Pharmacokinetics: Introduction to ADME, Absorption, and Administration Routes

Pharmacokinetics: Introduction and Absorption

Introduction to Pharmacokinetics

  • Pharmacokinetics describes the actions of the body on the drug, as previously covered in Lesson 9.
  • The study of pharmacokinetics involves four basic stages, commonly abbreviated as ADME:
    • Absorption: The initial process where medication enters the body and travels from the site of administration into the blood, specifically systemic circulation.
    • Distribution: The process by which the medication is spread throughout the body.
    • Metabolism: The breakdown or biotransformation of a drug molecule (e.g., the liver making drugs more water-soluble for easier excretion). This will be covered in detail in the second lecture.
    • Excretion: The final process where the body eliminates the drug and its metabolites (waste products) from the body.

Absorption

  • Definition: Absorption is the first crucial stage where a drug moves from its administration site into systemic circulation to reach its target site.
  • To achieve a therapeutic effect, a drug must cross several biological barriers.
  • Bioavailability (F):
    • Defined as the fraction of the administered dose that reaches its target site or systemic circulation, from which it can exert its effect.
    • For intravenous (IV) administration, bioavailability is F=1 (100%) because the drug is introduced directly into systemic circulation.
    • Bioavailability, and thus absorption, varies significantly depending on the route of administration.

Routes of Administration

  • Oral Administration (PO or per os - by mouth):
    • Advantages: Safe, convenient, cost-effective, and most commonly used.
    • Disadvantages:
      • Requires patient compliance (cooperation to take medication as prescribed).
      • Highly variable bioavailability due to numerous factors.
      • Primary site of absorption: Small intestine.
      • Transporters in the intestinal epithelium can expel the drug, preventing absorption.
      • Portal vs. Systemic Circulation:
        • Portal circulation: Blood flow from the digestive organs directly to the liver. Here, the liver processes nutrients and filters potentially harmful substances before blood enters systemic circulation.
        • Systemic circulation: Blood flow from the heart, through the lungs for oxygenation, back to the heart, and then distributed throughout the rest of the body.
      • First-Pass Metabolism (or First-Pass Effect): When drugs enter the portal circulation and reach the liver, they can be metabolized (broken down or biotransformed). This often results in a reduced amount of active drug reaching systemic circulation and, consequently, the target site. This will be explained further in the second lecture.
      • Other factors affecting oral bioavailability:
        • Insolubility of some drugs due to low pH levels.
        • Destruction of some drugs by digestive enzymes.
        • Vomiting due to irritation of the GI mucosa.
        • Irregularities in absorption in the presence of food and other drugs.
      • Bioavailability for oral drugs can be as low as F=0.05 (5%).
  • Parenteral Injection (IV, Subcutaneous (SC), Intramuscular (IM)):
    • Advantages:
      • Rapid and predictable drug effect.
      • More precise dosage control.
      • Suitable when drugs are poorly absorbed in the GI tract.
      • Useful for unconscious, uncooperative, or patients unable to take anything by mouth.
    • Bioavailability: IV administration has 100% bioavailability (F=1). SC and IM administration typically have a minimum bioavailability of F ext{ or } rac{75}{100} (75%), which is significantly higher than many oral routes.
    • Disadvantages:
      • Injectable medications can be costly.
      • Injection sites can be painful or become infected.
      • Can be difficult for patients to self-administer.
      • SC injections specifically: Not suitable for large volumes or tissue-irritating drugs, as this can cause pain, necrosis, and sloughing of skin and surrounding tissues.
  • Transmucosal Drug Administration:
    • Involves drug absorption through a mucosal epithelium via transcellular or paracellular passive diffusion directly into systemic circulation.
    • Advantages: Can bypass or significantly reduce first-pass metabolism, avoid GI degradation, provide rapid onset of action, and are easy for patients or caregivers to administer.
    • Examples:
      • Sublingual (below the tongue), Translingual (on top of the tongue), and Buccal (in the cheek): Common during end-of-life care.
      • Intranasal: Commonly used for nasal decongestants (colds, allergies).
      • Rectal: Safe and convenient for pediatric and geriatric patients. Note: First-pass metabolism is not entirely bypassed; approximately 50% of the drug absorbed from the rectum will bypass the liver.
      • Vaginal: Most commonly used for local rather than systemic effects (e.g., treating local infections or hormone-responsive conditions).
  • Transdermal Administration:
    • Dependent on the surface area of application and the drug's lipid solubility, as drugs must permeate skin layers by passive diffusion to reach systemic circulation.
    • Advantages: Results in slow, steady drug delivery without the first-pass effect. Particularly useful when medication needs to be administered over a longer period to control symptoms.
    • Examples: Transdermal patches for tobacco smoking withdrawal, motion sickness, hormone replacement therapy, birth control, and pain medication.
  • Topical Administration:
    • In contrast to transdermal, topical administration is typically for a localized effect, not systemic.
    • Examples: Topical antibiotic ointment for superficial skin wounds, eye drops for ocular conditions.
  • Inhalation Administration:
    • Drugs are absorbed through the pulmonary epithelium.
    • Advantages: Rapid and direct access to systemic circulation due to the lung's large surface area. Also allows for local application of a drug at its desired site of action.
  • Intraosseous Administration:
    • A rapid and temporary method for delivering drugs and fluids directly into the bone marrow.
    • Typically used in pediatric or emergency cases when IV access is difficult or impossible.
  • Intrathecal Administration:
    • Useful when drugs need to reach the Central Nervous System (CNS - brain and spinal cord) rapidly.
    • Bypasses the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier, which normally impede drug entry into the CNS due to p-glycoprotein efflux pumps and other transporters.
    • Drugs (e.g., for anesthesia or chemotherapy) are injected directly into the spinal subarachnoid space (which contains CSF, located between meningeal layers surrounding the spinal cord and brain).

