Chapter 3 · Module 1 of 4 · Pharmacodynamics

Drug-Receptor Interactions

Receptor families, binding affinity and the equilibrium dissociation constant, agonist types, and the three mechanisms of antagonism

The four receptor superfamilies differ fundamentally in signal transduction mechanism and response timescale: GPCRs operate through second messenger cascades (seconds to minutes), ligand-gated ion channels open directly on binding (milliseconds), enzyme-linked receptors activate phosphorylation cascades (minutes to hours), and nuclear receptors regulate gene transcription (hours to days)
Binding affinity is quantified by the equilibrium dissociation constant Kd — the drug concentration at which 50% of receptors are occupied; lower Kd means higher affinity; receptor occupancy follows a hyperbolic curve on a linear scale and sigmoidal curve on a log scale
Duration of receptor effect is governed by the dissociation rate (koff), not plasma drug levels — slow koff produces prolonged effect even after drug clearance, as exemplified by tiotropium vs. ipratropium at the muscarinic M3 receptor; irreversible binding (aspirin and cyclooxygenase) persists until new receptor protein is synthesized
Agonists are classified by efficacy: full agonists reach Emax, partial agonists plateau below Emax and act as functional antagonists in the presence of a full agonist, and inverse agonists suppress constitutive receptor activity below the basal baseline
Antagonism takes three mechanistic forms: competitive reversible (right shift of dose-response curve, Emax preserved, surmountable), irreversible (Emax depressed, duration set by receptor resynthesis), and non-competitive/allosteric (Emax depressed without right shift; positive allosteric modulators enhance agonist response)

Section 1 — The Four Receptor Families

Section 1

Receptor Classification — Structure, Signal, and Speed

Receptor Type 1

G Protein-Coupled Receptors

Seven-transmembrane structure
Signal via Gs, Gi, Gq proteins
Second messengers: cAMP, IP₃/DAG
Onset: seconds to minutes
Examples: beta-adrenergic, opioid, muscarinic receptors

Receptor Type 2

Ligand-Gated Ion Channels

Binding site and ion channel in same protein
Ion flux within milliseconds of binding
Fastest-acting receptor class
Onset: milliseconds
Examples: GABA-A, nicotinic acetylcholine, NMDA receptors

Receptor Type 3

Enzyme-Linked Receptors

Intracellular kinase domain
RTKs dimerize on activation
Activate phosphorylation cascades
Onset: minutes to hours
Examples: insulin receptor, EGFR; targeted by imatinib, trastuzumab

Receptor Type 4

Nuclear Receptors

Intracellular transcription factors
Lipophilic ligands cross cell membrane
Regulate gene transcription directly
Onset: hours to days
Examples: glucocorticoid, thyroid hormone, estrogen receptors

Section 2 — Drug-Receptor Binding and Affinity

Section 2

Affinity, Kd, Receptor Occupancy, and Dissociation Rate

Affinity and the Equilibrium Dissociation Constant

Kd = drug concentration at which 50% of receptors are occupied. Lower Kd = higher affinity. At a drug concentration equal to Kd, receptor occupancy is exactly 50%. As dose increases above Kd, occupancy approaches 100% asymptotically — hyperbolic on a linear scale, sigmoidal on a log-dose scale. Affinity determines how much drug is needed; it does not determine how large an effect that occupied receptor produces.

Dissociation Rate (koff) and Duration of Effect

Duration of receptor effect is governed by koff, not plasma drug levels. Slow koff = prolonged effect even after the drug has been cleared from plasma. Clinical example: tiotropium vs. ipratropium — both block the muscarinic M3 receptor, but tiotropium dissociates far more slowly, enabling once-daily dosing vs. multiple daily doses. Irreversible binding (aspirin acetylating COX): effect persists until new receptor protein is synthesized, regardless of drug plasma levels.

Section 3 — Agonists — Full, Partial, and Inverse

Section 3

Agonist Types and Dose-Response Behavior

Type	Effect at Receptor	Dose-Response Curve	Clinical Example
Full Agonist	Produces maximum system response (Emax)	Reaches Emax ceiling	Morphine (mu-opioid), epinephrine (adrenergic)
Partial Agonist	Submaximal response even at full receptor occupancy; ceiling below Emax	Curve plateaus below Emax of full agonist	Buprenorphine (mu-opioid), aripiprazole (dopamine D2)
Inverse Agonist	Suppresses constitutive receptor activity below basal level	Curve falls below zero-agonist baseline	Metoprolol, carvedilol at beta-1 adrenergic receptors

Partial Agonist Dual Behavior

Alone: net receptor activation (below full agonist ceiling). In the presence of a full agonist or high endogenous ligand tone: competes for the same receptors but delivers less signal per occupied receptor — functional antagonism. Buprenorphine can precipitate withdrawal in opioid-dependent patients if administered before the full agonist has dissociated from the receptor.

Section 4 — Antagonism

Section 4

Three Mechanisms of Antagonism

Antagonism Type 1

Competitive Reversible

Binds same site as agonist
Displaced by increasing agonist concentration
Parallel right shift of dose-response curve
Emax unchanged — surmountable
Examples: naloxone, beta-blockers, losartan

Antagonism Type 2

Irreversible

Covalent or near-covalent binding
Cannot be displaced by agonist at any concentration
Emax depressed — insurmountable
Duration set by receptor resynthesis, not drug clearance
Examples: phenoxybenzamine (alpha-adrenergic), aspirin (COX)

Antagonism Type 3

Non-Competitive / Allosteric

Binds site distinct from agonist binding site
Reduces receptor's ability to transduce signal
Emax depressed without right shift of curve
Positive allosteric modulators enhance agonist response
Example: benzodiazepines (positive allosteric modulator at GABA-A — require GABA co-presence)

Benzodiazepines vs. Barbiturates at the GABA-A Receptor

Benzodiazepines: positive allosteric modulators — enhance channel opening frequency in response to GABA but cannot open the channel without it. Built-in safety ceiling. Barbiturates: can open the GABA-A chloride channel directly at high doses, independent of GABA. No ceiling on CNS depression. This mechanistic difference explains the dramatically higher overdose lethality of barbiturates compared with benzodiazepines.

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