•
`
`•
`
`•
`
`,.
`
`'
`
`
`
`' • C •
`
`•
`
`•
`
`'
`
`•
`
`'
`
`l
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`'
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`GSK Exhibit 1033 - Page 1 of 75
`
`

`

`Entered according to Act of Congress, in the year 1885 by Joseph P H.emington,
`in the Office of the Librarian of Congress, at Washington, DC
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`Copyright 1926, 1936, by Joseph P Remington Estate
`Copyright 1948, 1951, b:y: The Philadelphia College of Pharmacy and Scie_nce
`Copyright© 1956, 1960, 1965, 1970, 1975, 1980, 1985, by The Philadelphia College of.Pharmacy and
`Sc:ience
`
`All Rights Reserved
`
`Library of Congress C11tlllog Card No 60-53334
`ISBN 0-912734-03-G
`
`The use of portions of the text of USP XX, NF XV, and USAN and the USP Dictionary of Drug
`Names is by permission of the USP Convention. The Convention is not responsible for any
`inaccuracy of quotation or for any false or misleading implication that may arise from
`separation of excerpts from the original context or by obsolescence resulting from
`publication of a supplement.
`
`NOTICE-This text is not intended to represent, nor shall it be interpreted to be, the equivalent
`of or a substitute for the official United States Pharmacopeia ( USP) and/or the National
`Formulary (NF). In the event of any difference or discrepancy between the current official
`USP or NF standards of strength, quality, purity, packaging and labeling for drugs and
`representations of them herein, the context and effect of the official compendia shall
`prevail.
`
`Printed in the United States of America by the Mack Printing Company, Easton, Pennsylvania
`
`

`

`Table of Contents
`
`Part 1
`
`Orientation
`
`1 Scope
`2 Evolution of Pharmacy
`3 Ethics
`4 Pharmacists In Practice
`5 Pharmacists in Industry
`6 Pharmacists in Government
`7 Drug Information
`8 Research
`
`Part 2
`
`Pharmac•utics
`
`9 Metrology and Calculation
`10 Statistics
`11 Computer Science
`12 Calculus
`13 Molecular Structure, Properties, and States of
`Matter
`14 Complexation .
`15 Thermodynamics .
`16 Solutions and Phase Equilibria
`Ionic Solutions and Electrolytic Equilibria
`17
`18 Reaction Kinetics •
`lnterfaclal Phenomena
`19
`20 Colloidal Dispersions
`21 Particle Phenomena and Coarse Dispersions
`22 Rheology •
`
`Part I
`
`Pharmac•utical Ch•mistry
`
`Inorganic Pharmaceutical Chemistry
`23
`24 Organic Pharmaceutical Chemistry
`25 Natural Products
`26 Drug Nomenclature-United States Adopted
`Names
`27 Structure-Activity Relationship and Drug Design
`
`3
`8
`19
`27
`34
`42
`49
`59
`
`69
`104
`140
`148
`
`161
`186
`198
`207
`230
`249
`258
`271
`301
`330
`
`349
`374
`397
`
`428
`
`435
`
`Part4
`
`Radioisotopes in Pharmacy and M•dicin•
`
`.
`28 Fundamentals of Radioisotopes • .
`29 Medical Applications of Radioisotopes
`
`Part 5
`
`T•sting and Analysis
`
`30 Analysis of Medicinals
`31 Biological Testing •
`. • .
`32 Clinical Analysis
`. •
`33 Chromatography .
`Instrumental Methods of Analysis
`34
`. • • • • •
`.
`.
`.
`35 Dissolution
`
`453
`471
`
`500
`550
`559
`593
`619
`653
`
`Part 6
`
`Pharmac•utical and M•dicinal A99nts
`
`36 Diseases: Manifestations and Pathophysiology
`
`37 Drug Absorption, Action, and Disposition
`. •
`.
`.
`• .
`38 Basic Pharmacokinetics
`39 Principles of Clinical Pharmacokinetlcs
`• •• •• • • • •
`40 Topical Drugs
`41 Gastrointestinal Drugs . • . • • •
`42 Blood, Fluids, Electrolytes, and Hematologic
`•
`Drugs . . . . .
