I. Pharmacodynamics A. The response following administration of a drug is directly related to the concentration of the drug at the site of its action which is a function of the dose administered. The extent and rate of the following processes are important in determining what this concentration will be. AbsorptionDistributionTissue LocalizationBiotransformationExcretion This unit will explain the interrelationship of these processes and pharmacokinetic principles applied and this knowledge should result in more satisfactory therapeutic results. However, they should supplement but not substitute for clinical monitoring and judgement. B. Movement of Drugs Across Biological Membranes (Biotransport) Biotransport is the translocation of a solute from one phase to another phase without a change in the form of the solute. The phases are separated by a biological barrier usually anatomic. The barrier surrounding a cell as well as many cellular organelles are characterized by a lipoidal membrane. Likewise, the barrier surrounding the various tissues and organs is lipoidal and differs in that it may be from one to several cell layers in thickness. Whether the biologic membrane be a tissue or organ, the wall of the intestine, a capillary or a particular cell, the solute passes through by first penetrating the cell membrane. The characteristics of the cell membranes is basically the same for all barriers. Schematic drawing of a section of cell membrane depicting the phospholipid bilayer, with the hydrophilic heads as circles and hydrophobic fatty acid chains as wavy lines. Globular proteins dispersed throughout the membrane penetrate the lipid phase, providing channels of communication between the external environment and the cell interior. (From Singer, S.J., and Nicolson, G.L. The fluid mosaic model of the structure of cell membranes. Science 175:720-731, Feb. 18, 1982. Copyright 1872 by the American Association for the Advancement of Science.) The Davson-Danielli diagram of the cell membrane showing a double layer of lipid molecules covered by a protein coat. The hydrophobic end of each molecule it directed inward, while its hydrophilic end faces outward toward the protein coat. (From H. Davson and J.F. Danielli, The Permeability of Natural Membranes. Cambridge, Eng.: Cambridge University Press, 1952. P. 64.) I.B.2 Characteristics of the drug (solute) and the physicochemical factors influencing transport. a. Molecular size and shape b. Lipid solubility i. Partition coefficient - relation to lipid solubility ii. Weak acids - weak bases For such compounds the pH will influence the % of ionized and unionized ions. Each substance has a value called pKa which represents the pH at which the substance is 50% ionized. From the Henderson-Hasselback equation, one can derive the following formulae to determine the degree of ionization, remembering that the unionized particle is lipid soluble and the one that crosses the cell membrane. For acids, pKa = pH + log (unionized/ionized) For bases, pKa = pH + log (ionized/unionized) Lipid diffusion: A large number of drugs are weak bases or weak acids. The pH of the medium determines the fraction of molecules charged (ionized) if the molecule is a weak acid or base. If the pKa of the drug and the pH of the medium are know, the fraction of ionized molecules can be predicted by means of the Henderson-Hasselbalch equation: "
means associated with a proton (a hydrogen ion); this form of the equation applies to both acids and bases. Ionization of weak acids and bases: Weak bases are ionized-and therefore more polar and more water-soluble--when they are protonated; weak acids are not ionized--and so less water soluble--when they are protonated. * The following equations summarize these points: The Henderson-Hasselbalch relationship is clinically important when it is necessary to accelerate the excretion of drugs by the kidney, eg, in the case of an overdose. Most drugs are freely filtered at the glomerulus, but sufficiently lipid soluble drugs can be reabsorbed from the tubular urine. When a patient takes an overdose of a weak acid drug, its excretion may be accelerated by alkalinizing the urine, eg, by giving bicarbonate. This is because a weak acid dissociates to its charged, polar, form in alkaline solution and this form can not readily diffuse from the renal tubule back into the blood. Conversely, excretion of weak bases is accelerated by acidifying the urine, eg, by administering ammonium chloride, see Figure 1-1. In general, acid drug in an acid medium are poorly ionized but in a basic medium are high ionized. Just the opposite is true for basic drugs. The concept of ion trapping in stomach, urine and breast milk will be presented as examples. II. Mechanism of Biotransport A. Passive Processes 1. Passive diffusion is the direct movement of a solute through a biologic barrier from the phases of higher concentration to a phase of lower concentration. There is no requirement of energy. This is the most common mechanism of