5.2 Mechanisms of Action of Drugs and Biologics
Key Takeaways
- Drug mechanisms of action fall into six broad categories: receptor modulation, enzyme inhibition or activation, ion-channel blockade, transport inhibition, nucleic acid synthesis inhibition, and replacement therapy.
- Autonomic drugs act through adrenergic (alpha, beta) and cholinergic (muscarinic, nicotinic) receptors; receptor selectivity determines both therapeutic use and adverse-effect profile.
- Monoclonal antibody nonproprietary names encode target (-tu-, -li-, -ci-), source (-o-, -xi-, -zu-, -mu-), and class (-mab), allowing rapid identification of structure and indication.
- Biosimilars are not generics — they are highly similar but not identical to reference biologics, carry residual immunogenicity risk, and require separate approval pathways.
- Targeted oncology therapies exploit specific molecular lesions (kinase inhibitors) and immune checkpoints (PD-1, PD-L1, CTLA-4 antibodies) to improve selectivity over cytotoxic chemotherapy.
Categories of Mechanism of Action
A drug's mechanism of action (MOA) is the specific biochemical interaction through which it produces its pharmacological effect. MOAs can be grouped into six broad categories:
- Receptor agonism or antagonism — beta-agonists, beta-blockers, antihistamines
- Enzyme inhibition or activation — ACE inhibitors, statins (HMG-CoA reductase), allopurinol (xanthine oxidase)
- Ion channel modulation — local anesthetics (Na+ channel blockade), CCBs (L-type Ca2+), sulfonylureas (K-ATP channel closure)
- Transport inhibition — SSRIs (serotonin reuptake), proton-pump inhibitors (H+/K+ ATPase), loop diuretics (NKCC2)
- Nucleic acid synthesis inhibition — fluoroquinolones (DNA gyrase), antifolates (trimethoprim, methotrexate)
- Replacement or supplementation — insulin, levothyroxine, electrolytes, vitamins
Autonomic Pharmacology MOAs
The autonomic nervous system transmits signals via adrenergic and cholinergic receptors. Adrenergic agonists are classified by receptor selectivity: alpha-1 (phenylephrine — vasoconstriction), alpha-2 (clonidine — central sympatholysis), beta-1 (dobutamine — increased contractility), beta-2 (albuterol — bronchodilation). Adrenergic antagonists include nonselective alpha-blockers (phenoxybenzamine), selective alpha-1 blockers (tamsulosin), and beta-blockers whose selectivity for beta-1 (metoprolol) versus nonselectivity (propranolol) determines pulmonary and metabolic effects.
Cholinergic pharmacology uses muscarinic agonists (bethanechol for urinary retention, pilocarpine for glaucoma) and antagonists (atropine for bradycardia, oxybutynin for overactive bladder), plus nicotinic neuromuscular blockers (succinylcholine, rocuronium) used in anesthesia.
Major Drug Class MOAs and Therapeutic Uses
| Drug class | MOA | Representative therapeutic use |
|---|---|---|
| ACE inhibitors (enalapril) | Block conversion of Ang I to Ang II; reduce afterload and preload | Hypertension, heart failure, diabetic nephropathy |
| ARBs (losartan) | Block Ang II type-1 receptors | Hypertension, heart failure (ACE-intolerant) |
| Beta-blockers (metoprolol) | Block beta-1 adrenergic receptors; reduce heart rate, contractility, renin | Post-MI, heart failure, hypertension, arrhythmia |
| Dihydropyridine CCBs (amlodipine) | Block L-type Ca2+ channels in vascular smooth muscle | Hypertension, angina |
| Statins (atorvastatin) | Inhibit HMG-CoA reductase; lower LDL | Atherosclerosis, primary and secondary prevention |
| Warfarin | Inhibits vitamin-K epoxide reductase; reduces active factors II, VII, IX, X, protein C/S | Anticoagulation (narrow TI) |
| DOACs (apixaban, rivaroxaban) | Directly inhibit factor Xa; dabigatran inhibits IIa | Anticoagulation (predictable, no routine monitoring) |
| SSRIs (sertraline) | Inhibit serotonin reuptake at SERT | Depression, anxiety |
| SNRIs (venlafaxine) | Inhibit serotonin and norepinephrine reuptake | Depression, neuropathic pain |
| Benzodiazepines (lorazepam) | Potentiate GABA-A receptor (increase Cl- channel opening frequency) | Anxiety, status epilepticus, alcohol withdrawal |
| Typical antipsychotics (haloperidol) | D2 receptor antagonism | Psychosis, delirium |
