Bio 117 Module 2 PDF

PALAWAN STATE UNIVERSITY College of Sciences BIO 117 - BASIC PHARMACOLOGY PHARMACOKINETICS AND PHARMACODYNAMICS MODULE 2  Table of Contents Content Page Learning Objectives ………………………………………………...

PALAWAN STATE UNIVERSITY College of Sciences BIO 117 - BASIC PHARMACOLOGY PHARMACOKINETICS AND PHARMACODYNAMICS MODULE 2  Table of Contents Content Page Learning Objectives ……………………………………………………….. 2 Overview ………………………………………………………………........ 3 Initial Activity ……………………………………………………………..... 4 I. Pharmacokinetics……………………………………....……..……….. 5 Learning Check 2.1....................................................................... 23 II. Pharmacodynamics and drug-receptor interactions.….…….…….. 24 Learning Check 2.2 ………………………………………………….. 41 Evaluation ……………………………………………………………….... 42 Written Output................................................................................... 43 Grading Rubric.................................................................................. 44 Reflection.......................................................................................... 45 References ………………………………………………………………... 46 2 Page 1  Learning Outcomjes After going through in this module, you should be able to:  Describe the process of drug absorption, distribution, metabolism and excretion;  Outline the interaction between drug and receptor;  Relate pharmacokinetics to pharmacodynamics. 3 Page 2  Discussion IV. PHARMACOKINETICS The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination Pharmacokinetic Principles In practical therapeutics, a drug should be able to reach its intended site of action after administration by some convenient route. In many cases, the active drug molecule is sufficiently lipid-soluble and stable to be given as such. In some cases, however, an inactive precursor chemical that is readily absorbed and distributed must be administered and then converted to the active drug by biologic processes— inside the body. Such a precursor chemical is called a prodrug. The human body restricts access to foreign molecules; therefore, to reach its target within the body and have a therapeutic effect, a drug molecule must cross a number of restrictive barriers en route to its target site. Following administration, the drug must be absorbed and then distributed, usually via vessels of the circulatory and lymphatic systems; in addition to crossing membrane barriers, the drug must survive metabolism (primarily hepatic) and elimination (by the kidney and liver and in the feces). ADME, the absorption, distribution, metabolism, and elimination of drugs, are the processes of pharmacokinetics (Figure 1.8). The absorption, distribution, metabolism, and excretion of a drug involve its passage across numerous cell membranes. Mechanisms by which drugs cross membranes and the physicochemical properties of molecules and membranes that influence this transfer are critical to understanding the disposition of drugs in the human body. 4 The characteristics of a drug that predict its movement and availability at sites of action are its molecular size and structural features, degree of ionization, relative lipid solubility of its ionized and nonionized forms, and its binding to serum and tissue proteins. Although physical barriers to drug movement may be a single layer of cells (e.g., intestinal epithelium) or several layers of cells and associated extracellular protein (e.g., skin), the plasma membrane is the basic barrier. Page 5  Discussion IV. PHARMACOKINETICS Pharmacokinetics is the study of the effect the body has on a medicine. Absorption: How the medicine gets in to the body Distribution: Where the medicine goes in the body Metabolism: How the body chemically modifies the medicine Excretion: How the body eliminates the medicine. 5 Figure 1.8 The processes of pharmacokinetics Source: https://toolbox.eupati.eu/resources/key-principles-of-pharmacology/ Page 6  Discussion Absorption of Drugs Absorption is the transfer of a drug from its site of administration to the bloodstream. The rate and efficiency of absorption depend on the route of administration. For IV delivery, absorption is complete; that is, the total dose of drug reaches the systemic circulation. Drug delivery by other routes may result in only partial absorption and, thus, lower bioavailability. For example, the oral route requires that a drug dissolve in the GI fluid and then penetrate the epithelial cells of the intestinal mucosa, yet disease states or the presence of food may affect this process. A. Transport of a drug from the GI tract Depending on their chemical properties, drugs may be absorbed from the GI tract by either passive diffusion or active transport. 1. Passive diffusion The driving force for passive absorption of a drug is the concentration gradient across a membrane Figure 1.9 Schematic representation separating two body compartments; that is, the drug of drugs crossing a cell membrane of moves from a region of high concentration to an epithelial cell of the gastrointestinal one of lower concentration. Passive diffusion tract. ATP = adenosine triphosphate; 6 does not involve a carrier, is not saturable, and ADP = adenosine diphosphate. shows a low structural specificity. The vast Source: Lippincott’s Illustrated Reviews: majority of drugs gain access to the body by this Pharmacology. 4th ed. mechanism. Lipid-soluble drugs readily move across most biologic membranes due to their solubility in the membrane bilayers. Water-soluble drugs penetrate the cell membrane through aqueous channels or pores (Figure 1.9). Other agents can enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules. These carrier proteins undergo conformational changes allowing the passage of drugs or endogenous molecules into the interior of cells, moving them from an area of high concentration to an area of low concentration. This process is known as facilitated diffusion. This type of diffusion does not require energy, can be saturated, and may be inhibited. Page 7  Discussion IV. PHARMACOKINETICS Absorption of Drugs A. Transport of a drug from the GI tract 2. Active transport This mode of drug entry also involves specific carrier proteins that span the membrane. A few drugs that closely resemble the structure of naturally occurring metabolites are actively transported across cell membranes using these specific carrier proteins. Active transport is energy-dependent and is driven by the hydrolysis of ATP (see Figure 1.9). It is capable of moving drugs against a concentration gradient, that is, from a region of low drug concentration to one of higher drug concentration. The process shows saturation kinetics for the carrier, much in the same way that an enzyme- catalyzed reaction shows a maximal velocity at high substrate levels where all the active sites are filled with substrate. 3. Endocytosis and exocytosis This type of drug delivery transports drugs of exceptionally large size across the cell 7 membrane. Figure 1.9 Schematic representation of drugs crossing a cell membrane of Endocytosis involves engulfment of a drug an epithelial cell of the gastrointestinal molecule by the cell membrane and transport into tract. ATP = adenosine triphosphate; the cell by pinching off the drug-filled vesicle. ADP = adenosine diphosphate. Source: Lippincott’s Illustrated Reviews: Exocytosis is the reverse of endocytosis and is Pharmacology. 