transport. The rate of diffusion is related to lipid solubility and polarity, pH, etc. previously discussed. The concentration gradient is the most important factor in determining rate. The rate of diffusion can be expressed by the following equation. (Ficks Law of Diffusion) Rate of diffusion = KA (C1 - C2)/d K = diffusion constant, (M.W., shape of molecule degree of ionization, lipid solubility). A = surface area available d = thickness of membrane C1-C2 =concentration gradient NOTE: For a given membrane A and will be constant Example Passive Process FIGURE: Passive absorption of phenobarbital from the small intestine of the rat. Each point on the curve represents the mean absorption in 4 to 6 rats calculated from the amount of drug remaining in the intestine at the end of the indicated time interval. A.2. Filtration Involves the bulk flow of water related to osmotic and hydrostatic pressures. Small water soluble, polar and non-polar, substances are transported by this process. It is most probable that these substance pass through spaces between cells rather than across the cell membrane. It is a purely physical process and the most important force is a pressure gradient. Examples include water and urea. B. Specialized Transport Mechanisms Specialized transport mechanisms give the membrane selectively so that it can control the transport of specific substances into and out of the cell or across the cell membrane. 1. Facilitated diffusion or transport This is a carrier mediated transport system characterized by: Selectivity Competitiveness Saturability Concentration gradient No energy is required for this transport. The rate of transport is at first related to the concentration gradient but as the gradient but as the gradient increased the rate reaches a limiting or maximal rate. 2. Active transport This too is a carrier mediated transport system, but energy is required and the transport is against a concentration gradient. It too, however, is characterized by saturability, selectivity, and competitiveness. 3. Pinocytosis A transport mechanism which requires energy. The transport mechanism is by invagination of the cell membrane to form a vesicle and the engulfing of the invagination. B.1. Facilitated Diffusion FIGURE: Facilitated diffusion of glucose into human red blood cells. Abscissa: glucose concentration (uM) in the bathing medium. Ordinate: uM glucose entering intracellular water (1 ml) of red blood cells during 15-second incubation at 5oC. (Modified from W.D. Stein, The Movement of Molecules Across Cell Membranes. New York: Academic, 1967. P. 134.) Comparing Active and Passive Transport FIGURE: Passive diffusion, facilitated diffusion and active transport. X is a lipid-soluble drug, freely diffusible in the membrane. Y is a lipid-soluble drug which combines with carrier, C, at the outside surface of the membrane to form a complex, CY, which moves across the lipid membrane. At the inner surface of the membrane, CY dissociates to release Y into the intracellular space. Both X and Y are transferred with the concentration gradient. This a drug, insoluble in the membrane, which combines the carrier C1. Z is actively transported against a concentration gradient. B3. Example Pinocytosis Stages of pinocytosis. Macromolecular solutes in contact with the membrane are trapped in microscopic cavities or cups - invaginations - formed on the surface of the membrane. The membrane fuses around and completely encloses the fluid to form a vesicle. The vesicle is pinched off, passing some fluid and solutes, across the membrane into the interior of the cell. III. Drug Absorption Pharmacodynamics is the study of the relationship of drug concentration and the biologic effect (physiological or biochemical). For most drugs it is necessary to know the site of action and mechanism of action at the level of the organ, or tissue levels. For example, the drug effect may be localized to the brain, the neuromuscular junction, the heart, kidney, etc. Often the mechanism can be described in biochemical or molecular terms. Most drugs exert effects on several organs or tissues and have unwanted as well as therapeutic effects. There is a dose-response relationship for wanted or unwanted effects. Patient factors affect drug response- age, weight, sex, diet, race, genetic factors, disease states, trauma, concurrent drugs, etc. The response of a drug is related to its concentration at the site of action. To produce its characteristic effects or therapeutic effect, a drug must be present in appropriate concentrations at the site of action. It is therefore important to know the interrelationship of absorption, distribution, binding, biotransformation and excretion of a drug and its concentration at its site of action. The quantitative study of drug disposition in the body is known as pharmacokinetics. To know pharmacodynamics one must also know pharmacokinetics, the two are so closely interrelated. Pharmacodynamic is what the drug does to the organism and pharmacokinetics