`% Sci;éric0e0a0i%hd Practice
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`0 .
`Pharmacy
`
`Volume I
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`MYLAN ET AL. - EXHIBIT 1013
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`MYLAN ET AL. - EXHIBIT 1013
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` Remington: The
`
`Sc[iénce*a‘né| Practice
`5 of Pharmacy
`
`Volume II
`
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`5......__
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`Entered according to Act of Congress, in the year l88’5 by Joseph P Remington,
`in the Ofiice of the Librarian of Congress, at Washington DC
`.
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`Copyright 1889, 1394, 1905, 1907,19'17, byJosephPRemihgtoh
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`Copyright 1 926, 1936, by the Joseph P Remington Estate
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`Copyright 1948, 1 95 1, by The Philadelphia College of Pharmacy and Science
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`Copyright 1956, 1960, 1965,1970, 1975, 1980, 1985, 1990, 1995, by The Philatlelphia College. of
`Pharmacy and Science
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`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.
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`NOTICE—This text is not intended to represent, nor shall it be interpreted to be, the equivalent
`ofor a substitntefor the oficial United States Pharmacopeia (USP) and / or the National
`Formnlary (NF). In the event ofany difference or discrepancy between the current ofiicial
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`representations ofthem herein, the context and efiect ofthe ofiicial compenolia shall prevail.
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`Printed in the United States of/lmerica by the Mach Printing Company, Easton, Pennsylvania
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`0003
`
`
`
`CHAPTER36
`
`Tonicity, Osn1oticity,.Osmolali_fy and Qsmolcirity
`
`Irwin Reich, BS:
`Instructor and Manager, Pharmacy Laboratory
`
`lulouger Schnoore, PhD
`Professor of Pharmacy
`
`Basic Definitions
`
`If a‘ solution is placed incontact with’ a membranethat 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
`concentrdtigngradient across itself.
`,
`T
`‘
`AssuméS,§olution A is on one side of themembrane, and
`Solution Bqbf the same solute but of a higher concentration is
`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-
`motic pressure.
`It is definedas the excess pressure, 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 from A to B. 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 byvthe degree of ionizatiorior aggregation
`of the solute. ' See Chapter 16 for review of colligative prop-
`erties of solutions.
`V
`T
`'
`V
`Body fluids, including blood and lacrimal fluid, normally
`have an osmoticpressure 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 norma ange is much wider than that of most body fluids.
`The 0.9% sodium chloride solution is said to be 7330-‘osmotic
`with physiological fluids. The term isotonic, meaning equal
`tone, is in medical usage commonly used interchangeably
`with isoosmotic. However, terms such 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-point depression) of two liquids, neither of which
`may be_a physiological fluid, or which may be aphysiological
`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 ‘l' Sugita, PhD
`Professor and Chairman, Pharmaceutics Dept
`Philadelphia College of Phurrnocy_orid Science
`Philadelphia, PA 19104
`‘
`
`another example, a. .“chemically defined elemental
`not. ,‘
`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
`hypotonic. Physiological solutions having agreater osmotic
`pressure are termed hypertonic.
`,
`T
`.
`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 anonelectrolyte, in a dilute solu-
`tion, generally is equal to its gram-molecular-weight. A mil-
`liosmol, abbreviated mOsm, istheweight 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. v It is the amount
`of solutewhich willprovide one Avogadrds number (6102 X
`1O23)'of particles in solution and it is the amount of solute
`which, on dissolution-in 1 kg ofwater, will result in an osmotic
`pressure increase of 17,000 torr at 0° or 19,300vtorr at 37°‘.
`One mOsmol 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 180 g. One mOsmol would be 180
`mg. Thus 180' mg of this solute dissolved in 1 kg of water will
`produce an increase in osmotic pressure of 19.3 torr at body
`temperature.
`'
`‘
`‘
`For a solution of an electrolyte such as sodium chloride, one
`molecule of sodium chloride represents one sodium and one
`chloride ion. Hence, one mol will represent 2 osmols of
`sodium chloride theoretically. Accordingly, 1 osmol_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
`solutions infer very dilute solutions or infinite dilution.
