2.2 Distribution

Drug distribution is a crucial aspect of pharmacokinetics, determining how drugs move through the body after administration. It involves the transfer of drugs from the bloodstream to various tissues and organs, affecting their efficacy and potential side effects.

Understanding distribution is key to optimizing drug dosing and predicting therapeutic outcomes. Factors like plasma protein binding, tissue affinity, and physiological barriers all play roles in how drugs spread throughout the body and reach their target sites.

Routes of drug administration

• The route of drug administration is the path by which a drug is introduced into the body, which can have a significant impact on the drug's efficacy, safety, and patient compliance
• Different routes of administration are chosen based on factors such as the drug's physicochemical properties, desired onset and duration of action, and patient-specific considerations

Oral administration

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• Most common and convenient route of drug administration
• Drugs are swallowed and absorbed through the gastrointestinal tract (stomach and intestines)
• Advantages include ease of administration, patient compliance, and cost-effectiveness
• Disadvantages include potential for first-pass metabolism, variable absorption, and gastrointestinal side effects (nausea, vomiting)

Parenteral administration

• Involves the delivery of drugs directly into the body, bypassing the gastrointestinal tract
• Routes include intravenous, intramuscular, subcutaneous, and intradermal administration
• Advantages include rapid onset of action, precise dosing, and avoidance of first-pass metabolism
• Disadvantages include invasiveness, risk of infection, and requirement for trained personnel to administer

Topical administration

• Application of drugs directly to the skin or mucous membranes (eyes, nose, ears)
• Aims to achieve local effects or systemic absorption through the skin
• Advantages include targeted delivery, reduced systemic side effects, and ease of use
• Disadvantages include limited absorption, potential for local irritation, and difficulty in controlling the dose

Rectal administration

• Delivery of drugs through the rectum and absorbed through the rectal mucosa
• Used when oral administration is not feasible (unconscious patients, nausea, vomiting)
• Advantages include avoidance of first-pass metabolism and rapid absorption
• Disadvantages include limited patient acceptability, variable absorption, and potential for rectal irritation

Inhalation

• Delivery of drugs directly into the lungs via inhalation
• Commonly used for respiratory disorders (asthma, COPD)
• Advantages include rapid onset of action, targeted delivery to the lungs, and reduced systemic side effects
• Disadvantages include difficulty in controlling the dose, potential for airway irritation, and requirement for specialized devices (inhalers, nebulizers)

Factors affecting route selection

• Physicochemical properties of the drug (solubility, stability, molecular size)
• Desired onset and duration of action
• Target site of action (local vs systemic effects)
• Patient factors (age, comorbidities, preference, compliance)
• Formulation and availability of the drug

Absorption of drugs

• Absorption refers to the process by which a drug moves from its site of administration into the bloodstream
• The extent and rate of absorption depend on various factors related to the drug, the dosage form, and the patient

Mechanisms of absorption

• Passive diffusion: Movement of drug molecules across membranes from high to low concentration gradient, driven by the concentration difference
• Active transport: Energy-dependent process involving carrier proteins that move drugs against their concentration gradient
• Facilitated diffusion: Carrier-mediated transport that moves drugs along their concentration gradient without energy expenditure
• Endocytosis: Uptake of drug molecules by the invagination of the cell membrane, forming vesicles that transport the drug into the cell

Factors affecting absorption

• Physicochemical properties of the drug (lipophilicity, solubility, ionization, molecular size)
• Dosage form and formulation (tablets, capsules, solutions, suspensions)
• Site of absorption (gastrointestinal tract, skin, mucous membranes)
• Gastrointestinal factors (pH, motility, presence of food, enzymes, transporters)
• Patient factors (age, gender, genetic variations, disease states)

Bioavailability

• Fraction of the administered dose that reaches the systemic circulation unchanged
• Determined by the extent of absorption and first-pass metabolism
• Influenced by the route of administration, dosage form, and patient factors
• Oral bioavailability is often lower compared to parenteral routes due to incomplete absorption and first-pass metabolism

