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I now have comprehensive material from Goodman & Gilman and Katzung. Let me compile the full classification.
Pharmacology Classification by Mechanism of Action
Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics; Katzung's Basic and Clinical Pharmacology, 16th Ed.
Overview: How Drugs Are Classified by Mechanism
The actions of the vast majority of drugs can be ascribed to their interactions with a relatively small number of protein classes:
- Receptors for endocrine and paracrine factors
- Enzymes
- Voltage-gated ion channels and other ion channels
- Membrane transporters
Drugs almost always alter the rate or magnitude of intrinsic cellular or physiological processes — they do not create biologically novel phenomena.
I. Drugs Acting on Receptors
A. Types of Drug–Receptor Interactions
| Interaction Type | Description | Clinical Example |
|---|---|---|
| Full Agonist | Binds + activates receptor; saturates system to produce maximal effect | Morphine (μ-opioid), Salbutamol (β₂-AR) |
| Partial Agonist | Intermediate affinity for both R (inactive) and R* (active) conformations; submaximal effect even at saturation | Buprenorphine, Buspirone |
| Inverse Agonist | Higher affinity for inactive (R) conformation; reduces constitutive (basal) receptor activity | Rimonabant (CB₁), some antihistamines |
| Competitive Antagonist | Binds receptor; prevents agonist access; effect overcome by ↑ agonist dose | Atropine (muscarinic), Naloxone (opioid) |
| Irreversible/Pseudoirreversible Antagonist | Binds very tightly; cannot be displaced by increasing agonist concentration | Phenoxybenzamine (α-adrenoceptor) |
| Allosteric Modulator (PAM) | Binds separate (allosteric) site; potentiates agonist response — ↑ potency (left EC₅₀ shift) or ↑ efficacy (↑ Emax) | Benzodiazepines (GABA-A), LY2119620 (muscarinic M2) |
| Allosteric Modulator (NAM) | Binds allosteric site; inhibits agonist response — ↓ EC₅₀ and Emax; not overcome by ↑ agonist dose | Amlodipine (allosterically modulates L-type Ca²⁺ channel) |
| Indirect Agonist | Inhibits breakdown/reuptake of endogenous agonist | Neostigmine (inhibits AChE → ↑ ACh), SSRIs |
B. Receptor Superfamilies — The Core Classification
Drawn directly from Table 3-1 of Goodman & Gilman:
1. G Protein–Coupled Receptors (GPCRs)
- Families: Adhesion, Frizzled, Glutamate, Rhodopsin, Secretin (GkBARS classification)
- Ligands: Enormous diversity — catecholamines, opioids, histamine, cannabinoids, prostaglandins, many hormones
- Transducers & 2nd messengers:
- Gₛ: ↑ adenylyl cyclase → ↑ cAMP (e.g., β-adrenoceptor agonists)
- Gᵢ: ↓ adenylyl cyclase (e.g., α₂-agonists, opioids), stimulates delayed rectifier K⁺ channel, inhibits N-type Ca²⁺ channel
- Gq: ↑ Phospholipase C-β → ↑ IP₃ + DAG → ↑ Ca²⁺ (e.g., α₁-agonists, muscarinic M1/M3)
- G₁₂/₁₃: Activates Rho GEFs
- Arrestins: MAP kinases, nonreceptor tyrosine kinases, transcription factors
- Drug classes: β-blockers, α-agonists/antagonists, opioids, antihistamines, anticholinergics, antipsychotics, prostaglandin analogs
2. Ligand-Gated Ion Channels (Ionotropic Receptors)
- Subclasses: Glutaminergic (AMPA, NMDA), Nicotinic cholinergic, P2X (purinergic), 5-HT₃, TRP channels, GABA-A, Glycine
- Ions gated:
- Excitatory: Na⁺, K⁺ (and Ca²⁺ in certain subtypes)
- Inhibitory: Cl⁻ (GABA-A, Glycine)