4th ed. used by cells to secrete many substances by a similar vesicle formation process. For example, vitamin B12 is transported across the gut wall by endocytosis. Certain neurotransmitters (for example, norepinephrine) are stored in membrane-bound vesicles in the nerve terminal and are released by exocytosis. Page 8  Discussion IV. PHARMACOKINETICS Absorption of Drugs B. Effect of pH on drug absorption Most drugs are either weak acids or weak bases. Acidic drugs (HA) release an H+ causing a charged anion (A-) to form: HA H + + A- Weak bases (BH+) can also release an H+. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B): BH+ B + H+ 1. Passage of an uncharged drug through a membrane A drug passes through membranes more readily if it is uncharged (Figure 1.10). Thus, for a weak acid, the uncharged HA can permeate through membranes, and A- cannot. For a weak base, the uncharged form, B, penetrates through the cell membrane, but BH+ does not. Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms. 8 The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the pKa (Figure 1.11). [Note: The pKa is a measure of the strength of the Figure 1.10 A. Diffusion of interaction of a compound with a proton. The lower the pKa the non-ionized form of a of a drug, the more acidic it is. Conversely, the higher the weak acid through a lipid pKa, the more basic is the drug.] membrane. B. Diffusion of the nonionized form of a Note: Highly lipid-soluble drugs rapidly cross weak base through a lipid membranes and often enter tissues at a rate determined by membrane. blood flow. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 9  Discussion IV. PHARMACOKINETICS Figure 1.11 The distribution of a drug between its ionized and non-ionized forms depends on the ambient pH and pKa of the drug. For illustrative purposes, the drug has been assigned a pKa of 6.5. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Absorption of Drugs 2. Determination of how much drug will be found on either side of a membrane: The relationship of pKa and the ratio of acid-base concentrations to pH is expressed by the Henderson-Hasselbalch equation. This equation is useful in determining how much drug will be found on either side of a 9 membrane that separates two compartments that differ in pH, for example, stomach (pH 1.0 - 1.5) and blood plasma (pH 7.4). [Note: The lipid solubility of the non-ionized drug directly determines its rate of equilibration.] Page 10  Discussion IV. PHARMACOKINETICS Absorption of Drugs C. Physical factors influencing absorption 1. Blood flow to the absorption site Blood flow to the intestine is much greater than the flow to the stomach; thus, absorption from the intestine is favored over that from the stomach. Note: Shock severely reduces blood flow to cutaneous tissues, thus minimizing the absorption from SC administration. 2. Total surface area available for absorption: Because the intestine has a surface rich in microvilli, it has a surface area about 1000-fold that of the stomach; thus, absorption of the drug across the intestine is more efficient. 3. Contact time at the absorption surface If a drug moves through the GI tract very quickly, as in severe diarrhea, it is not well absorbed. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. Note: Parasympathetic input increases the rate of gastric emptying, whereas sympathetic input (prompted, for example, by exercise or stressful emotions), as well as anticholinergics (for example, dicyclomine), prolongs gastric emptying. 10 Note: The presence of food in the stomach both dilutes the drug and slows gastric emptying. Therefore, a drug taken with a meal is generally absorbed more slowly. Page 11  Discussion IV. PHARMACOKINETICS Bioavailability Bioavailability is the fraction of administered drug that reaches the systemic circulation. It is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form. For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or 70%. Factors that influence bioavailability 1. First-pass hepatic metabolism When a drug is absorbed across the GI tract, it enters the portal circulation before entering the systemic circulation (see Figure 1.5). If the drug is rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is decreased. Many drugs, such as propranolol or lidocaine, undergo significant biotransformation during a single passage through the liver. 2. Solubility of the drug Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes. Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely hydrophobic, yet have some 11 solubility in aqueous solutions. This is one reason why many drugs are weak acids or weak bases. There are some drugs that are highly lipid-soluble, and they are transported in the aqueous solutions of the body on carrier proteins such as albumin. 3. Chemical instability Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes. 4. Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. Page 12  Discussion IV. PHARMACOKINETICS Drug Distribution Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. The delivery of a drug from the plasma to the interstitium primarily depends on blood flow, capillary permeability, the degree of binding of the drug to plasma and tissue proteins, and the relative hydrophobicity of the drug. Factors that affect drug distribution A. Blood flow The rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs. Blood flow to the brain, liver, and kidney is greater than that to the skeletal muscles; adipose tissue has a still lower rate of blood flow. This differential blood flow partly explains the short duration of hypnosis produced by a bolus IV injection of thiopental. The high blood flow, together with the superior lipid solubility of thiopental, permit it to rapidly move into the central nervous system (CNS) and produce anesthesia. Slower distribution to skeletal muscle and adipose tissue lowers the plasma concentration sufficiently so that the higher concentrations within the CNS decrease, and consciousness is regained. Although this phenomenon occurs with all drugs to some extent, redistribution accounts for the extremely short duration of action of thiopental and compounds of similar chemical and pharmacologic properties. B. Capillary permeability 12 Capillary permeability is determined by capillary structure and by the chemical nature of the drug. 1. Capillary structure Capillary structure varies widely in terms of the fraction of the basement membrane that is exposed by slit junctions between endothelial cells. In the brain, the capillary structure is continuous, and there are no slit junctions (Figure 1.12). This contrasts with the liver and spleen, where a large part of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass. Page 13  Discussion Drug Distribution Blood-brain barrier: To enter the brain, drugs must pass through the endothelial cells of the capillaries of the CNS or be actively transported. For example, a specific transporter for the large neutral amino acid transporter carries levodopa into the brain. By contrast, lipid-soluble drugs readily penetrate into the CNS because they can dissolve in the membrane of the endothelial cells. Ionized or polar drugs generally fail to enter the CNS because they are unable to pass through the endothelial cells of the CNS, which have no slit junctions. These tightly juxtaposed cells form tight junctions that constitute the so-called blood-brain barrier. 