Pharmacokinetics Notes (Golan et al. 4e)

Pharmacology explores drug interactions with living systems. Pharmacokinetics (PK) focuses on what the body does to the drug (absorption, distribution, metabolism, excretion), while Pharmacodynamics (PD) describes what the drug does to the body.

Drugs navigate biological barriers, primarily cell membranes. Movement occurs via:

  1. Aqueous diffusion (small, water-soluble drugs).

  2. Lipid diffusion (small, nonpolar/lipophilic drugs, influenced by concentration gradient and ionization state, described by Fick’s law).

  3. Active transport (energy-dependent, carrier-mediated).

  4. Facilitated diffusion (carrier-mediated, energy-independent).

  5. Receptor-mediated endocytosis.

Absorption and Bioavailability

Bioavailability (F) is the fraction of administered drug reaching systemic circulation, influenced by route, incomplete absorption, first-pass metabolism (especially oral routes), and protein binding. Routes like oral transmucosal and inhalational offer rapid uptake and bypass hepatic first-pass metabolism, unlike standard oral administration which is subject to gastric acid, duodenal pH, and liver metabolism. Intravenous (IV) administration provides 100% bioavailability.

Ionization and pH

Most drugs are weak acids or bases. Their ionization state (charged) is largely determined by the environmental pH and the drug's pKa, as described by the Henderson–Hasselbalch equation. Unionized forms are lipid-soluble and cross membranes easily, while ionized forms are water-soluble and cross poorly. Ion trapping can occur when a drug moves into an environment with a different pH, becoming ionized and unable to easily cross back.

Drug Distribution

Distribution involves delivering the drug to target organs via the circulatory system. Key factors include:

  1. Plasma protein binding: Only the free (unbound) drug is active and can diffuse to tissues. Highly protein-bound drugs have a lower apparent volume of distribution (Vd).

  2. Blood flow to tissues: Dictates the rate of tissue exposure.

  3. Membrane permeability: Unionized drugs cross more readily.

  4. Tissue uptake: Influenced by blood flow, concentration gradients, and barriers (e.g., blood–brain barrier).

Volume of distribution (Vd) is a hypothetical fluid volume representing the extent of tissue distribution. A high Vd indicates extensive distribution into tissues beyond the bloodstream. Distribution often follows a multi-compartment model (e.g., Vessel Rich Group, Muscle Group, Fat Group).

Biotransformation (Metabolism) and Elimination

Metabolism, primarily in the liver, converts lipid-soluble drugs into water-soluble, excretable forms. Outcomes include inactivation, activation of prodrugs, formation of active/toxic metabolites, or enhanced excretion.

  • CYP450 system: A major enzyme system in the liver (CYP3A4/5, CYP2D6 are key isoforms) responsible for about 75% of drug metabolism (Phase I oxidative reactions). Enzyme induction increases metabolism; inhibition decreases it, leading to drug interactions.

  • Phase I reactions: Functionalization reactions like oxidation, reduction, and hydrolysis, often exposing functional groups.

  • Phase II reactions: Conjugation with endogenous substrates (e.g., glucuronic acid) to form highly polar, water-soluble metabolites, usually inactive and easily excreted.

Elimination (clearance) is the body's ability to remove a drug through metabolism and excretion, primarily via hepatic (biliary) and renal routes.

  • Hepatic clearance depends on blood flow and intrinsic enzyme activity.

  • Renal clearance involves glomerular filtration (free drug only), tubular secretion (carrier-mediated), and tubular reabsorption (favors unionized forms). Urine pH manipulation can enhance excretion.

Elimination kinetics:

  • First-order kinetics (common): A fixed fraction of drug is eliminated per unit time; the elimination rate is proportional to drug concentration, and half-life is constant (dose-independent).

  • Zero-order kinetics (saturation): A fixed amount of drug is eliminated per unit time, occurring when metabolic enzymes are saturated.

Half-life (t{1/2}) is the time for plasma concentration to decrease by 50%. It depends on Vd and clearance (t{1/2} = (0.693 \times V_d) / CL). Context-sensitive half-time and decrement time are used to predict recovery from infusions based on drug redistribution and elimination after stopping administration.

Understanding PK principles is crucial for determining drug dosing, onset, duration, and recovery, and for managing drug interactions and individual variability.