Basic principles of pharmacology
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I now have substantial content from authoritative pharmacology textbooks. Let me now compile the comprehensive answer based on the wealth of content gathered from Katzung's Basic and Clinical Pharmacology (16th ed.) and Goodman & Gilman's Pharmacological Basis of Therapeutics.
Basic Principles of Pharmacology
Pharmacology is the study of how chemical substances (drugs) interact with living systems to produce biological effects. It is classically divided into two core domains: pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body).
1. What Is a Drug?
A drug is any substance that brings about a change in biologic function through its chemical actions. Most drugs interact with a specific target molecule called a receptor, acting either as an agonist (activator) or antagonist (inhibitor). A few exceptions exist:
- Chemical antagonists interact directly with other drugs (e.g., protamine neutralizing heparin)
- Osmotic agents act primarily by interacting with water molecules
- Biologicals/large molecules (monoclonal antibodies, mRNA vaccines) act like receptors themselves
"The dose makes the poison" - Paracelsus (1493-1541). Any substance can be harmful at the wrong dose. - Katzung's Basic and Clinical Pharmacology, 16th Ed.
2. Physical Nature of Drugs
Size
Molecular weight ranges from very small (lithium ion, MW 7) to very large (alteplase, MW ~59,050; antibodies >145,000). Most drugs fall between MW 100-1000:
- Lower limit (~100): Needed for receptor specificity - the molecule must be unique enough in shape and charge to bind only its intended receptor
- Upper limit (~1000): Dictated by the need to diffuse between body compartments
Physical states
Drugs may be solid (aspirin, atropine), liquid (nicotine, ethanol), or gaseous (nitrous oxide, isoflurane) - a factor that determines the best route of administration.
Ionization and pH
Many drugs are weak acids or weak bases. The degree of ionization depends on the drug's pKa and the pH of the surrounding environment (Henderson-Hasselbalch relationship):
- Ionized (charged) form: Hydrophilic, poorly membrane-permeable, poor CNS penetration
- Unionized (uncharged) form: Lipophilic, crosses membranes readily
This has major clinical implications - for example, weak acid drugs (aspirin, pKa 3.5; warfarin, pKa 5.0; phenobarbital, pKa 7.4) are better absorbed in the acidic stomach, while weak bases (atropine, pKa 9.7; morphine, pKa 9.9) are better absorbed in the alkaline intestine. Alkalinizing the urine promotes excretion of weak acids (used in aspirin overdose).
3. Pharmacokinetics (ADME)
Pharmacokinetics describes the movement of drugs through the body: Absorption, Distribution, Metabolism, Excretion.
A. Absorption
The process by which a drug moves from its site of administration into the systemic circulation. Key factors:
- Route of administration: IV (100% bioavailability, fastest), oral, sublingual, transdermal, inhalation, rectal
- Bioavailability (F): The fraction of administered drug that reaches systemic circulation unchanged. Oral bioavailability is reduced by first-pass hepatic metabolism (e.g., lidocaine has near-zero oral bioavailability due to extensive first-pass effect; nitroglycerin is given sublingually or transdermally for the same reason)
- Passive diffusion is the most common mechanism - driven by concentration gradient and lipophilicity
B. Distribution
Once in the bloodstream, drugs distribute to tissues. Key concepts:
- Volume of distribution (Vd): A theoretical volume relating the amount of drug in the body to its plasma concentration. A high Vd (e.g., chloroquine, >200 L) means drug has distributed extensively into tissues; a low Vd means it stays in plasma
- Plasma protein binding: Drugs bound to albumin or alpha-1-acid glycoprotein are pharmacologically inactive (only free drug acts). Protein binding affects Vd and half-life
- Blood-brain barrier: Highly lipophilic, unionized drugs cross freely; ionized or large molecules do not
- Redistribution: Highly lipophilic drugs like thiopental rapidly enter the brain (highly perfused), then redistribute to fat/muscle, shortening effect duration
C. Metabolism (Biotransformation)
The liver is the primary site of drug metabolism. The goal is to convert lipophilic drugs into more polar (water-soluble) metabolites for excretion. Metabolism occurs in two phases:
| Phase | Reaction | Enzymes | Result |
|---|---|---|---|
