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Pharmacodynamics — Undergraduate Notes
Sources: Lippincott Illustrated Reviews: Pharmacology; Katzung's Basic & Clinical Pharmacology; Goodman & Gilman's Pharmacological Basis of Therapeutics; Schwartz's Principles of Surgery
1. Definition
Pharmacodynamics describes the actions of a drug on the body — what the drug does to the body (as opposed to pharmacokinetics, which describes what the body does to the drug).
Most drugs produce effects by interacting with specialized target macromolecules called receptors. The drug-receptor complex initiates alterations in biochemical and/or molecular activity via a process called signal transduction.
2. Drug Receptors
2.1 What Are Receptors?
Receptors are typically proteins (or glycoproteins) located on the cell surface, within the cytoplasm, or in the nucleus. A drug must bind to its receptor to initiate a pharmacologic effect.
2.2 Types of Receptors (by Signal Transduction Mechanism)
| Receptor Type | Location | Mechanism | Speed of Response | Examples |
|---|---|---|---|---|
| Ligand-gated ion channels (ionotropic) | Cell membrane | Ion channel opens on agonist binding | Milliseconds | Nicotinic ACh receptor, GABA-A receptor |
| G protein-coupled receptors (GPCRs) | Cell membrane | Activates G protein → second messengers | Seconds–minutes | Muscarinic, adrenergic, opioid receptors |
| Enzyme-linked receptors (receptor tyrosine kinases) | Cell membrane | Ligand binding → intracellular kinase activation | Minutes–hours | Insulin receptor, growth factor receptors |
| Intracellular/nuclear receptors | Cytoplasm / nucleus | Drug enters cell → binds receptor → alters gene transcription | Hours–days | Steroid, thyroid hormone receptors |
Ligand-gated ion channels
Binding of agonist opens a pore, allowing ion flow. Example:
- Nicotinic ACh receptor: Na⁺ influx + K⁺ efflux → depolarization → action potential → muscle contraction
- GABA-A receptor: Cl⁻ influx → hyperpolarization → reduced neuronal firing
G protein-coupled receptors (GPCRs)
All GPCRs have three subunits (α, β, γ). The α subunit binds GTP. On agonist binding, the α-GTP complex dissociates from the βγ complex, activating cellular effectors:
| G Protein | Effect on Adenylyl Cyclase | Second Messenger | Result |
|---|---|---|---|
| Gₛ | Activates | ↑ cAMP | Activates protein kinase A |
| Gᵢ | Inhibits | ↓ cAMP | Inhibits protein kinase A |
| Gq | — | ↑ IP₃ + DAG | Ca²⁺ release; PKC activation |
Enzyme-linked receptors
Ligand binding causes receptor dimerisation and autophosphorylation of tyrosine residues → phosphorylation cascade. Example: insulin receptor.
Intracellular receptors
Lipid-soluble drugs (steroids, thyroid hormone) cross the membrane, bind cytosolic/nuclear receptors → receptor-drug complex acts as a transcription factor → altered gene expression.
3. Agonists and Antagonists
3.1 Key Terms
| Term | Definition |
|---|---|
| Agonist | Drug that binds a receptor and activates it, mimicking the endogenous ligand |
| Full agonist | Produces the maximum response (100% efficacy) |
| Partial agonist | Binds and activates the receptor, but produces a submaximal response even at full receptor occupancy |
| Inverse agonist | Binds the receptor and produces the opposite effect to an agonist |
| Antagonist | Binds the receptor but does NOT activate it; blocks agonist access |
3.2 Types of Antagonism
Competitive (reversible) antagonist:
- Competes with agonist for the same receptor binding site
- Effect can be overcome by increasing agonist concentration
- Shifts the dose-response curve to the right (higher EC₅₀), but Emax is preserved
- Example: atropine at muscarinic receptors
Non-competitive (irreversible) antagonist:
- Binds to a different site (allosteric) OR binds the same site irreversibly
- Emax is reduced regardless of agonist concentration
- Example: phenoxybenzamine at α-adrenoceptors
4. Dose–Response Relationships
4.1 Graded Dose–Response Curve
As drug concentration increases, the pharmacologic effect gradually increases until all receptors are occupied (maximum effect = Emax). The sigmoidal curve plotted on a log-dose axis is used to determine:
4.2 Potency
- A measure of the amount of drug needed to produce a given effect
- Expressed as EC₅₀ (concentration producing 50% of maximal effect)
- Lower EC₅₀ = higher potency (less drug needed)
- Potency ≠ efficacy; a highly potent drug is not necessarily the better clinical choice
4.3 Efficacy (Intrinsic Activity)
- The maximum response a drug can produce (Emax)
- A drug with higher efficacy produces a greater maximal effect
- Clinically, efficacy is usually more important than potency
Key distinction: Two drugs may have equal efficacy but different potencies. Example: morphine and codeine are both opioid agonists, but morphine has much higher efficacy and potency.
