mfinton: The
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`S¢cien%f¢c e( and Practice
`
`Pharmac)’
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`T
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`Volume I
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`ARGENTUM PHARM. 1040
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`ARGENTUM PHARM. 1040
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`
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`1 9TH
`
`EDITION
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`A
`
`Remington:
` Practice of
`
`ALFONSO R GENNARO
`Chairman of the Editorial Board
`and Editor
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`1995
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`MACK PUBLISHING
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`COMPANY
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`Easton,PennsyIvania18042
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`Entered according to Act: of Congressgin the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, atWashington DC
`‘
`
`Copyright 1889, 1894, 1905, 19o7,i917,by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951 , by The Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960,1965, 1970, 1975, 1980,1985, 1990, 1995, byThe Philadelphia College of
`Pharmacy and Science
`—.
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`
`ISBN 0—912734—o4—3
`
`The use ofstructuralformulasfrom USAN and the USP Dictionary ofDrug Names is by
`permission ofThe USP Convention. The Convention is not responsiblefor any inaccuracy
`contained herein.
`
`N0T1cE——This text is not intended to represent, nor shall it be interpreted to be, the equivalent
`ofor a substitutefor the ofilcial United States Pharmacopeia (USP) and / or the National
`Formulary (NF). In the event ofany difierence or discrepancy between the current ofiicial
`USP or NFstandards 0fstrength, quality, purity, packaging and labelingfor drugs and
`representaticms ofthem herein, the context and efiect ofthe ojficial compendia shall prevail.
`
`P7"im€d '5'” the United States ofAmerica by the Mach Printing Company, Easton, Pennsylvania
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`\
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`A-,_..a._..c...t..._.-__.~,.._...._.,.__,_.,,,..._.’-.—......._.
`
`Alfie
`
`. a treatise on the theory
`.
`Remington: The Science and Practice of Pharmacy .
`and practice of the pharmaceutical sciences, with essential
`information aboutpharmaceutical and medicinal agents,-V also a guide
`to the professional responsibilities ofthe pharmacist as the
`drug—information specialist of the health team .
`.
`. A textbook
`and reference Work forpharmacists, physicians and other
`practitioners of the pharmaceutical and medical sciences.
`
`EDITORS
`
`Alfonso R Gennaro, Chairman
`
`Thomas Medwick
`
`Grafton D Chase
`
`Ara DerMarderosian
`
`Glen R Hanson
`
`Daniel A Hussar
`
`Edward G Rippie ’
`Joseph B Schwartz: A
`
`T
`
`H Steve White
`
`Gilbert L Zink
`
`AUTHORS
`
`The 1 12 chapters of this edition of Remington were written by the
`editors, byrnembers of the Editorial Board, and by other authors _
`
`'
`
`listed on pages x to xii.
`
`Managing Editor
`
`John E Hoover, BSC (Pharm)
`
`Editorial Assistant
`
`Bonnie Brigham Packer, RNC, BA
`
`Director
`
`Allen Misher 1985-1995
`
`Nineteenth Edition~——’I 995
`
`Published in the 1 75th year of the
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
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`

`
`Remington Historical/Biographical Data
`
`The following is a record of the editors and the dates of publication of successive editions of this book, prior to the 13th‘
`Edition known as Remington ’s Practice of Pharmacy and subsequently as Remington '5 Pharmaceutical Sciences
`through the 18th Edition.