is what the organism does to the drug. The movement of the solute (drug) from the site of administration into the blood stream or the lymphatic system unchanged is defined as absorption. The rate of absorption is important since this determines the onset of drug action and course of drug effect. Absorption rate will also influence the dosage. Many other factors to be discussed later are also related. A. Factor which modify absorption: 1. Physicochemical factors of transport mechanism (most of this has been discussed or alluded to.) 2. Drug product - Form of preparation administered drug solubility, ease of dissolution, concentration administered, tablet, capsule, solution, suspension, etc. 3. Site of absorption - Area of absorbing surface Blood supply to absorbing surface 4. Route of Administration - The route of administration determines the absorbing surface. Drugs are administered either for a local effect or a systemic effect. When the local effect is desired, the drug is placed appropriately in a local area and usually no systemic effect is desired. For local effect a preparation of a drug is applied to the skin, or a mucous membrane. Some drugs are given orally for a local effect on gastrointestinal tract (laxative, antacids) or urinary tract (urinary antiseptic). Drugs given for systemic effects are administered by the following routes. There are advantages and for each route. Most drugs cannot be administered by all routes. The rate of absorption is directly related to the areas of absorbing surface and the blood supply. a. Enteral - administered through mucous membrane (mm) of gastrointestinal tract - from mouth to anus. i. Oral ii. Sublingual, buccal (mm of mouth) iii. Rectal (mm of rectum) b. Parenteral (refers to other routes than oral). There are special requirements and techniques - advantages anddisadvantagess. i. Inhalation - pulmonary absorption, type of substances - particle size ii. Intravenous (i.v.); intra-arterial iii. Intramuscularly (i.m.) iv. Subcutaneously (hypo-subcut) v. Intrathecally vi. Percutaneous Inunction Iontophoresis Dimethyl Sulfoxide (DMSO) 5. Time release preparations: a. Oral -- controlled-release, timed-release, sustained-release, prolonged action, etc. partly dependent upon its rate of dissolution in G.I. tract - designed to produce slow, uniform absorption for 8 hours or longer. Theoretical advantages: better compliance, maintain effect over night, eliminate extreme peaks and troughs. accomplished by 1) coating particles with wax or related water insoluble material, 2) embedding drug in matrix from which it is released slowly as it passes through G.I. tract. 3) complexing drug with ion exchange. There may be wide patient variability. Dosage form may fail and result in "
and in toxicity. b. Parental administration except intravenous, may be prolonged by using insoluble salts or suspensions in non-aqueous vehicles. c. Topical - patches 1) containing scopolamine, 2) NT2 impregnated polymer. NOTES ON ROUTES OF ADMINISTRATION Oral - Advantages - -safest, most convenient, most economical Disadvantages - - various drugs differ in disadvantages 1. irritation to gastric mucosa - nausea and vomiting 2. destruction of drugs by gastric acid and digestive juices 3. precipitation or insolubility of some drugs in G-I fluids 4. formation of non absorbable complexes between drugs and food 5. variable rates of absorption due to variable gastric emptying time, motility and mixing 6. effect too slow for emergencies 7. unable to use in unconscious patient 8. unpleasant taste of some drugs 9. "
metabolism Many of the disadvantages may be overcome or reduced. Oral mucosa - (sublingual) Advantages - - avoid "
- avoid disadvantages of oral administration Disadvantages - - unpleasant taste - irritating effects - all drugs can not be administered by this route Rectal - usually administered in the form of suppositories - some in the form of liquids (enema) Advantages - - useful in unconscious patients- or when patient vomiting - avoids "
Disadvantages - - irritation - inconvenience - distasteful Injection Routes (parenteral) - i.v., i.m., subcutaneous (hypodermic) - intra-arterial, bone marrow, intrathecal Advantages - - more prompt response - more accurate dosage - useful in vomiting and unconsciousness Disadvantages - -because of rapid onset - little time to combat adverse drug reactions and accidental overdoses - sterile dosage forms - aseptic procedures - may be painful - relatively expensive - patients can not usually administer to themselves Intravenous Route - Advantages- - rapid drug action - in emergency situations - continuous control of effect - greater accuracy in drug dosage - larger volumes of solution over long period of time - ability to administer irritating, hypertonic acidic or alkaline solutions because of dilution in a large volume of fluid Disadvantages - - dangerous - speed of onset of pharmacologic action - overdose can not be withdrawn or absorption be stopped - safe doses given too rapidly may be toxic - some drugs may precipitate at pH of blood - suspensions or oily liquids may not be used - embolism - sterile preparations and aseptic techniques required Skin - for local effects: - drugs applied in the form of ointments, liniments, lotion, creams, plasters, etc., not ordinarily used for systemic effects but for local effect Absorption from skin for some drugs by the following methods will produce systemic effects. 