Pharmacokinetics I: Absorption and Distribution Lecture Notes 2024 PDF

PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION Block: Foundations Block Director: James Proffitt, PhD Session Date: Tuesday, August 20, 2024 Time: 9:00 - 10:00 am Instructor: Patrick Ronaldson, PhD Department: Pharmacology Email: prona...

PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION Block: Foundations Block Director: James Proffitt, PhD Session Date: Tuesday, August 20, 2024 Time: 9:00 - 10:00 am Instructor: Patrick Ronaldson, PhD Department: Pharmacology Email: [email protected] INSTRUCTIONAL METHODS Primary Method: IM13: Lecture ☐ Flipped Session Resource Types: RE18: Written or Visual Media (or Digital Equivalent) INSTRUCTIONS Please read lecture objectives and notes prior to attending session. READINGS REQUIRED Reading: for all 4 Pharmacokinetics lectures: Chapters 3-4. Katzung BG, Masters SB, Trevor AJ. Basic & Clinical Pharmacology, 12E (2012). McGraw-Hill Medical. [AccessMedicine E-BOOK] RECOMMENDED Reading: for all 4 Pharmacokinetics lectures: Chapters 2 and 6, Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th edition, 2011. Laurence L. Brunton, Bruce A. Chabner, Bjorn C. Knollmann. [AccessMedicine E-Book] LEARNING OBJECTIVES 1. List the clinically used routes of drug administration 2. Define and use appropriately the following terms: a. Absorption b. Bioavailability c. Distribution d. Apparent Volume of Distribution 3. Explain how drugs can travel from the site of drug administration to the site of action 4. Describe how pH affects the charge of weak acids and bases and the implications of charge for drug distribution. 5. Explain how plasma protein binding can affect drug distribution between plasma and tissues. 6. Describe the relationship between dose, plasma concentration, and apparent volume of distribution. 7. Explain how apparent volume of distribution differs between lipophilic and hydrophilic drugs. Block: Foundations | RONALDSON [1 of 14] PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION CURRICULAR CONNECTIONS Below are the competencies, educational program objectives (EPOs), block goals, disciplines and threads that most accurately describe the connection of this session to the curriculum. Related Related Competency\EPO Disciplines Threads COs LOs CO-01 LO #1 MK-06: The foundations of Pharmacology EBM: Research therapeutic intervention, including Methods concepts of outcomes, treatments, and prevention, and their relationships to specific disease processes CO-01 LO #2 MK-06: The foundations of Pharmacology EBM: Research therapeutic intervention, including Methods concepts of outcomes, treatments, and prevention, and their relationships to specific disease processes CO-02 LO #3 MK-06: The foundations of Pharmacology EBM: Research therapeutic intervention, including Methods concepts of outcomes, treatments, and prevention, and their relationships to specific disease processes CO-02 LO #4 MK-01: Core of basic sciences Pharmacology EBM: Research Methods CO-02 LO #5 MK-01: Core of basic sciences Pharmacology EBM: Research Methods CO-02 LO #6 MK-06: The foundations of Pharmacology EBM: Research therapeutic intervention, including Methods concepts of outcomes, treatments, and prevention, and their relationships to specific disease processes CO-02 LO #7 MK-06: The foundations of Pharmacology EBM: Research therapeutic intervention, including Methods concepts of outcomes, treatments, and prevention, and their relationships to specific disease processes 1. INTRODUCTION Pharmacokinetics is the quantitative description of the rates of the various steps of drug disposition. It specifically deals with absorption, distribution, biotransformation (metabolism), and excretion of drugs (ADME). These processes, coupled with dosage, determine the concentration of a drug in the systemic circulation and at its sites of action and, hence, the intensity of its effects (Figure 1). Block: Foundations | RONALDSON [2 of 14] PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION Figure 1: Relationship between Pharmacokinetics and Pharmacodynamics Pharmacokinetics is how the body deals with a drug. All things are to be considered including the dose given, the route of administration, how well the drug distributes throughout the body, how a drug can be chemically altered by enzymes, and how the drug is eliminated. It differs from pharmacodynamics, which is the science that studies how a drug acts on the body to produce biological changes. Lung Heart Other Arterial Tissues Venous Blood Blood Kidney Renal Excretion Intraveno Block: Foundations | RONALDSON [3 of 14] us dosing Gut Wall Liver PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION Figure 2. Drug absorption, distribution, and elimination throughout the body. Figure 2 provides a schematic diagram of what happens to a drug once it is administered. The drug moves from its site of administration into the blood and is distributed to various organs of the body. There are two principal organs of elimination, the liver and kidneys (other organs play a more minor role including lungs, skin, gastrointestinal tract, etc.). The liver is the organ that is most often responsible for drug metabolism. After metabolism, the modified drugs can return to the blood to be excreted by the kidneys, or can be secreted into the bile and eliminated by the gastrointestinal tract. The kidneys are the primary site for excretion of a drug. The lungs are an important route for eliminating volatile chemicals, for example gaseous anesthetics. 