4.4 Quantal Dose–Response Curve
- Plots the proportion of a population showing a defined all-or-nothing response vs. dose
- Used to determine:
- ED₅₀: dose effective in 50% of the population
- LD₅₀: lethal dose in 50% of animals
- TD₅₀: toxic dose in 50% of humans
4.5 Therapeutic Index (TI)
$$TI = \frac{TD_{50}}{ED_{50}}$$
- A high TI = wide margin of safety (e.g., penicillin)
- A narrow TI = small difference between effective and toxic doses; requires careful monitoring (e.g., digoxin, warfarin, lithium, phenytoin)
5. Receptor Regulation
5.1 Desensitization and Tachyphylaxis
- Desensitization: Prolonged or repeated agonist exposure → receptor phosphorylation → receptor becomes unresponsive to agonist
- Tachyphylaxis: Rapidly diminishing response to successive doses of a drug
- Downregulation: Receptors are internalized within the cell → fewer surface receptors → reduced sensitivity
- Clinical example: Repeated morphine use → downregulation of opioid receptors → tolerance (higher doses needed for same effect)
5.2 Upregulation
- Repeated exposure to an antagonist → receptors are inserted into the membrane → increased receptor number
- Makes cells more sensitive to agonists
- Clinical example: Chronic β-blocker use → β-receptor upregulation → rebound tachycardia/hypertension on abrupt withdrawal
6. Signal Transduction Pathways (Summary)
Agonist binds receptor
↓
GPCRs → G protein activation → ↑/↓ cAMP, IP₃, DAG → kinase cascades → cellular effect
Ion channels → immediate ion flux → membrane potential change
Tyrosine kinase receptors → phosphorylation cascades → gene expression changes
Nuclear receptors → transcription factor activation → new protein synthesis
7. Drug–Receptor Binding
Affinity vs. Activity
- Affinity: How tightly a drug binds to its receptor (expressed as Kd = dissociation constant; lower Kd = higher affinity)
- Intrinsic activity (efficacy): Ability to activate the receptor once bound (ranges from 0 for antagonists to 1 for full agonists)
Selectivity
- No drug acts on only one receptor type, but drugs vary in their selectivity — preference for one receptor subtype over others
- Selectivity determines therapeutic utility and side-effect profile
- Example: β₁-selective blockers (metoprolol) preferred in asthmatics over non-selective β-blockers (propranolol)
8. Spare Receptors
- Maximum response can be achieved when only a fraction of receptors are occupied
- The "unoccupied" receptors at maximum effect are called spare receptors (or receptor reserve)
- Implication: A drug may have low affinity (high EC₅₀) but still produce full efficacy because of spare receptors
9. Key Clinical Concepts
| Concept | Definition | Clinical Relevance |
|---|---|---|
| Tolerance | Decreased drug response with repeated use | Opioids, benzodiazepines, nitrates |
| Tachyphylaxis | Rapid tolerance (minutes-hours) | Ephedrine, nitroglycerin |
| Sensitization | Increased response with repeated use | Cocaine, levodopa dyskinesias |
| Idiosyncratic reaction | Abnormal, unpredictable response | G6PD deficiency + primaquine → hemolysis |
| Drug selectivity | Preference for one receptor vs. another | Basis for targeted therapy |
| Therapeutic window | Range between minimum effective and minimum toxic dose | Guides dosing decisions |
10. Quick Reference Summary
Pharmacodynamics = what the drug does to the body
RECEPTOR TYPES:
• Ion channels → fast (ms): nicotinic, GABA-A
• GPCRs → medium (sec-min): muscarinic, adrenergic
• Tyrosine kinases → slow (min-hr): insulin, growth factors
• Nuclear receptors → very slow (hr-days): steroids, thyroid
AGONIST vs ANTAGONIST:
• Full agonist: binds + full activation
• Partial agonist: binds + submaximal activation
• Competitive antagonist: reversible; shifts curve right; Emax preserved
• Non-competitive antagonist: reduces Emax
POTENCY vs EFFICACY:
• Potency = EC50 (lower EC50 = more potent)
• Efficacy = Emax (maximum possible effect)
• Therapeutic Index = TD50/ED50 (higher = safer)
RECEPTOR REGULATION:
• Downregulation (agonist excess) → tolerance
• Upregulation (antagonist excess) → rebound on withdrawal
— Lippincott Illustrated Reviews: Pharmacology, pp. 82–96 | Katzung's Basic & Clinical Pharmacology, 16th ed. | Goodman & Gilman's, 14th ed. | Schwartz's Principles of Surgery, 11th ed., p. 2057
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