1. inunction 2. iontophoresis - drug in solution in contact with an electrode placed against the skin and a galvanic current applied to both the drug electrode and another electrode placed elsewhere on the body. 3. patches - nitroglycerin, scopolamine, clonidine Respiratory tract - extensive absorbing surface and extensive blood supply - good absorption for sprays, aerosols, dust, gases - administration of drugs require special equipment and technique Many physiologic variables and pathologic states alter absorption, infections, ciliary action, mucus coating - size of particles important - particles greater than 10 u are deposited in nasal passages. Particles less than 2 u penetrate deeper. (For significant penetration to the alveoli particles must be 2 u or less.) Topical application a. Mucous membrane conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra, urinary bladder - usually for topical effect b. Eye - usually local effects c. Skin - inunction - ointments - creams Drug nomenclature 1. Formal chemical name 2. Code name 3. Proprietary or trade name 4. USAN or generic * * Selected by USAN council sponsored by AMA, APA, USP Convention B. Bioavailability (F) The specific net result of absorption is Bioavailability - the rate and extent of drug absorption from a dosage form, best measured by AUC (area under curve). (See Figure #10) Chemical equivalence (Pharmaceutical) refers to dugs product that contains the same compound (chemical) in the same amount on two or more dosages forms and meet present official standards inactive ingredients may differ. Bioequivalence refers to chemical equivalents that when administered to the same individual in the same dosage regimen result in equivalent concentration of drug in blood and tissues. For drugs to be bioequivalent the (AUC) area under the curves derived after administration after administration of different formulations of the same drug, the peak concentration and time to reach peak concentration should not be significantly different. (see figure) Therapeutic equivalence refers to two drug products that when administered to the same individual in the same dosage regimen provide essentially the same therapeutic effect or toxicity; they may or may not be bioequivalent. Figure 10: A model drug-blood level curve such as might seen following oral administration of a drug. The parameters important in evaluating the bioavailability of this drug are: (1) peak height concentration, (2) time of peak concentration, and (3) area under the serum concentration time curve. (From D.J. Chodos and A.R. DiSanto, Basics of Bioavailability. Kalamazoo, Michigan: Upjohn, 1973). Figure 11: A comparison of the drug-blood level curves of two formulations of a hypnotic compound. MTC = minimum toxic concentration; MEC = minimum effective concentration. The areas under the serum concentration curves are identical for the two formulation; therefore, equal amounts of both are absorbed. Formulation A, however, would produce its effects sooner; it would produce toxic effects (i.e., levels exceed MTC); and its effects would be terminated earlier than those of formulations B (i.e., levels fall below MEC). Formulation B would induce sleep later (about 2 hr following administration); it would not be expected to produce any signs of toxicity; and its effects would persist much longer. (From D.J. Chodos and A.R. DiSanto, Basics of Bioavailability. Kalamazoo, Michigan, Up john, 1973). Three mechanisms for increasing surface area of the small intestine. (From T.H. Wilson, Intestinal Absorption. Philadelphia, Saunder, 1962, P. 2). Blood flow to some important tissues of the body (based on a 70-kg human). TABLE 1: Tissue Mass (kg) Blood Flow(mL/min) Flow (percentof Cardiac Output)Brain 1.4 750 13.9Heart 0.3 250 4.9Liver 2.9 1500 27.8Kidneys 0.3 1260 23.3Skeletal muscle 34.4 840 15.6Skin 4.0 462 8.6Placenta and fetal (term) 3.8 500 9Whole body 70 5400 100 IV. Distribution After absorption, a drug undergoes distribution - a dynamic and complex process - since other processes as metabolism and excretion are going on at the same time. Distribution is determined by the principles of transport as for any membrane. The rate of entry of a drug into a tissue is determined by the mass of the tissue and its blood supply. Distribution may be unequal in many tissues because of protein binding, regional variations in pH and characteristic permeability of various membranes. After distribution equilibrium, the concentration in the plasma reflects the concentration in tissues and extracellular fluids and vice versa. A. There are basically