`
`First Edition, 1886
`Second Edition, 1889
`Third Edition, 1897
`Fourth Edition, 1905
`
`Fifth Edition, 1907
`Sixth Edition, 1917
`
`Seventh Edition, 1926
`
`Editors
`E Fullerton Cook
`Charles H LaWall
`
`Eighth Edition, 1 906
`Editors
`E Fullerton Cook
`Charles H LaWall
`
`Ninth Edition, 1948
`Tenth Edition, 1951 _
`
`Eleventh Edition, 1956
`
`Editors
`Eric W Martin
`E Fullerton Cook
`
`Twelfth Edition, 1961
`
`Editors
`Eric W Martin
`E Fullerton Cook
`E Emerson Leuollen
`Arthur Osol
`Linwood F Tice
`Clarence T Van Meter
`
`Thirteenth Edition, 1965
`
`Editor-in~Chief
`Eric W Martin
`Editors
`Grafton D Chase
`Herald R Cox
`Richard A Deno
`Alfonso R Gennoro
`Stewart C Harvey
`
`Joseph P Remington
`
`Joseph P Remington
`Assisted by
`E Fullerton Cook
`
`Associate Editors
`lvor Griffith
`
`Adley B Nichols
`Arthur Osol
`
`Editors
`E Fullerton Cook
`Eric W Martin
`
`Associate Editors
`E Emerson Leuallen
`Arthur Osol
`Linwood F Tice
`Clarence T Van Meter
`
`Assistant to the Editors
`John E Hoover
`
`Managing Editor
`John E Hoover
`
`Robert E King
`E Emerson Leuollen
`Arthur Osol
`Ewart A Swinyard
`Clarence T Van Meter
`
`Fourteenth Edition, 1970
`
`Chairman, Editorial Board
`Arthur Osol
`’
`Editors
`~
`Grafton D Chase
`Richard A Deno
`Alfonso R Gennaro
`Melvin R Gibson
`Stewart C Harvey
`
`Fifteenth Edition, 1975
`
`Chairman, Editorial Board
`Arthur Osol
`. Editors
`John T Anderson
`Cecil L Bendush
`Grafton D Chase
`Alfonso R Gennoro
`Melvin R Gibson
`
`Sixteenth Edition, 1980
`
`Chairman, Editorial Board
`Arthur Osol
`Editors
`Grafton D Chase
`Alfonso R Gennoro
`Melvin R Gibson
`
`Seventeenth Edition, 1985
`
`Chairman, Editorial Board
`Alfonso R Gennoro
`Editors
`Grafton D Chase
`Ara Der Marderosian
`Stewart C Harvey
`Daniel A Hussar
`Thomas Medwick
`
`Eighteenth Edition, 1990
`
`Chairman, Editorial Board
`Alfonso R Gennoro
`
`4
`Editors
`Grafton D Chas
`Ara Der Marderosian
`Stewart C Harvey
`Daniel A Hussar
`Thomas Medwick
`
`Managing Editor
`John E Hoover
`
`Robert E King
`Alfred N Martin
`Ewart A Swinyard
`Clarence T Van Meter
`
`Managing Editor
`John E Hoover
`
`C Boyd Granberg
`Stewart C Harvey
`Robert E King
`Alfred N Martin
`Ewart A Swinyard
`
`C Boyd Granberg
`Stewort C Harvey
`Robert E King
`Alfred N Martin
`Ewart A Swinyard
`Gilbert L Zink
`
`,
`
`Edward G Rippie
`Joseph D Schwartz
`Ewart A Swinyard
`Gilbert L Zink
`
`Managing Editor
`John E Hoover
`Editorial Assistant
`Bonnie Packer
`
`Edward G Rippie
`Joseph D Schwartz
`Ewart A Swinyard
`Gilbert L Zink
`
`vm
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`

`
`CHAPTER 36 "
`
`roniciry. osmloticity. Osmlolality ancdiosmolamy
`
`Irwin Reich, BS:
`Instructor and Manager, Pharmacy Laboratory
`
`Roger Schnaare, PhD
`Professor of Pharmacy
`
`Basic Definitions
`
`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 often is called semi-
`permeable. As the several types of membranes of the body
`vary in their permeability, it is well to note that they are
`selectively permeable. Most normal living-cell membranes
`maintain various solute concentration gradients. A selec-
`tively 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 concentra-
`tion gradient across itself. Osmosis, then, is the diffusion of
`water through a membrane that maintains at least one solute
`concentration gradient across itself.