`43 Cardiovascular Drugs
`
`• • • . • • • . • • • •
`
`669
`713
`741
`762
`773
`792
`
`816
`843
`
`xv
`
`44 Respiratory Drugs
`45 Sympothomimetic Drugs •
`46 Cholinomimetic (Parasympathomimetlc) Drugs
`47 Adrenergic and Adrenergic Neuron Blocking Drugs
`
`48 Antimuscarinic and Antispasmodic Drugs
`49 Skeletal Muscle Relaxants
`50 Diuretic Drugs
`51 Uterine and Antimlgraine Drugs
`52 Hormones •
`53 Vitamins and Other Nutrients .
`•
`54 Enzymes
`55 General Anesthetics
`56 Local Anesthetics •
`57 Sedatives and Hypnotics .
`58 Antiepileptics
`59 Psychopharmacologic Agents
`60 Analgesics and Antlpyretics
`61 Histamine and Antihistamines
`62 Central Nervous System Stimulants
`63 Antineoplastic and lmmunosuppressive Drugs .
`64 Antimicrobial Drugs •
`65 Parasiticides .
`66 Pesticides • • •
`,
`67 Diagnostic Drugs
`68 Pharmaceutical Necessities
`69 Adverse Effects of Drugs •
`70 Pharmacogenetics
`71 Pharmacological Aspects of Drug Abuse
`Introduction of New Drugs
`72
`
`866
`876
`894
`
`902
`911
`921
`933
`946
`951
`1002
`1005
`1009
`1048
`1059
`1075
`1084
`1099
`1124
`1133
`1139
`1158
`1234
`1241
`1264
`1278
`1321
`1336
`1341
`1j57
`
`Part 7
`
`Diological Products
`
`73 Principles of Immunology
`Immunizing Agents and Diagnostic Skin Anti(cid:173)
`74
`gens
`75 Allergenic Extracts •
`
`•
`
`1371
`
`1380
`1396
`
`Part8
`
`Pharmac•utical Pr•parations and Th9ir
`Manufa~tur•
`
`76 Preformulation .
`77 Bioav!Jilabillty and Bioequlvalency Testing
`78 Separation
`79 Sterilization
`80 Tonicity, Osmoticity. Osmolality, and Osmolarlty .
`81 Plastic Packaging Materials
`82 Stability of Pharmaceutical Products
`83 Quality Assurance and Control
`84 Solutions, Emulsions. Suspensions, and Extrac-
`tives
`85 Parenteral Preparations
`lntrayenous Admixtures
`86
`87 Ophthalmic Preparations
`88 Medicated Applications
`89 Powders
`90 Oral Solid Dosage Forms •
`91 Coating of Pharmaceutical Dosage Forms .
`92 Sustained Release Drug Delivery Systems
`93 Aerosols
`
`Part 9
`
`Pharmaceutical Prectice
`
`94 Ambulatory Patient Care
`Institutional Patient Care
`95
`96 Long.Term Care Facilities
`
`1409
`1424
`1432
`1443
`1455
`1473
`1478
`1487
`
`1492
`1518
`1542
`1553
`1567
`1585
`1603
`1633
`1644
`1662
`
`1681
`1702
`1723
`
`

`

`97 The Pharmacist and Public Health
`96 The Patient: Behavioral Determinants .
`99 Patient Communication
`100 Patient Compliance •
`101 The Prescription
`102 Drug Interactions
`103 Utilization and Evaluation of Clinical Drug
`Literature
`104 Health Accessories
`
`1737
`1749
`1757
`1764
`1776
`1796
`
`1817
`1824
`
`105 s·urgicol Supplies .
`106 Poison Control
`107 Lows Governing Pharmacy
`106 Pharmaceutical Economics and Management
`109 Dental Services
`
`lnHx
`
`Alphabetic Index .
`
`1669
`1679
`1690
`1917
`1935
`
`1946
`
`xvi
`
`

`

`CHAPTER 80
`
`Tonicity, Osmoticity, Osmolality, and
`Osmolarity
`
`Frederick P Sleg•I. PhD
`Professor of Pharmaceutics
`College of Pharmacy, University ol lllinols
`Chicago, IL 60612
`
`It is generally accepted that osmotic effects have a major
`place in the maintenance of homeostasis (the state of equi(cid:173)
`librium in the living. body with respect to various fUI1ctions
`and to the chemical composition of the fluids a:nd tissues, eg,
`temperature, heart rate, blood pressure, water content, blood
`sugar, etc). To a great extent these effects occur within or
`between cells and tissues where they cannot be measured.