two water compartments in the body, intracellular and extracellular. The extracellular may be divided into a plasma compartment and interstitial. The values commonly used for these compartments are as follows: Extracellular 17% of body weight (12 liters)*Plasma 4% of body weight (3 liters)Interstitial 13% of body weight (9 liters)Intracellularly 41% of body weight (28.5 liters) Total body water (58% of body weight) or (40.5 liters) *70 kg man. Using certain reference compounds whose distribution is well known, the volume of these various compartments can be determined. Plasma 131 I tagged albumin, Evans BlueExtracellular Mannitol, tagged sodium thiocyanateTotal body water Heavy water or triturated water B. Vd. The apparent volume of distribution gives a quantitative estimate of the tissue localization of a drug. It is that volume in which a drug seem to be distributed to give the concentration in the plasma at equilibrium and following the administration of a known quantity of the drug. Absorption must be rapid and one assumes there is no elimination. This hypothetical value is calculated from the total dose divided by the plasma concentration at zero time. This concentration is value extrapolated from the linear curve log concentration of plasma against time. This value is compared with the values obtained with the reference compounds. (See Figure #15) Vd = Q (mg/kg) = ml/kg of body weight to Co (mg/ml) Q = total quantity administered Co = concentration in plasma at 0 time Vd (liters) = total amount of drug in (Gm) concentration of drug in plasma (Gm/1) Interpretation: The lower the plasma concentration, the greater the distribution. If the Vd is greater than the total body water it is taken up by some tissue. FIGURE 14: Distribution and concentration of a drug in the various fluid compartments of the body in relation to its permeability characteristics. The values of water content of the plasma, extracellular and intracellular compartments are only approximate. These figures do not include the inaccessible water in bone, or the water in the cavities of the stomach, intestine, tracheobronchial tree, cerebrospinal fluid or in the anterior chamber of the eye (total 7 to 10 percent). TABLE 2: Volume of Distribution of Various Drugs and Reference Compounds Volume of distribution (ml/kg body weight) Theoretic plasma level after 10 mg/kg dose(ug/ml)Reference compounds 131 Albumin(plasma volume)Mannitol(extracellular volume)3H2O(total body water)DrugsDecamethoniumAntipyrineClonidineMeperineChlorpromazine 40 20060018051512,50020,000100,000 55.019.50.80.050.01 TABLE: Theoretical Relationship Between Elimination Half-Time and Volume of Distribution in the Human Being Table 3: Drug Distributed in Mechanisms of Urinary Excretion Plasma Water Extracellular Fluid Body Water (3,000 ml) (12,000 ml) (41,000 ml) Glomerular filtration 16 min 64 min 219 min 130 ml/min Tubular secretion 3 min 13 min 44 min * Entries in each column are values of the fastest possible elimination half-time. Elimination half-times have no upper limit; renal clearance may be extremely low (near zero) if a drug is extensively reabsorbed or protein-bound, or has an apparent volume of distribution greater than total body water due to extensive tissue binding. Source: Modified from A. Goldstein, L. Aronow and S.M. Kalma, Principles of Drug Action. New York, Hoeber Med. Div., Harper and Row, 1968, P. 197. C. Drug Sequestration and Protein Binding Drugs in the blood stream partly as free drug and partly as bound drug, depending on the drug. Most drugs are bound to some extent to plasma proteins. Many plasma proteins can bind drugs, however, albumin is the most important. Both acidic and basic drugs bind but acidic drugs are bound more extensively. Since only free drug diffuses into extravascular space, drugs tightly bound have limited distribution. There is a limited number of binding sites on proteins. These sites can become saturated and additional drug will exist as free drug and varying consequences result. Drugs vary in their affinity for proteins. Those having a strong affinity will displace those of a lesser affinity (drug interaction). Protein binding generally leads to slower excretion and slow metabolism. There are, however, exceptions. Since the protein bound drug is released as the free drug is cleared from plasma, protein bound drug may act as a reservoir. D. Redistribution Redistribution involves the sequestration of a drug in a tissue, the fat, liver, etc. These drugs reach an equilibrium with the plasma and as a drug is loss from the plasma it is replaced by drug from the tissue. At times sequestration of a drug in a tissue may lead to local toxicity. If the drug s released from the tissue in adequate amounts it may serve as a reservoir; if too slowly released, it may be simply ineffective. E. Distribution of Drug in Special Compartments Blood Brain Barrier Placental Barrier These barriers influence the distribution of drugs. The blood brain barrier is of particular