Exam 1: Dose Response Relationship

Question 1

Dose-Response

Relationships

Answer 1

How a drug concentration relates to a drug effect.

Need to know drug target.

Need to know how drug interacting with target elicits effect.

Question 2

Drug Targets

Answer 2

Drug must interact with a molecular target to elicit physiological/therapeutic response.

Question 3

Drug Binding

Answer 3

Drugs exert effects by binding to specific site on a target.

Ligand (L) can bind reversibly to receptor (R).

Question 4

Dissociation constant

( K_d )

Answer 4

K_d = concentration at which half of the receptors are occupied by the drug.

[R_o] = total # of receptors = [R] + [LR]

When [L] = Kd ⇒ [LR]/[R_o] = 0.5

K_d determines the affinity of a drug for a receptor.

Question 5

Concentration Dependent

Effects

Answer 5

Assumption:

Drug response ∝ [LR]

E = effect of drug

[L] = drug concentration

EC₅₀ = concentration at which a half-max effect obtained

Question 6

Graded Dose-Effect

Curves

Answer 6

Continuous function curves describing magnitude of response as a function of drug concentration.

E_max = max effect observed for specific response in specific cell, tissue, organ, or organism.

EC₅₀ = dose required for half-maximal response

Question 7

E_max is the measure of a drug’s…

Answer 7

efficacy

Question 8

EC₅₀ is a measure of a drug’s…

Answer 8

potency

(EC₅₀ may or may not equal K_d)

Question 9

Drug A vs Drug B

Graded Dose-Effect Curve

Answer 9

Drug A is more potent than Drug B ⇒ EC₅₀

Both have the same efficacy ⇒ E_max

Question 10

Drug-Receptor

Interactions

Answer 10

A functional response requires conformational change of a receptor:

Inactive (R) ⇒ active (R*)

1st equilibrium is drug binding ⇒ potency

2nd equilibrium is activation of the receptor ⇒ efficacy

Question 11

Compounds that bind and promote a conformational change to an active receptor are called…

Answer 11

agonists

Question 12

Compounds that bind to the receptor but do not promote a conformational change are called…

Answer 12

antagonists

Question 13

Physiological Antagonists

Answer 13

Activation of an opposing physiological mechanism to reduce an undesirable response or state.

Ex. Sudafed vasoconstricts vessels of nasal mucosa

Conteracts vasodilation by histamine

Does not affect histamine release or interact with histamine receptor

Question 14

Pharmacological Antagonists

Answer 14

Compound that interacts directly with the target of an endogenous ligand.

Ex. Allegra binds histamine H₁ receptor

Prevents histamine from binding

Question 15

Competitive Antagonists

Answer 15

• Binds reversibly to the active site of a receptor
  
  • Does not induce a conformation change / receptor activation
    
    • Efficacy = 0
• Interferes with binding of agonist to its receptor
  
  • Reduces potency of agonist ⇒ EC₅₀ higher
  • No effect on maximal efficacy ⇒ E_max unchanged
    
    • Can be outcompeted by ↑ [agonist]
• Net effect ⇒ shift dose-response curve to higher concentrations
• Examples:
  
  • Metoprolol ⇒ β₁-adrenergic receptor competitive antagonist
  • Prazosin ⇒ α₁-adrenergic receptor competitive antagonist
  • Lovastatin ⇒ HMG-CoA reductase competitive antagonist

Question 16

Non-competitive Antagonists

Answer 16

• Binds either:
  
  • Irreversibly to active site
    
    • Cannot be outcompeted w/ ↑ [agonist]
  • Reversibly to allosteric site
    
    • ↓ receptor activation even when agonist bound to active site
• Maximum effect of agonist reduced without changing midpoint of dose-resonse curve
  
  • Decreases efficacy ⇒ ↓ E_max
  • EC₅₀ unchanged
• Example:
  
  • Aspirin irreversibly binds COX-1 active site
  • Ketamine reversibly binds NMDA allosteric site

Question 17

Partial Agonists

Answer 17

Binds to the active site of the receptor but cannot elicit a maximal response, even when receptor fully occupied.

• Lower efficacy than full agonists ⇒ lower E_max
• Partial agonist will ↓ effect of full agonist
  
  • Looks like a competitive antagonist

Question 18

Partial Agonists

as a

Competitive Antagonist

Answer 18

At max [partial agonist] ⇒ see reduction of activity equal to efficacy of partial agonist.

Acts like a competitive antagonist w/ built-in safety margin.

An overdose will not completely reduce activity.

Question 19

Inverse Agonists

Answer 19

Inhibits the constitutive activity of an unoccupied receptor

• R* form always on ⇒ constitutive activation
• Deactivates receptors that are active in the absence of agonists
  
  • A competitive antagonist would have no effect in this situation
  • No agonists are there to compete with
• Ex. inverse agonists for cannabinoid CB₁ receptors
  
  • Reduces appetite

Question 20

Spare Receptors

Answer 20

Max effect obtained at a lower dose than required for receptor saturation.

EC₅₀ < K_d

• Mostly due to signal transduction cascade e.g. amplification
• Ex. Epi binds β-adrenergic receptor
  
  • Many adenylate cyclase activated
    
    • Lots of cAMP produced
      
      • Many PKA activated
        
        • Etc.

Question 21

Quantal Dose-Response

Relationships

Answer 21

• Determine % of subjects who achieve a specified criterion at a certain dose
  
  • 10 mmHg dec. in BP
  • Survivial @ 60 days s/p MI
• Yes/No definition ⇒ quantal response
• Effect seen at a range of doses ⇒ normal curve

Question 22

ED₅₀

Answer 22

ED₅₀ = median effective dose to produce a therapeutic response

Question 23

TD₅₀

Answer 23

TD₅₀ = median effective dose to produce a toxic response

Question 24

LD₅₀

Answer 24

LD₅₀ = median dose estimated to kill subjects

(Based on animal studies)

Question 25

Therapeutic Index

Answer 25

Therapeutic index = (TD₅₀/ED₅₀)

The greater the number, the better the relative margin of safety in a population.

(The larger the “therapeutic window”)

Ex. Digoxin has a very small therapeutic index e.g. difference between an effective and toxic dose is very small.

Question 26

Margin of Safety

Answer 26

Margin of safety = LD₁/ED₉₉

ED₉₉ ⇒ dose that gives the desired response in the entire population

LD₁ ⇒ dose that is lethal to the most sensitive 1% of the population

Question 27

Agonist vs Antagonist

Summary

Answer 27