`One of the most troublesome problems in clinical medicine
`is the maintenance of adequate body fluids and proper balance
`between extracellular and intracellular fluid volwnes in se(cid:173)
`riously ill patients. It should be kept in mind, however, that
`fluid and electrolyte abnormalities are not diseases, but are
`the manifestations of disease.
`The physiologic mechanisms which control water intake
`and output appear to respond primarily to serum osmoticity.
`Renal regulation of output is influenced by variation in rate
`of release of pituitary antidiuretic hormone (ADH) and other
`factors in response to changes in serum osmoticity. Osmotic
`changes also serve as a stimulus to moderate thirst. This
`mechanism is sufficiently sensitive to -Limit variations in os(cid:173)
`moticity in the normal individual to less than about 1 %. Body
`fluid continually oscillates within this narrow range. An in(cid:173)
`crease of plasma osmoticity of 1 % will stimulate ADH release,
`result in reduction of urine flow, and at the same time stim(cid:173)
`ulate thirst that results in increased water intake. Both the
`increased renal reabsorption of water (without solute) stim(cid:173)
`ulated by circulating ADH and the increased water intake
`tend to lower serum osmoticity.
`The transfer of water through the cell membrane occurs so
`rapidly that any lack of osmotic equiHbriwn between the two
`fluid compartments in any given tissue is usually corrected
`within a few seconds, and at most within a minute or so.
`However, this rapid transfer of water does not mean that
`complete equilibration occurs between th~ extracellular and
`intracellular compartments throughout the whole body within
`this same short period of time. The reason for this is that
`fluid usually enters the body through the gut and must then
`be transported by the circulatory system to all tissues before
`complete equilibration can occur. In the normal person it
`may require 30-60 minutes to achieve reasonably good
`equilibration throughout the body after dr.inking water.
`Osmoticity is the property that largely determines the phys(cid:173)
`iologic acceptability of a variety of solutions used for thera(cid:173)
`. peutic and nutritional purposes.
`Pharmaceutical and therapeutic consideration of osmotic
`effects has been to· a great extent directed toward the side
`effects of ophthalmic and parenteral medicinals due to ab(cid:173)
`normal osmoticity, and to either formulating to avoid the side
`effects or finding methods of administration to minimize
`them. More recently this consideration has been extended
`The author grawfully acknowledges suggestions receiv_!!d from Dr
`Dwight L Deardorff, Emeritus Professor of Pharmacy, College of Phar(cid:173)
`macy, University of Illinois, who established the framework for this chapter
`in the 16th edition.
`
`to total (central) parenteral nutrition, to enteral hyperali(cid:173)
`mentation ("tube" feeding) and to concentrated-fluid infant
`formulas. 1 Also, in recent years the importance of osmometry
`of serum and urine in the diagnosis of many pathological
`conditions has been recognized.
`There are a number of examples of the direct therapeutic
`effect of osmotic action, such as the intravenous use of man(cid:173)
`nitol as a diuretic which is filtered at the glomeruli and thus
`increases the osmotic pressure of tubular urine. Water must
`then be reabsorbed against a higher osmotic gradient than
`otherwise, so reabsorption is slower and diuresis is observed.
`The same fundamental principle applies to the intravenous
`administration of 30% urea used to affect intraora.nial pressure
`in the control of cerebral edema. . Peritoneal dialysis fluids
`tend to be somewhat hyperosmotic to withdraw water and
`nitrogenous metabolites. Two to five percent sodium chloride
`solutions and a 40% glucose ointment are used topically for
`corneal edema. Ophthalgan (Ayerst) is ophthalmic glycerin
`employed for its osmotic effect to clear edematous cornea to
`facilitate an ophthalmoscopic or genioscopic examination.
`Glycerin solutions in 50-75% concentrations (Glyrol (Cooper
`Vision), Osmoglyn (Alcon)) and isosorbide solution [Ismotic
`(Alcon)] are oral osmotic agents for reducing intraocular
`pressure. The osmotic principle also .applies to plasma ex(cid:173)
`tenders such as polyvinylpyrrolidone and to saline laxatives
`such as magnesium sulfate, magnesium citrate solution,
`magnesium hydroxide (via gastric neutralization), sodium
`sulfate, sodium phosphate and sodium biphosphate oral so(cid:173)
`lution and enema (Fleet).
