Pharmacology
Drug-Receptor Interaction
Pharmacodynamics — agonists, antagonists, and the dose-response curve
Pharmacodynamics is what the drug does to the body. Most drugs act on receptors — proteins (often GPCRs, ion channels, kinases, nuclear receptors) that transduce chemical signals. Agonists bind and activate (full, partial, inverse). Antagonists bind without activating, blocking endogenous ligands (competitive or non-competitive). Affinity is how tightly a drug binds (Kd); efficacy is how much response it produces (Emax). Therapeutic index = TD50/ED50; narrow indices (warfarin, digoxin, lithium) demand careful monitoring.
- Receptor typesGPCR, ion channel, kinase, nuclear
- AffinityKd — concentration for half-maximal binding
- PotencyEC50 — concentration for half-maximal response
- EfficacyEmax — maximum response
- Therapeutic indexTD50/ED50
- Narrow TI examplesWarfarin, digoxin, lithium
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Why pharmacodynamics matters
- Drug selection. Match receptor selectivity to disease — β1-selective metoprolol for asthmatic with HTN.
- Dose titration. Start low, go slow with elderly; start high in sepsis to ensure target attainment.
- Antidote design. Naloxone displaces opioids; flumazenil reverses benzos; protamine reverses heparin.
- Receptor desensitization. Drug holidays restore β-agonist efficacy; opioid rotation reduces tolerance.
- Genetic variation. CYP2D6 ultrarapid metabolizers convert codeine to dangerous morphine levels.
- Drug repurposing. Sildenafil (PDE5 inhibitor) — angina trial → erectile dysfunction → pulmonary hypertension.
- Adverse effects. Off-target binding explains anticholinergic side effects of TCAs and antipsychotics.
Common misconceptions
- Higher dose always gives more effect. Above Emax, only side effects increase.
- Affinity equals efficacy. A drug can bind tightly without activating (antagonist).
- "Natural" drugs have no receptors. Herbal compounds bind same targets — St. John's wort induces CYP3A4 strongly.
- Generic equals brand always. True for most; narrow TI drugs may differ slightly.
- Half-life determines duration of effect. For irreversible binders (aspirin, omeprazole), duration depends on enzyme/receptor turnover.
- Receptor downregulation is bad. Sometimes therapeutic — desensitization underlies tolerance and safety.
Frequently asked questions
What types of receptors exist?
G-protein coupled receptors (~30% of all drug targets) — beta-blockers, opioids, antihistamines. Ligand-gated ion channels — benzodiazepines on GABA-A. Voltage-gated channels — local anesthetics on Na, calcium channel blockers. Receptor tyrosine kinases — insulin, EGFR. Nuclear receptors (slow, gene transcription) — steroids, thyroid hormone, vitamin D. Enzyme-linked receptors. Transporters and enzymes count as targets too (PPIs on H/K ATPase; statins on HMG-CoA reductase).
Agonist versus antagonist?
Full agonist: maximal response (morphine on μ-opioid). Partial agonist: less than full response even at saturation (buprenorphine). Inverse agonist: stabilizes inactive receptor, reduces baseline activity. Competitive antagonist: binds same site as agonist; surmountable with higher dose (naloxone). Non-competitive antagonist: separate site or irreversible; insurmountable (aspirin acetylates COX).
How is dose-response measured?
Sigmoid log-dose vs response curve. EC50: dose for half-maximal effect (potency). Emax: ceiling response (efficacy). Curves shifted right with competitive antagonists (more agonist needed; same Emax). Non-competitive antagonists lower Emax (can't overcome). Spare receptors: tissues respond maximally before all receptors are bound — explains receptor reserve in heart, intestine.
What is therapeutic index?
TD50/ED50 — ratio of toxic dose to effective dose. Wide TI: penicillin (>100). Narrow TI: warfarin, digoxin, lithium, theophylline, phenytoin, aminoglycosides. Narrow TI drugs need plasma level monitoring (vancomycin trough, digoxin level), dose individualization, and pharmacist oversight. FDA classifies generics for narrow TI drugs more strictly.
What is tolerance and tachyphylaxis?
Tolerance: reduced response with repeated dosing. Mechanisms: receptor downregulation (β-receptors with chronic agonist), desensitization (uncoupling from G protein), enzyme induction (CYP3A4 with rifampin lowers many drug levels). Tachyphylaxis: rapid tolerance over hours to days (ephedrine — depletes norepinephrine stores). Cross-tolerance: between similar drugs (alcohol/benzodiazepines).
How do drugs reach receptors?
Pharmacokinetics — Absorption, Distribution, Metabolism, Elimination (ADME). Oral drugs face first-pass metabolism in liver. Distribution depends on lipophilicity, protein binding, tissue perfusion. Metabolism: phase I (CYP450 oxidation), phase II (conjugation). Elimination: renal (hydrophilic) or biliary (lipophilic conjugates). Half-life dictates dosing frequency; steady state in ~5 half-lives.
What about drug interactions?
Pharmacokinetic: CYP inhibitors raise levels (e.g., clarithromycin + statin → rhabdomyolysis); inducers lower levels (rifampin lowers OCP efficacy). Protein-binding displacement (warfarin + sulfonamides). Pharmacodynamic: additive (alcohol + benzos → respiratory depression); antagonistic (beta-blocker + albuterol). Always check P-glycoprotein and CYP3A4 substrates. QT-prolonging combinations cause torsades.