`’
`7
`"
`'
`‘
`Assume Solution A is on one side of the membrane, and
`Solution B of the same solute but of a higher concentration is
`on the other side; the solvent will tend to pass into the more
`concentrated solution untilequilibrium has been established.
`The pressure required to prevent this movement is the os-
`motic pressure.
`It is defined as the excesspressure, or pres-
`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 fromA to B.
`I The concen-
`tration of a solution with respect to effect on osmotic pressure
`is’ related to the number of particles (unionized 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 colligative prop-
`erties of solutions.
`'_
`,
`'
`.
`Body fluids, including blood and lacrimal fluid, normally
`have an osmotic pressure which often is described as corre-
`sponding to_ that of a 0.9% solution of sodium chloride. The
`body also attempts to keep the osmotic pressure of the con-
`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 iso-osmotic
`with physiological fluids. The term z'{s0_t077}t'c, meaning equal
`tone, is in medical usage commonly used interchangeably
`with isoosmotic. However, terms su_ch as isotonic and tonic-
`ity should be used only with reference to a physiologic fluid.
`Isoosmotic actually is a physical term which compares the
`osmotic pressure (or another colligative property, such as
`freezing-pointdepression) of two liquids,—,neith_er of which
`may be a physiological fluid, or which may be a physiological
`fluid only under certain circumstances. For example, a solu-
`tion 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 mol-
`ecules of boric. acid pass freely through the erythrocyte mem-
`brane regardless of concentration. Thus, isotonicity infers a
`sense of physiological compatibility where isoosmoticity need
`
`Edwin T Sugita, PhD
`Professor and Chairman, Pharmaceutics Dept
`Philadelphia College of Pharmacy and Science
`Philadelphia, PA 19104
`
`not. As another example, a “chemically defined elemental
`diet” or enteral nutritional fluid can be iso-osmotic with the
`contents of the gastrointestinal tract, but would not be consid-
`ered a physiological 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 other change in the cell when it is
`in contact with that solution. Physiological solutions with an
`osmotic pressure lower than that of body fluids, or of 0.9%
`sodium chloride solution, are referred to commonly as being
`hypotcmic. Physiological solutions having a greater osmotic
`pressure are termed hypertomlc.
`_
`Such qualitative terms are of limited value, and it has
`become necessary to state osmotic properties in quantitative
`terms." To.do so, a term must be used that will represent all
`the particles which 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), which is osmotically
`equivalent to a mole of an ideally behaving nonelectrolyte.
`Thus, the osmol-weight of a nonelectrolyte, in a dilute solu-
`tion, generally is equal to its gram-molecular-weight.’ A mil-
`liosmol, abbreviated'mOsrn, 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 also
`may define an osmol in the following ways.-
`It is the amount
`of solute which will provide one Avogadro’s number (6.02 X
`1023) of particles in solution and it is the amount of solute
`which, on dissolution in 1 kg of water, will result in an osmotic
`pressure increase‘ of 17,000 torr at 0° or 19,800 torr at 37°.
`One mOsrnol is one-thousandth of an osmol. For example, 1
`mole of anhydrous dextrose is equal to 180 g. One osmol of
`this nonelectrolyte is also 1 80 g. One _mOsmol would be 180
`mg; Thus 1 80 mg of this solute dissolved in 1 kg of Water will
`produce‘ an increase in osmotic pressure of 19.3 torr at body
`temperature. '
`‘
`'
`‘
`'
`'
`X’
`y
`’ For a solution of an electrolyte such as sodium chloride, one
`molecule of sodium chloride represents onevsodium and one
`chloride ion. Hence, one mol will represent 2 osmols of
`sodiumchloride theoretically. ‘ Accordingly, 1 osmol NaCl =
`58.5 g'/ or 29.25 g. ’ This quantity represents the sum total
`of 6.02‘ ><_ 1023 ions as the total number of particles.
`Ideal
`solutions infer very dilute solutions or infinite dilution.