`An interesting osmotic laxative which is a nonelectrolyte
`is a lactulose solution. Lactu1ose is a nonabsorbable disac(cid:173)
`ch1Uide which is colon specific, wherein colonic bacteria de(cid:173)
`grade some of the disaccharide to lactic and other simple or(cid:173)
`ganic acids. These, in toto, lead to an osmotic effect and
`laxation. An extension of this therapy is iUustrated by
`Cephulic (Merrell-National) solution, which uses the acidi(cid:173)
`fication of the colon via lactulose degradation to serve as a trap
`for ammoµia migrating from the blood to the colon. The
`conversion of ammonia of blood to the ammonium ion in the
`colon is ul~imately coupled with the osmotic effect and laxa(cid:173)
`tion thus expelling undesirable levels of blood ammonia. This
`product is employed to prevent and treat frontal systemic
`encaphalopathy.
`Osmotic laxation is known with the oral or rectal use of
`glycerin and sorbitol. Epsom salt has been used in baths and
`compresses to reduce edema assoc.iated with sprains. A rel(cid:173)
`atively new approach is the indirect application of the osmotic
`effect in therapy via osmotic pump drug delive~y systems.2
`If a solution is placed in contact with a membrane that is
`permeable to molecules·of the solvent, but not to molecules
`of the solute, the movement of solvent through the membrane
`is called osmosis. Such a membrane is often called semi(cid:173)
`permeable. As the several types of membranes of the body
`vary in their permeability, it is well to note that they are se-
`1455
`
`

`

`1456
`
`CHAPTER 80
`
`lectiuely permeable. Most normal living-cell membranes
`maintain various solute concentration gradients. A selectively
`permeable membrane may be defined either as one that does
`not permit free, unhampered diffusion of all the solutes
`present, or as one that maintains at least one solute coricen(cid:173)
`tration gradient across itself. Osmosis then is the diffusion
`of water through a membrane that maintains at least one so(cid:173)
`lute concentration gradient across itse_lf.
`Assume a solution A on one side of the membrane, and a
`solution B of the same solute but of a higher concentration on
`the other side; the solvent will tend to pass into the more
`concentrated solution until equilibrium has been established.
`The pressure required to prevent this movement is the os(cid:173)
`motic pressure. It is defined as the excess pressure, or pres(cid:173)
`sure greater than that above the pure solvent, which must be
`applied to solution B to prevent passage of solvent through
`a perfect semipermeable membrane from A to B. The con(cid:173)
`centration of a solution with respect to effect on osmotic
`pressure is related to the number of particles (un-ionized
`molecules, ions, macromolecules, aggregates) of solute(s) in
`solution and thus is affected by the degree of ionization or
`aggregation of the solute. See Chapter 16 for review of colli(cid:173)
`gative properties of solutions.
`Body fluids, including blood and lacrimal fluid, normally
`have an osmotic pressure which is often described as corre(cid:173)
`sponding to that of a 0.9% solution of sodium chloride. The
`body also attempts to keep the osmotic pressure of the con(cid:173)
`tents of the gastrointestinal tract at' about this level, but there
`the normal range is much wider than that of most body fluids.
`The 0.9% sodium chloride solution is said to be isoosmotic
`with physiologic fluids. The term isotonic, meaning equal
`tone, is in medical usage commonly used interchangeably with
`isoosmotic. However, terms such as isotonic and tonicity
`should be used only with reference to a physiologic fluid.
`Isoosmotic is actually a physical term which compares the
`osmotic pressure (or another colligative property, such as
`freezing point depression) of two liquids, neither of which may
`be a physiologic fluid, or which may be a physiologic fluid only
`under certain circumstances. For example, a solution of boric
`acid that is isoosmotic with both blood and lacrimal fluid is
`isotonic only with the lacrimal fluid. This solution causes
`hemolysis of red blood cells because molecules of boric acid
`pass freely through the erythrocyte membrane regardless of
`concentration. Thus isotonicity infers a sense of physiologic
`compatibility where isoosmoticity need not. As another ex(cid:173)
`ample, a "chemically defined elemental diet" or enteral nu(cid:173)
`tritional fluid can be isoosmotic with the contents of the gas(cid:173)
`trointestinal tract, but would not be considered a physiologic
`fluid, or suitable for parenteral use.
