3.3 Drug distribution and plasma protein binding

Drug distribution is a crucial part of pharmacokinetics, moving drugs from the bloodstream to tissues and organs. It affects how drugs work, including when they start, how long they last, and how strong their effects are. This process helps determine the right dosing and predict potential drug interactions.

Plasma protein binding is when drug molecules attach to blood proteins. Only unbound drugs can enter cells and have effects. Highly protein-bound drugs last longer but may not reach tissues easily. This binding can lead to drug interactions and affect how drugs work in different patients.

Drug distribution in pharmacokinetics

Process and importance of drug distribution

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• Drug distribution moves drugs from bloodstream to tissues and organs after absorption
• Crucial component of pharmacokinetics influences drug concentration at target site and overall therapeutic effect
• Affects onset, duration, and intensity of drug's pharmacological effects
• Essential for determining appropriate dosing regimens and predicting potential drug-drug interactions
• Influenced by factors like blood flow, lipid solubility, and protein binding
  • These factors determine drug's ability to cross biological membranes and reach its site of action
• Examples of distribution patterns:
  • Lipophilic drugs (diazepam) distribute widely throughout the body
  • Hydrophilic drugs (gentamicin) have more limited distribution, primarily in extracellular fluid

Physicochemical properties and barriers affecting distribution

• Molecular size impacts ability to cross membranes
  • Smaller molecules (ethanol) distribute more easily than larger ones (heparin)
• Lipid solubility determines ease of membrane penetration
  • Highly lipophilic drugs (THC) cross membranes readily
  • Hydrophilic drugs (metformin) have limited membrane permeability
• Ionization state affects distribution across membranes
  • Unionized forms generally cross membranes more easily
• Physiological barriers limit drug distribution to certain tissues
  • Blood-brain barrier restricts entry of many drugs into the central nervous system
  • Placental barrier regulates drug transfer between mother and fetus
• Specialized transport systems influence distribution
  • P-glycoprotein pumps certain drugs (digoxin) out of cells or across barriers

Plasma protein binding in drug distribution

Mechanism and impact of protein binding

• Reversible attachment of drug molecules to blood proteins (albumin, α1-acid glycoprotein)
• Only unbound (free) fraction of drug diffuses across cell membranes and exerts pharmacological effects
• Bound fraction acts as reservoir, prolonging drug action
• Degree of plasma protein binding affects:
  • Volume of distribution
  • Clearance
  • Half-life
• Highly protein-bound drugs have:
  • Longer duration of action due to slower elimination
  • Limited tissue penetration
• Examples of highly protein-bound drugs:
  • Warfarin (99% bound)
  • Diazepam (98% bound)

Clinical implications of protein binding

• Competition for binding sites leads to drug-drug interactions
  • Displacing a highly bound drug increases its free fraction and potential for toxicity
• Changes in plasma protein concentrations impact free drug fraction
  • Hypoalbuminemia in liver disease can increase free fraction of protein-bound drugs
• Altered protein binding affects drug dosing and monitoring
  • May require dose adjustments for highly bound drugs in certain patient populations
• Examples of drug-drug interactions due to protein binding displacement:
  • Warfarin displaced by NSAIDs, increasing bleeding risk
  • Phenytoin displaced by valproic acid, potentially causing toxicity

Factors influencing drug distribution

Physiological and patient-specific factors

• Tissue perfusion and regional blood flow affect distribution rate and extent
  • Highly perfused organs (brain, liver, kidneys) receive higher initial drug concentrations
• Patient-specific factors alter distribution patterns:
  • Age affects body composition and organ function
    • Neonates have higher body water content, altering distribution of water-soluble drugs
    • Elderly patients may have reduced perfusion to certain organs
  • Body composition impacts drug distribution
    • Obesity increases volume of distribution for lipophilic drugs (benzodiazepines)
  • Disease states alter plasma proteins, tissue perfusion, and membrane permeability
    • Cirrhosis reduces albumin production, affecting protein-bound drug distribution
• Tissue binding and sequestration lead to drug accumulation in specific areas
  • Tetracyclines accumulate in bones and teeth
  • Amiodarone concentrates in adipose tissue

Drug-specific properties and interactions

• Lipid solubility determines tissue penetration
  • Highly lipophilic drugs (cannabinoids) distribute extensively into fatty tissues
• Molecular size affects distribution across membranes
  • Large molecules (heparin) have limited tissue distribution
• Ionization state influences membrane crossing
  • Weak acids distribute more readily in acidic environments
  • Weak bases accumulate in more alkaline compartments
• Drug-drug interactions alter distribution patterns
  • P-glycoprotein inhibitors (verapamil) increase brain penetration of certain drugs
• Examples of drugs with unique distribution characteristics:
  • Gentamicin concentrates in renal cortex, increasing nephrotoxicity risk
  • Chloroquine accumulates in melanin-containing tissues (eyes, skin)

Volume of distribution and clinical significance

Concept and calculation of volume of distribution

• Theoretical volume relating amount of drug in body to plasma concentration
• Expressed in liters or liters per kilogram of body weight
• Calculated as ratio of total drug amount in body to plasma drug concentration
• Formula: $Vd = \frac{Amount\:of\:drug\:in\:body}{Plasma\:drug\:concentration}$
• Indicates extent of drug distribution in body
  • Large Vd suggests extensive tissue distribution or sequestration
  • Small Vd indicates limited distribution outside plasma compartment
• Examples of drugs with varying Vd:
  • Gentamicin: small Vd (0.25 L/kg), primarily in extracellular fluid
  • Digoxin: large Vd (7-8 L/kg), extensively distributed in tissues

Clinical applications and significance

• Used to determine loading doses for drugs
  • Especially important for rapid achievement of therapeutic concentrations
  • Loading dose calculation: $Loading\:dose = Vd \times Desired\:plasma\:concentration$
• Helps predict potential for drug-drug interactions and tissue accumulation
  • Drugs with large Vd may have prolonged effects after discontinuation
• Indicates likelihood of drug removal by elimination processes
  • Drugs with small Vd (gentamicin) more easily removed by hemodialysis
• Changes in Vd impact drug dosing regimens
  • Particularly important for drugs with narrow therapeutic indices
  • Altered Vd in specific patient populations requires dose adjustments
    • Increased Vd in edematous patients may require larger doses of hydrophilic drugs
    • Obesity increases Vd for lipophilic drugs, potentially requiring weight-based dosing
• Examples of clinical scenarios affected by Vd:
  • Aminoglycoside dosing in patients with altered fluid status
  • Antipsychotic dose adjustments in obese patients