Pharmacodynamics · signaling

Drug–receptor interplay

Affinity · efficacy · antagonism · intracellular & membrane signaling

⚖️ Affinity · potency · efficacy

  • Affinity – ability of a drug to bind to its receptor
    • Inversely related to Kd (lower Kd = higher affinity)
    • Analogous to Km in enzyme kinetics
    • Read from dose–response curves: curve closer to y‑axis → higher affinity (parallel curves)
  • Potency – dose required to produce a given effect (usually 50% of max)
    • Comparative only for drugs with same mechanism (parallel slopes)
    • More potent = curve leftward; less potent = rightward
  • Efficacy – maximal effect a drug can achieve (ceiling)
    • Analogous to Vmax in enzyme kinetics
    • Full agonists achieve 100% efficacy; partial agonists have lower ceiling
  • Affinity and potency are often confused: potency depends on affinity AND efficacy. A highly potent drug may have low efficacy.

🎯 Full vs partial agonists

  • Full agonist – produces maximal tissue response (100% efficacy)
  • Partial agonist – cannot produce full response even at saturation
    • Lower intrinsic activity; ceiling effect below 100%
    • Dual nature: can act as antagonist when co‑administered with a full agonist
  • Potency comparisons
    • Between two partial agonists: compare EC50 (leftward = more potent)
    • Between full and partial: no single potency ranking; depends on response level
Full agonist → 100% effect ↔ Partial agonist → ceiling < 100% + full agonist ➜ antagonism
  • Partial agonists are useful when full agonism causes excessive effects (e.g., buprenorphine, aripiprazole).

🛡️ Antagonism & potentiation

  • Competitive antagonist
    • Binds reversibly to agonist binding site
    • Dose‑response curve shifts rightward in parallel (same maximal effect)
    • Overcome by increasing agonist concentration
  • Non‑competitive antagonist
    • Binds irreversibly or to allosteric site
    • Reduces efficacy (lower maximal response); curve may flatten
  • Potentiation – one drug enhances the effect of another (not via receptor binding)
  • Classic competitive antagonist: atropine (muscarinic), naloxone (opioid).

🧬 Intracellular receptors

  • Location – cytosol or nucleus
  • Ligands – lipophilic hormones (steroids, thyroid, vitamin D, retinoids)
  • Mechanism
    • Ligand binding → release of chaperone proteins
    • Receptor‑ligand complex translocates to nucleus
    • Binds to hormone response elements (HRE) → modulates gene transcription
  • Time course – onset slow (minutes to hours), duration prolonged
  • Examples
    • Glucocorticoid receptor: anti‑inflammatory gene expression
    • Estrogen / androgen receptors

⚡ Ion channel–linked receptors

  • Nicotinic ACh receptor – Na⁺/K⁺ channel
    • Located: ANS ganglia, NMJ, CNS
    • Targets: nicotine, choline esters, ganglion blockers, muscle relaxants
  • GABAA receptor – Cl⁻ channel
    • Modulated by benzodiazepines, barbiturates, anticonvulsants
    • Allosteric enhancement of inhibitory neurotransmission
  • No second messengers – rapid, millisecond responses

🔁 G‑protein–coupled receptors (GPCR)

  • Structure – 7 transmembrane domains; serpentine
  • Gs – stimulates adenylyl cyclase → ↑cAMP
    • β‑adrenergic, D1, glucagon, H2, prostacyclin
  • Gi – inhibits adenylyl cyclase → ↓cAMP
    • α₂‑adrenergic, M2, D2, opioid receptors
  • Gq – activates phospholipase C (PLC)
    • PLC → PIP₂ → IP₃ + DAG
    • IP₃ → Ca²⁺ release from SR
    • DAG + Ca²⁺ → protein kinase C (PKC) activation
    • Receptors: M1/M3, α₁, angiotensin II, serotonin (5‑HT2)
G-proteinEffectorSecond messengerExample receptors
GsAdenylyl cyclase ↑cAMP ↑β₁, β₂, D₁
GiAdenylyl cyclase ↓cAMP ↓α₂, M₂, D₂
GqPLC ↑IP₃, DAG, Ca²⁺α₁, M₁/M₃, 5‑HT₂

⚙️ Enzyme / transporter targets

  • Enzyme inhibitors
    • ACE inhibitors, COX inhibitors, HMG‑CoA reductase, PDE inhibitors
    • Acetylcholinesterase, carbonic anhydrase, reverse transcriptase, etc.
  • Transporter inhibitors
    • Reuptake blockers: SSRIs, SNRIs, dopamine transporter inhibitors
    • Na⁺/K⁺‑ATPase inhibitors (digoxin)
  • Receptor‑enzymes (transmembrane)
    • Insulin receptor, EGFR, PDGFR – tyrosine kinase domains
    • Ligand binding → dimerization → autophosphorylation → downstream signaling
    • Guanylyl cyclase–linked: ANP receptor → cGMP ↑
  • Tyrosine kinase inhibitors: imatinib (specific), sorafenib (multikinase).

📡 Cytokine receptors · JAK‑STAT

  • Receptors – erythropoietin, growth hormone, interferons
  • Mechanism
    • Ligand binding → receptor dimerization
    • Associated Janus kinases (JAKs) phosphorylate each other
    • JAKs phosphorylate STAT transcription factors
    • STATs dimerize → translocate to nucleus → alter gene expression
  • Clinical relevance – cytokine therapies, JAK inhibitors (tofacitinib)