`A solution is isotonic with a living cell if there is no net gain
`or loss of water by the cell, or otht'lr change in the cell when it
`is in contact with that solution. Physiologic solutions with
`an osmotic pressure lower than that of body fluids, or of 0.9%
`sodium chloride solution, are commonly referred to as being
`hypotonic. Physiologic solutions having a greater osmotic
`pressure are termed hypertonic.
`Such qualitative terms are of limited value, and it has be(cid:173)
`come necessary to state osmotic properties in quantitative
`terms. To do so a term must be used that will represent all
`particles that may be present in a given system. The term
`used is osmol: An osmol is defined as the weight in grams of
`a solute, existing in a solution as molecules (and/or ions,
`macromolecules, aggregates, etc), that is osmotically equiv(cid:173)
`alent to the gram-molecular-weight of an ideally behaving
`nonelectrolyte. Thus the osmol-weight of a nonelectrolyte,
`in a dilute solution, is generally equal to its gram-molecular(cid:173)
`weight. A milliosmol, abbreviated mOsm, is the weight stated
`in milligrams.
`If one extrapolates this concept of relating an osmol and a
`mole of a nonelectrolyte as being equivalent, then one may also
`
`define an osmol in these following ways. It is the amount of
`solute which will provide one ~vogadro's number, 6.02 X 1023
`particles in solution and it is the amount of solute which on
`dissolution in one kg of water will result in an osmotic pressure
`increase 6f 22.4 atmospheres. This is derived from the gas
`equation, PV = nRT, assuming ideal conditions and standard
`temperature of0°. This is equivalent to an increase of 17,000
`mm Hg or 19,300 mm Hg at 37°. A milliosmol (mOsm) is
`one-thousandth of an osmol. For example, one mole of an(cid:173)
`hydrous dextrose is equal to 180 g. One Osm of this non(cid:173)
`electrolyte is also 180 g. One mOsm would be 180 mg. Thus
`180 mg of this solute dissolved in one kg of water will produce
`an increase in osmotic pressure of 19.3 mm Hg at body tem(cid:173)
`perature.
`For a solution of an electrolyte such as sodium chloride, one
`molecule of sodium chloride represents one sodium and one
`chloride ion. Hence, one mole will represent 2 osmols of so(cid:173)
`dium chloride theoretically. Accordingly, one Osm NaCl =
`58.5 g/2 or 29.25 g. This quantity represents the sum total of
`6.02 X 1023 ions as the total number of particles. Ideal solu(cid:173)
`tions infer very dilute solutions or infinite dilution. However,
`as concentration is increased, other factors enter. With strong
`electrolytes, interionic attraction causes a decrease in their
`effect on colligative properties. In addition, and in opposi(cid:173)
`tion, for all solutes, including nonelectrolytes, solvation and
`possibly other factors operate to intensify their colligative
`effect. Therefore it is very difficult and often impossible to
`predict accurately t he osmoticity of a solution. It may be
`possible to do so for a dilute solution of a single, pure and
`well-characterized solute, but not for most parenteral and
`enteral medicinal and/or nutritional fluids; experimental
`determination is likely to be needed.
`
`Osmolality and Osmolarity
`
`It is necessary to use several additional terms to define ex(cid:173)
`pressions of concentration in reflecting the osmoticity of so(cid:173)
`lutions. The terms include osmolality, the expression of os(cid:173)
`molal concentration, and osmolarity, the expression of osmolar
`concentration.
`Osmolality-A solution has an osmolal concentration of
`one when it contains one osmol of solute per kilogram of water.
`A solution has an osmolality of n when it contains n cismols
`per kilogram of water. Osmolal solutions, like their.coun(cid:173)
`terpart molal solutions, reflect a weight to weight relationship
`between the solute and the solvent. All solutions with the
`same molal concentrations, irrespective of solute, contain the
`same mole fraction (/ ,,;,) of solute. In water
`f _
`moles solute
`m - moles solute + moles solvent
`thus, for a one molal solution
`f m =
`1 mole solute
`1 mole solute + 55.5 moles water per kg
`Since an osmol of any nonelectrolyte is equivalent to one mole
`of that compound, then a one osmolal solution is synonymous
`to a one molal solution for a typical nonelectrolyte.
