Drug is a crucial aspect of , 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 , , and 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 , 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, )
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 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
refers to the speed at which a drug is absorbed into the bloodstream
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)
and blood flow
Tissue affinity and binding (target receptors, storage sites)
and transport mechanisms
Physiological barriers (, , )
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 (>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
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
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 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