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Questions and Answers
Which factor has the least influence on the distribution of hydrophilic drugs?
Which factor has the least influence on the distribution of hydrophilic drugs?
Large molecules are more likely to remain in the extracellular fluid rather than enter the plasma.
Large molecules are more likely to remain in the extracellular fluid rather than enter the plasma.
True
What is the term used to describe the reversible transfer of a drug between the blood and the extravascular fluids?
What is the term used to describe the reversible transfer of a drug between the blood and the extravascular fluids?
Drug Distribution
Drugs that are lipophilic tend to have a _____ volume of distribution as they readily diffuse into tissues.
Drugs that are lipophilic tend to have a _____ volume of distribution as they readily diffuse into tissues.
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Match the factors affecting drug distribution with their descriptions.
Match the factors affecting drug distribution with their descriptions.
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Which of the following statements accurately describes the concept of volume of distribution (Vd)?
Which of the following statements accurately describes the concept of volume of distribution (Vd)?
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Acidic drugs generally have lower tissue binding than basic drugs.
Acidic drugs generally have lower tissue binding than basic drugs.
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What is the typical volume of distribution for a drug that is primarily retained in the vascular compartment?
What is the typical volume of distribution for a drug that is primarily retained in the vascular compartment?
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Drugs with a volume of distribution greater than 20L can penetrate in various __________.
Drugs with a volume of distribution greater than 20L can penetrate in various __________.
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Which drug is an example of one that has a volume of distribution approximately equal to the extracellular compartment?
Which drug is an example of one that has a volume of distribution approximately equal to the extracellular compartment?
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Match the drug to its primary compartment based on its volume of distribution:
Match the drug to its primary compartment based on its volume of distribution:
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Competitive drug displacement can occur when two drugs bind to the same plasma protein.
Competitive drug displacement can occur when two drugs bind to the same plasma protein.
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Name one consequence of plasma protein binding on drug efficacy.
Name one consequence of plasma protein binding on drug efficacy.
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Which plasma protein primarily binds acidic drugs?
Which plasma protein primarily binds acidic drugs?
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Covalent bonds in drug-protein binding are typically reversible.
Covalent bonds in drug-protein binding are typically reversible.
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What is the term for the equilibrium present between free and bound drug molecules in plasma?
What is the term for the equilibrium present between free and bound drug molecules in plasma?
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___ is the factor that affects the fraction of unbound drug in plasma among different drugs.
___ is the factor that affects the fraction of unbound drug in plasma among different drugs.
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Match the drug binding proteins with the type of drugs they bind:
Match the drug binding proteins with the type of drugs they bind:
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What can lead to competitive drug displacement?
What can lead to competitive drug displacement?
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Higher free drug concentration results in a larger percentage of drug being bound to plasma proteins.
Higher free drug concentration results in a larger percentage of drug being bound to plasma proteins.
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Name one biological factor that influences drug distribution in the body.
Name one biological factor that influences drug distribution in the body.
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Study Notes
Drug Distribution
- Drug distribution is the reversible transfer of a drug between the blood and the body's extravascular fluids and tissues (e.g., fat, muscle, brain tissue).
- Drugs enter the bloodstream after absorption.
- Drugs move from plasma across capillary membranes into interstitial space then across cell membranes into intracellular fluid.
- Factors affecting drug distribution include chemical factors and biological factors.
Chemical Factors
- Molecular Weight: Very large molecules remain in plasma; large molecules typically remain in extracellular fluid.
- Binding to plasma proteins: Primarily albumin; hydrophilic/ionized drugs distribute in extracellular space, influenced by pKa (ionization constant). Lipophilic compounds easily diffuse into tissues, yielding high volume of distribution.
Biological Factors
- Blood flow to tissues: Initial blood flow is determined by organ perfusion (e.g., lungs (14 ml/min/g), kidneys (4 ml/min/g), heart (1 ml/min/g), liver (1 ml/min/g); Modified by tissue affinity (e.g., thiopental-- muscle/fat; chlorpromazine--liver; lead--bone).
- Capillary: Determined by porosity (pore size).
Plasma Proteins
- Plasma mainly consists of ~90% water, ~8% plasma proteins, and ~2% other organic/inorganic species.
- Types of plasma proteins: albumin, globulins (α₁, α₂, β, γ), and fibrinogen.
Binding of Drug to Proteins
- Many drugs bind to plasma proteins due to low water solubility.
- When in circulation, a fraction of drug molecules binds to plasma proteins (e.g., albumin); a fraction remains unbound.
- Plasma protein binding is always in equilibrium, regardless of drug amount in circulation.
Drug-Protein Binding Effects on Drug Distribution
- A fraction of a drug binds to plasma proteins, another fraction remains free.
- Free drug + protein = Drug-Protein Complex.
- Key locations for drug action/effects (Absorption, Systemic circulation, Tissue reservoirs, Biotransformation, Excretion)
Major Drug-Binding Proteins in Plasma
- Albumin: Binds mostly acidic drugs.
- α₁-acid glycoprotein: Binds mostly basic drugs.