`With a typical electrolyte like sodium chloride, one.osmol
`is approximately 0.5 mole of sodium chloride. Thus it follows
`that a one osmolal solution of sodium chloride is essentially
`equivalent to a 0.5 molal solution. Recall that one osmolal
`solutions of dextrose or sodium chloride will each contain the
`same particle concentration. In the dextrose solution there
`will be 6.02 X 1023 molecules per kilogram of water and in the
`sodium chloride solution one will have 6.02 X 1023 total ions
`per kilogram of water, one-half of which are Na+ ions and the
`other half c1- ions. The mole fraction in terms of total par(cid:173)
`ticles will be the same and hence the same osmotic pres(cid:173)
`sure.
`
`I
`
`I
`
`I,
`
`

`

`TONICITY, OSMOTICITY, OSMOLALITY, AND OSMOLARITY
`
`1457
`
`As . in molal solutions, osm.olal solutions are usually em(cid:173)
`p1oyed where quantitative precision· is required, as in the
`measurement of p_hysical and chemical properties of solutions
`(ie, colligative properties). The advantage to the weight to
`weight relationship is that the concentration of the system is
`not influenced by temperature.
`Osmolarity-The relationship that we observed between
`molality and osmo1ality is similarly shared between molarity
`and osmolarity. A solution has an osmolar concentration of
`one when it contains one osmol·of solute per liter of solution.
`Likewise, a solution has an osmolarity of n when it contains
`n osmols per liter of solution. Osmolar solutions, unlike os(cid:173)
`molal solutions, reflect a weight in volume relationship be(cid:173)
`tween the solute and final solution. A one molar and one
`osmolar solutions would be synonymous for nonelectrolytes.
`For sodium chloride a one osmolar solution· wo.uld contain one
`osmol of sodium chloride per liter which approximates a 0.5
`molar solution. The advantage of employing osmolar con(cid:173)
`centrations over osmolal concentrations is the ability to relate
`a specific number of osmols or milliosmols to a volume, such
`as a liter or mL. Thus the osmolar concept is simpler and
`more practical. The osmolal concept does not allow for this
`convenience because of the w/w relationship. Also, additional
`data such as the density are usually not available. Volumes
`of solution rat}:,.er than weights of solution are more practical
`in the delivery of liquid dosage forms.
`Many health professionals do not have a clear under(cid:173)
`standing of the difference between osmolality and osmolarity.
`In fact, the terms have been us~d _interchangeably. This is
`partly due to the circumstance that until recent years most
`of the systems involved were body fluids in which the differ(cid:173)
`ence between the numerical values of the two concentration .
`expressions is small and similar fomagnitude to the error in(cid:173)
`volved in their determination. The problem may partly
`center around the interpretation by·some to view one kilogram
`of water in the osmolalc_oncept as being equivalent to one liter,
`and more importantly, the interpretation that to make up to
`volume of one liter as in osmolarity is reasonably the same as
`plus one liter (a distortion of the osmolal concept). The es(cid:173)
`sential difference resides in the error introduced which re(cid:173)
`volves around the volume of water occupied by the solute. A
`one osmolar solution of a solute will always be more concen(cid:173)
`trated than a one osmolal solution. With dilute solutions the
`difference may be acceptably small. Nine grams of sodium
`chloride per liter of aqueous solution is approximately
`equivalent to 9 g in 996.5 mL of water. This represents an
`error under one percent when comparing the osmoticlty of
`0.9% w/v solution to a solution of 9 g plus one kilogram of
`water. Using dextrose in a parallel comparison, ~mors range
`from approximately 3.5% in osmoticity with 50 g dextrose per
`liter versus 50 g plus one kilogram water to a difference of
`about 25% in osmoticity with 250 g dextrose per liter versus
`250 g plus one kilogram water. The confusion appears to be
`without cause for concern at this time. However, one should
`be alerted to the sizeable errors with concentrated solutions
`or fluids such as those employed in total parenteral nutrition,
`enteral hyperalimentation, and oral nutritional fluids for in(cid:173)
`fants.