2. Drug structure The chemical nature of a drug strongly influences its ability to cross cell membranes. Hydrophobic drugs, which have a uniform distribution of electrons and no net charge, readily move across most biologic membranes. These drugs can dissolve in the lipid membranes and, therefore, permeate the entire cell’s surface. The major factor influencing the hydrophobic drug's distribution is the blood flow to the area. Hydrophilic drugs, which have either a nonuniform distribution of electrons or a positive or negative charge, 13 do not readily penetrate cell membranes, and therefore,. must go through the slit junctions C. Binding of drugs to plasma proteins Drug molecules may bind to plasma proteins (usually albumin). Bound drugs are pharmacologically inactive; only the free, unbound drug can act on target sites in Figure 1.12 Cross-section of the tissues, elicit a biologic response, and be available to liver and brain capillaries. the process of elimination. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Note: Hypoalbuminemia may alter the level of free drug. Page 14  Discussion C. Binding of Drugs to Plasma Proteins Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows their transfer out of the vascular compartment. Binding is relatively nonselective as to chemical structure and takes place at sites on the protein to which endogenous compounds, such as bilirubin, normally attach. Plasma albumin is the major drug-binding protein and may act as a drug reservoir; that is, as the concentration of the free drug decreases due to elimination by metabolism or excretion, the bound drug dissociates from the protein. This maintains the free-drug concentration as a constant fraction of the total drug in the plasma. Drug Metabolism Drugs are most often eliminated by biotransformation and/or excretion into the urine or bile. The process of metabolism transforms lipophilic drugs into more polar readily excretable products. The liver is the major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues, such as the kidney and the intestines. Note: Some agents are initially administered as inactive compounds (pro-drugs) and must be metabolized to their active forms. A. Kinetics of metabolism 1. First-order kinetics: The metabolic transformation of drugs is catalyzed by enzymes, and most of the reactions obey Michaelis-Menten kinetics: 14 In most clinical situations, the concentration of the drug, [C], is much less than the Michaelis constant, Km, and the Michaelis-Menten equation reduces to, That is, the rate of drug metabolism is directly proportional to the concentration of free drug, and first-order kinetics are observed (Figure 1.13). This means that a constant fraction of drug is metabolized per unit of time. Page 15  Discussion IV. PHARMACOKINETICS Drug Metabolism A. Kinetics of metabolism 2. Zero-order kinetics: With a few drugs, such as aspirin, ethanol, and phenytoin, the doses are very large. Therefore [C] is much greater than Km, and the velocity equation becomes The enzyme is saturated by a high free-drug concentration, and the rate of metabolism remains constant over time. This is called zero-order kinetics (sometimes referred to clinically as nonlinear kinetics). A constant amount of drug is metabolized per unit of time. B. Reactions of drug metabolism The kidney cannot efficiently eliminate lipophilic Figure 1.13 Effect of drug drugs that readily cross cell membranes and are dose on the rate of reabsorbed in the distal tubules. Therefore, lipid-soluble metabolism. agents must first be metabolized in the liver using two Source: Lippincott’s Illustrated general sets of reactions, called Phase I and Phase II Reviews: Pharmacology. 4th ed. (Figure 1.14). 15 Figure 1.14 The biotransformation of drugs. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 16  Discussion IV. PHARMACOKINETICS Drug Metabolism B. Reactions of drug metabolism 1. Phase I Phase I reactions function to convert lipophilic molecules into more polar molecules by introducing or unmasking a polar functional group, such as -OH or -NH2. Phase I metabolism may increase, decrease, or leave unaltered the drug's pharmacologic activity. a. Phase I reactions utilizing the P450 system The Phase I reactions most frequently involved in drug metabolism are catalyzed by the cytochrome P450 system (also called microsomal mixed function oxidase): Drug + O2 + NADPH + H+ Drugmodified + H2O + NADP+ The oxidation proceeds by the drug binding to the oxidized form of cytochrome P450, and then oxygen is introduced through a reductive step, coupled to NADPH:cytochrome P450 oxidoreductase. b. Summary of the P450 system The P450 system is important for the metabolism of many endogenous compounds (steroids, lipids, etc.) and for the biotransformation of exogenous substances (xenobiotics). 16 Cytochrome P450, designated as CYP, is composed of many families of heme- containing isozymes that are located in most cells but are primarily found in the liver and GI tract. The family name is indicated by an arabic number followed by a capital letter for the subfamily (for example, CYP3A). Another number is added to indicate the specific isozyme (CYP3A4). There are many different genes, and many different enzymes; thus, the various P450s are known as isoforms. Six isozymes are responsible for the vast majority of P450-catalyzed reactions: CYP3A4, CYP2D6, CYP2C9/10, CYP2C19, CYP2E1, and CYP1A2. The percentages of currently available drugs that are substrates for these isozymes are 60, 25, 15, 15, 2, and 2 percent, respectively. Note: An individual drug may be a substrate for more than one isozyme. Page 17  Discussion IV. PHARMACOKINETICS Drug Metabolism B. Reactions of drug metabolism 1. Phase I b. Summary of the P450 system Considerable amounts of CYP3A4 are found in intestinal mucosa, accounting for first- pass metabolism of drugs such as chlorpromazine and clonazepam. As might be expected, these enzymes exhibit considerable genetic variability, which has implications for individual dosing regimens, and even more importantly, as determinants of therapeutic responsiveness and the risk of adverse events. CYP2D6, in particular, has been shown to exhibit genetic polymorphism. Mutations result in very low capacities to metabolize substrates. Some individuals, for example, obtain no benefit from the opioid analgesic codeine because they lack the enzyme that O- demethylates and activates the drug. This reaction is CYP2D6- dependent. The frequency of this polymorphism is in part racially determined, with a prevalence of 5-10% in European Caucasians as compared to less than 2% of Southeast Asians. c. Inducers The cytochrome P450-dependent enzymes are an important target for pharmacokinetic drug interactions. One such interaction is the induction of selected CYP isozymes. 