PhARM

Pharmacokinetic Principles

• Pharmacokinetics is the quantitative study of absorption, distribution, metabolism, and excretion of drugs and their metabolites. These processes determine the drug concentration at the site of action.
• It details the relationship between drug dose and drug concentration in the body or at the site of action.
• Clinically, it describes how the plasma concentration of a drug changes over time, assuming plasma equilibrates with an effect compartment to produce a pharmacodynamic effect.

Objectives

• The presenter aims to review the concept of pharmacokinetics and specific pharmacokinetic parameters.
• They will review pharmacokinetic rates of reactions, types of pharmacokinetics, and relevant parameters for anesthesia.
• Compartmental modeling is also included.

Pharmacokinetics - Absorption

• Absorption is the passage of drug molecules through physiological/biological barriers to reach the vascular system.
•  It describes the process of a drug being absorbed into the body, typically from an extravascular site. (e.g., oral administration)
• Systemic absorption is influenced by chemical structure and properties of the drug, the drug product, dosage form, and anatomy and physiology at the absorption site.
• The non-ionized form of a drug is more lipid-soluble and can cross the lipophilic cell membrane more easily.
• Factors influencing absorption rate include cell membrane characteristics, surface area at the absorption site, pH, and blood flow to the site.

Passage of Drugs Across Cell Membranes - Passive Diffusion

• Passive diffusion is the main mechanism by which most drugs cross cell membranes. 
• It's a movement of drug molecules from an area of higher concentration to an area of lower concentration, and it doesn't require energy. 
• Factors influencing passive diffusion include concentration gradient, surface area, diffusion coefficient, and membrane thickness. Passive diffusion is governed by Fick's law.

Passage of Drugs Across Cell Membranes - Active Transport

• Active transport is a carrier-mediated process that moves drugs against a concentration gradient.
• This process requires energy.
• Active transport is important in renal and biliary secretion of drugs.

Passage of Drugs Across Cell Membranes - Facilitated Diffusion

• Facilitated diffusion is a carrier-mediated process that moves drugs along a concentration gradient.
• It doesn't require energy, but it may involve a protein carrier.

Ionization

• Many drugs in anesthesia are weak acids or weak bases and exist in both ionized and nonionized forms.
• Weak acids and bases are administered as salts.
• The ionized form of a drug tends to remain in the filtrate, while the nonionized form is more likely to be reabsorbed.
• Ionization is influenced by the pH of the environment.

Characteristics of Ionized and Nonionized Drug Molecules

Identifying Weak Acids and Weak Bases from Drug Names

• Weak acids donate H+ ions and form salts with cations
• Weak bases accept H+ ions and form salts with anions.

Henderson-Hasselbalch Equation

• The Henderson-Hasselbalch equation can predict the degree of ionization of a drug in solution.
• It relates drug ionization to the pH of the solution and the drug's pKa.
• For weak acids and bases, the pH determines the relative amount of ionized and nonionized form.

Effect of pH on Drug Absorption and Distribution

• Non-ionized drugs are more lipid-soluble and easily cross cell membranes
•  Changes in pH affect the ionization of drugs. A drug's relative ionization or non-ionization is altered by a change in pH
• Weak acid drugs are more nonionized at lower pH, and weak base drugs are more nonionized at higher pH.

Calculation Questions and pH Relationships

• Drugs' ionization/non-ionization is affected by the pH related to the pKa of the drug, and this affects drug absorption
• The form in which the drug predominates is determined by whether the pH is higher than or lower than the drug's pka.

Ion Trapping Mechanism

• A concentration difference of total drug can be generated.
• The nonionized, lipid-soluble form of a drug crosses cell membranes readily
• The ionized form is less prone to cross cell membranes, therefore it will be trapped on one side of the cell membrane where it is more concentrated
• This can lead to toxicities depending on the difference in pH

Classification of Drug Routes of Administration

• Routes of administration include intravascular (e.g., IV, intra-arterial) and extravascular (e.g., oral, intramuscular, transdermal).
• The choice of route affects the bioavailability (i.e., how much of an administered dose reaches a target site)
• Absorption by extravascular routes is important for drugs to reach the circulation and action sites

Oral Administration

• Oral administration is a common route, but absorption can be unpredictable.
• It is affected by the rate and extent of drug absorption in different regions of the gastrointestinal tract; it can have variable absorption.
• The duodenum is generally the optimum site for absorption.

Transmucosal Administration

• Rapid onset.
• Bypass the hepatic first pass effect in sublingual & buccal administrations.

Rectal Administration

• Useful for unconscious or vomiting patients.
• Depending on the location within the rectum, the drug can or cannot bypass the first-pass effect.

Transdermal Administration

• Sustained drug release with reduced fluctuations in plasma levels is an advantage.
• A good transdermal medication will take advantage of lipid solubility; a low molecular weight (important property) and suitable pH.

