GP 07 - Pharmacodynamics 2

Question 1

Define the following values: E_max, EC₅₀, B_max, K_D, ED₅₀, TD₅₀, LD₅₀, TI, therapeutic window.

Answer 1

• E_max - maximal response produced by a drug
• EC₅₀ - [drug] that produces 50% E_max
• B_max - the total concentration of receptor sites
• K_D - the equilibrium dissociation constant which is the [drug] required to occupy half of all receptors
• ED₅₀ - the median effective dose, which is the [drug] at which 50% of people exhibit the specified effect
• TD₅₀ - the median toxic dose, which is the [drug] required to produce a particular toxic effect in 50% of animals
• LD₅₀ - the median lethal dose, which is the [drug] required to cause death in 50% of animals
• TI - the therapeutic index, a ratio of the TD₅₀ or LD₅₀ to the ED₅₀, which is an estimate of the safety of a drug
• Therapetic Window - the [drug] range between the minimum effective therapeutic dose and the minimum toxic dose

Question 2

What is a dose-response curve? How many types are there? What are they used for?

Answer 2

• Dose response curves are graphs relating drug concentration (dose) to drug effect (response). There are two major types:
  
  • Graded - compares drug dose to the magnitude of drug effect. These curves are used to find the E_max and EC₅₀ of a drug
  • Quantal - compares drug dose to the percentage of the population that experience a desired drug effect. These curves are used to find the ED₅₀, TD₅₀, LD₅₀, and the therapeutic index/window.

Question 3

What is the graded dose response equation?

Answer 3

Question 4

What is a binding curve and what is it used for?

Answer 4

Binding curves are graphs relating [drug] to the percentage or receptors bound. They are used to determine K_D and B_max.

Question 5

What is the binding curve equation?

Answer 5

Question 6

What value is used to characterize a receptors affinity for a drug?

Answer 6

K_D

If low, binding affinity is high

Question 7

How do you determine if there are more receptors than necessary to elicit an Emax

Answer 7

The EC₅₀ will be lower than the K_D

Question 8

Define and differentiate drug efficacy from potency. How are these values determined?

Answer 8

Efficacy is the magnitude of the response a drug produces. Maximal efficacy is determined by qunatifying the effect when the drug is at E_max

Potency is a measure of the [drug] necessary to produce a desired effect. This is usually the EC₅₀ of a drug

Question 9

Compare and contrast the efficacy and potency of these drugs.

Answer 9

Efficacy - A = B and C is lower

Potency - A > B > C

Question 10

What is more clinically relevant, a drugs efficacy or its potency? Why?

Answer 10

Efficacy, because it usually makes little difference whether a patient has to take 1mg or 10mg in order to achieve a certain level of effect

Question 11

What is the effect of an antagonist in the absence of an agonist?

Answer 11

Nothing

Question 12

List and define the types of antagonism

Answer 12

• Receptor Antagonism
  
  • Competitive - competes with agonist at site of agonist binding
  • Noncompetitive (aka - allosteric) - binds to receptor at a site different from the agonist binding site and reduces the action of the agonist
• Nonreceptor Antagonism
  
  • Functional
    
    • Indirect - binds to a molecule in the signal pathway
    • Physiological - opposes effect via another receptor
  • Chemical - reacts with agonist to form an inactive product

Question 13

How do the different types of antagonism effect E_max and EC₅₀?

Answer 13

• Reversible Competitive - increases EC₅₀
• Irreversible Competitive - decreases E_max
• Noncompetitive - decreases E_max

We don’t need to know how the other types of antagonism affect these values

Question 14

What is the key difference between an irreversible competitive antagonist and a noncompetitive antagonist?

Answer 14

Irreversible competitive antagonists bind at the agonist binding site

Noncompetitive antagonists do not

Question 15

What is an inverse agonist?

Answer 15

An agonist that reverses the constitutive activity of a receptor (receptor activity in the absence of an agonist)

Question 16

What is drug selectivity? How is it quantified? When is a drug considered to be selective and why?

Answer 16

All drugs bind more than one receptor. A drug is said to be selective if its affinity for its primary receptor (the one that elicits the therapeutic effects) is at least 10 times stronger than its affinity for its secondary receptor (the one that elicits the adverse effects). This is because at a 10 fold difference, the primary receptors K_D can be reached with minimal activation of the secondary receptor.

Selectivity is measured by comparing K_D or EC₅₀ values for the different receptors.

Question 17

When does drug selectivity become clinically insignificant?

Answer 17

When it gets above a 100 fold difference

Question 18

Define the following terms:

• Desensitisation
• Tolerance
• Refractoriness
• Drug Resistance
• Tachyphylaxis

Answer 18

• Desensitisation = Tachyphylaxis - when the effect of a drug gradually diminshes when given continuously or repeatedly, usually developing in a few minutes
• Tolerance - desensitisation that takes days or weeks to develop
• Refractoriness - term sometimes used in relation to the loss of therapeutic efficacy
• Drug Resistance - loss of effectiveness of antimicrobial or antitumor drugs

Question 19

What are the mechanisms leading to desensitization that we need to know?

Answer 19

• Change in receptors (e.g. - phosphorylation)
• Receptor internalization
• Mediator exhaustion
• Increased metabolic degradation of drug
• Physiological adaptation (opposition by a homeostatic response)

Question 20

How is the TI of a drug calculated?

Answer 20

By one of the following:

• TI = TD₅₀/ED₅₀

or

• TI = LD₅₀/ED₅₀

The TI of a drug in humans is almost never known with real precision

Question 21

Answer 21

A