`However, ' as the concentration’ is increased, other factors
`enter. With strong.electrolytes, interionic attraction causes
`a_decrease in their effect on colligative properties.‘ , In addi-
`tion, and in opposition, for all solutes, including nonelectro-
`lytes, solvation and possibly other_factors operate to intensify
`their colligative effect. Therefore, it is very difiicult and of-
`ten impossible to predict accurately the 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 likely is required.
`
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`
`614
`
`CHAPTER 36
`
`Therapeutic Considerations
`
`It generally is accepted that osmotic eifects have a major
`place in the maintenance of homeostasis (the state of equilib-
`rium in the living body with respect to various functions and to
`the chemical composition ofthe fluids and tissues, eg, tempera-
`ture, heart rate, blood pressure, water content or blood sugar).
`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 extracel-
`lular and intracellular fluid volumes in seriously ill patients.
`It should be kept in mind, however, that fluid and electrolyte
`abnormalities are not diseases, but are the manifestations of
`disease.
`The physiological 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 osmo-
`ticity in _the normal individual to less than about 1%. Body
`fluid continually oscillates within this narrow range. An in-
`crease of plasma osmoticity of 1% will stimulate ADH release,
`result in reduction of urine flow and, at the same time, stimu-
`late thirst that results in increased water intake. Both the
`increased renal reabsorption of water (without solute) stirnu-
`lated 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 equilibrium between the two
`fluid compartments in any given tissue usually is 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 the extracellular and
`intracellular compartments throughout the entire body within
`this same short period of time. The reason is that fluid usu-
`ally enters the body through the gut and then must be trans-
`ported by the circulatory system to all tissues before complete
`equilibration can occur.
`In the normal person it may require
`30 to 60 min to achieve reasonably good equilibration through-
`out the body after drinking water. Osmoticity is the property
`that largely determines the physiologic acceptability of a vari-
`ety of solutions used for therapeutic 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 abnor-
`mal 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 to total
`(central) parenteral nutrition, to. enteral hyperalimentation
`(“tube” feeding) and to ‘concentrated-fluid infant formulas}
`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 manni-
`tol 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 intracranial pres-
`sure 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 or dispersions in an oleaginous base (Muro,
`Bausch & Lamb) and a 40% glucose ointment are used topi-
`cally for corneal edema. Ophthalgan (Wyeth-Ayerst) is oph-
`thalmic glycerin employed for its osmoticeffect to clear edema-
`tous cornea to facilitate an ophthalrnoscopic or gonioscopic
`examination. Glycerin solutions in 50% concentration [Os-
`moglyn (Alcon)] and isosorbide solution [Ismotic (Alco'n)]
`
`are oral osmotic agents for reducing intraocular pressure.
`The osmotic principle also applies to plasma extenders’ such
`as polyvinylpyrrolidone and to saline laxatives such as magne-
`sium sulfate, magnesium citrate solution, magnesium hydrox-
`ide (via gastric neutralization), sodium sulfate, sodium phos-
`phate and sodium biphosphate oral solution and enema (Fleet).
`An interesting osmotic laxative which is a nonelectrolyte is
`a lactulose solution. Lactulose is a nonabsorbable disaccha-
`ride which is colon-specific, wherein colonic bacteria degrade
`some of the disaccharide to lactic and other simple organic
`acids. These, in toto, lead to an osmotic effect and laxation.
`An extension ofthis therapy is illustrated by Cephulac (Marion
`Merrell Dow) solution, which uses the acidification of the
`colon via lactulose degradation to serve as a trap for ammonia
`migrating from the blood to the colon. The conversion of
`ammonia of blood to the ammonium ion in the colon ulti-
`mately is coupled with the osmotic effect and laxation, thus
`expelling undesirable levels of blood ammonia. This prod-
`uct is employed to prevent and treat frontal systemic encepha-
`lopathy.
`.
`Osmotic laxation is observed with the oral or rectal use of
`glycerin and sorbitol. Epsom salt has been used in baths and
`compresses to reduce edema associated with sprains.
