Pharmacokinetics: Volume of Distribution Quiz

Introduction to Pharmacokinetics

• Pharmacokinetics is the quantitative study of how drugs are absorbed, distributed, metabolized, and excreted (ADME) by the body.
• This process determines the drug concentration at the site of action.
• It is crucial for understanding drug efficacy and toxicity.

Objectives

• Review the concept of pharmacokinetics
• Examine specific pharmacokinetic parameters
• Review pharmacokinetic rates of drug reactions
• Understand different types of pharmacokinetics
• Evaluate pharmacokinetic parameters in the context of anesthesia
• Review compartmental modeling

Pharmacokinetics

• The quantitative study of the drug's absorption, distribution, metabolism, and excretion.
• Describes how the body affects the dosage of a drug.
• Focuses on the relationship between drug dose and drug concentration in the plasma or at the site of action.

Pharmacokinetic Measurements/Concepts

• Bioavailability: The fraction of the administered dose that reaches the systemic circulation.
• Volume of distribution (Vd): A theoretical volume that reflects the apparent distribution of a drug in the body.
• Clearance (Cl): The volume of plasma cleared of a drug per unit of time.
• Elimination half-life: The time it takes for the drug concentration to decrease by 50%.
• Context-sensitive half-time (t1/2): The time it takes for the plasma concentration of a drug given by continuous infusion to decrease by 50% after stopping the infusion. It is more relevant to continuous drug infusions like those used in anesthesia..
• Effect-site equilibration time: The time required for the drug to reach equilibrium at the site of action in the body.

Absorption

• Absorption is the passage of drug molecules throughout physiological barriers before reaching systemic circulation.
• Critical for extravascular administration (e.g., oral, intramuscular).
• Factors affecting absorption include the drug's chemical structure, drug form, drug release system, anatomical site, and physiological functions.
• Passive diffusion is the main process for drug absorption when there’s a concentration gradient. Passive diffusion does not require energy.
• Factors influencing passive diffusion include membrane surface area, membrane thickness, diffusion coefficient, concentration gradient, and blood flow rate.
• Active transport and facilitated diffusion are also mechanisms for absorption, using proteins and requiring energy when needed.

Ionization

• Many anesthetic drugs are weak acids or bases, existing in both ionized and nonionized forms in the body.
• The degree of ionization depends on the pH and pKa.
• Ionized form generally is not permeable to cell membranes.
• The Henderson-Hasselbalch equation is used to predict the degree of ionization.

Characteristics of Nonionized and Ionized Drug Molecules

Identifying Weak Acids and Weak Bases

• Weak acids donate hydrogen ions.
• Weak bases accept hydrogen ions.
• The cation or anion prefixes in drug names (e.g., "sodium," "chloride") indicate whether they are weak acids or bases.

The Henderson-Hasselbalch Equation

• The equation relates pH to pKa, determining ionization.
• A drug's ionization affects its ability to cross membranes, affecting absorption and onset of action.

Effect of pH and pKa on Drug Absorption and Distribution

• The pH of the environment affects the ionization state of a drug, which impacts its ability to cross cell membranes and penetrate tissues.
• Acidic environment favors nonionized drug.
• Alkaline environment favors ionized drug.
• Changes in pH can significantly affect drug absorption, distribution, and ultimately clinical response.

Calculations of Volume of Distribution (Vd)

• V=Dose / Concentration
• This provides a representation of the drug distribution in the body.
• This is used for estimations, not precise measurements.

Protein Binding

• Protein binding affects distribution.
• Only unbound (free) drug can cross membranes.
• Highly protein-bound drugs have a lower Vd.
• Protein binding affects drug clearance.

Metabolism

• Biotransformation, the chemical conversion of a drug.
• The primary result is the conversion to water soluble metabolites, enhancing elimination.
• Liver is the primary organ for drug metabolism using mainly CYP450 enzymes.

Pathways of Drug Metabolism

• Phase I functionalization reactions introduce functional groups, increasing polarity.
• Phase II conjugation reactions modify the structure to further enhance water solubility and facilitate excretion.

CYP 450 System

• Important enzymes for drug metabolism often located in the liver.
• Inhibitors and inducers can cause significant drug-drug interactions

Excretion

• The removal of drug and metabolites from the body.
• Kidney is typically the primary excretion organ.
• Factors like pH and drug polarity affect excretion.
• Elimination is typically through renal excretion (glomerular filtration, active tubular secretion, and passive tubular reabsorption), biliary excretion, or pulmonary (exhalation).
• Other organs can be involved in metabolism.

Clearance

• Drug elimination determined by clearance (CL), which is the rate of removal of a drug.
• Clearance depends on metabolic and excretory processes.
• Clearance depends on hepatic blood flow and hepatic extraction ratio (ER).
• Clearance is primarily determined by the liver for those drugs metabolized there.
• Higher extraction ratio for the liver indicates hepatic clearance is dependent on the blood flow to the liver, influencing how much drug is extracted.

Hepatic Clearance

• Affected by hepatic blood flow, drug binding, hepatic enzyme activity.
• High hepatic extraction ratio drugs are mostly affected by hepatic blood flow (flow rate limiting).
• Low hepatic extraction ratio drugs are mostly affected by hepatic enzyme activity.

Renal Clearance

• Primarily responsible for water soluble drugs.
• Glomerular filtration, active tubular secretion, and passive tubular reabsorption.
• Acidic urine favors excretion of weak bases; alkaline urine favors excretion of weak acids.

Biliary Excretion

• Transfer of drug and metabolites via hepatocytes to the bile.
• Drugs excreted in the bile can be reabsorbed.
• Enterohepatic recirculation prolongs the duration of action

Enterohepatic Circulation

• Cycle of drug/metabolite excretion, reabsorption from the GI tract, and re-excretion.

Compartmental Models

• Used for drug distribution and elimination in the body.
• One-compartment model: Drug distributes uniformly and clearance is constant.
• Multi-compartment model: Drug distribution involves several body compartments with variable transfer rates.; useful for understanding how drugs distribute and are eliminated more efficiently.
• Two-compartment and three-compartment Models: Two or three distinct tissue compartments.

One-Compartment Model

• Assumes instant equilibrium, first-order elimination.

Multi-Compartment Model

• Describes drug distribution/elimination through multiple compartments.

Redistribution

• Movement of drug from highly perfused tissue to less perfused tissue (e.g., muscle).
• This can affect duration of drug action.

Rate & Capacity of Tissue Uptake of Drugs

• Affected by various factors that influence tissue uptake.

Elimination Half-Life

• Time to reach 50% of concentration after absorption and distribution phase.
• Influenced by volume of distribution and clearance.

Steady-State

• Achieved when administration rate = elimination rate.
• Plasma concentrations remain constant (or relatively so).

Context-Sensitive Half-Time

• Time to reach 50% of plasma concentration decrease after stopping a continuous infusion.
• Useful in anesthesia.
• Takes into account the combined effects of distribution, metabolism, and infusion duration.

Zero-Order Kinetics

• Constant amount of drug eliminated per unit time; enzymes are saturated.

First-Order Kinetics

• Constant percentage of drug eliminated per unit time.