2. DRUG ADMINISTRATION Drugs can be administered by a variety of routes. The most common are: Oral: Medications that are taken by mouth. They are absorbed from the gastrointestinal tract into the portal circulation. After passing through the liver (i.e., first pass effect), they enter the systemic circulation. Intravenous: Drugs are injected directly into the systemic circulation, on the venous side. Intramuscular: Medications are injected directly into skeletal muscle. They are then absorbed through muscle capillaries into the blood and pass into the venous circulation. Subcutaneous: Drugs are injected into subcutaneous tissue (the tissue beneath the skin). They are absorbed through capillaries into the blood and pass into the venous circulation. Block: Foundations | RONALDSON [4 of 14] PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION Transmucosal: Medications are placed in the mouth and absorbed through the oral mucosa into capillaries and into the bloodstream and pass into the venous circulation. Transdermal: Medications placed on the skin diffuse through the skin and are absorbed through subcutaneous capillaries into the venous circulation. 3. DRUG ABSORPTION Absorption describes the process by which a Maximum effective drug reaches the systemic circulation, from which the i.v. oral Drug Plasma Concentration concentration drug has access to its site of action. Delays or losses Therapeutic Range of drug during absorption may contribute to variability in drug response and, occasionally, may result in failure of drug therapy. Although the site of action Minimum effective concentration may not be in the circulation, it is only in the circulation that we can measure the amount of drug Duration on board. Therefore, when a dose of drug is Onset administered we know what dose was given and can directly measure, from the circulation, the Time concentration over time of the parent (non-metabolite) Figure 3: Blood-drug concentration drug (Figure 3). We then can determine a number of after an i.v. or oral dose things over time that include time of “onset” (i.e., minimal amount of drug that needs to be in circulation that results in a therapeutic effect), therapeutic range (i.e., the minimum of drug in circulation to produce an effect and the maximum amount needed in which there is no more effect no matter how high the dose) and the duration of action (i.e., the time period in which a drug produces therapeutic effects) (Figure 3). For routes of administration other than intravenous, a drug needs to move across one or more biological membranes in order to gain access to the circulation. In some cases, drugs travel across membranes by facilitated transport processes mediated by drug transport proteins. More often, they cross membranes by passive diffusion governed by the concentration gradient of the drug. The rate of passive diffusion is proportional to the magnitude of the concentration gradient and is governed by Fick’s law. Fick’s Law of Diffusion predicts the rate of movement of molecules across a barrier: Rate = (C1 – C2) x Permeability Coefficient x Surface Area Barrier Thickness where C1 is the concentration on the side of administration and C2 is the concentration on the other side of the membrane. Drugs that cross membranes by transporters or by endocytosis or pinocytosis are NOT governed by Fick’s Law. Block: Foundations | RONALDSON [5 of 14] PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION Another important factor that determines the rate of diffusion of a drug across a membrane is molecular charge. When drugs are weak acids or weak bases and therefore exist in equilibrium between charged and uncharged forms, the uncharged forms are those that are capable of diffusing across membranes since charged compounds are very insoluble in the hydrophobic lipid core of the membrane. The ionization of a drug depends on the Henderson-Hasselbalch equation: pH = pKa + log (Unprotonated/Protonated) for acids pH = pKa + log [A-]/[AH] for bases pH = pKa + log [B]/[BH+] Lumen Gastric Blood Lumen Gastric Blood Mucosa Mucosa A- A- B - A- A- A B B B A- B B A- A- B A- H+ H+ H+ H+ BH+ AH BH+ AH BH+ AH AH BH+ AH BH+ BH+ AH BH+ + AH BH+ BH pH = 2.5 Weak Base pH = 7.5 pH = 2.5 Weak Acid pH = 7.5 Example is Aspirin pKa = 3.5 Example is Methamphetamine pKa = 10 At a pH of 3.5 = 50% AH and 50% A- At a pH of 10 = 50% B and 50% BH+ At a pH of 2.5 = 90% AH and 10% A- At a pH of 2.5 = 