`Reference bas been made to the terms hypertonic and hy(cid:173)
`potonic. Analogous terms are hyperosmotic and hypoos(cid:173)
`motic. The significance of hyper- and hypo-osmoticity for
`medicinal and nutritional Quids will be discussed in later
`sections. The values which correspond to those terms for
`serum may be approximately visualized from the following
`example. Assuming norcmal serum osmolality to be 285·
`mOsm/kg, as serum osmolality increases.due to water deficit
`the following signs and symptoms usually are found to pro(cid:173)
`gressively ~ccumu1ate at approximately these values:.
`294-298-thirst (if the patient is alert and communicative);
`299-313-dry mucous membranes; 314-329- weakness,
`
`doughy skin; above 330-disorientation, postural hypotension,
`severe weakness, fainting, CNS changes, stupor, coma. As
`serum osmolality decreases due to water excess the following
`may occur: 275- 261-headache; 262-251-drowsiness,
`weakness; 250-233- disorientation, cramps; below 233-
`seizures, stupor, coma.
`As indicated previously, the body's mechanisms actively
`combat such major changes by limiting the variation in os(cid:173)
`molality for normal individuals to less than about 1% (ap(cid:173)
`proximately in the range 282-288 mOsm/kg, based on the
`above assumption).
`.
`The value given for normal serum osmolality above was
`described as an assumptio.n because of the variety of values
`found in the references. Serum osmolality is often loosely
`stated to be about 300 mOsm/L. Apart from that, and more
`specifically, two references state it as 280-295 mOsm/L; other
`references give it as 275-300 mOsm/L, 290 mOsm/L, 306
`mOsm/L, and 275-295 mOsm/kg. There is a strong tendency
`to call it osmolality but to state it as mOsm/L (not as
`m9sm/~g). In the light of these varying values, one may ask
`about the reproducibility of the experimental ~easurements,
`assuming that is their source. It has been stated that most
`osmometers are accurate to 5 mOsm/L. With that type of
`reproducibility, the above variations .may perhaps be .ex(cid:173)
`pected. The difference between liter and kilogram is-probably
`insignificant for se~um and urine. It is difficult to measure
`kilograms of water in a solution, and easy to express body f}.µid
`quantities in litets. Perhaps no harm has been done to date
`byt hls practice for body fluids. H~wever, loose terminology
`here may lead to· loose terminology when dealing with "the
`rather concentrated fluids used at times in parenteral and
`enteral nutrition.
`Reference pas been made to confusion in the use of the
`terms osmolality and osmolarity, a distinction of special im(cid:173)
`portance for nutritional fluids. Awareness of high concen(cid:173)
`trations of formula should give warning as to possible risks.
`Unfortunately, the osmotici:ty of infant formulas, tube feed(cid:173)
`ings, and total parenteral nutrition solutions has not been
`adequately described either in textbooks or in the literature,3
`and the labels of many commercial nutritional fluids do not
`in any way state their osmoticity. Only recently have enteral
`fluids been characterized in terms of osmoticity. Some
`product lines are .now accenting isoosmotic enteral nutritional
`supplements. Often, when the term osmolarity is used, one
`cannot discern whether this is simply incorrect terminology,
`or if osmolarity has actually been calculated from osmolality.
`Another current practice that can cause confusion is the use
`of-the terms normal and/or physiological for .isotonic sodium
`chloride solution (0.9%). The solution is surely isoosmotic.
`However, as to being physiological, the ions are each of 154
`mEq/L concentration while serum contains about 140 mEq
`of sodium and about 103 mEq of chloride.
`The range of mOsm values found for serum raises the
`question as to what fa really meant by the terms hypotonic and
`hypertonic for medicinal and nutritional fluids. One can find
`the statement that fluids with an osmolaljty of 50 mOsm or
`more above normal are nypertonic, and if 50 mOsm or more
`below normal are hypotonic. One can also fmd the statement
`that peripheral infusions should not have an osmolarity ex(cid:173)
`ceeding 700-800 mOsm/L.4 Examples of osmol concentra(cid:173)
`tions of solutions used in peripheral infusions are: ·· D5W-252
`-mOsm/L; Dl0W- 505 mOsm/L; Lactated Ringer's 5% Dex(cid:173)
`trose-525 mOsm/L. When a fluid is hypertonic, undesirable
`effects can often be decreased by using relatively slow rates
`of infusion, and/or relatively short periods of infusion.
