Mechanisms of Drug Action

Why This Matters

Every drug you'll study in pharmacology works because it interacts with the body at a molecular level—and you're being tested on your ability to explain how and why these interactions produce therapeutic effects. The mechanisms covered here form the foundation for understanding drug classes from antihypertensives to chemotherapeutics. When you encounter a new drug, your first question should always be: "What is this drug doing at the cellular or molecular level?"

These mechanisms demonstrate core principles like receptor theory, enzyme kinetics, membrane physiology, and signal transduction. Exam questions rarely ask you to simply name a mechanism—they want you to predict what happens when a drug binds, explain why one drug works differently than another, or troubleshoot why a patient isn't responding to therapy. Don't just memorize definitions—know what molecular target each mechanism involves and what physiological outcome it produces.

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Receptor-Based Mechanisms

Most drugs work by interacting with receptors—specialized proteins that recognize specific molecules and translate that recognition into cellular responses. The type of receptor determines the speed, duration, and nature of the drug's effect.

Receptor Binding and Activation

• Receptor specificity—drugs bind to particular receptor types (G-protein coupled, ligand-gated ion channels, nuclear receptors), and the receptor class determines response timing from milliseconds to hours
• Binding reversibility affects duration of action; irreversible binding produces longer effects but may require new receptor synthesis for recovery
• Receptor location matters—cell surface receptors mediate rapid responses while intracellular/nuclear receptors alter gene transcription for slower, sustained effects

Agonist and Antagonist Effects

• Agonists activate receptors to mimic endogenous ligands and produce biological responses; efficacy describes how well they activate once bound
• Antagonists block receptors without activating them, preventing endogenous ligands or other drugs from producing effects
• Partial agonists produce submaximal activation even at full receptor occupancy—critical concept for understanding drugs like buprenorphine

Allosteric Modulation

• Allosteric sites are distinct from orthosteric (primary) binding sites, allowing modulators to fine-tune receptor activity without directly competing with endogenous ligands
• Positive allosteric modulators (PAMs) enhance the effect of the primary ligand; negative allosteric modulators (NAMs) reduce it
• Clinical advantage—allosteric modulators often preserve physiological signaling patterns, potentially reducing side effects compared to direct agonists/antagonists

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Enzyme-Targeted Mechanisms

Enzymes catalyze biochemical reactions throughout the body, making them powerful drug targets. By inhibiting specific enzymes, drugs can increase or decrease concentrations of key molecules in metabolic pathways.

Enzyme Inhibition

• Competitive inhibitors bind the active site and compete directly with substrate; their effects can be overcome by increasing substrate concentration
• Non-competitive inhibitors bind elsewhere on the enzyme, reducing catalytic activity regardless of substrate levels—cannot be overcome by more substrate
• Therapeutic applications include ACE inhibitors (blocking angiotensin conversion), statins (blocking cholesterol synthesis), and MAO inhibitors (blocking neurotransmitter breakdown)

Antimetabolite Action

• Antimetabolites structurally resemble natural substrates and get incorporated into metabolic pathways, disrupting normal cellular processes
• DNA synthesis disruption—drugs like methotrexate (inhibits dihydrofolate reductase) and 5-fluorouracil (inhibits thymidylate synthase) block nucleotide production
• Selectivity for rapidly dividing cells makes antimetabolites particularly useful in cancer chemotherapy, though this also explains bone marrow and GI toxicity

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Membrane and Channel Mechanisms

Cell membranes control what enters and exits cells, and many drugs work by modifying this gatekeeping function. Ion channels and transport proteins are key targets for drugs affecting excitable tissues like neurons, cardiac muscle, and smooth muscle.

Ion Channel Modulation

• Drugs can block, open, or modify ion channels that control $Na^+$, $K^+$, $Ca^{2+}$, and $Cl^-$ flow across membranes
• Calcium channel blockers reduce cardiac contractility and vascular smooth muscle tone; sodium channel blockers decrease neuronal excitability and cardiac conduction velocity
• State-dependent binding—many channel blockers preferentially bind open or inactivated channel states, producing use-dependent effects in rapidly firing cells

Transporter Interactions

• Transport proteins move molecules across membranes against concentration gradients or facilitate diffusion; drugs can inhibit or enhance this activity
• SSRIs block serotonin reuptake transporters (SERT), increasing synaptic serotonin concentration—the basis for their antidepressant effects
• Pharmacokinetic implications—transporter inhibition can alter drug absorption, distribution, and elimination, leading to significant drug-drug interactions

Membrane Disruption

• Some drugs physically disrupt lipid bilayers, causing cell lysis or altered permeability—particularly important for antimicrobials
• Polymyxins and daptomycin target bacterial membranes; amphotericin B binds ergosterol in fungal membranes
• Selectivity depends on membrane composition differences between human cells and pathogens (e.g., ergosterol vs. cholesterol)

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Nucleic Acid and Signaling Mechanisms

Some drugs work at the level of genetic information or the complex signaling cascades that translate receptor activation into cellular responses. These mechanisms often produce profound, long-lasting effects on cell function.

DNA/RNA Interactions

• Direct nucleic acid binding can inhibit replication, transcription, or translation—mechanisms exploited by many anticancer and antiviral agents
• Alkylating agents (cyclophosphamide) form covalent bonds with DNA; intercalating agents (doxorubicin) insert between base pairs; antimetabolites disrupt nucleotide synthesis
• Antiviral applications include nucleoside analogs like acyclovir that get incorporated into viral DNA and cause chain termination

Signal Transduction Pathways

• Intracellular signaling cascades amplify and diversify receptor signals through second messengers ($cAMP$, $IP_3$, $Ca^{2+}$) and kinase cascades
• Targeted therapies can inhibit specific kinases (imatinib blocks BCR-ABL tyrosine kinase) or modify second messenger levels (phosphodiesterase inhibitors increase $cAMP$)
• Pathway crosstalk means drugs targeting one pathway may have unexpected effects on others—important for understanding both therapeutic effects and adverse reactions

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Quick Reference Table

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Self-Check Questions

1. A patient on warfarin starts taking a new medication and experiences increased bleeding. The new drug is a competitive inhibitor of the same enzyme warfarin targets. Explain why competitive inhibition at the same site would increase rather than decrease warfarin's effect—or identify what's wrong with this scenario.

2. Compare and contrast how SSRIs and cocaine both increase synaptic monoamine levels. What transporter differences explain their different clinical profiles?

3. Which two mechanisms would you expect to produce the fastest onset of drug effect: nuclear receptor activation, ion channel blockade, enzyme inhibition, or G-protein coupled receptor activation? Explain your reasoning.

4. A cancer drug is described as an antimetabolite that inhibits dihydrofolate reductase. What cellular process is disrupted, and why does this preferentially affect cancer cells?

5. An FRQ asks you to explain why benzodiazepines have a ceiling effect for sedation while barbiturates can cause fatal respiratory depression, even though both enhance GABA signaling. Use the concept of allosteric modulation vs. direct activation in your answer.