STEPTRACKERPHARMACOLOGY | PHARMACODYNAMICS | HIGH-YIELD REVIEW

Dose-Response & Receptors

What a drug does at its target and how strongly — read every dose-response graph by asking whether the curve moved sideways (potency) or down (efficacy).

FOCUS ON

Potency = dose needed for a given effect (EC₅₀); lower EC₅₀ = more potent; curve shifts left. Efficacy = maximal effect (Emax); curve height. Competitive antagonist: binds the same site reversibly → curve shifts right, same Emax (surmountable): ↓ potency. Noncompetitive antagonist (allosteric or irreversible): ↓ Emax, can't be overcome: ↓ efficacy. Partial agonist: lower Emax than full agonist even at full occupancy; with a full agonist present it acts as an antagonist (buprenorphine, pindolol, aripiprazole). Inverse agonist: lowers constitutive activity. Therapeutic index = TD₅₀ ÷ ED₅₀ (safety); narrow index → monitor levels. Receptor types: ligand-gated ion channels (fast), GPCRs (Gs, Gi, Gq), enzyme-linked (tyrosine kinase, JAK-STAT), intracellular (steroid, thyroid). Tolerance, tachyphylaxis and up/down-regulation.

CONCEPT

DEFINITION

GRAPH EFFECT

EXAMPLE

Potency

Concentration giving 50% of max effect (EC₅₀)

Left = more potent

Fentanyl more potent than morphine

Efficacy

Maximal response (Emax), independent of potency

Higher plateau

Loop diuretics more efficacious than thiazides

Full agonist

Produces maximal receptor response

Reaches Emax

Morphine at μ receptors

Partial agonist

Lower intrinsic activity; competes with full agonist

Lower plateau; alone it agonizes, with full agonist it antagonizes

Buprenorphine (precipitates withdrawal), pindolol, varenicline, aripiprazole

Competitive antagonist

Reversible binding at the agonist site

Right shift, same Emax (surmountable)

Naloxone, atropine, propranolol, cimetidine

Noncompetitive antagonist

Binds an allosteric site or binds irreversibly

↓ Emax, not surmountable

Phenoxybenzamine (irreversible α), ketamine at NMDA

Inverse agonist

Reduces baseline receptor activity

Below baseline

Some antihistamines, β-blockers

Physiologic antagonist

Opposite effect via a different receptor

—

Epinephrine vs histamine in anaphylaxis · glucagon vs insulin

Chemical antagonist

Binds the drug itself

—

Protamine for heparin, chelators, digoxin Fab

Therapeutic index

TD₅₀ ÷ ED₅₀ (or LD₅₀ ÷ ED₅₀) · therapeutic window = range between minimum effective and toxic levels

Wide = safe

Narrow: warfarin, digoxin, lithium, theophylline, aminoglycosides, phenytoin

Spare receptors

Max effect before all receptors are occupied

EC₅₀ < Kd

Irreversible antagonist first shifts right, then lowers Emax

Tolerance · tachyphylaxis

Gradual ↓ response · rapid ↓ after repeated doses

—

Opioids, benzodiazepines · nitrates (nitrate-free interval), ephedrine

Up/down-regulation

Receptor number changes with chronic exposure

—

Abrupt β-blocker stop → rebound tachycardia, angina

Picture it — reading dose-response curves

Competitive antagonistSame binding site, reversible: more agonist overcomes it, so the curve shifts right (↓ potency) with the same maximum.

Noncompetitive antagonistAllosteric or irreversible: extra agonist can't restore the response, so the maximum falls (↓ efficacy).

Partial agonistEven at full occupancy it produces a smaller maximal effect; given with a full agonist it lowers the response.

Therapeutic indexThe gap between the dose that helps half of patients (ED₅₀) and the dose that harms half (TD₅₀); a narrow gap needs level monitoring.

Schematic diagrams, not to scale.

Mechanism — G-protein receptors

Gs↑ adenylyl cyclase → ↑ cAMP → PKA

Gi↓ cAMP

GqPLC → IP₃ (↑ Ca²⁺) + DAG (PKC)

Gs: β1, β2, D1, H2, V2 · Gi: M2, α2, D2 · Gq: α1, M1, M3, H1, V1.

Reading curves

CHANGE

POTENCY

EFFICACY

Competitive antagonist

↓ (right shift)

Same

Noncompetitive antagonist

Same

↓

Partial agonist alone

Any

< full agonist

More potent agonist

↑ (left shift)

Same

How it's tested

COMMON CONFUSIONPotency is about dose; efficacy is about maximum. A more potent drug isn't necessarily better — a more efficacious one does more.

THE TRAPGiving buprenorphine to someone with full-agonist opioids on board precipitates withdrawal — it displaces them with weaker activity.

YOUR APPROACHCompare the curves: horizontal shift → potency (competitive); lowered top → efficacy (noncompetitive or partial agonist).

If you see… think…

Curve shifts right, same maximum → competitive antagonist

Lower maximum, can't be overcome → noncompetitive antagonist

Lower maximum alone, blocks full agonist → partial agonist

Withdrawal after buprenorphine in a heroin user → partial agonist displacement

EC₅₀ → potency

Emax → efficacy

TD₅₀ ÷ ED₅₀ → therapeutic index

Epinephrine reversing histamine effects → physiologic antagonism

Protamine neutralizing heparin → chemical antagonism

Diminishing response to nitrates → tachyphylaxis (nitrate-free interval)