used to plot drug concentration vs. response on a graded dose-response curve
  • Examples of graded response include: effect of GTN on arterial pressure, streptomycin on protein synthesis etc.
Quantal response
  • Measures the efficacy of a receptor-effector in a population, where the effect is binary on each individual (present or absent)
  • Measures effect on a percentile scale, describing the size of population in which the effect is seen
  • Used to plot drug dose vs outcome occurrence on a quantal dose-response curve
  • Examples include: effect of aspirin in reducing MI occurrence etc.

Question No. 8

Q: What is potency and how is it described?

Answer No. 8

Term
Definition
Description
Potency
A measure of the quantity of drug needed to produce maximal effect
  • Drugs of high potency produce an effect bind at low concentration compared with drugs of low potency which require a high concentration to bind to a critical number of receptors
  • Potency of a drug is described by it's ED50 or EC50 depending upon the use of graded or quantal response

Question No. 9

Q: Describe what is meant by EC50 and ED50?

Answer No. 9

Graded Response

EC50


(Median Effective Concentration)
The concentration of a drug that produces a specific response that is exactly halfway between baseline and maximum
Quantal Response

ED50


(Median Effective Dose)
The dose of a drug that induces a specific response in exactly 50% of the population who take it

Question No. 10

Q: How can we compare the potency of two different drugs?

Answer No. 10

  • Potency of a drug is described by it's ED50 or EC50 depending upon the use of graded or quantal response
  • EC50 / ED50 are best represented using a dose-response curve (efficacy vs dose)

Question No. 11

Q: Can you draw a quantal dose-response curve for an agonist? How would you describe the shape of the curve?

Answer No. 11

Description
  • The x-axis is labelled with drug dose (mg). It is linear in nature
  • The y-axis is labelled % of population
  • The curve is a rectangular hyperbola passing through the origin and demonstrates how fractional occupancy varies with concentration of drug
  • The graph is again identical to a binding curve except for the y-axis
  • ED50 can be demonstrated and is a marker of the potency of the specific drug

Question No. 12

Q: Can you draw a semi-log dose-response curve?

Answer No. 12

Description
  • The x-axis is labelled with drug dose (mg). It is logarithmic in nature with each point 10x greater than the previous
  • The y-axis is labelled with % of population responding
  • The curve sigmoid in shape with a linear middle portion and demonstrates how fractional occupancy varies with concentration of drug
  • The graph is identical to a log binding curve except for the axis labels
  • ED50 can be demonstrated and is a marker of the potency of the specific drug

Question No. 13

Q: What is the advantage of using a semi-log plot?

Answer No. 13

  • Has the advantages of:
    • Better assessment of the effects of low doses and for a wide range of doses on the same plot
    • Easier comparison of different drugs on the same plot

Question No. 14

Q: How would the curve for a drug with a lower potency compare to a drug with a higher potency?

Answer No. 14

Description
  • The graph is a log dose-response curve with x-axis as drug dose (mg) in a logarithmic nature, and the y-axis as % of population responding
  • The curves for each drug are sigmoid in nature
  • A drug with increased potency has a lower ED50, thus shifting the curve to the left
  • A drug with decreased potency has a higher ED50, thus shifting the curve to the right

Question No. 15

Q: What else would make the curve move to the right?

Answer No. 15

  • A similar right shift of the curve us seen with the addition of a competitive reversible antagonist:
Description
  • The graph is a log dose-response curve with log drug dose on the x-axis and % of maximal effect on the y-axis
  • A standard sigmoid curve represents a full agonist alone
  • A second curve to the right of the first curve can be drawn to show the effect of the addition of a competitive reversible inhibitor
    • The curve sits to the right due to decreased potency of the agonist in the presence of the antagonist
    • This can be demonstrated by plotting the ED50 for both curves

Question No. 16

Q: What is the relationship between occupancy, efficacy, affinity and potency?

Answer No. 16

  • Classical receptor theory suggests that the response seen will be proportional to the percentage of receptors occupied
    • In this situation when the relationship between receptor occupancy and response is linear
      • Occupancy is directly proportional to efficacy
      • Affinity is directly proportional to potency, with KD = EC50
    • If a simple dose-occupancy curve for a full agonist is plotted on the same axes as a dose–response curve they would be identical
  • However, this relationship usually does not bear true:
    • Receptor Reserves:
      • It is often the case that only 5–10% occupancy is needed to produce a full response
      • Indicates that ∼90% of receptors are not needed to elicit a maximum response and hence form the receptor reserve
      • Results in dose-response response lying to left of the binding curve in full agonist (EC50 less than KD)
    • Partial agonism:
      • Implied that at a full response can be produced with full receptor occupancy
      • For a partial agonist, even at 100% occupancy a full response (similar to the full agonist) cannot be produced
      • Spare receptors are not pooled or hidden; they are simply surplus to requirements

Question No. 17

Q: Besides the ED50 / EC50 which other markers of a drugs potency can be described?

Answer No. 17


TD50


(Median Toxic Dose)
The concentration of a drug that produces a specific response that is exactly halfway between baseline and maximum

LD50


(Median Lethal Dose)
The dose of a drug that induces a specific response in exactly 50% of the population who take it

Question No. 18

Q: What is the therapeutic index?

Answer No. 18

  • The therapeutic index is the ratio of the dose that produced toxicity to the dose that produces a clinically desired effect:

TI = \frac{TD_{50}}{ED_{50}}

  • It is a statement of the relative safety of a drug - the larger the TI, the safer the drug
  • In animal models, the LD50 may be used instead of the TD50 when calculating the therapeutic index

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