Chapter 1 · Module 3
Section 1
Drug Targets — The Four Receptor Superfamilies
Superfamily 1
G Protein-Coupled Receptors
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
Response: milliseconds
Binding opens an ion pore directly — no intermediary. Fastest receptor type. Found at fast synapses. Examples: nicotinic acetylcholine receptor, gamma-aminobutyric acid-A receptor, glutamate receptors.
Superfamily 3
Enzyme-Linked Receptors
Response: minutes – hours
Transmembrane protein with intracellular kinase domain. Ligand binding activates enzyme activity and phosphorylation cascades. Examples: insulin receptor, growth factor receptors. Targeted by many 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
Agonists and Antagonists
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
Can act as a functional antagonist in the presence of a full agonist by competing for receptors while producing less effect. Example: buprenorphine at opioid receptors — ceiling effect on respiratory depression.
Binds and reduces activity below baseline
Only relevant when a receptor has constitutive (spontaneous) activity. Produces the opposite effect to an agonist. Some drugs previously called antagonists are now recognized as inverse agonists.
Blocks the agonist site reversibly — surmountable
Higher agonist concentrations overcome blockade. Shifts dose-response curve right; maximum response preserved. Examples: naloxone (opioid), atropine (muscarinic), beta-blockers (beta-adrenergic).
Reduces maximum response — not surmountable
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.
Read from the horizontal axis — left shift = more potent
Fentanyl is more potent than morphine: the same effect requires a much smaller dose. But both can produce the same maximum analgesia.
Concept 2
Efficacy
The maximum effect a drug can produce, regardless of dose.
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 the codeine dose.
Wide Therapeutic Index
Large margin between effective and toxic dose
Considerable flexibility in dosing. Errors are less likely to cause harm.
Examples: penicillins, most statins
Narrow Therapeutic Index
Toxic dose close to effective dose
Requires precise dosing, patient-specific adjustment, and drug level monitoring.
Examples: digoxin, warfarin, lithium, phenytoin, aminoglycosides
Section 4
Tolerance and Receptor 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
Fewer receptors available → reduced maximum effect at any agonist concentration → tolerance requires higher doses. 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 response. Clinical rule: taper, do not stop. Beta-blockers, clonidine, benzodiazepines, opioids all carry this risk.