PHA2022 Chap.1 Drug Targets, Receptors and Dose–Response

Drug Targets, Receptors and Dose–Response

Pharmacodynamics asks what a drug does to a biological system and how the measured response changes with concentration. Begin with the target: receptor, enzyme, transporter, ion channel or other molecule. Binding alone is not the final effect. Target engagement changes signalling, signalling interacts with cellular state, and the assay records one response at a defined time.

Every curve therefore belongs to a preparation, outcome and condition.

Agonists have affinity for a receptor and efficacy in activating it. Full and partial describe maximal response relative to the system, not whether a drug is strong in everyday language. An antagonist can bind without activating and reduce agonist action.

Competitive antagonism is surmountable in the simplified equilibrium model: more agonist can restore the maximum while the concentration–response curve shifts right. Non-competitive or irreversible effects may reduce the achievable maximum.

Potency concerns the concentration or dose needed for a specified effect. EC50 is the concentration giving half of that drug's maximal measured effect.

Efficacy concerns the achievable response in the system. A partial agonist can have a lower EC50 than a full agonist yet a lower maximum. Calling it more powerful confuses two dimensions and says nothing direct about therapeutic value, exposure or toxicity.

A common graded model is E = Emax × C/(EC50 + C). It describes a saturating relation under assumptions; it is not a universal law.

At low concentration, response can be sensitive to changes in C. Near the plateau, additional concentration produces little extra desired response while off-target or adverse effects may continue. Parameters depend on tissue, receptor reserve, endpoint and time.

Quantal responses classify individuals as reaching a defined outcome and generate proportions across dose.

ED50 and TD50 refer to the dose producing the specified effect or toxicity in half the studied population. They are not the same as a graded EC50. A therapeutic index can provide a rough ratio, but the clinical therapeutic window, severity of outcomes and monitoring matter more than one summary number.

Receptor reserve and signal amplification can separate occupancy from effect.

A full response may occur before all receptors are occupied, so the concentration producing half-maximal effect need not equal the binding affinity parameter. Desensitisation, internalisation and downstream feedback can shift response over time.

The phrase more receptors does not predict effect unless coupling and system state are known.

Worked comparison: Drug A reaches 50% of maximum at 1 micromolar and plateaus at 60 response units; Drug B reaches half of its own maximum at 10 micromolar and plateaus at 100 units. A is more potent in that assay, while B has greater efficacy.

If the needed therapeutic response is 80 units, A cannot achieve it there regardless of concentration. Safety still requires exposure and adverse-response data.

Experimental controls define whether a response can be attributed to the drug. Vehicle control addresses the solvent, baseline defines spontaneous activity, and a positive control shows the assay can respond.

Replicates estimate variability but technical repeats from one preparation do not create independent biological samples. Report concentration units, exposure time and normalisation so the curve can be interpreted and reproduced.

For the laboratory threshold component, show the raw-to-processed path, justify exclusions before seeing a preferred result, and distinguish observation from mechanism.

For quizzes and the exam, translate every potency question into horizontal position, every efficacy question into vertical maximum, and every antagonist question into a predicted curve change. Then state the clinical boundary.

Curve comparison should also report uncertainty. Parameter estimates can be correlated, and sparse concentrations near the top make Emax unstable.

Plot observations with variability, inspect residual pattern and compare models justified by mechanism. If the fitted EC50 lies outside the tested range, extra decimal places do not create information.

The conclusion should distinguish an observed shift from a precise receptor interpretation and state which additional concentrations or antagonist experiments would make the mechanism discriminating.

Finish every curve answer with the assay unit, parameter uncertainty and the new experiment that would distinguish the nearest rival mechanism.

What this chapter covers

• 01

  agonist

• 02

  EC50

• 03

  therapeutic window

• 04

  connect molecular target engagement to graded and quantal responses using potency, efficacy and uncertainty correctly

• 05

  A concentration–response curve describes the measured system; it does not by itself establish clinical dose, benefit or safety.

Compare potency and efficacy

Key terms

agonist

A ligand that binds a receptor and produces receptor activation with measurable efficacy.

EC50

The concentration producing half of a defined maximal effect in a specified system.

therapeutic window

The exposure range in which desired effects are expected without unacceptable toxicity for the defined use.

Drug Targets, Receptors and Dose–Response FAQ

Exam move

Retrieve the target or decision, trace concentration and time, work one changed case, then write the translational boundary.

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