17 Certain drugs, most notably phenobarbital, rifampin, and carbamazepine, are capable of increasing the synthesis of one or more CYP isozymes. This results in increased biotransformations of drugs and can lead to significant decreases in plasma concentrations of drugs metabolized by these CYP isozymes, as measured by AUC, with concurrent loss of pharmacologic effect. For example, rifampin, an antituberculosis drug, significantly decreases the plasma concentrations of human immunodeficiency virus (HIV) protease inhibitors, diminishing their ability to suppress HIV virion maturation. Figure 1.15 lists some of the more important inducers for representative CYP isozymes. Page 18  Discussion Drug Metabolism B. Reactions of drug metabolism 1. Phase I d. Inhibitors Inhibition of CYP isozyme activity is an important source of drug interactions that leads to serious adverse events. The most common form of inhibition is through competition for the same isozyme. Some drugs, however, are capable of inhibiting reactions for which they are not substrates (for example, ketoconazole), leading to drug interactions. Numerous drugs have been shown to inhibit one or more of the CYP-dependent biotransformation pathways of warfarin. For example, omeprazole is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism. If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater inhibition of coagulation and risk of hemorrhage and other serious bleeding reactions. Note: The more important CYP inhibitors are erythromycin, ketoconazole, and ritonavir, 18 because they each inhibit several CYP isozymes.] Cimetidine blocks the metabolism of theophylline, clozapine, and warfarin. Figure 1.15 Some representative isozymes Natural substances such as grapefruit juice may inhibit drug metabolism. Grapefruit juice inhibits Source: Lippincott’s Illustrated CYP3A4 and, thus, drugs such as amlodipine, Reviews: Pharmacology. 4th ed. clarithromycin, and indinavir, which are metabolized by this system, have greater amounts in the systemic circulation, leading to higher blood levels and the potential to increase therapeutic and/or toxic effects of the drugs. Page 19  Discussion IV. PHARMACOKINETICS Drug Metabolism B. Reactions of drug metabolism 1. Phase I d. Inhibitors Inhibition of drug metabolism may lead to increased plasma levels over time with long- term medications, prolonged pharmacological drug effect, and increased drug-induced toxicities. e. Phase I reactions not involving the P450 system These include amine oxidation (for example, oxidation of catecholamines or histamine), alcohol dehydrogenation (for example, ethanol oxidation), esterases (for example, metabolism of pravastatin in liver), and hydrolysis (for example, of procaine). 2. Phase II This phase consists of conjugation reactions. If the metabolite from Phase I metabolism is sufficiently polar, it can be excreted by the kidneys. However, many Phase I metabolites are too lipophilic to be retained in the kidney tubules. A subsequent conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in polar, usually more water-soluble compounds that are most often therapeutically inactive. A notable exception is morphine- 6-glucuronide, which is more potent than morphine. Glucuronidation is the most common and the most important conjugation reaction. 19 Neonates are deficient in this conjugating system, making them particularly vulnerable to drugs such as chloramphenicol, which is inactivated by the addition of glucuronic acid. Note: Drugs already possessing an -OH, -NH2, or -COOH group may enter Phase II directly and become conjugated without prior Phase I metabolism. The highly polar drug conjugates may then be excreted by the kidney or bile. 3. Reversal of order of the phases Not all drugs undergo Phase I and II reactions in that order. For example, isoniazid is first acetylated (a Phase II reaction) and then hydrolyzed to isonicotinic acid (a Phase I reaction). Page 20  Discussion Drug Elimination Removal of a drug from the body occurs via a number of routes, the most important being through the kidney into the urine. Other routes include the bile, intestine, lung, or milk in nursing mothers. A patient in renal failure may undergo extracorporeal dialysis, which removes small molecules such as drugs. C. Renal elimination of a drug 1. Glomerular filtration Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. Free drug (not bound to albumin) flows through the capillary slits into Bowman's space as part of the glomerular filtrate (Figure 1.16). The glomerular filtration rate (125 mL/min) is normally about 20% of the renal plasma flow (600 mL/min). Note: Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate. 2. Proximal tubular secretion Drugs that were not transferred into the glomerular 20 filtrate leave the glomeruli through efferent arterioles, which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule. Figure 1.16 Drug elimination by the kidney. Secretion primarily occurs in the proximal Source: Lippincott’s Illustrated th Reviews: Pharmacology. 4 ed. tubules by two energy-requiring active transport (carrier-requiring) systems, one for anions (for example, deprotonated forms of weak acids) and one Note: Premature infants and for cations (for example, protonated forms of weak neonates have an incompletely bases). Each of these transport systems shows low developed tubular secretory specificity and can transport many compounds; mechanism and, thus, may retain thus, competition between drugs for these carriers certain drugs in the glomerular can occur within each transport system (for example, filtrate. probenecid). Page 21  Discussion Drug Elimination 3. Distal tubular reabsorption As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space. The drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation. Manipulating the pH of the urine to increase the ionized form of the drug in the lumen may be used to minimize the amount of back-diffusion, and hence, increase the clearance of an undesirable drug. As a general rule, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. This process is called ion-trapping. For example, a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate, which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption. If overdose is with a weak base, such as cocaine, acidification of the urine with NH4Cl leads to protonation of the drug and an increase in its clearance. 21 4. Role of drug metabolism Most drugs are lipid soluble and without chemical Figure 1.17 Effect of drug modification would diffuse out of the kidney's tubular metabolism on reabsorption in lumen when the drug concentration in the filtrate becomes the distal tubule. greater than that in the perivascular space. To minimize Source: Lippincott’s Illustrated this reabsorption, drugs are modified primarily in the liver Reviews: Pharmacology. 4th ed. into more polar substances using two types of reactions: Phase I reactions that involve either the addition of The conjugates are ionized, hydroxyl groups or the removal of blocking groups from and the charged molecules hydroxyl, carboxyl, or amino groups, and Phase II cannot back-diffuse out of reactions that use conjugation with sulfate, glycine, or the kidney lumen (Figure glucuronic acid to increase drug polarity. 