`D25W--4 .. 25% Amino Acids .is a representative example of a
`highly osmotic hyperalimentation solution. It has been stated
`that when osmolal loading is needed, a maximum safe toler(cid:173)
`ance for a normally hydrated subject would be an approximate
`increase of 25 mOsm per kg of water over 4 hours.3
`·
`
`

`

`1458
`
`CHAPTER 80
`
`The derivation of the osmolar concentrations from the stated compo(cid:173)
`sition of the solution may be verified by calculations using equation (1)
`above for the nonelectrolyte dextrose, and equation (2) £or the electro(cid:173)
`lytes.
`
`.
`= 252.3 mOsm/hter
`
`50g X 1000
`7
`198
`
`_1
`
`Dextrose
`
`Sodium Chloride
`6 g X 2 X 1000 ~ 205_33 mOsm/liter {(102.66 mOsm Na+)
`(102.66 mOsm CI-)
`58.44
`Potassium Chloride
`0.3 gX 2 X 1000 = 8_04 0 m/1·
`{' (4.02 mOsm K+)
`m 8
`iter (4.02 mOsm CJ-)
`74.55
`Calcium Chloride
`/I"
`{(1.8 mOsm Ca2+)
`0.2 g X 3 X 1000
`--=--- -- = . m sm 1ter
`5 4 0
`(3.6 mOsm Cl-J
`110.99
`Sodium Lactate
`/l"t {(27.66 mOsm Na+)
`3.1 g X 2 X 1000
`55 32 0
`· m sm 1 er (27.66 mOsm lactate)
`=
`112.06
`The total osinolar concentration of the five solutes in the solution is
`526.4, in good agreement with the labeled total osmolar concentration of
`-approximately 524 mOsm/liter.
`The mOsm of sodium in one liter of the solution is the sum of the mOsm
`of the ion from i;od.iu.m !=hloride and sodium lactate, ie, 102.66 + 27 .66 =
`130.32 mOsm. Chloride ions come from the sodium chloride, potassium
`chloride, and calcium chloride, the total osmolar concentration being
`1~2.66 + 4.02 + 3.6 = 110.3 mOsm. The mOsm values of potassium, cal(cid:173)
`cium, and lactate are calculated to be 4.02, 1.8, and 27.66, respectively.
`Thus, with the possible exceptµ>n of calcium, there is close agreement with
`the labeled mEq .content of ea.ch of these ions.
`The osmolarity of a mixture of complex composition, such
`as an enteral hyperalimentation fluid, probably cannot be
`calculated with any acceptable degree of certainty, and
`therefore the osmolality of such preparations probably should
`·
`be determined experimentally. .
`The approximate osmolarity of mixtures of two solutions
`can be computed from the following relationship (the method
`is known as alligation medial):
`osm0 X V0
`OSmfinal =
`Vrfaal
`
`osmb X Vb
`+ --"----'-
`Vfinal
`
`where
`Va = volume of component a
`Vb = volume of component b
`Vnnal = volume of final solution
`osm0 = osmolarity of component a
`osmb = osmolarity of component b
`OSIDfinal = osmolarity of final solution
`For example, to calculate the osmolarity of a mixture of 500 mL of a
`solution of osmolarity 850 and 500 mL of a solution of osmolarity.252:
`252 X 500
`850 X 500
`OSIDfinal =
`1000 +
`1000
`= 425 mOsm/L + 126°mOsm/L = 551 mOsm/L
`
`This example illustrates the ease of calculating the osmo(cid:173)
`ticity, by use of osmolarity, when solutions are mixed. Such
`a calculation would be much less valid if osmolality values
`were used. From the previous example one can see how to
`calculate the approximate effect if an additional solute is
`added.
`
`Undesirable Effects of Abnormal Osmotlclty
`Ophthalmic Medication-It has been generally accepted
`that ophthalmic preparations intended for instillation into
`the cul-de-sac of the eye should, if possible, be approximately
`isotonic to avoid irritation (see Chapter 87). It has also been
`
`Computation of Osmolarity
`Several methods are used to obtain numerical values of
`osmolarity.· The osmolar concentration sometimes referred
`to as the "theoretical osmolarity" is calculated from the wt/vol
`concentration using one of the following equations:
`(1) For a nonelectrolyte
`gram~/liter X 1000 = mOsm/liter
`mo wt
`(2) For a strong electrolyte
`grams/liter X number of