Chapter 3  ·  Module 1  ·  Pharmacodynamics

Drug-Receptor Interactions

Receptor families, binding affinity, agonists, and antagonists at a glance

The Four Receptor Families

Receptor type 1

G Protein-Coupled Receptors

  • Seven-transmembrane structure
  • Signal via Gs, Gi, Gq G proteins
  • Second messengers: cyclic adenosine monophosphate, inositol trisphosphate/diacylglycerol
  • Onset: seconds to minutes
  • Examples: beta-adrenergic, opioid, muscarinic receptors

Receptor type 2

Ligand-Gated Ion Channels

  • Binding site and channel in same protein
  • Ion flux within milliseconds
  • Fastest-acting receptor class
  • Onset: milliseconds
  • Examples: gamma-aminobutyric acid type A, nicotinic acetylcholine, N-methyl-D-aspartate receptors

Receptor type 3

Enzyme-Linked Receptors

  • Intracellular kinase domain
  • Receptor tyrosine kinases dimerize on activation
  • Phosphorylation cascade
  • Onset: minutes to hours
  • Examples: insulin receptor, epidermal growth factor receptor; targeted by imatinib, trastuzumab

Receptor type 4

Nuclear Receptors

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

Affinity, Kd, and Receptor Occupancy

Key Relationships

Kd = drug concentration at which 50% of receptors are occupied. Lower Kd = higher affinity. At drug concentration equal to Kd, occupancy is 50%. As dose increases above Kd, occupancy approaches 100% asymptotically — hyperbolic on a linear scale, sigmoidal on a log scale.

Dissociation Rate and Duration

Duration of receptor binding is set by the dissociation rate (koff), not just plasma drug levels. Slow koff = prolonged effect even after drug is cleared from plasma. Tiotropium vs. ipratropium: both block the muscarinic M3 receptor, but tiotropium dissociates far more slowly — once-daily dosing vs. multiple times daily. Irreversible binding (aspirin acetylating cyclooxygenase): effect lasts until new receptor protein is synthesized.

Agonist Types

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 Buprenorphine (mu-opioid), aripiprazole (dopamine D2)
Inverse agonist Suppresses constitutive receptor activity below basal level Curve goes below zero-agonist baseline Metoprolol, carvedilol (beta-1 adrenergic)

Partial Agonist Dual Behavior

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

Types 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
  • Emax depressed — insurmountable
  • Duration set by receptor resynthesis, not drug clearance
  • Examples: phenoxybenzamine (alpha-adrenergic), aspirin (cyclooxygenase)

Antagonism type 3

Non-Competitive / Allosteric

  • Binds site distinct from agonist site
  • Reduces ability of receptor to transduce signal
  • Emax depressed without right shift
  • Positive allosteric modulation enhances agonist response
  • Example: benzodiazepines (positive allosteric modulator at gamma-aminobutyric acid type A receptor — require gamma-aminobutyric acid co-presence)

Benzodiazepines vs. Barbiturates at the Gamma-Aminobutyric Acid Type A Receptor

Benzodiazepines: positive allosteric modulators — enhance channel opening frequency in response to gamma-aminobutyric acid but cannot open the channel without it. Built-in ceiling. Barbiturates: can open the gamma-aminobutyric acid type A chloride channel directly at high doses, independent of gamma-aminobutyric acid. No ceiling. Explains the dramatically higher overdose lethality of barbiturates.