1.17). Page 22  Learning Check LEARNING CHECK 2.1 Provide the process of pharmacokinetics corresponding to each question below in the red boxes. (5 points) Page 23  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS Pharmacodynamics is the study of the biochemical, cellular, and physiological effects of drugs and their mechanisms of action. The effects of most drugs result from their interaction with macromolecular components of the organism. The term drug receptor or drug target denotes the cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular or systemic response. Drugs commonly alter the rate or magnitude of an intrinsic cellular or physiological response rather than create new responses. Drug receptors are often located on the surface of cells but may also be located in specific intracellular compartments, such as the nucleus, or in the extracellular compartment, as in the case of drugs that target coagulation factors and inflammatory mediators. Many drugs also interact with acceptors (e.g., serum albumin), which are entities that do not directly cause any change in biochemical or physiological response but can alter the 23 pharmacokinetics of a drug’s actions. Most drugs exert their effects, both beneficial and harmful, by interacting with receptors - that is, specialized target macromolecules - present on the cell surface or intracellularly. Figure 1.18 The recognition of a drug Receptors bind drugs and initiate events by a receptor triggers a biologic leading to alterations in biochemical and/or response biophysical activity of a cell, and consequently, Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. the function of an organ (Figure 1.18). Page 24  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS In each case, the formation of the drug-receptor complex leads to a biologic response, and the magnitude of the response is proportional to the number of drug- receptor complexes: Drug + Receptor Drug-receptor complex Biologic effect Most receptors are named to indicate the type of drug/chemical that interacts best with it; for example, the receptor for histamine is called a histamine receptor. Cells may have tens of thousands of receptors for certain ligands (drugs). Cells may also have different types of receptors, each of which is specific for a particular ligand. On the heart, for example, there are β1 receptors for norepinephrine, and muscarinic receptors for acetylcholine. These receptors dynamically interact to control vital functions of the heart. This concept is closely related to the formation of complexes between enzyme and substrate, or antigen and antibody; these interactions have many common features, perhaps the most noteworthy being specificity of the receptor for a given ligand. However, the receptor not only has the ability to recognize a ligand, but can also couple or transduce this binding into a response by causing a conformational change or a biochemical effect. Remember: Not all drugs exert their effects by interacting with a receptor; for example, antacids chemically neutralize excess gastric acid, reducing the symptoms of “heartburn.” 24 Review: Pharmacodynamics studies the influence of drug concentrations on the magnitude of the response. It deals with the interaction of drugs with receptors, the molecular consequences of these interactions, and their effects in the patient. Drugs only modify underlying biochemical and physiological processes; they do not create effects de novo (new). Source: https://www.lecturio.com/magazine/biological-interaction/ Page 25  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS Chemistry of Receptors and Ligands Interaction of receptors with ligands involves the formation of chemical bonds, most commonly electrostatic and hydrogen bonds, as well as weak interactions involving van der Waals forces. These bonds are important in determining the selectivity of receptors, because the strength of these noncovalent bonds is related inversely to the distance between the interacting atoms. Therefore, the successful binding of a drug requires an exact fit of the ligand atoms with the complementary receptor atoms. The bonds are usually reversible, except for a handful of drugs (for example, the nonselective α-receptor blocker phenoxybenzamine, and acetylcholinesterase inhibitors in the organophosphate class) that covalently bond to their targets. The size, shape, and charge distribution of the drug molecule determines which of the myriad binding sites in the cells and tissues of the patient can interact with the ligand. The metaphor of the “lock and key” is a useful concept for understanding the interaction of receptors with their ligands. The precise fit required of the ligand echoes the characteristics of the “key” whereas the opening of the “lock” reflects the activation of the receptor. The interaction of the ligand with its receptor thus exhibits a high degree of specificity. The induced-fit model has largely replaced the lock-and-key concept as the preferred model describing the interaction of a receptor and a ligand. In the presence of a ligand, the receptor undergoes a conformational change to bind the ligand. The change in conformation of the receptor caused by binding of the agonist activates the receptor, which leads to the pharmacologic effect. This model suggests that the receptor is flexible, not 25 rigid as implied by the lock-and-key model. Source: https://pediaa.com/what-is-the-difference-between-induced-fit-and-lock-and-key/ Page 26  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS MAJOR RECEPTOR FAMILIES Pharmacology defines a receptor as any biologic molecule to which a drug binds and produces a measurable response. Thus, enzymes and structural proteins can be considered to be pharmacologic receptors. However, the richest sources of therapeutically exploitable pharmacologic receptors are proteins that are responsible for transducing extracellular signals into intracellular responses. These receptors may be divided into four families: 1) ligand-gated ion channels, 2) G protein-coupled receptors, 3) enzyme-linked receptors, and 4) intracellular receptors (Figure 1.19). The type of receptor a ligand will interact with depends on the nature of the ligand. Hydrophilic ligands interact with receptors that are found on the cell surface (families 1, 2, and 3). In contrast, hydrophobic ligands can enter cells through the lipid bilayers of the cell membrane to interact with receptors found inside cells (family 4). 26 Figure 1.19 Transmembrane signaling mechanisms. A. Ligand binds to the extracellular domain of a ligand-gated channel. B. Ligand binds to a domain of a serpentine receptor, which is coupled to a G protein. C. Ligand binds to the extracellular domain of a receptor that activates a kinase enzyme. D. Lipid-soluble ligand diffuses across the membrane to interact with its intracellular receptor. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 27  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS MAJOR RECEPTOR FAMILIES A. Ligand-gated ion channels Ligand-gated ion channels are responsible for regulation of the flow of ions across cell membranes (see Figure 1.19A). The activity of these channels is regulated by the binding of a ligand to the channel. Response to these receptors is very rapid, having durations of a few milliseconds. Examples: nicotinic receptor and the γ-aminobutyric acid (GABA) receptor. Their functions are modified by numerous drugs. Stimulation of the nicotinic receptor by acetylcholine results in sodium influx, generation of an action potential, and activation of contraction in skeletal muscle. Benzodiazepines enhance the stimulation of the GABA receptor by GABA, resulting in increased chloride influx and hyperpolarization of the respective cell. Although not ligand-gated, ion channels, such as the voltage- gated sodium channel, are important drug receptors for several drug classes, including local anesthetics. B. G protein-coupled receptors 27 These receptors are comprised of a single peptide that has seven membrane-spanning regions, and these receptors are linked to a G protein (Gs and others) having three subunits, an α-subunit that binds guanosine triphosphate (GTP) and a βγ subunit (Figure 1.20). Figure 1.20 The recognition of chemical signals by G protein- coupled membrane receptors triggers an increase (or, less often, a decrease) in the activity of adenylyl cyclase. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 28  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS MAJOR RECEPTOR FAMILIES B. G protein-coupled receptors Binding of the appropriate ligand to the extracellular region of the receptor activates the G protein so that GTP replaces guanosine diphosphate (GDP) on the α-subunit. Dissociation of the G protein occurs, and both the α-GTP subunit and the βγ- subunit subsequently interact with other cellular effectors, usually an enzyme or ion channel. These effectors then change the concentrations of second messengers that are responsible for further actions within the cell. Stimulation of these receptors results in responses that last several seconds to minutes. Second messengers These are essential in conducting and amplifying signals coming from G protein-coupled receptors. A common pathway turned on by Gs, and other types of G proteins, is the activation of adenylyl cyclase by α-GTP subunits, which results in the production of cyclic adenosine monophosphate (cAMP), a second messenger that regulates protein phosphorylation. G proteins also activate phospholipase C, which is 28 responsible for the generation of two other second messengers, namely inositol-1,4,5-trisphosphate and diacylglycerol. These effectors are responsible for the regulation of intracellular free calcium concentrations, and of other proteins as well. This family of receptors transduces signals derived from odors, light, and numerous neurotransmitters, including norepinephrine, dopamine, serotonin, and acetylcholine. Figure 1.20 The recognition of chemical signals by G protein- coupled membrane receptors triggers an increase (or, less often, a decrease) in the activity of adenylyl cyclase. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 29  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS MAJOR RECEPTOR FAMILIES C. Enzyme-linked receptors This family consists of those having cytosolic enzyme activity as an integral component of their structure or function (see Figure 1.19C). Binding of a ligand to an extracellular domain activates or inhibits this cytosolic enzyme activity. Duration of responses to stimulation of these receptors is on the order of minutes to hours. Most common enzyme-linked receptors: epidermal growth factor, platelet-derived growth factor, atrial natriuretic peptide, insulin. These have a tyrosine kinase activity as part of their structure. Typically, upon binding of the ligand to receptor subunits, the receptor undergoes conformational changes, converting from its inactive form to an active kinase form. The activated receptor autophosphorylates, and phosphorylates tyrosine residues on specific proteins. The addition of a phosphate group can substantially modify the three- dimensional structure of the target protein, thereby acting as a molecular switch. For example, when the peptide hormone insulin binds to two of its receptor subunits, their intrinsic tyrosine kinase activity causes autophosphorylation of the receptor itself. In turn, the phosphorylated receptor phosphorylates target molecules - insulin-receptor substrate peptides - that subsequently activate other important cellular signals such as IP3 and the mitogen-activated protein kinase system. This cascade of activations results in a multiplication of the initial signal, much like that which occurs with G protein-coupled receptors. 29 Source: https://membranereceptors.com/transduction-process/enzyme-linked-receptors/ Page 30  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS MAJOR RECEPTOR FAMILIES D. Intracellular receptors This family differs considerably from the other three in that the receptor is entirely intracellular and, therefore, the ligand must diffuse into the cell to interact with the receptor (Figure 1.21). This places constraints on the physical and chemical properties of the ligand in that it must have sufficient lipid solubility to be able to move across the target cell membrane. Because these receptor ligands are lipid soluble, they are transported in the body attached to plasma proteins, such as albumin. For example, steroid hormones exert their action on target cells via this receptor mechanism. Mechanism: The activated ligand-receptor complex migrates to the nucleus, where it binds to specific DNA sequences, resulting in the regulation of gene expression. The time course of activation and response of these receptors is much longer than that of the other mechanisms described above. Because gene 30 expression and, therefore, protein synthesis is modified, cellular responses are not observed until considerable time has elapsed (thirty minutes or more), and the duration of the response (hours to days) is much greater than that of other receptor families. Figure 1.21 Mechanism of intracellular receptors. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 31  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS SOME CHARACTERISTICS OF RECEPTORS A. Spare receptors A characteristic of many receptors, particularly those that respond to hormones, neurotransmitters, and peptides, is their ability to amplify signal duration and intensity. For example is the family of G protein-linked receptors. Two phenomena account for the amplification of the ligand-receptor signal: First, a single ligand-receptor complex can interact with many G proteins, thereby multiplying the original signal many-fold. Second, the activated G proteins persist for a longer duration than the original ligand-receptor complex. For example, the binding of albuterol may only exist for a few milliseconds, but the subsequent activated G proteins may last for hundreds of milliseconds. Because of this amplification, only a fraction of the total receptors for a specific ligand may need to be occupied to elicit a maximal response from a cell. Systems that exhibit this behavior are said to have spare receptors. Spare receptors are exhibited by insulin receptors, where it has been estimated that 99% of the receptors are “spare.” This constitutes an immense functional reserve that ensures adequate amounts of glucose enter the cell. On the other end of the scale is the human heart, in which about 5-10% of the total β- adrenoceptors are spare. Implication: little functional reserve exists in the failing heart; 31 most receptors must be occupied to obtain maximum contractility. Source: https://en.wikipedia.org/wiki/Insulin_receptor Page 32  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS SOME CHARACTERISTICS OF RECEPTORS B. Desensitization of receptors Repeated or continuous administration of an agonist (or an antagonist) may lead to changes in the responsiveness of the receptor. To prevent potential damage to the cell (for example, high concentrations of calcium, initiating cell death), several mechanisms have evolved to protect a cell from excessive stimulation. When repeated administration of a drug results in a diminished effect, the phenomenon is called tachyphylaxis. The receptor becomes desensitized to the action of the drug (Figure 1.22). In this phenomenon, the receptors are still present on the cell surface but are unresponsive to the ligand. Other types of desensitization occur when receptors are down-regulated. Binding of the agonist results in molecular changes in the membrane-bound receptors, such that the receptor undergoes endocytosis and is sequestered from further agonist interaction. 