Chapter 1 · Module 3 of 6 · General Principles
Drug targets, receptor pharmacology, agonism and antagonism, dose-response relationships, and tolerance — the molecular logic behind drug action
Section 1
Drug Targets — Receptor Superfamilies and Non-Receptor Targets
Superfamily 1
G Protein-Coupled Receptors (GPCRs)
Response: seconds – minutes
Seven transmembrane segments. Activation couples to G proteins triggering intracellular second messenger cascades. Largest drug target family. Examples: muscarinic, adrenergic, opioid, histamine receptors.
Superfamily 2
Ligand-Gated Ion Channels (LGICs)
Response: milliseconds
Binding opens an ion pore directly — no intermediary. Fastest receptor type; found at fast synapses. Examples: nicotinic acetylcholine receptor, GABA-A receptor, glutamate receptors.
Superfamily 3
Enzyme-Linked Receptors
Response: minutes – hours
Transmembrane protein with intracellular kinase domain. Ligand binding activates phosphorylation cascades. Examples: insulin receptor, growth factor receptors. Targeted by many tyrosine kinase inhibitor cancer drugs.
Superfamily 4
Nuclear Receptors
Response: hours – days
Intracellular transcription factors activated by lipophilic ligands. Regulate gene expression directly. Effect persists after drug leaves. Examples: glucocorticoid, thyroid hormone, sex steroid receptors.
Section 2
Agonist Types and Antagonist Mechanisms
Binds and produces the maximum possible response
High affinity and high efficacy. Examples: morphine at opioid receptors, epinephrine at adrenergic receptors.
Binds and activates but produces a submaximal response
Acts as a functional antagonist in the presence of a full agonist — competes for the same receptor while producing less effect. Example: buprenorphine at opioid receptors — ceiling effect on respiratory depression makes it safer in overdose.
Binds and reduces activity below the constitutive baseline
Only relevant when a receptor has constitutive (spontaneous) activity without a ligand. Produces the opposite effect to an agonist. Some drugs previously classified as antagonists are now recognized as inverse agonists.
Blocks the agonist site reversibly — effect is surmountable
Higher agonist concentrations overcome blockade. Shifts dose-response curve rightward; maximum response is preserved. Examples: naloxone (opioid), atropine (muscarinic), beta-blockers (beta-adrenergic).
Reduces maximum response — not surmountable by more agonist
Binds irreversibly or at a separate allosteric site. Adding more agonist cannot restore the maximum response. Example: phenoxybenzamine (irreversible alpha-adrenergic blocker).
Section 3
Potency, Efficacy, and the Therapeutic Index
Concept 1
Potency
The dose required to produce a given effect. More potent drugs work at lower doses. Measured by the ED₅₀ — the dose producing 50% of the maximum effect.
Read from the horizontal axis — left shift = more potent
Fentanyl is more potent than morphine: the same analgesic effect requires a far smaller dose. But both can produce the same maximum analgesia — potency says nothing about ceiling.
Concept 2
Efficacy
The maximum effect a drug can produce, regardless of dose. A partial agonist has lower efficacy than a full agonist at the same receptor.
Read from the vertical axis — higher plateau = more efficacious
Morphine has higher efficacy than codeine as an analgesic: morphine can control severe pain that codeine cannot, no matter how much codeine is given.
Wide Therapeutic Index
Large margin between effective and toxic dose
Considerable flexibility in dosing. Errors are less likely to cause serious harm. TI = TD₅₀ ÷ ED₅₀.
Examples: penicillins, most statins
Narrow Therapeutic Index
Toxic dose close to the effective dose
Requires precise dosing, patient-specific adjustment, and plasma level monitoring.
Examples: digoxin, warfarin, lithium, phenytoin, aminoglycosides
Section 4
Tachyphylaxis, Down-Regulation, and Up-Regulation
Rapid loss of response within minutes to hours
Typically from depletion of a releasable mediator store. Nitrate tolerance requires drug-free intervals to restore responsiveness. Indirect sympathomimetics lose effect as norepinephrine stores are exhausted.
Prolonged agonist exposure reduces receptor number — tolerance
Fewer receptors available → reduced maximum effect at any agonist concentration → tolerance requires higher doses to achieve the same effect. Example: beta-adrenergic receptor down-regulation with chronic beta-agonist use in asthma.
Prolonged antagonist exposure increases receptor number — rebound on stopping
Abrupt discontinuation exposes up-regulated receptors to endogenous ligand → exaggerated rebound response. Clinical rule: taper, never stop abruptly. Beta-blockers, clonidine, benzodiazepines, and opioids all carry this risk.
References
| Author / Source | Title | Publication |
|---|---|---|
| Katzung BG, ed. | Basic and Clinical Pharmacology, 15th edition | McGraw-Hill, 2021 |
| Brunton LL, Knollmann BC, eds. | Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th edition | McGraw-Hill, 2023 |
| Ritter JM, Flower R, Henderson G, Loke YK, MacEwan D, Rang HP | Rang & Dale's Pharmacology, 9th edition | Elsevier, 2019 |
| Brunton LL, Hilal-Dandan R, Knollmann BC, eds. | Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th edition | McGraw-Hill, 2018 |
| Kenakin T | Pharmacology in Drug Discovery and Development: Understanding Drug Response | Academic Press, 2017 |
| Limbird LE | Cell Surface Receptors: A Short Course on Theory and Methods, 3rd edition | Springer, 2004 |
| Waller DG, Sampson AP | Medical Pharmacology and Therapeutics, 5th edition | Elsevier, 2018 |
| Katzung BG, Trevor AJ, eds. | Basic and Clinical Pharmacology, 15th edition | McGraw-Hill, 2021 |