Interpreting Concentration-Time Curves

  • A graphical representation showing the concentration of a drug in the blood plasma over time, from administration until full excretion.
  • Absorption Phase: The period during which drug concentration in plasma increases as the drug enters systemic circulation faster than it is eliminated.
  • Cmax: The peak (maximum) drug concentration achieved in the plasma.
  • Tmax: The time it takes for the drug to reach its Cmax.
  • Lag Period: The initial period after administration until the plasma drug concentration reaches the Minimum Effective Concentration (MEC).
  • Minimum Effective Concentration (MEC): The lowest plasma drug concentration required to produce a therapeutic effect. Below MEC, the drug is considered subtherapeutic.
  • Onset of Action: The time from drug administration until the plasma drug concentration reaches MEC.
  • Duration of Action: The length of time the plasma drug concentration remains above the MEC.
  • Termination of Action: The point at which the drug concentration falls below MEC, typically associated with metabolism and excretion.
  • Post-Absorption / Elimination Phase: The period after Cmax where the drug is eliminated from the body faster than it is absorbed, causing plasma drug concentration to decrease.
  • Elimination: Encompasses all processes (notably metabolism and excretion) that remove a drug from the body.
  • Maximum Safe Concentration (MSC): The upper limit of drug concentration; above this level, the drug is considered toxic.
  • Therapeutic Window: The range of plasma drug concentrations between the MEC and the MSC, where the drug provides efficacy without causing adverse side effects.
  • Route of Administration and Curves:
    • IV Administration: Shows an immediate Cmax (T_{max}=0 minutes) and 100% bioavailability, resulting in the highest Cmax. This also means the highest risk of adverse effects due to rapid and high peak concentration.
    • Lag Period/Tmax Comparison: The lag period and Tmax are progressively greater for IV < IM < SC < PO administration.

Area Under the Curve (AUC)

  • Definition: The total area under the concentration-time curve.
  • Significance: Represents the total exposure of the body to the drug over time and is used to measure a drug's overall effect.
  • Provides a single numerical value quantifying the overall amount of a drug that has entered the systemic circulation, accounting for both its concentration and the duration it remains in the body.
  • A larger AUC signifies that the body has been exposed to a higher overall concentration of the drug for a longer duration.
  • AUC values are a key method for measuring and comparing bioavailability.

Bioavailability and Bioequivalence

  • Absolute Bioavailability:
    • The fraction of an administered dose that reaches its target site or systemic circulation relative to an intravenous (IV) dose (which has 100% bioavailability).
    • Determined by comparing the AUC of a non-IV dose (e.g., oral tablet) to the AUC of an IV dose.
  • Relative Bioavailability:
    • The fraction of an administered dose that reaches its target site or systemic circulation relative to a different formulation (e.g., comparing a capsule to a liquid formulation of the same drug).
  • Bioequivalence:
    • Established using AUC values.
    • Drug products are considered bioequivalent if they are therapeutically equivalent.
    • For a generic drug to be deemed bioequivalent to a brand-name drug, it must contain the same active ingredients and be identical in strength, concentration, formulation, and route of administration.

Learning Objectives Covered

After this lecture, you should be able to:

  • Define the stages of pharmacokinetics (ADME).
  • Compare various routes of administration.
  • Explain bioavailability, first-pass effect, the distinction between portal and systemic circulation, and bioequivalence.
  • Interpret concentration-time curves, utilizing concepts such as lag period, MEC, therapeutic window, Cmax, Tmax, absorption and elimination phases, onset of action, duration of action, and AUC.
  • Distinguish between absolute and relative bioavailability and interpret AUC values.