99% BH+ and 1% B Low pH favors absorption of acids from Stomach & opposes absorption of bases It is important to note that most currently marketed drugs are either weak acids or weak bases. Two factors affect the fraction of a weakly acidic drug that is in the uncharged form. The weaker the acid (higher pKA), the greater the fraction of drug that will be uncharged. The lower the pH, the higher the fraction of drug that will be uncharged. Figure 4: Movement of a weak acid or weak base across a biological membrane Block: Foundations | RONALDSON [6 of 14] PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION In understanding absorption of drugs, it is important to consider that not all body compartments are of neutral pH. For example, the stomach has a pH range of 1.9-2.6 while the intestine has a pH range of 6.4-7.6. Blood pH is tightly buffered by the carbonic anhydrase system and is approximately 7.4. Therefore, the relative pH in different physiological compartments can greatly affect the distribution of a weakly acidic or weakly basic drug across a biological membrane. For a weak acid, a more alkaline environment on one side of the membrane will tend to shift the equilibrium toward the dissociated (i.e., charged) form by reducing the concentration of free protons. Therefore, the concentration of the uncharged protonated drug will be low and the rate of movement from that side will be low, compared to the rate of movement from the opposite, more acidic side. This will tend to “trap” a weakly acidic drug in the alkaline environment. The concept of charged drug being “trapped” on one side of a membrane plays an important clinical role in cases of drug overdose. An overdose of amphetamine (a weak base) can be more rapidly removed from the body by trying to acidify the urine. Amphetamine overdose patients can be given intravenous ammonium chloride (NH4Cl), which is filtered by the kidney. In the renal tubule, NH4Cl acts as a proton donor, an effect that decreases pH of the urine. Therefore, amphetamine in the presence of protons becomes charged and “trapped” within the kidney tubule and eventually excreted (Figure 5). Pyrimethamine is a weak base of pKa = 7.0 Urine pH can be adjusted from 5.5 to 8.0 To acidify urine use NH4CL To alkaline urine use NaHCO3 NH4CL Overdose of a Weak Base Acidify urine using NH4CL Overdose of a Weak Acid Alkalinize urine using NaHCO3 Ionized Not Reabsorbed Rapidly excreted Figure 5: Ion “trapping” by the kidney NOTE: When NH4Cl or NaHCO3 are used to increase elimination of drugs, the resultant change in pH will occur in the urine and not in the blood. Blood pH is tightly controlled by the carbonic anhydrase buffer system and cannot be easily decreased or increased. Urine does not have such a buffer system and, therefore, its pH can be modified by pharmacological methods. ORAL ADMINISTRATION Block: Foundations | RONALDSON [7 of 14] PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION Oral ingestion is the most common method of drug administration. The first consideration in thinking about oral absorption is the formulation of the drug. Oral dosage formulations include tablets, capsules, suspensions, or elixirs. These differences in formulation can lead to differences in oral absorption, which is based upon the need for drug liberation and dissolution. A drug must be released from a solid form and dissolved in gastrointestinal fluids before it is capable of crossing the gut membrane and reaching the blood stream. As shown in Figure 6, a drug must pass sequentially from the gastrointestinal lumen, through the gut wall, and through the liver, before entering the general circulation. It passes through the liver because blood perfusing nearly all gastrointestinal tissues drains into the liver via the portal vein with the exception of within the mouth and the rectum. GI lumen GI Wall (CYP 3A4) Portal Vein Liver (Many CYPs) To Heart via Hepatic Vein & into Systemic To Exit Metabolism or Metabolism or Circulation PGP excretion into Biliary excretion GI lumen Figure 6: Oral Absorption of a Drug Drugs can cross biological membranes either by passive diffusion or by carrier-mediated transport. Large or polar drugs usually move through the tight junctions between epithelial cells (i.e., paracellular permeability). Permeability for these drugs drops off sharply with molecular weights greater than 500 Da. Smaller and less polar drugs may pass through cell membranes (i.e., transcellular permeability) The best examples of carrier-mediated transport are -lactam and cephalosporin antibiotics, which are substrates for the proton-driven dipeptide transporter. In this process, there are several possible sites for loss of an orally administered drug. One is the gastrointestinal lumen where decomposition of a drug may occur due to chemical instability or metabolism by luminal enzymes (CYP3A4) or bacteria. Or, if drugs are poorly absorbed, they will remain in the gastrointestinal lumen and pass into the