Chapter 1  ·  Module 2

Pharmacokinetics: How the Body Handles Drugs

Sections 1–4

The Four Pharmacokinetic Processes

A

Absorption

Drug moves from administration site into blood. Oral route subject to first-pass effect in liver.

D

Distribution

Drug spreads from blood into tissues. Extent reflects lipophilicity, protein binding, and tissue affinity.

M

Metabolism

Liver enzymes convert lipophilic drug to water-soluble form. Phase I then Phase II reactions.

E

Elimination

Drug and metabolites excreted, primarily by kidneys into urine. Half-life governs rate.

Sections 1 & 2

Absorption and Distribution

First-Pass Effect

  • Oral drug absorbed into portal circulation
  • Passes through liver before reaching systemic blood
  • Liver enzymes metabolize a fraction on first pass
  • Reduces bioavailability below 100 percent
  • Sublingual and intravenous routes bypass first-pass
  • Clinical example: nitroglycerin given sublingually

Volume of Distribution

  • Describes how widely drug distributes into tissues
  • Small volume → drug stays in plasma (e.g. warfarin)
  • Large volume → drug accumulates in tissues
  • Very large volume → dialysis cannot remove drug effectively
  • Only free (unbound) drug is pharmacologically active
  • Low albumin increases free fraction of protein-bound drugs

Section 3

Drug Metabolism

Phase I

Functionalization — make the drug more polar

Oxidation, reduction, or hydrolysis introduces or exposes a polar group. Carried out primarily by cytochrome P450 enzymes in the liver. May produce active metabolites or begin inactivation.

Phase II

Conjugation — attach a water-soluble group for excretion

Glucuronic acid, sulfate, or acetyl group is attached to the drug or Phase I metabolite. Product is highly water-soluble, usually inactive, and readily excreted by kidneys or bile.

Prodrug

Inactive until metabolized

Prodrugs require metabolic activation to produce the active compound. Example: enalapril (inactive) → enalaprilat (active angiotensin-converting enzyme inhibitor). Hepatic impairment may block activation.

Section 4

Half-Life and Steady State

Drug concentration remaining after each half-life

t½ × 1

50%

t½ × 2

25%

t½ × 3

12.5%

t½ × 4

6.25%

t½ × 5

3.1%

Steady state is reached after 4–5 half-lives of regular dosing — the same rule applies in reverse for drug washout after stopping.

Section 5

Clinical Pharmacokinetic Adjustments

Hepatic Impairment

  • Reduced phase I and II metabolism → drug accumulates
  • Reduced albumin → increased free fraction of protein-bound drugs
  • Reduced first-pass effect → increased oral bioavailability
  • Prodrugs may fail to activate

Renal Impairment

  • Renally cleared drugs accumulate with repeated dosing
  • Half-life is effectively prolonged
  • Dose reduction or interval extension required
  • Estimated glomerular filtration rate guides adjustment