2. Drug-receptor interactions. Dose-response relations, therapeutic concepts Flashcards
At what threshold would the effect of a drug be seen?
When sufficient numbers of receptors are occupied we may see effect
The fraction of receptors in each state are dependent on…
Dissociation constant Kd

- Concentration of ligand at which 50% of available receptors are occupied*
- Lower Kd indicates a tighter drug-receptor interaction (high affinity)*
Pharmacodynamics of a drug
Relationship between dose of drug and organism’s response to that drug
Graded dose-response curve
Demonstrates effect of a drug as a function of its dose
Max drug-receptor binding occurs when…
[LR] (cc of ligand-receptor complexes)
=
[Ro] (cc of receptors)
or [LR]/[Ro]=1
EC50
Potency of drug (cc at which drug elicits 50% of its max effect)
Emax
Efficacy (max response produced by a drug)
Potency & efficacy relationship
Not intrinsically related, a drug can be extremely potent but have little efficacy & vice versa

Quantal dose-response relationship
Describes cc of a drug that produces a given effect in a population
- Goal is to generalise a result to a population rather than examine grade of effect of different drug doses on a single individual
ED50
Dose that produces therapeutic response in 50% of population

TD50
Toxic dose in 50% of the population
LD50
Death in 50% of the population
Agonist
Drugs that bind to its receptor and favour active receptor conformation
- More potent drugs are those that have a higher affinity for their receptors
- More efficacious drugs are those drugs that cause a higher proportion of receptors to be activated
Partial agonist
Binds to a receptor at its active site but produces only a partial response
Because partial and full agonists bind to the same site on a receptor…
A partial agonist can reduce response produced by a full agonist
(Competetive agonist)
Inverse agonist
- The receptor must have a basal level activity in the absence of any ligand
- Decreases activity below basal level
Antagonist
Drug that prevents activation of receptor by the agonist
- Can bind to active/allosteric site of receptor for agonist
- Reversible/irreversible
Competetive antagonist
Reduces the potency of the agonist
Non-competitive antagonist
Reduces efficacy of agonist
Chemical non-receptor antagonist
Inactivate an agonist before it has the opportunity to act, by chemical neutralisation
Physiological non-receptor antagonist
Cause a physiological effect opposite to that induced by an agonist, by blocking or activating a receptor
Therapeutic window
Range of doses of a drug that elicits a therapeutic response, without unacceptable adverse effects in a population
- Can be quantified by therapeutic index

Therapeutic index =
[LD50]/[ED50]
- Provides a single number that quantifies the relatively safety margin
- Large TI = Large/wide therapeutic window, TI = 10
- Small TI = Small/narrow therapeutic window, TI = 5
What is shown?

Continuous dose-response curve
What is shown?

Quantal dose-response curves
Effects on the population
Affinity
The degree to which a drug tends to combine with a receptor
Efficacy
The desire to produce a successful result

Full agonist: Heroin and others

Partial agonist - Buprenorphine
Title the figure

Occupancy model
Title the figure

Two-state model

Full agonist

Partial agonist

Neutral antagonist

Inverse agonist
Give an example of inverse agonists
Antihistamines

Full agonist

Partial Agonist

Partial agonist
Examples of competitive antagonists
- Morphine
- Benzodiazepines
- MACh
Give example of noncompetitive antagonists
- Ketamine (on NDMA receptors)
When looking at a dose-response curve, a drug is not safe if…
The LD50 crosses with the ED50

Compare:
- Which is more potent, butorphanol or morphine?
- Which is more effective, butorphanol or morphine?
- Butorphanol
- Morphine
Full agonist: Efficacy + affinity
High efficacy + affinity
Full antagonist: Efficacy + affinity
High affinity; no efficacy
Partial agonist: Efficacy + affinity
High affinity; partial activation of receptor
Inverse agonist: Example
Antihistamine
Reverses the function of the agonist