| Phase I | Oxidation, reduction, hydrolysis | CYP450 (CYP3A4, CYP2D6, CYP2C9, etc.) | Adds/unmasks polar group; may activate or inactivate |
| Phase II | Conjugation (glucuronidation, sulfation, acetylation, methylation) | Transferases (UGTs, SULTs, NATs) | Typically inactivates; increases water solubility |
Important consequences:
- Prodrugs require Phase I metabolism to become active (e.g., codeine → morphine via CYP2D6; enalapril → enalaprilat)
- Drug-drug interactions via CYP induction (e.g., rifampin, carbamazepine) or inhibition (e.g., ketoconazole, grapefruit juice)
- First-pass effect: Orally absorbed drugs pass through the portal circulation to the liver before reaching systemic circulation
D. Excretion
- Renal excretion: Primary route for most drugs. Involves glomerular filtration, tubular secretion, and tubular reabsorption. pH manipulation affects reabsorption of ionizable drugs
- Biliary/fecal excretion: Important for larger molecules (MW >300); some drugs undergo enterohepatic recirculation, prolonging their effect
- Other routes: Lungs (volatile anesthetics), breast milk, sweat, saliva
Key PK Parameters
| Parameter | Definition | Formula |
|---|---|---|
| Half-life (t½) | Time for plasma concentration to fall by 50% | t½ = 0.693 × Vd / CL |
| Clearance (CL) | Volume of plasma cleared of drug per unit time | CL = dose / AUC |
| Steady state | Achieved after ~4-5 half-lives of repeated dosing | When rate in = rate out |
| Loading dose | Initial large dose to rapidly achieve therapeutic levels | LD = Vd × target Cp / F |
| Maintenance dose | Dose to maintain steady state | MD = CL × target Cp / F |
- Goodman & Gilman's Pharmacological Basis of Therapeutics: t½ = 0.693 × Vss / CL; steady-state plasma concentration (Css) = F × dosing rate / CL
4. Pharmacodynamics - Drug-Receptor Interactions
Receptors
Receptors are macromolecular targets (usually proteins) that drugs bind to produce their effects. Types:
- Ion channel receptors (ionotropic): Ligand-gated channels; rapid response (milliseconds) - e.g., nicotinic ACh receptor, GABA-A
- G protein-coupled receptors (GPCRs): Most common drug target; activate second messenger systems (cAMP, IP3/DAG) - e.g., beta-adrenoceptors, muscarinic receptors
- Receptor tyrosine kinases: Activated by growth factors, insulin; slower response (hours) - e.g., insulin receptor, EGFR
- Nuclear/intracellular receptors: Regulate gene transcription; slowest (hours to days) - e.g., glucocorticoid receptor, thyroid hormone receptor
Drug-Receptor Binding
The receptor exists in two conformations - inactive (Rq) and active (Ra). Drug binding shifts this equilibrium:
- Full agonist: High affinity for Ra; produces maximum effect (Emax). Example: morphine at opioid receptors
- Partial agonist: Intermediate affinity for both conformations; produces submaximal effect even at full receptor occupancy. Example: buprenorphine (partial mu-opioid agonist) - can block full agonists while still providing partial effect
- Antagonist: Equal affinity for both conformations; does not alter constitutive activity but blocks agonist binding. Examples: naloxone (competitive antagonist at opioid receptors)
- Inverse agonist: High affinity for Rq (inactive form); reduces constitutive activity below baseline. Example: some antihistamines at H1 receptors
Types of Antagonism
| Type | Mechanism | Effect on Dose-Response | Example |
|---|---|---|---|
| Competitive reversible | Competes with agonist at same site; reversible | Shifts curve right; Emax unchanged | Atropine, naloxone |
| Competitive irreversible | Binds covalently; cannot be displaced | Depresses Emax; curve shifts right | Phenoxybenzamine |
| Non-competitive | Acts at allosteric site | Depresses Emax | Ketamine (NMDA receptor) |
| Functional/physiological | Acts on different receptor with opposing effect | - | Epinephrine reversing anaphylaxis |
Dose-Response Relationships
The dose-response curve is sigmoidal (log scale). Key parameters:
- EC50 (ED50): Dose/concentration producing 50% of maximum effect - indicates potency
- Emax: Maximum possible effect - indicates efficacy (intrinsic activity)
- Therapeutic window: Range between minimum effective concentration and minimum toxic concentration
Potency vs. Efficacy: A drug can be highly potent (low EC50) but have low efficacy (low Emax), or vice versa. Morphine has greater efficacy (higher Emax) than codeine; fentanyl is more potent than morphine (lower EC50) but both have similar Emax.