`However, as the concentration is increased, other factors
`enter. Withstrong electrolytes, interionic attraction causes
`a decrease in their effect on colligative properties.
`In addi-
`tion,and in opposition, for all solutes, including n0nelectro_-
`lytes, solvation and possibly other factors operate to intensify
`their colligative efiect. Therefore, it is very difficult 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
`parenteraland enteral medicinal and/or nutritional fluids;
`experimental determination likely is required.
`
`0004
`
`
`
`614
`
`CHAPTER 36
`
`Therapeutic Considerations
`
`It generally is accepted that osmotic effects 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 serumosmoticity. Osmotic
`changes also serve as a stimulus to moderate thirst. This
`mechanism is sufliciently 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) stimu-
`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
`80 to 60 min to achieve reasonably good equilibration through-
`out the body after drinking water. Osmoticity is the property
`that largely determines thephysiologic 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
`an.d nitrogenous metabolites. Two to five percent sodium
`chloride solutions or dispersions in an oleaginous base (Muro,
`Bcmsch & Lamb) and a 40% glucose ointment are used topi-
`cally for corneal edema. Ophthalgan (Wyeth-Ayerst) is oph-
`thalmic glycerin employed for its osmotic effect to clear edema-
`tous cornea to facilitate an ophthalmoscopic or gonioscopic
`examination. Glycerin solutions in 50% concentration [Os-
`moglyn (Al.co'n)] and isosorbide solution [Ismotic (Alco7L)]
`
`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 employedto prevent and treat frontal systemic&ncepha-
`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.
`.
`0smo1ality—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 71 when it contains Tb osmols/kg of
`water. Osmolalsolutions, like their counterpafltfgnolal solu-
`tions, reflect a weight-to-weight relationship betfgiieen the sol-
`ute and the solvent.
`Since an osmol of any nonéflectrolyte 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 concentration of 1
`when it contains 1 osmol of solute/L of solution. Likewise, a
`solution has an osmolarity ofn 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
`
`0005
`
`0005
`
`
`
`TONICITY, OSMOTICITY, OSMOLALITY AND OSMOLARITY
`
`615
`
`solution, rather than weights of solution, are more practical in
`the delivery of liquid dosage forms.
`.
`‘
`I
`‘
`r
`‘
`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/v solution of
`sodium chloride in water contains 9 g of sodium chloride/L of
`solution, equivalent to 0.308 osmolar; or 9 g ofsodium chlo-
`ride/996.5 g of water, equivalent to 0.309 osmolal, less than a
`1% error.
`« For concentrated solutions the % difference 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.
`.
`r
`.
`:
`,
`.
`,
`Reference has been made to the terms hypertonic and
`hypotonic. Analogous terms are hyperosmotic and hypo-
`osmotic. Assuming normal serum osmolality to be 285 mOs-
`mol/kg, .as serum osmolality increases due to water deficit,
`the following signs and symptoms usually are found to accu-
`mulate progressively at approximately these values;
`294 to
`298—thirst (if thepatient is alertand communicative); 299 to
`3l3—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: I 275 to , 26l—headache; 262 to
`251-drowsiness, weakness; 250 to 233'+disorientation,
`cramps; below 233—seizures, stupor and coma.
`J
`’
`'
`As indicated previously, the mechanisms of the bo_dyac-
`tively corn at such major changes by limiting the variation i_n
`osmolality,
`' r normal individualsto less than_about 1% (ap-
`proximatelifiglin the range 282 to 288 mOsmol/kg, based on the
`above assumption).
`'
`,
`_
`The value given for normal serum 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 300 mOsmol/L. Various references re-
`port 280 to 295 mOsmol‘/L, 275 to 300 mOsmol/L, 290
`, mOsmol/L,’ 306 mOsmol/L and 275 to 295,mOsrnol/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 riot been
`described adequately either in textbooks or inthe 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 acceriting 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 currentpractice 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 are each of 154 mEq/L while-serum contains
`about 140 mEq of sodium and about 103 mEq of chloride.