First-pass metabolism

• Metabolism of a drug by the liver or intestinal enzymes before it reaches the systemic circulation
• Occurs primarily with orally administered drugs absorbed from the gastrointestinal tract
• Can significantly reduce the bioavailability of drugs that undergo extensive first-pass metabolism (propranolol, lidocaine)
• Avoided by parenteral routes of administration or by using prodrugs that bypass first-pass metabolism

Absorption rate vs extent

• Absorption rate refers to the speed at which a drug is absorbed into the bloodstream
• Absorption extent refers to the total amount of drug absorbed into the bloodstream
• Both rate and extent of absorption influence the onset, intensity, and duration of drug action
• Factors affecting absorption rate include drug dissolution, gastrointestinal motility, and blood flow at the absorption site
• Factors affecting absorption extent include drug solubility, permeability, and first-pass metabolism

Distribution of drugs

• Distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues
• The extent and rate of distribution depend on various factors related to the drug, the body, and the specific tissues involved

Factors affecting distribution

• Physicochemical properties of the drug (lipophilicity, ionization, molecular size, protein binding)
• Tissue perfusion and blood flow
• Tissue affinity and binding (target receptors, storage sites)
• Membrane permeability and transport mechanisms
• Physiological barriers (blood-brain barrier, blood-testis barrier, blood-placenta barrier)

Plasma protein binding

• Reversible binding of drug molecules to plasma proteins (albumin, α1-acid glycoprotein, lipoproteins)
• Influences the distribution, elimination, and pharmacological effects of drugs
• Bound fraction is pharmacologically inactive and unable to cross membranes or interact with receptors
• Unbound (free) fraction is responsible for the pharmacological effects and is available for distribution and elimination
• Competition for protein binding sites can lead to drug interactions and altered pharmacokinetics

Tissue binding

• Binding of drug molecules to specific or nonspecific sites within tissues
• Can serve as a reservoir for the drug, prolonging its effects or delaying its elimination
• Specific binding to target receptors is responsible for the drug's pharmacological actions
• Nonspecific binding to proteins, lipids, or other macromolecules can influence the distribution and storage of the drug
• Examples of tissue binding include the binding of digoxin to cardiac muscle and the binding of thiopental to adipose tissue

Blood-brain barrier

• Selective barrier formed by tight junctions between endothelial cells of the brain capillaries
• Restricts the entry of many drugs and solutes into the central nervous system (CNS)
• Lipophilic and small molecules can cross the blood-brain barrier more easily than hydrophilic and large molecules
• Influx and efflux transporters (P-glycoprotein) can further regulate the entry and exit of drugs from the CNS
• Disruption of the blood-brain barrier in certain pathological conditions (inflammation, tumors) can alter drug distribution

Volume of distribution

• Theoretical volume that would be necessary to contain the total amount of a drug at the same concentration found in the plasma
• Reflects the extent of drug distribution throughout the body
• Calculated as the ratio of the amount of drug in the body to the plasma concentration at steady state
• Drugs with high volume of distribution (>1 L/kg) are extensively distributed in tissues (digoxin, chloroquine)
• Drugs with low volume of distribution (<0.3 L/kg) are primarily confined to the bloodstream (heparin, gentamicin)

Drug transport mechanisms

• Drug transport mechanisms are the processes by which drugs move across biological membranes and enter or exit cells and tissues
• These mechanisms can be broadly classified into passive and active processes, each with its own subtypes and characteristics

Passive diffusion

• Movement of drug molecules across membranes from high to low concentration gradient, driven by the concentration difference
• Does not require energy input or carrier proteins
• Rate of diffusion depends on the drug's lipophilicity, size, and concentration gradient
• Occurs primarily with small, lipophilic, and uncharged molecules (oxygen, ethanol, steroids)

Active transport

• Energy-dependent process involving carrier proteins (transporters) that move drugs against their concentration gradient
• Requires ATP hydrolysis or coupling with an electrochemical gradient (sodium or proton gradient)
• Exhibits saturation kinetics and can be inhibited by specific transporter inhibitors
• Examples include the uptake of glucose by SGLT1 and the efflux of drugs by P-glycoprotein

