MDG5204 Chap.7 Dose-Response, Agonism and Antagonism
Dose-Response, Agonism and Antagonism
Binding follows the law of mass action
The course treats drug-receptor binding as a reversible reaction whose rate depends on the concentrations of drug and receptor. At equilibrium, the equilibrium dissociation constant, KD, is the concentration that occupies half the receptors, and affinity is inversely related to it.
Binding alone is not enough: to produce a response, a drug must both occupy the receptor and activate it.
That second ability is efficacy, and it is distinct from clinical efficacy, which describes how well a treatment achieves its therapeutic goal.
Kinds of agonist and antagonist
A full agonist produces the maximal response the system can give; a partial agonist cannot, however high its concentration, because its intrinsic activity is lower despite high affinity; an inverse agonist reduces constitutive receptor activity below baseline; and a biased agonist favours one signalling pathway over another at the same receptor.
An antagonist has zero efficacy and works only by preventing an agonist from acting.
The course sorts antagonism into four types: receptor antagonism at the binding site, chemical antagonism in solution, physiological antagonism through opposing mechanisms, and pharmacokinetic antagonism through reduced absorption or increased elimination.
Reading concentration-response curves
Plotted against log concentration, a graded response curve rises from a threshold to a maximum.
EC50, the concentration giving half the maximal response, measures potency; Emax, the maximal response, measures efficacy. The Emax model describes the curve mathematically and shows that the effect changes fastest around the EC50 and saturates near the top.
A competitive antagonist shifts the curve to the right without lowering the maximum, while a non-competitive antagonist lowers the maximum. Allosteric modulators act away from the agonist site and can change potency, efficacy or both.
From individuals to populations
For all-or-none responses the course uses quantal curves, plotting the percentage of a population that responds at each dose.
ED50, TD50 and LD50 are the doses that produce the effect, toxicity or death in half the population, and the therapeutic index is TD50 divided by ED50.
The chapter ends with why responses change over time and between people: hysteresis, desensitisation, tolerance, down-regulation, spare receptors, and pharmacodynamic, pharmacokinetic, disease and environmental variation.
What this chapter covers
- 01
Law of mass action, KD and affinity
- 02
Occupancy against activation: efficacy and intrinsic activity
- 03
Full, partial, inverse and biased agonists
- 04
EC50 and Emax on graded concentration-response curves
- 05
Receptor, chemical, physiological and pharmacokinetic antagonism
- 06
Quantal curves, ED50, TD50, LD50 and the therapeutic index
Worked example · free
Telling competitive from non-competitive antagonism on a graph
- 2Classify X from its effect on EC50 and Emax.
- 2Classify Y from its effect on EC50 and Emax.
- 2Give one course example of each.
Key terms
- Affinity
- The ability of a drug to bind its target, quantified by the equilibrium dissociation constant.
- Efficacy
- The ability of a bound drug to produce a response from its target.
- Potency
- The amount of drug needed for a given effect, usually measured as the EC50.
- Inverse Agonist
- A ligand that suppresses constitutive receptor activity and lowers the basal response.
- Allosteric Modulator
- A ligand binding away from the agonist site that changes the agonist's potency or efficacy.
- Quantal Response
- An all-or-none response whose frequency in a population varies with dose.
- Down-Regulation
- A loss of receptors from the cell surface after prolonged agonist exposure.
Dose-Response, Agonism and Antagonism FAQ
Can a drug have high affinity but low efficacy?
Yes. A partial agonist binds strongly, with high affinity, but activates the receptor only weakly, so it cannot reach the full response of the system. An antagonist is the extreme case: it can bind with high affinity while having no efficacy at all.
Why is a large therapeutic index reassuring?
It means the dose that is toxic to half a population is many times the dose that is effective in half, so ordinary variation between patients is unlikely to push someone into toxicity. Drugs with a small index, such as warfarin, leave little room and are usually monitored.
What does hysteresis tell you about a drug?
It shows that the effect lags behind the plasma concentration. An anticlockwise loop points to delayed access to the site of action or slow receptor kinetics, so the timing of a blood level does not directly tell you the size of the effect at that moment.
Why do some drugs lose their effect with repeated use?
Repeated or continuous agonist exposure can desensitise receptors temporarily, most rapidly as tachyphylaxis, reduce receptor numbers by internalisation, which is down-regulation, or produce tolerance, in which larger doses are needed for the same effect after prolonged use.
Exam move
Sketch three curves from memory, a potent full agonist, a less potent full agonist and a partial agonist, then add a competitive and a non-competitive antagonist to copies of the first. Being able to draw the shift is faster in an examination than describing it.
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