- Drugs: Benzodiazepines & barbiturates (↑ GABA-A Cl⁻ influx), succinylcholine (nicotinic agonist), ketamine (NMDA antagonist), ondansetron (5-HT₃ antagonist)
3. Enzyme-Linked (Catalytic) Receptors
- Subclass: Receptor Tyrosine Kinases (RTKs)
- Ligands: Insulin, PDGF, EGF, VEGF, growth factors
- Transducers: Proteins with SH2 and PTB domains → MAP kinase cascade, PI3K/Akt
- Drugs: Imatinib (BCR-ABL TK inhibitor), trastuzumab (HER2 receptor antagonist), erlotinib (EGFR inhibitor)
4. Other Cell-Surface Membrane Receptors
| Sub-type | Ligands | Signaling |
|---|---|---|
| Receptor serine/threonine kinases | TGF-β family | SMADs |
| Membrane-bound guanylyl cyclase | Natriuretic peptides (ANP, BNP) | ↑ cGMP |
| Cytokine receptors | Interleukins, growth hormone, prolactin, IFN | JAK/STAT pathway |
| Toll-like receptors | PAMPs (pathogens) | TIRAP, TRAM → NF-κB |
| TNF-α receptors | TNF-α | TRADD, RIP-1, TRAF2 → apoptosis/inflammation |
- Drugs: Tofacitinib (JAK inhibitor), ruxolitinib, sacubitril targets ANP pathway
5. Nuclear (Intracellular) Receptors
- Subfamily 3 (Steroid Receptors): Ligands = corticosteroids, sex hormones (estrogens, androgens, progestins, mineralocorticoids)
- Subfamilies 1, 2, 4–6 (Non-steroid Receptors): Ligands = thyroxine, retinoic acid, hydroxycholesterols, bile acids, Vitamin D
- Mechanism: Drug–receptor complex acts as transcription factor → binds hormone response elements (HREs) on DNA → alters gene expression (slow onset, prolonged effect)
- Drugs: Prednisolone, dexamethasone, tamoxifen (estrogen receptor modulator — SERM), spironolactone (mineralocorticoid antagonist), tretinoin (retinoic acid receptor agonist)
II. Drugs Acting on Enzymes
| Mechanism | Description | Examples |
|---|---|---|
| Competitive inhibition | Reversible; competes with substrate at active site | Captopril (ACE inhibitor), methotrexate (DHFR inhibitor) |
| Irreversible inhibition | Covalent bond; permanent until new enzyme synthesized | Aspirin (COX acetylation), organophosphates (AChE) |
| False substrate / prodrug | Mimics substrate but produces inactive product | 5-fluorouracil (thymidylate synthase), 6-mercaptopurine |
| Allosteric enzyme inhibition | Binds non-active site; alters conformation | Rapamycin (mTOR), many kinase inhibitors |
| Enzyme induction | Upregulates enzyme activity | Rifampin (↑ CYP3A4), carbamazepine |
| Histone-modifying enzyme inhibition | Epigenetic regulation | Vorinostat (HDAC inhibitor), tazemetostat (EZH2 inhibitor) |
III. Drugs Acting on Ion Channels
Voltage-Gated Ion Channels
| Channel | Drug Class | Mechanism | Examples |
|---|---|---|---|
| Na⁺ channels | Local anesthetics, antiepileptics, antiarrhythmics (Class I) | Bind internal channel pore; use-dependent block; stabilize inactive state | Lidocaine, phenytoin, flecainide |
| Ca²⁺ channels (L-type) | Calcium channel blockers (CCBs) | Block L-type (CaV1.x); dihydropyridines act on vascular smooth muscle; non-DHP act on cardiac conduction | Amlodipine (DHP), verapamil (PAP), diltiazem (BTZ) |
| K⁺ channels | Antiarrhythmics (Class III), sulfonylureas | Block/open K⁺ channels | Amiodarone (↓ repolarization), glibenclamide (blocks KATP → ↑ insulin release) |
| HCN channels (If) | Bradycardic agents | Block funny current in SA node | Ivabradine |
IV. Drugs Acting on Membrane Transporters