stool. Intestinal epithelial cells contain various proteins that lower drug uptake by pumping a wide range of xenobiotics (compounds, like medications, which come from outside of the body) out of the cell and back into the intestinal lumen via an energy dependent process. The most important of these efflux pumps is P-glycoprotein, an ATP-dependent transporter that limits bioavailability and tissue penetration of hundreds of currently marketed drugs. Active drug efflux contributes to the low and variable absorption of a variety of drugs, including cyclosporine, Block: Foundations | RONALDSON [8 of 14] PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION ranitidine, and verapamil. Another mechanism for loss of an orally administered drug is metabolism within the gastrointestinal tract by enzymes localized to the gut wall (CYP3A4). Figure 7: Hepatic-Portal System Drug molecules that do cross the gut wall enter the portal circulation and are delivered to the liver (Figures 6 and 7). For many drugs, a significant percentage of drug molecules are metabolized by the liver BEFORE accessing the systemic circulation. This loss is called pre- systemic or first-pass metabolism. It is most commonly referred to as the first-pass effect. Drugs that are subject to a large first-pass effect are typically administered by other (non-oral) routes. Bioavailability = the fraction of drug absorbed into the systemic circulation Bioavailability (F) = AUC (route) x 100 AUC (i.v.) Intravenous AUC Plasma Conc. (Cp) 20 Oral AUC 10 0 5 10 15 Time (h) Figure 8: Oral Bioavailability of a drug Following oral administration, the concentration of drug in the blood will rise, reach a maximum (Cmax) and then decline when elimination processes become dominant. The relatively long time until Cmax is reached is due to the time required for the absorption processes to occur. Block: Foundations | RONALDSON [9 of 14] PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION The total area under the plasma concentration-time curve (area under the curve, AUC) can be used to evaluate the extent of absorption (Figure 8). Comparing the AUC after oral administration to that after intravenous administration allows us to determine the oral bioavailability (F), an index of the fraction of drug which gets absorbed into the bloodstream. The bioavailability may range from 0 to 1. It is equal to zero when a drug does not reach the systemic blood. It approaches 1 when a drug is completely absorbed into systemic blood. An example of a drug with low oral bioavailability due to extensive first-pass hepatic elimination is nitroglycerin, which is given for angina (chest pain due to inadequate myocardial blood flow). Nitroglycerin tablets are therefore taken sublingually (dissolved under the tongue and absorbed into the blood across the oral mucosa). Blood retuning from the oral mucosa goes directly into the systemic circulation and does not pass through the liver (i.e., no first pass effect). Drugs that undergo substantial first-pass metabolism tend to have large between-patient variations in the concentration of drug in the systemic circulation and subsequent large variations in drug response. Absorption of drugs undergoing substantial first-pass metabolism can be greatly influenced by alterations in hepatic biotransformation caused by the administration of other drugs, a form of drug-drug interaction. For example, the botanical St. John’s Wort decreases the systemic circulation of a number of pharmaceuticals by inducing the drug metabolizing enzyme CYP3A4. OTHER ROUTES OF ADMINISTRATION When drugs are injected intravenously as a bolus, the blood concentration rises very rapidly and the bioavailability is virtually 1. Drugs administered by other routes must cross membranes so there is a delay in the achievement of the maximum plasma concentration (Cmax) and bioavailability is almost always less than 1. 4. DISTRIBUTION After a drug is absorbed into the circulation, it is distributed throughout the body, possibly biotransformed (metabolized), and eventually eliminated. A fundamental hypothesis of clinical pharmacokinetics is that a relationship exists between the plasma or blood drug level and the pharmacological or toxic responses to the drug. In most cases, the concentration of drug in systemic blood is related to the concentration of drug at its sites of action. Block: Foundations | RONALDSON [10 of 14] PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION SITE OF ACTION OTHER TISSUES Receptor-Bound Free Free Bound BLOOD Absorption Excretion Free drug Protein- Bound drug Biotransformation Excretion Metabolites Figure 9: Inter-relationship between absorption, distribution, biotransformation, and excretion of a drug. After a drug is absorbed or injected into the bloodstream, it may be distributed into extravascular extracellular and intracellular fluids (Figure 9). Diffusion into the interstitial compartment occurs rapidly because of the highly permeable nature of capillary