`Another approach is the indirect application of the osmotic
`effect in therapy via osmotic pump drug delivery systems?
`
`osmolality and Osmolarity
`
`It is necessary to use several additional terms to define
`expressions of concentration in reflecting the osmoticity_of
`solutions. The terms include osmolality, the expression of
`osmolal concentration and osmolarity, the expression of osmo-
`lar concentration.
`.
`Osmolality-——-A solution has an osmolal concentration of
`one when it contains 1 osmol of solute/kg of water. A solu-
`tion has an osmolality of at when it contains 1; osmols/kg of
`water. Osmolal solutions, like their counterpart molal solu-
`tions, reflect a weight-to-weight relationship between the sol-
`ute and the solvent.
`Since an osmol of any nonelectrolyte is
`equivalent to 1 mol of that compound, then a 1 osmolal
`solution is synonymous to a 1 molal solution for a typical
`nonelectrolyte.
`With a typical electrolyte like sodium chloride, 1 osmol is
`approximately 0.5 mol of sodium chloride. Thus, it follows
`that a 1 osmolal solution of sodium chloride essentially is
`equivalent to a 0.5 molal solution. Recall that a 1 osmolal
`solution of dextrose or sodium chloride each will contain the
`same particle concentration.
`In the dextrose solution there
`will be 6.02 X 1023 molecules/kg of water and in the sodium
`chloride solution one will have 6.02 X 1023 total ions/kg of
`water, one-half of which are Na+ ions and the other half Cl“
`ions.
`
`As in molal solutions, osmolal solutions usually are em-
`ployed where quantitative precision is required, as in the
`measurement of physical and chemical properties of solutions
`(ie, colligative properties). The advantage of the w /w rela-
`tionship is that the concentration of the system is not influ-
`enced by temperature.
`‘
`Osmolarity—The relationship observed between molality
`and osmolality is shared similarly between molarity and
`osmolarity.
`‘A solution has an osmolar concentrationof 1
`when it contains 1 osmol of solute/L of solution. Likewise, a
`solution has an osmolarity of n when it contains at osmols/L of
`solution". Osmolar solutions, unlike osmolal solution, reflect
`a weight in volume relationship between the solute and final
`solution. A 1 molar and 1 osmolar solution would be identi-
`cal for nonelectrolytes. For sodium chloride a 1 osmolar
`solution would contain 1 osmol of sodium chloride per liter
`which approximates "a 0.5 molar solution. The advantage of
`employing osmolar concentrations over osmolal concentra-
`tions 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. Volumes of
`
`000008
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`
`TONICITY, OSMOTICITY, OSMOLALITY AND OSMOLARITY
`
`615
`
`dextrose solution——-505 mOsmol/L; Lactated Ringer’s 5% Dex-
`trose—-525 mOsmol/L. ‘ When a fluid is hypertonic, undesir-
`able‘ effects often can be decreased by using relatively slow
`rates of infusion, and/or relatively short periods of infusion.
`25% dextrose solution (D25W)—4.25% Amino Acids is a
`representative example of a highly osmotic hyperalimentation
`solution.
`It has been statedpthat when osmolal loading is
`needed, a maximum safe tolerance for a normally hydrated
`subject would be an approximate increase of 25 mOsmol/kg
`of water over 4 hours.3
`
`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 w /7;
`concentration using the following equation:
`osmol
`
`X
`
`1000 mOsmol
`' osmol
`
`mol
`
`mOsmol
`L
`
`1
`c 3
`
`— X —— x
`
`solution, rather than weights of solution, are more practical in
`the delivery of liquid dosage forms.
`1
`-
`Many health professionals do not have a clear understand-
`ing of the difference between osmolality and osmolarity.
`In
`fact, the terms have been used interchangeably. A 1 osmolar
`solution of a solute always will be more concentrated than a 1
`osmolal solution. With dilute solutions the difference may
`be acceptably small.