- Lipoproteins/Cortisol-binding globulin (transcortin): Binds mostly neutral drugs.
Factors Affecting Binding
- Quantity of drug bound depends on free drug concentration, protein concentration, and affinity for binding sites.
- Percentage bound = (bound drug/total drug) * 100.
- The fraction of unbound drug in plasma varies widely among drugs.
Types of Bonds in Drug-Protein Binding
- Reversible: weak chemical bonds (hydrogen bonds, van der Waals forces). Binding can be saturable at high drug concentrations, competitive displacement resulting.
- Irreversible: covalent chemical bonds (accounting for certain toxicities of some drugs at high doses, e.g., acetaminophen).
Relevance of Drug-Protein Binding
- Drug bound to protein is pharmacologically inactive.
- Drugs bound to proteins do not cross cell membranes.
- Bound drugs affect distribution, metabolism, and excretion.
Factors Affecting Drug-Protein Binding
- Drug physicochemical properties and concentration.
- Protein physicochemical properties and concentration.
- Displacement by co-administered drugs (e.g., salicylic acid displaces warfarin).
Consequences of Strong Plasma Protein Binding
- Competitive displacement of other drugs/endogenous compounds.
- Pathophysiology leading to altered plasma protein levels.
- Decreased protein levels increase free drug concentration.
- Increased protein levels decrease drug effect.
- Delayed elimination and onset of effect.
Protein Binding - Competitive Displacement of Drugs
- Drugs that bind to and compete for one of two sites on albumin (Site I and Site II)
Protein Binding: Competitive Displacement of Drugs (cont.)
- Binding sites are not substrate-specific.
- Two or more drugs compete for the same binding sites, hence free forms of the substances to cause therapeutic and/or adverse effects.
- Case study: Warfarin (anticoagulant) is highly protein bound (98%) and takes a low dose, for example, 0.1 mg compared to a 5 mg dose. Therefore, Aspirin will displace Warfarin.
Extent of Drug Binding to Proteins
- Extensive binding (>90%) examples: glipizide, furosemide, nicardipine, digitoxin, ibuprofen, naproxen, diazepam, midazolam, ketoconazole, ceftriaxone, fluconazole, and gentamicin.
- Intermediate binding (10%-90%) examples; Oral antidiabetic, Cardiovascular, NSAIDs, Hypnotic-sedatives, Anti-infectives
- Rare binding (<10%) examples; Metformin, Metoprolol, Lisinopril, Ouabain, Aspirin, Paracetamol, Phenobarbitone, Fluconazole, and Gentamicin.
Competitive Displacement of Endogenous Compounds
- Sulfonamides displace bilirubin from plasma protein.
- Free bilirubin may enter the infant brain due to underdeveloped blood-brain barrier, causing Kernicterus.
- Caution regarding use of sulfonamides in infants and pregnant women.
- Ibuprofen displaces uric acid, resulting in increased uric acid excretion (beneficial effect)
Patient Pathophysiological State and Drug-Protein Binding
- Various conditions can lead to changes in plasma protein concentrations.
- Examples: Hepatic cirrhosis, burns, nephrotic syndrome, end-stage renal disease, pregnancy, myocardial infarction, surgery, Crohn's disease, trauma, and rheumatoid arthritis.
Pathophysiological State of an Organ
- Renal insufficiency leads to decreased blood flow to the kidneys, reducing drug delivery and elimination, which can extend therapeutic effects or cause drug toxicity.
Changes in Plasma [Albumin]
- Infusion of plasma or albumin, decreased catabolism, increased synthesis (eg, insulin), and contraction of vascular compartment (eg, vasoconstrictors) can influence serum albumin concentrations.
- Hypoalbuminemia (low albumin) or hyperalbuminemia (high albumin) requires attention since both can affect drug interaction and distribution resulting in toxicity.
Clinical Significance of Potential Binding - Displacement Interaction and Clinical Guidance
- Criteria to asses for clinically significant interaction:
- High hepatic extraction ratio
- IV administration
- Narrow therapeutic index
Protein Binding and Delayed Onset of Action
- Only free drug is pharmacologically active; bound drug is inactive.
- Drug-binding sites on albumin and tissue stores need to be saturated for therapeutic effectiveness.
- Loading doses are initial higher doses given to saturate drug binding sites to allow free drug to reach receptors/sites of action, before dropping to a lower maintenance dose.
Drug Distribution - Reservoirs and Sequestration
- Drug reservoirs/storage sites release free drug to replenish what is lost in plasma.
- Tissues like bone, muscle, and fat can sequester drugs.
- Drug reservoirs are potential sources for toxicity, due to the release of the drug.
- Examples: Tetracycline sequesters in bone, in teeth, possibly prolonging toxicity.
Types of Reservoirs for Drugs
- Includes plasma proteins, cellular (high affinity tissues proteins), fats (highly lipid-soluble drugs), transcellular (aqueous humor, synovial fluids), bones.
Drug Reservoirs (1)
- Plasma protein binding is a source of bound drugs, this process is dynamic, governed by law of mass action.