endothelial membranes. Initially drugs distribute from the blood to heart, liver, kidney, and other well-perfused organs. Delivery of drug to muscle, skin, and fat is slower. It is the free fraction of drug that distributes from blood to other tissues. Distribution may be limited by drug binding to plasma proteins, particularly to albumin for acidic drugs and to alpha- 1 acid glycoprotein for basic drugs, because an agent that is extensively and strongly bound to plasma proteins is in low free concentration in plasma. As a result of intracellular/extracellular pH gradients, binding to intracellular constituents, or partitioning into lipid, drugs may accumulate in tissues in higher concentrations than the free concentration in plasma. VOLUME OF DISTRIBUTION. Block: Foundations | RONALDSON [11 of 14] PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION Apparent volume of distribution (Vd) is a parameter that is used to describe drug distribution. The volume of distribution relates the amount of drug in the body to the concentration (C) of drug in the plasma (the extracellular portion of the blood).1 Volume of distribution (Vd) is the volume that relates the amount of drug in the body to the plasma concentration (units = volume) Vd = Amount of drug in the body (mg) Plasma drug concentration (mg/L) Vd = 20 = 10 2 Vd = 20 = 1.1 18 Figure 10: Diagram demonstrating two different drugs (A or B) demonstrating very different volumes of distribution. A has a very large volume of distribution while drug B has a relatively small volume of distribution. Apparent volume of distribution is a constant relating that relates amount of drug administered to the plasma concentration. It can be used to calculate the amount of drug that needs to be administered to reach a desired (therapeutic) plasma concentration. The units of this constant are units of volume, so it came to be called volume of distribution. It almost never relates to the volume of any anatomical portion of the body. For example: If 0.5 mg of digoxin (also known as digitalis is used in the treatment of various heart conditions, i.e., atrial fibrillation and heart failure) were in the body of a 70-kg person, an initial plasma concentration of approximately 1.02 ng/ml would be observed. Dividing the amount of drug given to the body by the plasma concentration yields a volume of distribution for digoxin of about 490 liters (0.5mg/0.00102mg/L = 490 L). This volume is more than 7 times greater than the total body volume (i.e., approximately 66 L). This occurs because digoxin is relatively hydrophobic; it distributes preferentially to muscle and adipose tissue and to its specific receptors, leaving a very small amount of drug in the plasma. Figure 11 illustrates the wide range of apparent volumes of distribution. Although volume of distribution almost never relates to the volume of any anatomical portion of the body, its size can sometimes be rationalized based on properties of the drug or a characteristic of the person. 1 Plasma concentration is the parameter most commonly measured in pharmacokinetics. It is used as an indirect index of the concentration of drug at the site of action. Block: Foundations | RONALDSON [12 of 14] PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION Factors that cause drug to be retained in the blood tend to keep the volume of distribution small and those that tend to cause drug to move out of the blood make it larger. Large volumes of distribution suggest extensive tissue distribution and/or tissue binding. For example, a lipophilic drug would be predicted to have a larger volume of distribution in an obese person due to distribution into body fat. Small volumes of distribution imply that the drugs do not have high affinity tissues and/or that the drugs are extensively bound to plasma proteins. It is important to consider that a small volume of distribution does not mean that a drug will be less effective. For example, the anticonvulsant drug phenytoin is considered to have a small volume of distribution; however, the percentage of drug that is able to leave the systemic circulation can distribute to the brain and effectively control seizures. Importantly, the volume of distribution can be used to calculate the dose of drug that needs to be administered to achieve a desired plasma concentration: Dose = Vd X Cp Vd = volume of distribution Cp = plasma concentration NOTE: Vd is sometimes expressed in units of volume (i.e., L) and sometimes in units of volume per body weight (i.e., L/kg). It is important to pay close attention to the units of measurement for Vd when calculating the required dose of a drug. For example, if the reported Vd is in units of L/kg, you would need to multiply Vd by the patient’s body weight in order to calculate the correct dose. Block: Foundations | RONALDSON [13 of 14] PHARMACOKINETICS I: ABSORPTION AND DISTRIBUTION Figure 11: The apparent volumes of distribution for selected drugs. Block: Foundations | RONALDSON [14 of 14]