`For example, a 0.9% w/11 solution of
`sodium chloride in water contains 9 g of sodium chloride/L of
`solution, equivalent to 0.308 osmolar; or 9 g of sodium chlo-
`ride/ 996.5 g of water, equivalent to 0.309 osmolal, less than a
`1% error.
`' For concentrated solutions the % diiference be-
`tween osmolarity and osmolality is much greater and may be
`highly significant; 3.5% for 5% w/v dextrose solution and
`25% for 25% w/v dextrose solution. One should be alerted
`to the sizable errors which may occur with concentrated solu-
`tions or fluids, such as those employed in total parenteral
`nutrition, enteral hyperalimentation and oral nutritional fluids
`for infants.
`1
`.
`-
`Reference has been made to the terms hypertonic and
`hypotonic. Analogous terms are hyperosmotic and hypo-
`osmotic. Assuming normal serum osmolality to be 28577103-
`mol/kg, as serum osmolality increases due to water deficit,
`the following signs and symptoms usually are foundgto accu-
`mulate progressively at approximately these values:
`294 to
`298——thirst (if the patient is alert and communicative); 299 to
`313.--dry mucous membranes; 314 to 329——weakness,
`doughy skin; above 330—disorientation, postural_hypoten-
`sion, severe weakness, fainting, CNS changes, stupor and
`coma. As serum osmolality decreases due to water excess
`the following may occur: , 275 to 26l—headache; 262 to
`251-drowsiness, weakness; 250 to 233——disorientation,
`cramps; below 233-.-seizures, stupor and coma.’ _,
`'
`As indicated previously, the mechanisms of the body ac-
`tively combat such major changes by limiting the variation in
`osmolality for normal individuals to less than about 1% (ap-
`proximately in the range 282 to 288 mOsmol/kg, based on the
`above assumption).
`The value given forlnormalserum osmolality above was
`described as an assumption because of the variety of values
`found in the literature. Serum osmolality often is stated
`loosely to be about 800 mOsmol/L.
`‘ Various references re-
`port 28O to 295 mOsmol/L, 275 to 300 mOsmol/L, 290
`mOsmol/L, 306 mOsmol/L and 275 to 295_mOsmol/kg‘.
`'
`Reference has been made to confusion in the use of the
`terms osmolality and osmolarity, a distinction of special impor-
`tance for nutritional fluids. Awareness of high concentra-
`tions of infant-formula should give warning as to possible
`risks. Unfortunately, the osmoticity of infant formulas, tube
`feedings and total parenteral nutrition solutions has not been
`described adequately 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 prod-
`uct lines now are accenting isoosmotic enteral nutritional
`supplements. Often, when the term osmolarity is used, one
`cannot discern whether this simply‘ is incorrect terminology,
`or if osmolarity actually has been calculated from osmolality.
`Another current practice which can cause confusion,’ is the
`use of the terms normal and/ or physiological for isotonic
`sodium‘ chloride solution (0.9%). The solution surely is
`isoosmotic. However, as to being physiological, the concen-
`tration of ions areeach of 154 mEq/ L while serumcontains
`about 140 mEq of sodium and about 103 mEq of chloride.
`7 The range of mOsmol values found for-serum raises the
`question as to what really is meant by the terms hypotonic and
`hypertonic for medicinal and nutritional fluids. One can find
`the statement that fluids with an osmolality of 50 mOsmol or
`more above normal are hypertonic and, if 50 mOsmol- or more
`below normal, "are hypotonic. One also can find the state-
`ment that peripheral infusions should not have an osmolarity
`exceeding 700 to 800 mOsmol/L.4 ' Examplesof osmol con-
`centrations of solutions used in peripheral infusions are:
`(D5W) 5% dextrose solution—252 mOsmol/L; (D10VV) 10%
`
`000009
`
`The number of osmols/_mol is equal to 1 for nonelectrolytes
`and is equal to the number of ions per molecule for strong
`electrolytes.
