PHC5005 Chap.7 Agonists, Antagonists and Concentration-Response
Agonists, Antagonists and Concentration-Response
Two steps to a response
A response needs two things from a drug: it must first fit and occupy its receptor, then switch it on. The course names the two abilities separately. Affinity is the ability to bind, quantified by the equilibrium dissociation constant. Efficacy is the ability to produce a response from the target once bound; it is graded, and it depends on the drug, the target and the tissue.
Clinical efficacy, how well a treatment achieves its therapeutic aim, is a different idea and should not be confused with drug efficacy.
Kinds of agonist
Full agonists drive the system to its ceiling.
Partial agonists cannot reach that maximum even at saturating concentrations; they bind tightly yet activate less, which the course expresses as intrinsic activity, the ratio of their maximal response to a full agonist's. Inverse agonists reduce basal responses by suppressing constitutive receptor activity, and the course classifies naloxone and naltrexone as partial inverse agonists at mu opioid receptors.
Biased agonists preferentially activate some signalling pathways over others at the same receptor. Agonists may bind the orthosteric site used by the endogenous ligand or an allosteric site elsewhere.
Concentration-response relationships
As concentration rises, response increases from a threshold to a maximum.
On a log scale the graded curve is sigmoid, with a steep middle where small concentration changes cause large changes in effect and a flat top where large changes do little. The Emax model describes it: effect equals Emax times concentration divided by the sum of concentration and EC50. EC50, the concentration giving half the maximal effect, measures potency; Emax measures efficacy.
Potency is inversely proportional to EC50, and efficacy proportional to Emax.
Antagonism
Antagonists have zero efficacy and block agonist action.
The course distinguishes receptor antagonism, where two ligands compete at the same receptor, from chemical antagonism, where drugs combine in solution, physiological antagonism, where opposing effects arise through different mechanisms, and pharmacokinetic antagonism, where one drug alters the disposition of another.
At the receptor, competitive antagonists are reversible and surmountable, shifting the agonist curve to the right without lowering its maximum; non-competitive antagonists are irreversible and insurmountable and lower the maximum.
Allosteric modulators can raise or lower potency, efficacy or both.
Applying it to patients
The tutorial uses an opioid overdose treated with naloxone and followed by buprenorphine to practise these distinctions, asks students to match drugs to dose-response curves, and introduces spare receptors, the unoccupied receptors that remain once a maximal response has been reached.
What this chapter covers
- 01
Affinity and efficacy as separate properties
- 02
Full, partial, inverse and biased agonists
- 03
Graded concentration-response and dose-response curves
- 04
The Emax model, EC50 as potency and Emax as efficacy
- 05
Receptor, chemical, physiological and pharmacokinetic antagonism
- 06
Competitive against non-competitive antagonism and allosteric modulation
- 07
Spare receptors and the opioid overdose tutorial case
Worked example · free
Identifying an antagonist from two curves
- 2Read what changed and what did not.
- 2Classify the antagonism.
- 1Calculate how much more agonist is needed for the same effect.
Key terms
- Agonist
- A ligand that binds and activates a receptor; a full agonist takes the system all the way to its ceiling.
- Partial Agonist
- An agonist that cannot produce the system's maximal response even at saturating concentrations.
- Inverse Agonist
- A ligand that reduces basal responses by suppressing constitutive or spontaneous receptor activity.
- Efficacy
- The ability of a drug to produce a response from its target, measured by Emax.
- Potency
- How much drug, by concentration or dose, is needed to reach a chosen size of effect, measured by EC50.
- EC50
- The concentration of a drug that produces 50 per cent of its maximal response.
- Competitive Antagonism
- Reversible, surmountable blockade that lowers agonist potency without lowering the agonist maximum.
- Spare Receptors
- Receptors that remain unoccupied once the maximal response has been reached.
- Intrinsic Activity
- The maximal response to a test agonist divided by the maximal response to a full agonist.
- Allosteric Modulator
- A ligand acting at an allosteric site that alters the potency or efficacy of an agonist.
Agonists, Antagonists and Concentration-Response FAQ
What is the difference between potency and efficacy?
Potency is about how much drug is needed: a more potent drug reaches a given effect at a lower concentration, so it has a lower EC50. Efficacy is about how much effect is possible: it is the maximal response, Emax. Two drugs can share one and differ in the other.
How can an antagonist bind strongly but do nothing?
Binding needs affinity and activation needs efficacy, and an antagonist has affinity with zero efficacy. It occupies the receptor, produces no response on its own, and prevents an agonist from activating the receptor while it is there.
Why does a competitive antagonist not lower the maximum response?
It competes reversibly for the same site, so raising the agonist concentration displaces it. At a high enough agonist concentration the receptors are again activated fully, and the curve reaches its original maximum, only further to the right.
What is physiological antagonism?
Two drugs acting through different mechanisms produce opposing effects at the tissue or organism level. The course's example is histamine stimulating acid secretion through receptors on parietal cells while omeprazole blocks the effect by inhibiting the proton pump.
Why can a partial agonist be a good medicine?
Clinical success depends on the therapeutic aim, not on reaching the system maximum. The course cites a widely used asthma bronchodilator that only weakly activates beta-2 receptors yet works well because airway smooth muscle expresses those receptors at high density.
Are spare receptors a waste?
No. Because a maximal response is reached with only a fraction of receptors occupied, a small amount of hormone or neurotransmitter can produce a full effect. The course describes this as economy of secretion achieved at the expense of making more receptors.
Exam move
Draw one agonist curve and then redraw it five times: more potent, less efficacious, with a competitive antagonist, with a non-competitive antagonist and with a positive allosteric modulator. Label which parameter moved each time. Most curve questions ask you to run that exercise in reverse.
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