32 These receptors may be recycled to the cell surface, restoring sensitivity, or alternatively, may be further processed and degraded, decreasing the total number of receptors available. Some receptors, particularly voltage-gated channels, require a finite time (rest period) Figure 1.22 Desensitization of following stimulation before they can be activated receptors. again. During this recovery phase they are said Source: Lippincott’s Illustrated Reviews: to be “refractory” or “unresponsive.” Pharmacology. 4th ed. Page 33  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS DOSE-RESPONSE RELATIONSHIPS An agonist is defined as an agent that can bind to a receptor and elicit a biologic response. The magnitude of the drug effect depends on the drug concentration at the receptor site, which in turn is determined by the dose of drug administered and by factors characteristic of the drug pharmacokinetic profile, such as rate of absorption, distribution, and metabolism. A. Graded dose-response relations As the concentration of a drug increases, the magnitude of its pharmacologic effect also increases. The response is a graded effect, meaning that the response is continuous and gradual. A graph of this relationship is known as a graded dose- response curve. Plotting the magnitude of the response against increasing doses of a drug produces a graph that has the general shape depicted in Figure 1.23A. The curve can be described as a rectangular hyperbola and can be applied to diverse biological events, such as ligand binding, enzymatic activity, and responses to pharmacologic agents. There are two properties of drugs that can be determined by 33 graded-dose response, potency and efficacy: 1. Potency This is a measure of the amount of drug necessary to produce an effect of a given magnitude. The concentration producing an effect that is 50% (EC50) of the maximum is used to determine potency. In Figure 1.23B, Drug A is more potent than Drug B. An important contributing factor to the dimension of EC50 is the affinity of the drug to the receptor. Figure 1.23 The effect of dose on the magnitude of pharmacologic response. Panel A is a linear graph. Panel B is a semilogarithmic plot of the same data. EC50 = drug dose that shows fifty percent of maximal response.. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 34  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS DOSE-RESPONSE RELATIONSHIPS A. Graded dose-response relations 2. Efficacy (Intrinsic activity) This is the second drug property that can be determined from graded dose-response plots. This is the ability of a drug to illicit a physiologic response when it interacts with a receptor. Efficacy is dependent on the number of drug- receptor complexes formed and the efficiency of the coupling of receptor activation to cellular responses. Analogous to the maximal velocity for enzyme- catalyzed reactions, the maximal response (Emax) or efficacy is more important than drug potency. Figure 1.24 Typical dose-response A drug with greater efficacy is more curve for drugs showing differences therapeutically beneficial than one that is more in potency and efficacy. (EC50 = potent. drug dose that shows fifty percent of maximal response.) Figure 1.24 shows the response to drugs of differing Source: Lippincott’s Illustrated 34 potency and efficacy. Reviews: Pharmacology. 4th ed. Page 35  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS DOSE-RESPONSE RELATIONSHIPS A. Graded dose-response relations Agonists If a drug binds to a receptor and produces a biologic response that mimics the response to the endogenous ligand, it is known as an agonist. For example, phenylephrine is an agonist at α1-adrenoceptors, because it produces effects that resemble the action of the endogenous ligand, norepinephrine. Upon binding to α1- adrenoceptors on the membranes of vascular smooth muscle, phenylephrine mobilizes intracellular Ca2+, causing contraction of the actin and myosin filaments. The shortening of the muscle cells decreases the diameter of the arteriole, causing an increase in resistance to the flow of blood through the vessel. Blood pressure therefore rises to maintain the blood flow. As this brief description illustrates, an agonist may have many effects that can be measured, including actions on intracellular molecules, cells, tissues, and intact organisms. All of these actions are attributable to interaction of the drug molecule with the receptor molecule. In general, a full agonist has a strong affinity for its receptor and good efficacy. Antagonists Antagonists are drugs that decrease the actions of another drug or endogenous ligand. Antagonism may occur in several ways. Many antagonists act on the identical receptor macromolecule as the agonist. 35 Antagonists, however, have no intrinsic activity and, therefore, produce no effect by themselves. Although antagonists have no intrinsic activity, they are able to bind avidly to target receptors because they possess strong affinity. If both the antagonist and the agonist bind to the same site on the receptor, they are said to be “competitive.” For example, the antihypertensive drug prazosin competes with the endogenous ligand, norepinephrine, at α1-adrenoceptors, decreasing vascular smooth muscle tone and reducing blood pressure. Page 36  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS DOSE-RESPONSE RELATIONSHIPS A. Graded dose-response relations Antagonists Plotting the effect of the competitive antagonist characteristically causes a shift of the agonist dose-response curve to the right. Competitive antagonists have no intrinsic activity. If the antagonist binds to a site other than where the agonist binds, the interaction is “noncompetitive” or “allosteric” (Figure 1.26). Note: A drug may also act as a chemical antagonist by combining with another drug and rendering it inactive. For example, protamine ionically binds to heparin, rendering it inactive and antagonizing heparin's anticoagulant effect. Functional antagonism Figure 1.26 Effects of drug An antagonist may act at a completely separate antagonists. EC50 = drug dose that receptor, initiating effects that are functionally shows fifty percent of maximal opposite those of the agonist. A classic example response.. is the antagonism by epinephrine to histamine- Source: Lippincott’s Illustrated Reviews: induced bronchoconstriction. Histamine binds to Pharmacology. 