`This calculation, omits consideration of factors such as
`solvation and interionic forces. By this method of calcula-
`tion O.9% sodium chloride has an osmolar concentration of
`308 mOsmol/L and a concentration of 154 mOsmol/L in
`either sodium or chloride ion.
`Two other methods compute osmolarity from values of
`osmolality. The determination of osmolality will be dis-
`cussed later. One method has a strong theoretical basis of
`physical-chemical principles5 using values of the partial molal
`volume(s) of the solute(s).' A 0.9% sodium chloride solution,
`found experimentally to have an osmolality of 286 mOsmol/
`kg, was calculated to have an osmolarity of 280 mOsmol/L,
`rather different from the value of 308 mOsmol/L calculated as
`above. The method, using partial molal volumes, is rela-
`tively rigorous, but ‘many systems appear to be too complex
`and/ or too poorly defined to be dealt with by this method.
`The other method is based on calculating the weight of
`water from the solution density and concentration
`
`g solute
`g solution .
`‘ g water" '
`mL solution _ mL solution — mL solution
`
`then’
`
`mOsmol
`
`osmolarity Em
`I
`5
`
`g water
`mOsmol
`_
`_ Osmolahty 1000 g water X mL solution
`The experimental value for the osmolality of 0.9% sodium
`chloride solution was 292.7 mOsmol/kg,‘ the value computed
`for osmolarity was 291.4 mOsmol/L. This method uses eas-
`ily obtained values of density of the solution and of its solute
`content and can be used with all systems. For example, the
`osmolality of a nutritional’ product was determined by the
`freezing-point depression method to be 625 mOsmol/kg;7 its
`"osmolarity was calculated as 625 X 0.839 = 524 mOsmol/L.
`Monographs in the USP for solutions which provide intrave-
`nous replenishment of fluid, nutrient(s) or electrolyte(s), and
`for osmotic diuretics such as (Mannitol Injection, require the
`osmolar concentration be stated on the label in osmols/L,
`except that where the contents are less than 100 mL, or where
`the label states the article is not for direct injection but is to be
`diluted before use, the label alternatively may state the total
`osmolar concentration in mOsmol/ mL.
`
`An example of the use of the first method described above is the
`computation of the approximate osmolar concentration (“theoretical os-
`molarity") of a Lactated Ringers 5% Dextrose Solution (Abbott), which is
`labeled to contain, per L, dextrose (hydrous) 50 g, sodium chloride 6 g,
`potassium chloride 300 mg, calcium chloride 200 mg and sodium lactate
`
`000009
`
`

`
`616
`
`CHAPTER 36
`
`3.1 g. Also stated is that the total osmolar concentration of the solution is
`approximately 524 mOsmol per L, in part contributed by 130 mEq of Nat,
`109 mEq ofCl‘, 4 mEq of K‘', 3 mEq of Ca“ and 28 mEq oflactate ion.
`The derivation of the osmolar concentrations from the stated composi-
`tion of the solution may be verified by calculations using Eq _1.
`Dextrose
`
`1 osmol
`1 mol
`50 g
`L X i98gX mol
`Sodium Chloride
`
`I L ,
`1000 mOsmol _ 252 O
`Osmol
`‘
`‘“ 5"‘°/
`
`X
`
`2 osmol
`1 mol
`6g
`L X 58.4gX mol
`
`X
`
`1000 mOsmol
`osmol
`'
`
`Potassium Chloride
`
`0.3 g
`L
`
`2 osmol
`1 mol
`X 74.6g X mol
`
`X
`
`mosmoj
`
`—
`
`L
`
`(102.7 mOsmol Na")
`
`(102.7 mOsmol 01-)
`
`
`
`1000 mOsmol
`osmol
`g_04 mosmoj
`
`(4.02 mOsmol K’*)
`
`Calcium Chloride
`
`T
`
`L
`
`(4.02 mOsmo1Cl‘)
`
`3 osmol
`1 mol
`0.2 g
`L Xlllgx mol
`
`X
`
`1000 mOsmol
`osmol
`
`5.41 mOsmol
`
`—
`
`. L
`
`(1-80 IT10Sm01 032+)
`
`(3.61 mOsmol Cl‘)
`
`
`
`SodiumLactate
`
`3.1 g
`L
`
`2 osmol
`1 mol
`X 112g X moi
`
`X
`
`1000 mOsmol
`osmol
`55,4 mOsmol
`
`(27.7 mOsmol N8.+)
`
`
`
`(27.7 mOsmol lactate)
`L
`_
`The total osmolar concentration of the live solutes in the solution is 526,
`in good agreement with the labeled total osmolar concentration of approxi-
`mately 524 mOsmol/L.