| Transporter | Drug Class | Mechanism | Examples |
|---|---|---|---|
| Monoamine transporters (NET, DAT, SERT) | Antidepressants, stimulants | Reuptake inhibition → ↑ synaptic monoamine | Fluoxetine (SERT), amphetamine (reversal of DAT), cocaine |
| Na⁺/K⁺-ATPase | Cardiac glycosides | Inhibit pump → ↑ intracellular Na⁺ → ↑ Ca²⁺ (via NCX) | Digoxin, digitoxin |
| H⁺/K⁺-ATPase | Proton pump inhibitors | Irreversible covalent inhibition of gastric H⁺ pump | Omeprazole, esomeprazole |
| SGLT-2 | Gliflozins | Inhibit renal glucose reabsorption | Empagliflozin, dapagliflozin |
| Drug efflux pumps (P-gp/MDR) | Resistance modifiers | Inhibit multidrug efflux | Elacridar, verapamil (at high dose) |
| GABA/amino acid transporters | Antiepileptics | Block reuptake of inhibitory transmitter | Tiagabine (GAT-1), vigabatrin (GABA-T inhibitor) |
V. Drugs with Physicochemical / Non-Receptor Mechanisms
| Mechanism | Examples |
|---|---|
| Osmotic diuretics / laxatives — osmotically active solutes | Mannitol, lactulose |
| Antacids — direct acid neutralization | Calcium carbonate, magnesium hydroxide |
| Chelation — bind heavy metals | Dimercaprol, EDTA, deferoxamine |
| Surfactant disruption (antimicrobials) — disrupt lipid membranes | Polymyxins, colistin |
| DNA intercalation (antineoplastics) | Doxorubicin, dactinomycin |
| Alkylation (antineoplastics) — covalent DNA crosslinks | Cyclophosphamide, cisplatin |
| Tubulin binding | Taxanes (↑ polymerization), vinca alkaloids (↓ polymerization) |
VI. Biological & Targeted Mechanisms (Modern Pharmacology)
| Category | Mechanism | Examples |
|---|---|---|
| Monoclonal antibodies | Block/deplete target proteins or cells (inflammatory mediators, checkpoint inhibitors, cell-surface molecules) | Trastuzumab (HER2), pembrolizumab (PD-1), adalimumab (TNF-α) |
| siRNA / Antisense oligos | Gene silencing — degrade target mRNA | Patisiran (transthyretin siRNA), eteplirsen (exon skipping) |
| Gene therapy (AAV vectors) | Replace/introduce functional genes | Voretigene (RPE65 for retinoblastoma), onasemnogene (SMN1) |
| CRISPR-Cas9 | Genomic editing at target sequences | Exa-cel (sickle cell disease) |
| CAR-T cell therapy | Chimeric antigen receptor on T cells | Tisagenlecleucel (anti-CD19) |
| Epigenetic modulators | HDAC inhibitors, histone methyltransferase inhibitors | Vorinostat, tazemetostat (EZH2) |
Quick Reference Summary
DRUG MECHANISM TREE
├── Receptor-mediated
│ ├── GPCRs (Gs/Gi/Gq/G12-13)
│ ├── Ligand-gated ion channels
│ ├── Enzyme-linked receptors (RTKs, JAK/STAT)
│ └── Nuclear receptors (steroids, thyroid, retinoic acid)
├── Enzyme-targeted
│ ├── Competitive/Irreversible inhibitors
│ └── Epigenetic enzymes (HDAC, EZH2)
├── Ion channel-targeted
│ ├── Voltage-gated (Na⁺, Ca²⁺, K⁺, HCN)
│ └── Ligand-gated (GABA-A, nAChR)
├── Transporter-targeted
│ ├── Monoamine reuptake inhibitors
│ ├── ATPase pumps (Na/K-ATPase, H/K-ATPase)
│ └── Cotransporters (SGLT-2, GAT-1)
├── Physicochemical
│ ├── Osmotic, chelation, surfactant, DNA-alkylation
│ └── Tubulin modulators
└── Biological/Targeted
├── Monoclonal antibodies
├── siRNA / gene therapy
└── Cell-based (CAR-T, CRISPR)
Goodman & Gilman's The Pharmacological Basis of Therapeutics (Table 3-1, Chapter 3) | Katzung's Basic and Clinical Pharmacology, 16th Ed. (Chapter 1–2)
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