Pharmacokinetics

Chapter 4: Pharmacokinetics

Application of Pharmacokinetics in Therapeutics

  • Pharmacokinetics involves the study of how drugs move through the body.

  • It plays a crucial role in determining the concentration of a drug at its sites of action, ultimately influencing the intensity and time course of therapeutic responses.

Passage of Drugs Across Membranes

  • Membrane Structure

    • Biological membranes are composed of lipid bilayers that form barriers for drug movement.

  • Three Ways to Cross a Cell Membrane

    1. Channels and Pores

      • Allow small ions and molecules to pass through the membrane.

    2. Transport Systems

      • Facilitated transport mechanisms assist various substances across cellular membranes.

        • Example: P-Glycoprotein (multidrug transporter protein)

        • Found in the liver, kidney, placenta, intestine, and brain capillaries; it helps transport a variety of drugs out of cells.

    3. Direct Penetration of the Membrane

      • Most drugs must dissolve in the lipid layer to cross membranes directly.

      • Polar Molecules cannot easily pass through lipid membranes.

      • Ions are also limited in their ability to cross membranes.

      • Quaternary Ammonium Compounds are charged molecules that cannot easily penetrate the lipid bilayer.

      • pH-Dependent Ionization influences drug absorption and permeability across membranes.

      • pH Partitioning (Ion Trapping) refers to the phenomenon where drugs accumulate on one side of a membrane due to pH differences.

Absorption

  • Factors Affecting Drug Absorption

    • Rate of Dissolution: Faster dissolution increases absorption rates.

    • Surface Area: Larger surface area correlates with improved absorption.

    • Blood Flow: Higher blood flow at the site enhances absorption.

    • Lipid Solubility: Lipid-soluble drugs are absorbed more readily.

    • pH Partitioning: Ionization state of drugs alters their absorption.

  • Characteristics of Commonly Used Routes of Administration

    1. Intravenous (IV)

    • Barriers to Absorption: None, as it directly enters the bloodstream.

    • Absorption Pattern: Rapid onset of action.

    • Advantages:

      • Immediate and precise control over drug levels.

      • Useful for large volumes and irritant drugs.

    • Disadvantages:

      • High cost, inconvenience, and risks of complications such as fluid overload, infection, embolism.

    1. Intramuscular (IM)

    • Barriers to Absorption: Vascularization affects absorption period.

    • Absorption Pattern: Variable depending on formulation.

    • Advantages:

      • Useful for depot preparations and non-soluble drugs.

    • Disadvantages:

      • Potential discomfort and inconvenience.

    1. Subcutaneous (SC)

    • Similar advantages and disadvantages as IM administration.

    1. Oral (PO)

    • Barriers to Absorption: Gastric and intestinal environments.

    • Absorption Pattern: Variability due to digestion and first-pass metabolism.

    • Advantages:

      • Easy, convenient, cost-effective, and safer.

    • Disadvantages:

      • Absorption variability; potential inactivation effects from digestive enzymes and liver metabolism.

  • Comparing Oral Administration with Parenteral Administration:

    • Oral administration (PO) has high variability and potential inactivation by stomach and liver compared to IV, which is more controlled.

  • Pharmaceutical Preparations for Oral Administration:

    • Tablets: Standard oral dosage forms.

    • Enteric-Coated Preparations: Designed to resist stomach acid, releasing in the intestine.

    • Sustained-Release Preparations: Formulated for slow drug release and prolonged effects.

  • Blood Flow to Tissues:

    • Influences distribution and effectiveness of the drug.

  • Additional Routes of Administration:

    • Routes that might include topical, inhalation, etc. affecting absorption efficiency.

Distribution

  • Exiting the Vascular System

    • Typical Capillary Beds: Drugs diffuse through spaces between cells.

    • Blood-Brain Barrier (BBB): Tight junctions require drugs to pass through cells, limiting drug access to the CNS.

    • Placental Drug Transfer: Membranes do not form an absolute barrier; drug movement follows similar principles as other membranes.

    • Protein Binding: Many drugs bind to plasma proteins (e.g., albumin), limiting their therapeutic effects due to reversible binding.

  • Entering Cells:

    • Drugs then must pass into the cells to exert their effects.

Metabolism

  • Definition of Drug Metabolism (Biotransformation):

    • The chemical alteration of drug structures, predominantly occurring in the liver mediated by enzyme systems.

  • Hepatic Drug-Metabolizing Enzymes:

    • Cytochrome P450 system is crucial in drug metabolism.

  • Therapeutic Consequences of Drug Metabolism:

    • Facilitates renal excretion by making drugs more hydrophilic.

    • Can lead to drug inactivation, increased therapeutic action, or even toxicity depending on metabolic pathways and interactions.

  • Special Considerations in Drug Metabolism:

    • Age: Metabolic capabilities may differ among different age groups.

    • Induction and Inhibition of Drug-Metabolizing Enzymes:

    • Inducers enhance enzyme activity while inhibitors reduce activity, affecting overall drug metabolism.

    • First-Pass Effect: Rapid inactivation of certain oral drugs as they pass through the liver.

    • Nutritional Status: It can affect enzyme functions.

    • Competition Between Drugs: Certain drugs may compete for the same metabolic pathways, affecting their metabolism rates.

  • Enterohepatic Recirculation:

    • Cycle involving the liver, bile, duodenum, and back to the liver, affecting drug availability.

Excretion

  • Renal Drug Excretion:

    • Steps in Renal Drug Excretion:

    1. Glomerular Filtration

    2. Passive Tubular Reabsorption: Highly lipid-soluble drugs may be reabsorbed.

    3. Active Tubular Secretion: Active transport mechanisms push drugs into urine.

    • Factors that Modify Renal Drug Excretion:

    • pH-Dependent Ionization: Affects ionization state and, consequently, excretion.

    • Competition for Active Tubular Transport: Multiple drugs competing for the same transporters.

    • Age: Renal function changes with age.

  • Non-Renal Routes of Drug Excretion:

    • Breast Milk: Potential risks for nursing infants.

    • Other Non-Renal Routes: Include respiratory, biliary, etc.

Time Course of Drug Responses

  • Plasma Drug Levels:

    • Critical for understanding therapeutic and toxic responses.

    • Clinical Significance of Plasma Drug Levels:

    • Minimum Effective Concentration (MEC): Below this level, therapeutic effects do not occur.

    • Toxic Concentration: Levels that may induce toxic effects.

    • Therapeutic Range: The range between MEC and toxic concentration.

  • Single-Dose Time Course:

    • Provides insights into the initial response of the drug.

  • Drug Half-Life:

    • Time taken for the amount of drug in the body to decline by 50%.

  • Drug Levels Produced with Repeated Doses:

    • After repeated administration, levels gradually rise, reaching plateau levels.

    • How Plateau Drug Levels are Achieved: Approximately 4 half-lives are required to reach steady state.

    • Time to Plateau: Is independent of dosage size, affecting height of plateau based on dosage.

    • Ways to Reduce Fluctuations in Drug Levels:

      • Administer smaller doses at shorter intervals, use continuous infusion, or depot preparations.

    • Loading Doses vs. Maintenance Doses:

      • A loading dose may be used to rapidly achieve effective levels, especially for drugs with long half-lives.

  • Decline from Plateau:

    • After administration is discontinued, approximately 94% of the drug will be eliminated within four half-lives, emphasizing the importance of understanding half-lives in dosing schedules.