Pharmacology, Medicinal Chemistry, and Toxicology
Receptor pharmacology
Master the vocabulary of affinity, intrinsic activity, potency, and efficacy. Full agonists have both affinity and full intrinsic activity; partial agonists have affinity but submaximal efficacy; competitive antagonists have affinity and zero efficacy; inverse agonists reduce constitutive activity. On dose-response curves, a competitive antagonist shifts the agonist curve right without lowering Emax, while a noncompetitive antagonist lowers Emax. Potency is measured by EC50 or Kd; efficacy by Emax.
Medicinal chemistry and metabolism
Know the pharmacophore concept, structure-activity relationships, bioisosteres, prodrugs, and stereochemistry. Ionization and pKa determine absorption and distribution; a drug must be sufficiently lipid-soluble to cross membranes but sufficiently soluble to dissolve. Phase I reactions (oxidation, reduction, hydrolysis) often introduce or expose functional groups; phase II reactions (glucuronidation, sulfation, acetylation, methylation, glutathione conjugation) increase water solubility. CYP induction lowers drug levels; CYP inhibition raises them. Prodrugs require metabolic activation, so inhibitors of that activation can reduce efficacy.
Toxicology
Recognize classic toxidromes: anticholinergic (dry, flushed, tachycardic, delirium), cholinergic (SLUDGE/DUMBELS), opioid (miosis, respiratory depression), sympathomimetic, and serotonin syndrome. Know antidotes: N-acetylcysteine for acetaminophen, naloxone for opioids, flumazenil for benzodiazepines (caution), sodium bicarbonate for salicylates, fomepizole or ethanol for methanol/ethylene glycol, and chelators for heavy metals. Zero-order drugs (ethanol, phenytoin, salicylate at high doses) do not have a constant half-life.
Rule of thumb
Affinity drives potency; intrinsic activity drives efficacy. If a question asks whether Emax changes, ask whether the antagonist can be overcome by more agonist.
Worked example
A drug has EC50 = 10 nM and Emax = 100%. A competitive antagonist shifts EC50 to 100 nM but Emax remains 100%; a noncompetitive antagonist leaves EC50 similar but reduces Emax to 40%.