Intravascular Administration

• Delivers drugs directly into the bloodstream, resulting in 100% bioavailability
• It is the fastest onset route.
• Administration can cause local tissue irritation.

Pharmacokinetics - Distribution

• Distribution is the movement of drug molecules from blood into tissues and organs, with lipid solubility being the most important factor. 
• Determinants of distribution include lipid solubility, protein binding, blood flow, molecular size, and drug ionization.
•  Only the free, unbound drug is available to cross membranes.

Volume of Distribution (Vd)

• Vd is a hypothetical volume used to relate the amount of drug in the body to the measured concentration in the plasma.
• It is calculated as the dose of drug divided by the resulting plasma concentration.
• Vd is affected by factors such as protein binding.
• Drugs with high protein binding tend to have lower Vd.

Protein Binding

• Protein binding affects drug distribution by limiting the amount of free drug available to cross membranes into tissues. 
• Vd is inversely proportional to protein binding: High protein binding leads to a smaller Vd, while low protein binding leads to a larger Vd
• This is clinically important because alterations in protein binding can significantly affect drug concentration 

Pharmacokinetics - Metabolism

• Metabolism is the chemical conversion of a drug into different compounds (frequently inactive metabolites or active ones.)
• Drug metabolism is typically catalyzed by enzymes in the liver (CYP 450), though other tissues play roles (e.g., kidneys, plasma, etc.)
• Common enzymes in drug metabolism include CYPs and others involved with oxidation, reduction, and hydrolysis.
• Metabolism can produce inactive compounds for easier excretion, or active compounds with unique effects.

Metabolic Pathways

• Phase I reactions (functionalization) introduce or expose functional groups to increase polarity and prepare for further metabolism or excretion.
• Phase II reactions (conjugation) involve the addition of an endogenous substrate onto a drug or metabolite, increasing polarity for kidney or bile excretion.

Cytochrome P-450 System

• CYP 450 enzymes are important in drug metabolism, particularly oxidation reactions
• They are found in the liver, small intestine, kidneys, brain, and lungs.
• Induction or inhibition of these enzymes can alter the metabolism of other drugs, resulting in clinically relevant interactions
• Drugs that have the ability to activate (inducers) or deactivate (inhibitors) this system should be known by health professionals to aid in drug administration

Excretion

• Excretion is the irreversible removal of a drug from the body.
• Major organs of excretion include the kidneys (water-soluble drugs and metabolites), liver (biliary excretion), and lungs (volatile anesthetics).

Clearance (CI)

• Clearance is the volume of plasma or blood cleared of a drug per unit of time
•  Factors influencing clearance can include blood flow, enzyme activity, and drug binding
• Clearance is directly proportional to the drug dose and blood flow of the clearing organ, but is inversely proportional to the drugs half life
•  Different elimination processes, such as zero-order kinetics and first-order kinetics, may have different drug clearance processes.

Hepatic Clearance

•  Hepatic clearance is the volume of blood cleared of a drug per unit of time
•  High ER drugs' clearance is almost exclusively dependent on blood flow to the liver, whereas low ER drugs' clearance is largely independent of blood flow.
• Protein binding and enzyme activity are other factors that influence liver clearance of drugs.

Renal Clearance

• The kidney filters and excretes drugs, metabolites, and other substances from the body
•  Renal clearance is dependent on glomerular filtration, active tubular secretion, and passive tubular reabsorption
•  Factors influencing renal clearance include blood flow, drug properties, and urine pH change.

One-Compartmental Models

• In one-compartment models, the body is viewed as a single compartment.
•  Assumptions include instantaneous distribution, first-order elimination, & consistency of drug concentration at the site of action and in the plasma after equilibrium.
• Useful for calculating drug concentrations and estimating doses for IV drugs

Multi-Compartmental Models

• In these models, the body is divided into multiple compartments.
• They are useful for describing the distribution and elimination of drugs with extensive distribution into peripheral tissues.

Redistribution

• Redistribution of drugs from the central to peripheral compartments can affect both duration and site of activity and effect on peripheral tissues, which can have clinical implications
• The rate of transfer declines with aging

Context-Sensitive Half-Time

• Describes the time required for the plasma drug concentration to reduce by 50% after discontinuing a drug infusion
• It's a useful parameter for drugs given continuously and critically relevant as a parameter in the clinical setting
• Important for drugs with extensive peripheral distribution, because duration of effect can be prolonged/ prolonged distribution phase

Zero-Order Kinetics

• Zero-order elimination refers to a constant amount of drug eliminated per unit of time, irrespective of concentration
• Usually occurs when enzymes or transporters involved in drug metabolism or excretion become saturated

First-Order Kinetics

• First-order elimination refers to a constant percentage of a drug eliminated per unit of time.
• Usually a direct relationship between drug concentration and rate of elimination, which can be used for calculation purposes