Exam 1: Dose Response Relationship Flashcards
Dose-Response
Relationships
How a drug concentration relates to a drug effect.
Need to know drug target.
Need to know how drug interacting with target elicits effect.
Drug Targets
Drug must interact with a molecular target to elicit physiological/therapeutic response.

Drug Binding
Drugs exert effects by binding to specific site on a target.
Ligand (L) can bind reversibly to receptor (R).

Dissociation constant
( Kd )
Kd = concentration at which half of the receptors are occupied by the drug.
[Ro] = total # of receptors = [R] + [LR]
When [L] = Kd ⇒ [LR]/[Ro] = 0.5
Kd determines the affinity of a drug for a receptor.

Concentration Dependent
Effects
Assumption:
Drug response ∝ [LR]
E = effect of drug
[L] = drug concentration
EC50 = concentration at which a half-max effect obtained

Graded Dose-Effect
Curves
Continuous function curves describing magnitude of response as a function of drug concentration.
Emax = max effect observed for specific response in specific cell, tissue, organ, or organism.
EC50 = dose required for half-maximal response

Emax is the measure of a drug’s…
efficacy
EC50 is a measure of a drug’s…
potency
(EC50 may or may not equal Kd)
Drug A vs Drug B
Graded Dose-Effect Curve
Drug A is more potent than Drug B ⇒ EC50
Both have the same efficacy ⇒ Emax

Drug-Receptor
Interactions
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

Compounds that bind and promote a conformational change to an active receptor are called…
agonists
Compounds that bind to the receptor but do not promote a conformational change are called…
antagonists
Physiological Antagonists
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
Pharmacological Antagonists
Compound that interacts directly with the target of an endogenous ligand.
Ex. Allegra binds histamine H1 receptor
Prevents histamine from binding
Competitive Antagonists
-
Binds reversibly to the active site of a receptor
- Does not induce a conformation change / receptor activation
- Efficacy = 0
- Does not induce a conformation change / receptor activation
- Interferes with binding of agonist to its receptor
- Reduces potency of agonist ⇒ EC50 higher
-
No effect on maximal efficacy ⇒ Emax 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

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

Partial Agonists
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 Emax
- Partial agonist will ↓ effect of full agonist
- Looks like a competitive antagonist

Partial Agonists
as a
Competitive Antagonist
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.

Inverse Agonists
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

Spare Receptors
Max effect obtained at a lower dose than required for receptor saturation.
EC50 < Kd
- 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.
- Many PKA activated
- Lots of cAMP produced
- Many adenylate cyclase activated

Quantal Dose-Response
Relationships
-
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

ED50
ED50 = median effective dose to produce a therapeutic response

TD50
TD50 = median effective dose to produce a toxic response

LD50
LD50 = median dose estimated to kill subjects
(Based on animal studies)

Therapeutic Index
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.

Margin of Safety
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

Agonist vs Antagonist
Summary