Facilitated diffusion

• Carrier-mediated transport that moves drugs along their concentration gradient without energy expenditure
• Involves specific carrier proteins that undergo conformational changes to facilitate drug movement
• Exhibits saturation kinetics and can be inhibited by competitive substrates
• Examples include the transport of nucleosides by nucleoside transporters and the uptake of catecholamines by norepinephrine transporter

Ion channels

• Transmembrane proteins that form pores or channels allowing the selective passage of ions (sodium, potassium, calcium, chloride)
• Can be gated by changes in membrane potential (voltage-gated channels) or by binding of ligands (ligand-gated channels)
• Some drugs can act as ion channel modulators, either blocking or enhancing ion flow (local anesthetics, benzodiazepines)
• Ion channels play a crucial role in the generation and propagation of electrical signals in excitable cells (neurons, muscle cells)

Endocytosis and exocytosis

• Endocytosis is the uptake of drug molecules by the invagination of the cell membrane, forming vesicles that transport the drug into the cell
• Can be receptor-mediated (clathrin-mediated endocytosis) or non-specific (pinocytosis)
• Exocytosis is the release of drug molecules from the cell by the fusion of intracellular vesicles with the cell membrane
• Plays a role in the secretion of neurotransmitters, hormones, and other signaling molecules
• Some drugs can exploit endocytosis for targeted delivery (antibody-drug conjugates, nanoparticles)

Drug reservoirs

• Drug reservoirs are tissues or sites in the body where drugs can accumulate and be stored for extended periods
• These reservoirs can influence the distribution, elimination, and pharmacological effects of drugs

Adipose tissue

• Lipophilic drugs can accumulate in adipose tissue due to their high affinity for lipids
• Serves as a storage site for drugs, prolonging their elimination and potential for toxicity
• Examples of drugs that accumulate in adipose tissue include thiopental, chloroquine, and DDT
• Accumulation in adipose tissue can lead to delayed onset and prolonged duration of action

Bone

• Some drugs can bind to bone matrix or accumulate in bone due to their affinity for calcium or other bone components
• Can serve as a reservoir for the drug, releasing it slowly over time
• Examples of drugs that accumulate in bone include tetracyclines, bisphosphonates, and lead
• Accumulation in bone can lead to delayed elimination and potential for long-term toxicity

Transcellular vs interstitial fluid

• Transcellular fluid refers to the fluid inside the cells, while interstitial fluid refers to the fluid in the spaces between the cells
• The distribution of drugs between transcellular and interstitial fluid depends on their physicochemical properties and transport mechanisms
• Lipophilic drugs can readily cross cell membranes and distribute into the transcellular fluid
• Hydrophilic drugs tend to remain in the interstitial fluid and have limited access to the intracellular space
• The relative distribution of drugs between these compartments can influence their pharmacological effects and elimination

Redistribution of drugs

• Redistribution is the process by which a drug moves from one tissue or compartment to another over time
• It can occur due to changes in blood flow, tissue binding, or concentration gradients

Factors affecting redistribution

• Tissue perfusion and blood flow: Drugs can redistribute from highly perfused tissues (brain, heart, kidneys) to less perfused tissues (muscle, fat) as the concentration gradient changes over time
• Tissue binding: Drugs can redistribute from tissues with high binding affinity (target sites) to tissues with lower binding affinity as the concentration of free drug changes
• Physicochemical properties: Lipophilic drugs can redistribute more readily between tissues compared to hydrophilic drugs
• Plasma protein binding: Changes in plasma protein binding (due to displacement or saturation) can alter the free drug concentration and drive redistribution