- Cellular sequestration takes place intracellularly in greater concentrations than extracellular, long-term administration of quinacrine shows accumulation and binding is observed in the liver.
- Active transport of drugs depends on phospholipids or nucleoproteins.
Drug Reservoirs (2)
- Fat acts as a depot for highly lipid-soluble drugs, potentially prolonging effects, but also posing a risk during starvation in individuals.
- Bone can store certain drugs, potentially causing harmful effects on teeth (e.g. tetracycline).
Drug Reservoirs (3)
- Many drugs accumulate in organs like liver
- High uptake of amphiphilic drugs is present in lungs, after injection.
Drug Reservoirs (4)
- Chemical and biological factors influence drug entry into the brain, which is limited by the blood-brain barrier (BBB).
- Drugs not easily crossing the BBB (e.g., ionized, protein-bound drugs, substrates for MDR transporters) face restricted entry.
- Osmotic opening and exporters are ways to overcome the barrier.
Effects of Drug Reservoirs
- Drug reservoirs decrease drug termination and often serve as a source for redistribution.
- Thiopental is a short-acting drug acting on the brain. Distribution to high blood flow organs results in storing, and it is later stored in less vascular tissues like muscle and fat, resulting in extended action.
Distribution of Drugs to Tissues - Placenta and Fetus
- The placenta selectively blocks certain drugs, but not others.
- Many drugs diffuse across, while some require facilitated or active transport mechanisms.
- Drug crossing can impact the fetus, especially for highly hydrophilic drugs and protein-bound drugs.
Binding/Sequestration and Volume of Distribution (Vd)
- Vd is the volume of fluid that would be required to bring the amount of drug in the body down to the same concentration as found in the plasma.
- Vd is considered apparent as it does not correspond to a specific physiological volume.
- Vd depends on the distribution of the drug.
- Calculation is essential: Dose (iv)/[Plasma Drug]
Drug-Protein Binding Affects Drug Distribution
- Drug distribution (Vd) depends on the volume of the plasma, volume of tissues, and free fractions of the drug in the plasma and tissues.
- Physicochemical properties are important factors in determining Vd.
Volumes of Body Fluids
- Key volumes of body fluids include extracellular fluid (plasma, interstitial fluid), intracellular fluid, and total body water.
Drug Distribution and Compartments
- Drugs are quickly distributed throughout tissues via systemic circulation.
- Drugs reach equilibrium between blood and tissues; the body behaves as one compartment, meaning concentration isn't equal across tissues.
- Compartment models (one, two, three, multiple) are essential in pharmacokinetic study.
One Compartment Model
- A steady-state concentration is reached when the rate of drug absorption equals the rate of drug clearance.
Two-Compartment Model
- Drugs distribute quickly between a central (plasma and highly perfused tissues) and peripheral compartment.
Multiple Compartments
- Compartment 1 is considered the central compartment (plasma and highly perfused tissues) where distribution of drugs is instantaneous.
- Compartments 2 and 3 (peripheral compartments—tissues) are for slow distribution of drugs.
Volume of Distribution
- Vd can exceed total body water if the drug distributes into other tissue compartments and binds to them or otherwise is sequestered.
Vd – One Compartment Model (Calculation)
- Calculating Vd using a simple example: calculating volume of a known concentration of drug in water using known mg of drug and volume of water, resulting in the volume of distribution.
Vd – Three Compartments
- In three-compartment models, drugs distribute between water, oil, and charcoal. The calculation of the apparent volume changes between the compartments depending on the amount of drug in each of them.
- Mass balance is required showing that amount of drug in each compartment is accounted for.
Vd Comments
- The calculated apparent volume depends on the sampled fluid.
- The volume of distribution depends on host and drug/metabolite properties.
- Apparent volume does not usually reflect actual physiological volume.
- Vd is a proportionality constant relating concentration to the amount of drug in the body.
Plasma Protein Binding Determines the Distribution
- Drugs with high lipid solubility, low ionization rates, or low plasma binding have high Vd.
- Drugs are more polar, highly ionized, or exhibit high plasma binding have low Vd.
- Vd correlates inversely with the extent of protein binding.
Clinical Importance of Drug Protein Binding
- Drugs highly bound to plasma proteins have low Vd.
- They are challenging to remove with dialysis
- Capacity limitations of the protein binding capacity exist causing a potential hazard when liver disease, ureaemia, and other scenarios negatively affect albumin and other protein levels, resulting in therapeutic doses becoming toxic.
- More than one drug competing for protein binding sites may lead to displacement interactions.
- Distribution of basic drugs is affected by higher tissue binding compared to acidic drugs.
V of Some Drugs Independent of Plasma Protein Binding
- Some drugs, including desipramine, imipramine, nortriptyline, and some others, do not show the expectation of correlation between plasma protein binding and volume of distribution. This may imply there are other factors involved such as tissue binding, hence caution.
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Description
Test your knowledge on the factors influencing the distribution of hydrophilic and lipophilic drugs. This quiz covers concepts like volume of distribution, drug binding, and the characteristics of various drugs in different compartments. Perfect for students in pharmacy or medicine!