`The mOsmol of sodium in 1 L ofthe solution is the sum of the mOsmol of
`the ion from sodium chloride and" sodium lactate, ie, 102 + 27.6 = 129.6
`mOsmol. Chloride ions come from the sodium chloride, potassium chlo-
`ride and calcium chloride, the total osmolar concentration being 102 +
`4.02 + 3.61 = 109.6 mOsmol. The mOsmol Values of potassium, cal-
`cium and lactate are calculated to be 4.02, 1.80 and 27.6, respectively.
`
`The osmolarity of a mixture of complex composition, such
`as an enteral hyperalimentation fluid, cannot be calculated
`with any acceptable degree of certainty and, therefore, the
`osmolality of such preparations should be determined experi-
`mentally.
`
`Undesirable Effects of Abnormal osmoticity
`
`Ophthalmic Medication——It is generally accepted that
`ophthalmic preparations intended for instillation into the cul-
`de—sac of the eye should, if possible, be approximately iso-
`tonic to avoid irritation (see Chapter 89).
`It also has been
`stated that the abnormal tonicity of Contact lens solutions can
`cause the lens to adhere to the eye and/ or cause burning or
`dryness and photophobia.
`Parenteral Medication-—Osmoticity is of great impor-
`tance in parenteral injections, itseffects depending on the
`degree of deviation from tonicity, the concentration, the loca-
`tion of the injection, the volume injected, the speed of the
`injection, the rapidity of dilution andvdiffusion, etc. When
`formulating parenterals, solutions otherwise hypotonic usu-
`ally have their tonicity adjusted by the addition of dextrose or
`sodium chloride. Hypertonic parenteral drug solutions can-
`not be adjusted.
`I-lypotonic and hypertonic solutions usually
`are administered slowly in small Volumes, or into a large vein
`such as the subclavian, where dilution and distribution occur
`rapidly.
`' Solutions that differ from the serum in tonicity gen-
`
`erally are stated to cause tissue irritation, pain on injection
`and electrolyte shifts, the effect depending on the degree of ~
`deviation from tonicity.
`.
`Excessive infusion of hypotonic fluids may cause swelling
`of red blood cells, hemolysis and water invasion of the body’s
`cells in general. When this is beyond the body’s tolerance for
`water, water intoxication results, with convulsions and edema,
`such as pulmonary edema.
`.
`Excessive infusion of isotonic fluids can cause an increase
`in extracellular fluid volume, which can result in circulatory
`overload.
`1
`Excessive infusion of hypertonic fluids leads to a wide
`variety of complications. For example, the sequence of
`events when the body is presented with a large intravenous
`load of hypertonic fluid, rich in dextrose,
`is as follows:
`hyperglycemia, glycosuria and intracellular dehydration, os-
`motic diuresis, loss of water and electrolytes, dehydration and
`coma.
`-
`One cause of osmotic diuresis is the infusion of dextrose at a
`rate faster than the ability of the patient to metabolize it (as
`greater than perhaps 400 to 500 mg/kg/hr for an adult on
`total parenteral nutrition). A heavy load of unmetabolizable
`dextrose increases the osmoticity of blood and acts as a di-
`uretic; the increased solute load requires more fluid for excre-
`tion, 1 0 to 20 mL