Consequences of redistribution

• Termination of drug action: Redistribution can lead to the rapid decline of drug concentration at the site of action, resulting in the termination of pharmacological effects (thiopental, lidocaine)
• Prolonged duration of action: Redistribution to tissues with high binding affinity or low perfusion can prolong the duration of drug action (diazepam, digoxin)
• Delayed toxicity: Redistribution from storage sites (fat, bone) can lead to delayed toxicity or rebound effects as the drug is slowly released over time (chloroquine, lead)
• Altered pharmacokinetics: Redistribution can change the apparent volume of distribution and elimination half-life of drugs, affecting their dosing and monitoring

Barriers to drug distribution

• Barriers to drug distribution are anatomical or physiological structures that restrict the entry or movement of drugs into specific tissues or compartments
• These barriers can influence the distribution, efficacy, and toxicity of drugs

Blood-brain barrier

• Tight junctions between endothelial cells of brain capillaries, restricting paracellular transport
• Presence of efflux transporters (P-glycoprotein) that actively pump drugs out of the brain
• Limits the entry of many drugs into the central nervous system (CNS), protecting the brain from potential toxins
• Lipophilic and small molecules can cross the blood-brain barrier more easily than hydrophilic and large molecules

Blood-testis barrier

• Formed by tight junctions between Sertoli cells in the seminiferous tubules of the testes
• Protects the developing germ cells from exposure to drugs and toxins
• Can limit the distribution of drugs into the testes, potentially affecting their efficacy in treating testicular conditions
• Some drugs (testosterone, FSH) can cross the blood-testis barrier and exert their effects on spermatogenesis

Blood-placenta barrier

• Consists of the syncytiotrophoblast layer of the placenta, which separates the maternal and fetal circulations
• Regulates the transfer of drugs and nutrients from the mother to the fetus
• Lipophilic drugs can cross the blood-placenta barrier more easily than hydrophilic drugs
• Some drugs (thalidomide, isotretinoin) can cross the barrier and cause fetal toxicity or teratogenicity

Physiochemical properties vs barriers

• The ability of drugs to cross these barriers depends on their physicochemical properties
• Lipophilicity: Lipophilic drugs can cross barriers more easily due to their ability to partition into cell membranes
• Molecular size: Small molecules (<500 Da) can pass through barriers more readily than larger molecules
• Ionization: Unionized drugs can cross barriers more easily than ionized drugs, as they are more lipophilic
• Protein binding: Highly protein-bound drugs may have limited ability to cross barriers, as only the free fraction can partition into membranes

Pharmacokinetic models

• Pharmacokinetic models are mathematical representations of the processes of drug absorption, distribution, metabolism, and excretion (ADME) in the body
• These models help to describe and predict the time course of drug concentrations in the body and guide dosing decisions

One-compartment model

• Simplest pharmacokinetic model, treating the body as a single, homogeneous compartment
• Assumes rapid and uniform distribution of the drug throughout the body
• Drug elimination follows first-order kinetics, with a constant fraction of the drug being eliminated per unit time
• Characterized by a single volume of distribution and elimination rate constant
• Suitable for drugs with rapid distribution and elimination (aspirin, ethanol)

Two-compartment model

• Divides the body into two compartments: a central compartment (plasma and well-perfused tissues) and a peripheral compartment (poorly perfused tissues)
• Assumes that drug distribution between the compartments follows first-order kinetics
• Characterized by two volumes of distribution (central and peripheral) and two rate constants (distribution and elimination)
• Suitable for drugs with more complex distribution patterns and slower elimination (digoxin, gentamicin)

Multi-compartment models

• Extend the two-compartment model to include additional compartments representing specific tissues or organs
• Used for drugs with complex distribution patterns or targeting specific sites of action
• Examples include physiologically based pharmacokinetic (PBPK) models, which incorporate anatomical and physiological parameters to describe drug disposition
• Require more extensive data and computational resources compared to simpler models

Noncompartmental analysis

• Model-independent approach that does not assume a specific compartmental structure
• Estimates pharmacokinetic parameters directly from the observed drug concentration-time data
• Calculates area under the curve (AUC), clearance, and mean residence time (MRT) without fitting the data to a specific model
• Useful for drugs with complex or unknown distribution patterns or when limited data