| Atypical antipsychotics (olanzapine) | D2 plus 5-HT2A antagonism | Schizophrenia, bipolar disorder |
| Opioids (morphine) | Mu receptor agonism → reduced pain transmission | Acute pain, palliative pain |
| Insulin | Binds insulin receptor (tyrosine kinase) → GLUT4 translocation, anabolism | Type 1 and type 2 diabetes |
| Metformin | Inhibits mitochondrial complex I; activates AMPK → reduced gluconeogenesis | Type 2 diabetes (first-line) |
| Sulfonylureas (glipizide) | Close K-ATP channels on beta cells → insulin release | Type 2 diabetes |
| Levothyroxine | Thyroid hormone receptor agonist (nuclear) → transcriptional regulation | Hypothyroidism |
| Beta-lactams (penicillins, cephalosporins, carbapenems) | Bind PBPs; inhibit bacterial cell wall synthesis | Bacterial infections (bactericidal) |
| Macrolides (azithromycin) | Bind 50S ribosomal subunit; inhibit translocation | Community-acquired pneumonia, atypicals |
| Fluoroquinolones (ciprofloxacin) | Inhibit DNA gyrase and topoisomerase IV | UTIs, GI infections, pseudomonal infections |
| Azoles (fluconazole) | Inhibit fungal lanosterol 14-alpha-demethylase; deplete ergosterol | Candidiasis, dermatophytes |
Biologics and Biosimilars
Biologics are therapeutic products derived from living organisms — proteins, monoclonal antibodies, fusion proteins, cytokines, vaccines, cell and gene therapies. They are structurally complex, heat-sensitive, and parenterally administered because oral proteolysis destroys them.
Monoclonal antibodies (mAbs) are named using a four-part convention defined by the WHO and USAN: a prefix, a target substem, a source substem, and the stem "-mab." The target substem indicates what the antibody binds (e.g., -tu- for tumor, -li- for immune, -ci- for cardiovascular, -vi- for viral, -ba- for bacterial). The source substem reflects the antibody's protein composition: -o- for murine fragment (historical), -xi- for chimeric (murine variable + human constant), -zu- for humanized (murine CDRs grafted onto human framework), and -mu- for fully human. The stem -mab identifies the molecule as a monoclonal antibody. For example, trastuzumab = trastu- (prefix) + -tu- (tumor target) + -zu- (humanized) + -mab.
Fusion proteins combine an extracellular domain (e.g., a receptor ectodomain) with an Fc segment of IgG to extend half-life — etanercept (TNFR-Fc), abatacept (CTLA4-Fc). Cytokine modulators include recombinant cytokines (pegylated interferons, erythropoietin, filgrastim) and anti-cytokine antibodies (tocilizumab against IL-6R, canakinumab against IL-1 beta).
Biosimilars vs Generics
A generic is chemically identical to its small-molecule reference and can be substituted at the pharmacy without prescriber notification. A biosimilar is highly similar to its reference biologic with no clinically meaningful differences in safety, purity, or potency, but it is not identical — post-translational modifications, glycosylation patterns, and aggregate content differ microscopically. Biosimilars require a separate approval (FDA 351(k) pathway), may carry residual immunogenicity, and pharmacy-level substitution rules vary by state and product.
Targeted Therapies and Immunotherapy
Kinase inhibitors block oncogenic signaling by competing with ATP at the kinase active site — imatinib (BCR-ABL in CML), erlotinib and osimertinib (EGFR-mutant lung cancer), sunitinib (multi-kinase, renal and GIST). Immunotherapy releases immune checkpoints that tumors exploit to evade T-cell attack: PD-1 antibodies (pembrolizumab, nivolumab) and PD-L1 antibodies (atezolizumab) restore T-cell effector function, while CTLA-4 antibodies (ipilimumab) enhance T-cell priming in lymph nodes. Combination checkpoint blockade improves response in melanoma and renal cell carcinoma but increases immune-related adverse events (colitis, pneumonitis, hepatitis, endocrinopathies).
Which combination of segments in the nonproprietary name "pembrolizumab" identifies the drug as a humanized monoclonal antibody that targets the immune system?
A patient with HER2-positive breast cancer is started on trastuzumab. What is the drug's structural class and broad mechanism?