`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 Examples ‘of osmol con-
`centrations of solutions used in peripheral infusions are:
`(D5VV) 5% dextrose solution—252 mOsmol/L; (D1OW)«10%
`
`dextrose solution—505 mOsmol/L; Lactated Ringer’s 5% Dex-
`trose—-—525 mOsmol/L. When afluid 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 hyperalirnentation
`solution.
`It has been stated that 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 /2)
`concentration using the following equation:
`
`1000 mOsmol _mOsmol
`‘osmol
`_
`L
`
`_
`osmol -
`mols
`(1)
`X mol X
`g
`L X
`The number of osmols/mol is equal to 1 for nonelectrolytes
`and is equal to the number of ions per molecule for stron
`A
`electrolytes.
`This calculation, omits consideration of factors such as
`solvation and interionic forces. By this method of calcula-
`tion 0.9% sodium chloride has an osmolar concentration of
`308 mOsmol/L and ahconcentration 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 principles? 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 mOsmo1/
`kg, was calculatedito 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 dealtwith by this method.
`The,other method is based on calculating the weight of
`water from the solution density and concentration
`
`,
`
`g water
`mL solution
`
`" g solute
`’
`’ g solution
`=mL solution mL solution
`
`then
`
`'
`
`osmolarity (
`
`VmOsIno1
`L solution ’
`
`,
`
`= osmolality (
`
`mOsmol
`1000 g water
`
`‘
`
`2 gwater 0.
`X mL solution
`
`The experimental value for theosmolality 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
`comp'utation’of the approximate osmolar concentration (“theoretical os-
`molarity”) of a Lactated Ringer's 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
`
`0006
`
`0006
`
`
`
`616
`
`CHAPTER 36
`
`3.1 g. Also stated is that the total osmolar concentration of the solution is
`approximately 524 m0smol per L, in part contributed by 130 mEq of Na*,
`.109 mEq of Cl‘, 4 mEq of K‘', 3 mEq of Ca2+ and 28 mEq of lactate ion.
`The derivation of the osmolar concentrations from the stated composi-
`tion of the solution may be verified by calculations using Eq 1.
`Dextrose.
`
`0 1000 mOsmol
`X
`Osmol
`
`= 252 mOsmol/L
`
`><
`
`1000 mOsmol
`osmol
`
`50g
`1 osmol
`1 mol
`_L X198gX mol
`Sodium Chloride
`1 mol
`2 osmol
`
`L
`
`58.4 g X mol
`
`5 mosmol
`L
`
`(102.7 m0smol Na‘“)
`(102.7 m0smol or)
`
`Potassium Chloride
`2 osmol
`.1 mol
`mol
`74.6 g
`
`X
`
`x
`
`1000 mOsmol
`osmol
`
`Calcium Chloride
`
`8.04 mOsmol I4-02 m05m01K+)
`L
`(4.02 mOsmol or)
`
`_
`
`3 osmol
`0.2 g ' 1 mol
`L
`X 111 g X mol
`
`X
`
`1000 mOsmol
`osmol
`
`541 mom, V (1.30 mosmol Ca2+)
`L
`(3.61 mOsmol 01-)
`
`_
`
`Sodium Lactate
`
`3.1g
`L
`
`2osmol
`lmol
`X 112 g X mol
`
`x
`
`1000 mosmoi
`, osmol
`
`55.4 mOsmol.[(27-7 m0sm0.1Na*)
`
`(2 7. 7 m0smol lactate)
`
`L
`
`The total osmolar concentration of the five 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 of the solution is the sum ofthe 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 + 3.6 1 = 1 09.6 mOsmol. The m‘Osrnol 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, its effects 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 and difiusion, 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. Hypotonic 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.
`1.
`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 awide
`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 metabolizeit (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, 10 to 20 mL of waterbeing required to excrete each gram
`of dextrose. Solutions, such as those for total parenteral
`nutrition, should be administered by means of a metered
`constant-infusion apparatus over a lengthy period (usually
`more than 24 hours) to avoid sudden hyperosmotic dextrose
`loads.