Therapeutic Index (TI)
$$\text{TI} = \frac{TD_{50}}{ED_{50}} \quad \text{or} \quad \frac{LD_{50}}{ED_{50}}$$
- Wide TI (safer drugs): Penicillins (TI >1000), benzodiazepines
- Narrow TI (dangerous, require monitoring): Digoxin, lithium, warfarin, aminoglycosides, phenytoin, cyclosporine
5. Drug Development and Evaluation
Preclinical Testing
Before human testing, drugs undergo extensive preclinical safety studies:
- Acute toxicity: Two species, two routes; determine no-effect dose, maximum tolerated dose, and sometimes LD50
- Subacute/chronic toxicity: Up to 2+ years to assess biochemical and physiologic effects
- Reproductive toxicity: Effects on fertility, embryogenesis, fetal development, birth defects
- Carcinogenicity: 2 years, two species (required for drugs intended for long-term use)
- Mutagenicity: Ames test (bacterial), mammalian cell culture, dominant lethal test
Clinical Trials (Phases I-IV)
| Phase | Subjects | Goal | Size |
|---|---|---|---|
| Phase I | Healthy volunteers (or patients with serious illness) | Safety, PK, dosing | 20-100 |
| Phase II | Patients with target disease | Preliminary efficacy, dose-ranging, safety | 100-500 |
| Phase III | Large patient population, randomized controlled trial | Efficacy vs. placebo/standard of care, adverse effects | 500-5000+ |
| Phase IV | Post-marketing surveillance | Long-term safety, rare adverse events, new indications | Thousands |
The randomized controlled trial (RCT) is the gold standard - subjects are randomly assigned to treatment or control groups, ideally with double-blinding (neither patient nor investigator knows the treatment assignment).
6. Selective Toxicity and Drug Safety
- Therapeutic index (TI): Quantifies the margin of safety. Narrow-TI drugs require plasma level monitoring
- Selectivity: Most useful drugs show selective effects at therapeutic doses (e.g., beta-1 selective blockers are relatively cardioselective vs. non-selective agents affecting both beta-1 and beta-2)
- Drug tolerance: Reduced response after repeated dosing due to receptor downregulation, tachyphylaxis, or metabolic adaptation
- Dependence: Physical or psychological reliance on a drug
Summary Diagram
PHARMACOLOGY
├── PHARMACOKINETICS (body → drug)
│ ├── Absorption (route, bioavailability, first-pass)
│ ├── Distribution (Vd, protein binding, BBB)
│ ├── Metabolism (Phase I: CYP450; Phase II: conjugation)
│ └── Excretion (renal, biliary; t½ = 0.693 × Vd / CL)
│
└── PHARMACODYNAMICS (drug → body)
├── Receptor types (ion channels, GPCRs, RTKs, nuclear)
├── Agonists / Partial agonists / Inverse agonists / Antagonists
├── Dose-response: Potency (EC50) vs. Efficacy (Emax)
└── Therapeutic index (TD50 / ED50)
Sources:
- Katzung's Basic and Clinical Pharmacology, 16th Edition - Chapter 1: General Principles; Chapter 2: Drug Receptors & Pharmacodynamics; Chapter 3: Pharmacokinetics
- Goodman & Gilman's The Pharmacological Basis of Therapeutics - Chapter 2: Pharmacokinetics (half-life, Vd, clearance, steady state)
- Harrison's Principles of Internal Medicine, 22nd Ed. - Chapter 71: Principles of Clinical Pharmacology
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