significance since it is desirable to attain therapeutic concentrations in the brain tissue of certain drugs. On the other hand, it is not desirable for many drugs. This barrier is basically anatomical but has a physiological component. The endothelial cells of the brain capillaries are tightly joined to one another. The glial connective tissue cells are closely applied to the basement membrane of the capillary endothelium. This makes for a barrier, especially for water soluble and polar substances. There is a slight difference in pH of the cerebrospinal fluid and plasma (7.3 and 7.4). These factors confer different permeability characteristics on the brain from other tissues. Lipid soluble compounds diffuse across the barrier the same as with other tissues. (See Figure 17) F. Placental Barriers The placenta also acts as a barrier between the maternal circulation and the fetal circulation. The same principles applied here as for other membranes. Lipid soluble drugs diffuse across more rapidly than polar compounds. A constant level of a drug in the maternal circulation will eventually each equilibrium with the fetal circulation. Fortunately, this requires time. The fastest possible time is estimated to be 40 minutes. Table 4: UPTAKE OF N-ACETYL-4-AMINOANTIPYRINE BY VARIOUS TISSUES OF CAT Tissues Conc. Tissue H2O S.E.Conc. Plasma H2OLiver 1.14 0.08Muscle 0.94 0.10Whole pituitary 0.89 0.09Area postrema 0.87 0.19Intercolumnar tubercle 0.67 0.10Hypothalamus 0.32 0.02Thalamus 0.32 0.04Cortex 0.31 0.02CSF 0.30 0.02 Certain parts of the brain do not have a barrier to the entrance of polar substance. N-acetyl-4-aminoantipyrine, a compound having a low lipid-solubility, enters the CSF and brain slowly but penetrates the area postrema, the intracolumnar tubercle, the anterior and posterior pituitary and the pineal gland at the same rate as it penetrates liver and muscle. It has been suggested that these tissues are not really part of the brain but merely contiguous with it; in fact, the cells of these areas are not said to be non-neuronal. V. Excretion The kidney is the major organ of excretion. There are, however, minor routes such as, intestines, saliva, sweat, breast milk, and lungs. The lungs become very important for volatile substances or volatile metabolites. Drugs which are eliminated by the kidney are eliminated by: a) Filtration - no drug is reabsorbed or secreted. b) Filtration and some of the drug is reabsorbed. c) Filtration and some secretion. d) Secretion By use of the technique of clearance studies, one can determine the process by which the kidney handles the drug. Renal plasma clearance = UxV ml/min U = conc. of drug in urine Cp Cp = conc. of drug in plasma V = urine flow in ml/min Renal clearance ratio = renal plasma clearance of drug (ml/min GFR (ml/min) Total Body Clearance = renal + non-renal Interpretation: If the renal clearance ratio is equal to one, the drug is filtered and not reabsorbed or secreted. If the renal clearance ratio is less than one, the drug is filtered and some is reabsorbed. If the renal clearance ratio is greater than one, then the drug is filtered and secreted. Filtration and reabsorption are governed by the same principles already discussed under transport mechanisms and absorption. In the kidney, one may use these principles to enhance the elimination or to prolong blood levels of a drug. The pH of void urine may vary from 4.3 to 8 and by the use of drugs the pH can be maintained or changed to acidic or basic as desired. Acidification of the urine will hasten the elimination of basic drugs and prolong the elimination of acidic drugs. If the urine is made basic just the opposite occurs (Henderson Hasselback equation) (phenobarbital, aspirin, methamphetamine). The overall extend that pH may influence the elimination depends on the percent of the drug cleared from the plasma by renal clearance. Tubular Secretion: Active tubular secretion of some drugs, weak organize acids and bases take place in the proximal tubule. This process is energy dependent and can be blocked by other drugs. It is specific and can be saturated. Each substance has a characteristic maximum (Tm). Anions and cations are handled by different transport systems. The anionic system generally handle metabolites conjugated with glycine, glucuronic, acid or sulfates. These various anionic compounds complete with each other transport (Probenecid-Penicillin). Similarly organic cations complete with each other but not with anionic compounds. Figure 18: Functional organization of nephron in relation to reabsorption of Na+ and water to formation of hypotonic and hypertonic urine. (Modified and redrawn from R.F. Pitts, The Physiological Basis of Diuretic Therapy, 1959. Charles C. Thomas, Publisher, Springfield, Illinois). * NOTE: These definitions and other data taken from Pharmacology Examination and Board Review by Bertram G. Katzung and Anthony Trevor, 9th Edition, Lange Medical Book Appleton & Lange. (In my opinion this is an excellent book, Dr. Tureman)