WK 5 - 3 Pharmacokinetics_Distribution

Pharmacokinetics - Distribution Notes

Course Overview

Course: PC2204Instructor: Robiul Islam, PhD, Pharmacy, College of Medicine and Dentistry

Learning Objectives

1. Drug Distribution: Explain the fundamental concepts of drug distribution across various body fluid compartments, which include:

   • Extracellular Water: The fluid outside of cells, which comprises plasma and interstitial fluid.

   • Interstitial Fluid: The fluid that occupies the spaces between cells, facilitating nutrient and waste exchange.

   • Intracellular Water: The fluid within cells, critical for cellular metabolism.

   • Plasma Volume: The liquid component of blood that carries cells and proteins throughout the body.

   • Transcellular Fluid: Specialized fluids (e.g., cerebrospinal fluid, synovial fluid) found in compartments like the brain and joints.

2. Volume of Distribution (Vd): Define and calculate the volume of distribution, a parameter that describes how extensively a drug disperses throughout body fluids.

3. Pharmacokinetic Calculations: Apply the formula Vd = Q / Cp (where Q is the drug amount and Cp is the plasma concentration) in pharmacokinetic scenarios.

4. Drug Binding Dynamics: Discuss the importance of drug binding to plasma proteins such as albumin and alpha-1-acid glycoprotein, and its implications for drug efficacy and potential toxicity.

Key Concepts on Drug Distribution

Definition and Mechanisms

• Drug Distribution: The process by which drugs equilibrate between circulation and various tissues. It shows how drugs move from the plasma to interstitial and intracellular spaces.

• Equilibrium: Achieved when concentrations of the drug in the blood and target tissues become equal, which is vital for drug action.

Distribution Patterns

• Variability in Distribution: Different drugs exhibit distinctive rates and patterns of distribution based on their physicochemical properties and the physiological state of the patient.

• Accessibility: Most drugs that are absorbed enter the bloodstream and can diffuse into the extracellular fluid due to permeable capillary walls.

Fluid Compartments and Volumes

• Extracellular Fluid: Approx. 15L consisting of interstitial fluid and lymph.

• Plasma Volume: Roughly 3L, providing a critical environment for drug interactions.

• Total Body Water: About 40L, including both intracellular water and interstitial fluid, highlighting the complexity of drug distribution.

• Body compartment characteristics impact drug behavior and efficacy, dictating therapeutic choices.

Factors Affecting Drug Distribution

Physicochemical Properties: Influence drug passage across membranes, such as:

• Molecular Weight: Heavier molecules may penetrate tissues less efficiently.

• Lipophilicity: Lipophilic drugs can cross cellular membranes, enhancing tissue penetration.

• Ionization: Affects solubility and membrane permeability, dictated by the pH of the environment.

• Presence of Transporters: Specific molecules facilitate the movement of drugs across cell membranes.

Physiological Factors: Additional aspects include:

• Cardiac Output: Impacts how quickly blood reaches different tissues, affecting distribution times.

• Regional Blood Flow: Varies across organs; highly perfused organs (like the liver and kidneys) receive drugs faster than less perfused areas (like muscle and fat).

• Capillary Permeability: Variances across tissue types influence how easily drugs enter cells.

Clinical Relevance

Understanding the Rate of Drug Distribution is crucial for:

• Predicting therapeutic effects and potential side effects.

• Anticipating interactions with other drugs that might either enhance or inhibit distribution by altering plasma protein binding.

• Adjusting dosages in patients with altered body composition, such as those who are obese or elderly.

Considerations for Plasma Protein Binding

• Major Plasma Proteins: Albumin and alpha-1-acid glycoprotein play significant roles in drug transport and availability, impacting pharmacological response.

• Binding Dynamics: The interaction between free drugs and these proteins is reversible, emphasizing the need to monitor plasma protein levels in clinical settings, as conditions like liver disease can alter these levels, increasing free drug fractions and potential toxicity.

Drug Partitioning

• Drug Interaction with Blood Cells: Some drugs exhibit preferences for blood cell components, influencing their pharmacokinetics.

• Pharmacokinetic Models: Understanding one-compartment vs. two-compartment models provides insight into how drugs distribute and equilibrate in various tissues post-administration.

Volume of Distribution Insights

• The Volume of Distribution (Vd) is a critical parameter in pharmacokinetics that informs dosing strategies:

  • Helps determine loading and maintenance doses.

  • Assists in understanding drug behavior in the body and its therapeutic