OIA1013 DRUG DISTRIBUTION
Understanding Drug Distribution
Definition and Overview of Drug Distribution
Drug distribution refers to the process by which a drug is dispersed throughout the body after entering systemic circulation.
It involves the movement of drugs between the blood and various tissues, including fat, muscle, and brain tissue, influencing the drug's therapeutic effects.
Drugs exist in two forms: free (active) which can cross cell membranes, and bound (inactive) to plasma proteins, limiting their distribution.
The distribution is not uniform; it varies based on the drug's properties and the body's physiological conditions.
Major Body Compartments and Their Volumes
Intracellular Fluid: Comprises 40% of body weight, approximately 28 liters, where most cellular processes occur.
Total Body Water: Accounts for 60% of body weight, roughly 42 liters in a 70 kg individual, including both intracellular and extracellular fluids.
Plasma: Represents 6% of body weight, about 4 liters, containing large molecular weight substances that bind to plasma proteins.
Extracellular Fluid: Comprises 20% of body weight, around 14 liters, facilitating drug movement between plasma and interstitial fluid.
Interstitial Volume: Accounts for 14% of body weight, approximately 10 liters, where drugs can diffuse into surrounding tissues.
Factors Influencing Drug Distribution
Physiological Factors
Regional Blood Flow: The rate of blood flow to organs affects drug distribution; organs like the heart, liver, and kidneys have high perfusion rates, leading to faster drug distribution.
Organ Size and Perfusion Rate: Larger organs with higher blood flow will receive drugs more quickly than smaller or less perfused tissues, such as adipose tissue.
Binding within Compartments: Drugs can bind to plasma proteins or extracellular components, affecting their availability and distribution.
Miscellaneous Factors: Conditions such as disease states, drug interactions, age, pregnancy, obesity, and diet can significantly alter drug distribution patterns.
Physicochemical Properties of Drugs
Molecular Size: Most drugs have a molecular weight of less than 500-600 Daltons, allowing them to cross capillary membranes easily; larger molecules may require specialized transport systems.
Degree of Ionization: The pH of blood and extravascular fluids influences drug ionization, affecting their ability to permeate cell membranes; non-ionized drugs diffuse more readily.
Partition Coefficient: This property indicates a drug's lipophilicity versus hydrophilicity; drugs that ionize at plasma pH (polar drugs) cannot easily penetrate lipid membranes.
Drug Distribution Patterns
Distribution Patterns in the Body
Drugs can be confined to the plasma compartment, distributed in the extracellular compartment, or spread throughout total body water.
Some drugs may concentrate in specific tissues, leading to localized effects or toxicity, depending on their physicochemical properties and binding affinities.
The distribution pattern is influenced by the drug's molecular size, ionization, and the presence of specialized transport mechanisms.
Summary of Factors Affecting Distribution
FactorDescriptionImpact on DistributionPermeabilityAbility of drug to cross tissue barriers based on physicochemical propertiesHigher permeability leads to faster distributionOrgan/Tissue SizeLarger organs receive drugs more quickly due to higher blood flowAffects the rate of drug reaching tissuesBinding within CompartmentsInteraction with plasma proteins or tissue componentsReduces free drug concentration in circulationMiscellaneous FactorsIncludes age, pregnancy, obesity, and dietCan alter drug metabolism and distribution
Capillary Permeability and Drug Transfer
Overview of Capillary Structure
Capillaries are small blood vessels that facilitate the exchange of substances between blood and tissues.
The size of capillaries and the presence of fenestrae (small openings) influence drug transfer through filtration.
Liver capillaries have larger fenestrae, allowing greater filtration potential compared to brain capillaries, which have smaller fenestrae.
Blood-Brain Barrier (BBB)
The BBB is a selective barrier formed by tight junctions between endothelial cells, preventing easy penetration of drugs into the CNS.
Drug penetration through the BBB is influenced by lipid solubility and ionization; highly lipid-soluble non-ionized drugs can cross easily (e.g., thiopental).
Conversely, drugs that are highly lipid-insoluble or ionized (e.g., hexamethonium) generally do not cross the BBB.
Placental Barrier
The placenta acts as a barrier between maternal and fetal circulatory systems, composed of several cell layers.
It is considered the 'leakiest' barrier, allowing many drugs to diffuse through based on lipid solubility.
Historical context: The thalidomide tragedy in the 1960s highlighted the risks of drug transfer across the placental barrier, leading to severe birth defects.
Blood-Testes Barrier and Drug Binding
Blood-Testes Barrier
Formed by tight junctions between Sertoli cells, creating a compartmentalized environment for germ cells.
This barrier restricts drug passage to protect developing sperm from potential toxins, providing an immunoprivileged environment.
Drug Binding Mechanisms
Drugs can bind to blood components (e.g., plasma proteins, blood cells) and extra-vascular tissues, affecting their distribution and action.
Plasma protein binding is reversible and can delay or prolong drug action; for example, warfarin is 97% bound to plasma proteins.
Types of Plasma Proteins
TypeCharacteristicsAlbuminPrimary serum protein for drug binding; has a strong affinity for weak acids.LipoproteinsBind lipid-soluble drugs; binding capacity varies with lipid content.Alpha1-acid glycoproteinBinds basic drugs; concentration increases with acute injury or stress.
Pharmacokinetics and Drug Elimination
Drug Elimination Processes
Drug elimination involves metabolism and excretion, which can compete with distribution to target organs.
Understanding elimination is crucial for determining drug dosing and efficacy.
Volume of Distribution (Vd)
Vd is a pharmacokinetic parameter indicating how extensively a drug distributes into body tissues versus remaining in plasma.
Formula: Volume of Distribution (L) = Amount of drug in the body (mg) / Plasma concentration of drug (mg/L).
A high Vd indicates extensive distribution into tissues, requiring higher doses to achieve desired plasma concentrations.
Implications of Vd on Drug Dosing
Drugs with a high Vd leave plasma and enter extravascular compartments, necessitating larger doses for effective plasma concentration.
Conversely, drugs with a low Vd remain in plasma, allowing for lower doses to achieve therapeutic effects.
Discussion questions
1/6
What are the key factors that influence drug distribution in the body, and how do they interact with each other?
Difficulty: Medium
2/6
How does the volume of distribution (Vd) relate to the pharmacokinetics of a drug, and what implications does it have for dosing?
Difficulty: Medium
3/6
In what ways do physiological barriers, such as the blood-brain barrier and placental barrier, affect drug distribution?
Difficulty: Hard
4/6
Discuss the role of physicochemical properties of drugs in determining their distribution patterns within the body.
Difficulty: Medium
5/6
How do disease states and physiological conditions like age and obesity impact drug distribution?
Difficulty: Hard
6/6
What is the significance of drug binding to plasma proteins in the context of drug action and distribution?
Difficulty: Easy