4th ed. 36 H1 histamine receptors on bronchial smooth muscle, causing contraction and narrowing of the bronchial tree. Epinephrine is an agonist at β2-adrenoceptors on bronchial smooth muscle, which causes the muscles to actively relax. This functional antagonism is also known as “physiologic antagonism.” Page 37  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS QUANTAL DOSE-RESPONSE RELATIONSHIPS Another important dose-response relationship is that of the influence of the magnitude of the dose on the proportion of a population that responds. These responses are known as quantal responses, because, for any individual, the effect either occurs or it does not. Even graded responses can be considered to be quantal if a predetermined level of the graded response is designated as the point at which a response occurs or not. For example, a quantal dose-response relationship can be determined in a population for the antihypertensive drug atenolol. A positive response is defined as at least a 5 mm Hg fall in diastolic blood pressure. Quantal Dose-response curves are useful for determining doses to which most of the population responds. A. Therapeutic index The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals: TD50 Therapeutic index = ED50 where TD50 = the drug dose that produces a toxic effect in half the population and 37 ED50 = the drug dose that produces a therapeutic or desired response in half the population. The therapeutic index is a measure of a drug’s safety, because a larger value indicates a wide margin between doses that are effective and doses that are toxic. Page 38  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS QUANTAL DOSE-RESPONSE RELATIONSHIPS B. Determination of therapeutic index The therapeutic index is determined by measuring the frequency of desired response, and toxic response, at various doses of drug. By convention, the doses that produce the therapeutic effect and the toxic effect in fifty percent of the population are employed; these are known as the ED50 and TD50, respectively. In humans, the therapeutic index of a drug is determined using drug trials and accumulated clinical experience. These usually reveal a range of effective doses and a different (sometimes overlapping) range of toxic doses. Although some drugs have narrow therapeutic indices, they are routinely used to treat certain diseases. Several lethal diseases, such as Hodgkin’s lymphoma, are treated with narrow therapeutic index drugs; however, treatment of a simple headache, for example, with a narrow therapeutic index drug would 38 be unacceptable. Figure 1.28 shows the responses to warfarin, an oral anti-coagulant with a narrow therapeutic index, and penicillin, an antimicrobial drug with a large therapeutic index. Figure 1.28 Cumulative percentage of patients responding to plasma levels of a drug. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 39  Discussion V. PHARMACODYNAMICS AND DRUG – RECEPTOR INTERACTIONS QUANTAL DOSE-RESPONSE RELATIONSHIPS B. Determination of therapeutic index 1. Warfarin (example of a drug with a small therapeutic index): As the dose of warfarin is increased, a greater fraction of the patients respond (for this drug, the desired response is a two-fold increase in prothrombin time) until eventually, all patients respond (see Figure 1.28A). However, at higher doses of warfarin, a toxic response occurs, namely a high degree of anticoagulation that results in hemorrhage. Note: that when the therapeutic index is low, it is possible to have a range of concentrations where the effective and toxic responses overlap. That is, some patients hemorrhage, whereas others achieve the desired two-fold prolongation of prothrombin time. Variation in patient response is, therefore, most likely to occur with a drug showing a narrow therapeutic index, because the effective and toxic concentrations are similar. Agents with a low therapeutic index - that is, drugs 39 for which dose is critically important - are those drugs for which bioavailability critically alters the therapeutic effects. 2. Penicillin (example of a drug with a large therapeutic index): For drugs such as penicillin (see Figure 1.28B), it is Figure 1.28 Cumulative percentage safe and common to give doses in excess (often about of patients responding to plasma ten-fold excess) of that which is minimally required to levels of a drug. achieve a desired response. In this case, bioavailability Source: Lippincott’s Illustrated Reviews: does not critically alter the therapeutic effects. Pharmacology. 4th ed. Page 40  Learning Check LEARNING CHECK 2.2 Provide the correct information to the numbered boxes using the following phrases or terms: (15 points) absorption drug concentration in systemic circulation distribution pharmacologic effect metabolism drug concentration at site of action elimination dose of drug administered toxicity drug-receptor interaction effectiveness drug metabolized or excreted pharmacokinetics clinical response pharmacodynamics 1. 2. 7. 3. 8. 14. 6. 4. 5. 9. 40 10. 15. 11. 12. 13. Page 41  Evaluation Performance Task 2 Kinetics of a drug after administration: oral vs. IV drug Draw a schematic diagram showing and comparing the kinetics of an oral (tablet) and an intravenous (injection) drugs. Use different colors of arrows for the two types of drugs. (20 points) 41 Page 42  References Textbooks  Brunton L, Hilal-Dandan R, Knollman BC. 2018. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. McGraw Hill-Education, United States of America.  Katzung, Bertram G. 2018. Basic and Clinical Pharmacology. 14th ed. McGraw Hill- Education, United States of America Online References  Pharmacokinetics and pharmacodynamics at https://www.lecturio.com/concepts/pharmacokinetics-and-pharmacodynamics/ YouTube links  Pharmacokinetics part 1: Overview, Absorption and Bioavailability at https://www.youtube.com/watch?v=0d2F-GKSVYw  Pharmacokinetics part 2: Distribution, Metabolism and Excretion at https://www.youtube.com/watch?v=QK5-SVTwS1I  Pharmacology - PHARMACOKINETICS (MADE EASY) at https://www.youtube.com/watch?v=NKV5iaUVBUI  Pharmacology - PHARMACODYNAMICS (MADE EASY) at https://www.youtube.com/watch?v=tobx537kFaI  How the Body Absorbs and Uses Medicine | Merck Manual Consumer Version at https://www.youtube.com/watch?v=IOf-z0D1mHk  Bioavailability and First Pass Metabolism at https://www.youtube.com/watch?v=BQQns7RAUzA  Aspirin Journey through the body - 3D Animation at 42 https://www.youtube.com/watch?v=Jiml3iGBs88  Pharmacodynamics - Part 1: How Drugs Act on the Body at https://www.youtube.com/watch?v=PhfhMBO-w9Q  Pharmacodynamics - Part 2: Dose-response Relationship at https://www.youtube.com/watch?v=VzrvklX5Wmw  Pharmacokinetics: How Drugs Move Through the Body at https://www.youtube.com/watch?v=L1W0q1kEof4  How does your body process medicine? At https://www.youtube.com/watch?v=uOcpsXMJcJk  Types of Drug Receptors at https://www.youtube.com/watch?v=WORIhbaRABg  Pharmacodynamics and Pharmacokinetics | A rapid review. at https://www.youtube.com/watch?v=jIkQI4cBaBE Page 46