`Such solutions may cause osmotic diuresis; if this 1
`occurs, water balance is likely to become negative because of
`the increased urinary volume, and electrolyte depletion may
`occur because of excretion of sodium and potassium second-
`ary to the osmotic diuresis.
`If such diuresis is marked, body
`weight falls abruptly and signs of dehydration appear. Urine
`should be monitored for signs of osmotic diuresis, such as
`glycosuria and increased urine volume.
`‘
`k»(
`If the intravenous injection rate of hypertonic so ntion is too
`rapid, there may be catastrophic effects on the circulatory and
`respiratory. systems. , Blood pressure may fall_ tohangerous
`levels, cardiac irregularities or arrest may ensue, respiration
`may "become shallow and ‘irregular and there may be heart
`failure and pulmonary edema. Probably the precipitating
`factor is a bolus of concentrated solute suddenly reaching the
`myocardium and the chemoreceptors in the aortic arch and
`carotid sinus.3
`0
`0
`'
`Abrupt changes in serum osmoticity can lead to cerebral
`hemorrhage.
`It has been shown experimentally that rapid
`infusions of therapeutic doses of hypertonic saline with os-
`motic loads produce a sudden rise in cerebrospinal fluid (CSF)
`pressure and venous pressure (VP) followed by a precipitous
`fall in CSF pressure. This particularly may be conducive to
`intracranial hemorrhage, as the rapid infusion produces an
`increase in plasma volume and venous pressure at the same
`time the CSF pressure is falling. During the CSF pressure
`rise, there is a drop in hemoglobin and hematocrit, reflecting a
`marked increase in blood volume.
`Hyperosmotic medications, such as sodium bicarbonate
`(osmolarity of 1560 at 1 mEq/mL), which are administered
`intravenously, should be diluted prior to use and should be
`injected slowly to allow dilution by the circulating blood.
`Rapid “pus ” injections may cause a significant increase in
`blood osmoticity.5
`.
`»
`'
`As to other possibilities, there may be crenation of red blood
`cells and general cellular dehydration. Hypertonic dextrose
`or saline, etc, infused through a peripheral vein with small
`blood volume may traumatize the vein and cause
`thrombophlebitis.
`Infiltration can cause trauma and necro-
`sis of tissues. Safety, therefore, demands that all intrave-
`nous injections, especially highly osmotic solutions, bevper-
`formed slowly, usually being given preferably over a period
`not less than that required for a complete circulation of the
`blood, eg, 1 minute. The exact danger point varies with the
`
`0007
`
`0007
`
`
`
`TONICITY, OSMOTICITY, OSMOLALITY AND OSMOLARITY
`
`617
`
`state of the patient, the concentration‘ of the solution, the
`nature of the solute and the rate of, administration. ‘
`Hyperosmotic solutions also should not be discontinued
`suddenly.
`In dogs, marked increase in levels of intracranial
`pressure occur when hyperglycemia produced by dextrose
`infusions is reversed suddenly by stopping the infusion and
`administering saline.
`It also has been shown that the CSF
`pressure in humans rises during treatment of diabetic ketoaci-
`dosis in association with a fall in the plasma concentration of
`dextrose and a fall in plasma osmolality. These observations
`may be explained by the different rates of decline in dextrose
`content of the brain andof plasma. The conc,entration' of
`dextrose in the brain may fall more slowly than in the plasma,
`causing a shift of fluid from the extracellularfluid space to the
`intracellular compartment of the CNS, resulting in increased
`intracranial pressure.
`
`Osmometry and the Clinical Laboratory
`
`Serum and urine osmometry may assist in the diagnosis of
`certain fluid and electrolyte problems. However, osmometry
`values have little meaning unless the clinical situation is known.
`Osmometry is used in renal dialysis as a check on the electro-
`lyte composition of the fluid.
`In the clinical laboratory, as
`stated above, the term ’ "osmo