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http://en.wikipedia.org/wiki/Plasma_osmolality
http://en.wikipedia.org/wiki/Osmometer
OSMOLALITY AND OSMOLARITY
Definitions:
www.osmolality.com
Solutions: A homogeneous mixture of solutes in a solvent
Solvent: The major, liquid component of a solution
Solutes: The minor components of a solution – usually solids
Concentration: The relative amount of solute in a solution. Can be expressed
in many ways: solute to solvent, solute to solution, mass to mass, mass to
volume, etc.
Molarity: Molar concentration: grams of solute per litre of solution
Molality: Molal concentration: grams of solute per kilogram of solvent
Measured by alteration of colligative properties
1. Elevation of boiling point
2. Depression of freezing point
3. Depression of vapour pressure
4. Elevation of osmotic pressure
Molecular weight: The sum of the atomic weights of all the atoms in a
molecule
Mole: Gram molecular weight, molecular weight expressed in grams. One
mole of sodium chloride weighs 58.44 grams.
Ionic solution: Certain molecules, when dissolved, dissociate into charged
particles called ions
Non-ionic solution: Certain molecules, when dissolved, do not dissociate or
ionize into charged particles.
Avogadro’s Number: The number of molecules in one mole (gram molecular
weight) of a substance. One mole of non-ionic solute (such as sucrose)
dissolved in one kilogram of water will yield Avogadro’s number of molecules.
One mole of ionic solute dissolved in one kilogram of water will yield almost
twice Avogadro’s number of particles.
Colligative / Concentrative properties: When a solute is dissolved in a solvent,
certain properties of the solvent (freezing point, boiling point, vapor pressure
and osmotic pressure) are changed nearly in proportion to the concentration
of the solute, expressed in dissolved particles. Avogadro’s number of particles,
regardless of their size or shape, when dissolved in a kilogram of water, will
change each of the concentrative properties a specific amount.
INTRODUCTION
Osmotic pressure plays a critical role in all biological processes that involve
diffusion of solutes or transfer of fluids through membranes. Osmosis occurs
when solvent but not solute molecules cross a semi-permeable membrane
from regions of lower to higher concentrations to produce equilibrium. The
knowledge of osmotic pressures is important for practitioners in determining
whether a parenteral solution is hypo-osmotic, iso-osmotic, or hyperosmotic.
A quantitative measure of osmotic pressure facilitates the dilution required to
render a solution iso-osmotic relative to whole blood.
OSMOTIC PRESSURE
The osmotic pressure of a solution depends on the number of particles in
solution, and is therefore referred to as a colligative property. A particle can
be a molecule or an ion or an aggregated species (e.g., a dimer) that can
exist discretely in solution. A solution exhibits ideal behavior when no
interaction occurs between solutes and solvent, except where solvent
molecules are bound to solutes by hydrogen bonding or coordinate covalency.
For such a solution containing a nondissociating solute, the osmotic pressure
( ) is directly proportional to its molality (number of moles of solute per
kilogram of the solvent):
= ( RT/1000)m,
where
is the density of the solvent at the temperature T (in the absolute
scale); R is the universal gas constant; and m is the molality of the solution.
For a real solution containing more than one solute, the osmotic pressure is
given by the formula:
= ( RT/1000)Σ imiΦm,i,
where
i is the number of particles formed by the dissociation of one
molecule of the ith solute;
i = 1 for non-ionic (nondissociating) solutes; mi is
the molality of the ith solute; and Φm,i is the molal osmotic coefficient of the
ith solute. The molal osmotic coefficient takes into account the deviation of a
solution from ideal behavior. Its value depends upon the concentration of the
solute(s) in solution, its chemical properties, and ionic characteristics. The
value of the molal osmotic coefficient of a solute can be determined
experimentally by measuring the freezing point depression at different molal
concentrations. At concentrations of pharmaceutical interest, the value of the
molal osmotic coefficient is less than one. The molal osmotic coefficient
decreases with the increase in concentration of the solute (Table 1).
OSMOLALITY
The osmolality of a solution
m is given by
m = Σ imiΦm,i.
The osmolality of a real solution corresponds to the molality of an ideal
solution containing nondissociating solutes and is expressed in osmoles or
milliosmoles per kilogram of solvent (Osmol per kg or mOsmol per kg,
respectively), a unit that is similar to the molality of the solution. Thus,
osmolality is a measure of the osmotic pressure exerted by a real solution
across a semi-permeable membrane. Like osmotic pressure, other colligative
properties of a solution, such as vapour pressure lowering, boiling point
elevation, and freezing point depression, are also directly related to the
osmolality of the solution. Indeed, the osmolality of a solution is typically
determined most accurately and conveniently by measuring freezing point
depression (∆Tf):
∆Tf = kf
m,
where kf is the molal cryoscopic constant, which is a property of the solvent.
For water, the value of kf is 1.860 per Osmol. That is, 1 Osmol of a solute
added to 1 kg of water lowers the freezing point by 1.860 .
OSMOLARITY
Osmolarity of a solution is a theoretical quantity expressed in osmoles per L
(Osmol per L) of a solution and is widely used in clinical practice because it
expresses osmoles as a function of volume. Osmolarity cannot be measured
but is calculated theoretically from the experimentally measured value of
osmolality.
Sometimes, osmolarity ( c) is calculated theoretically from the molar
concentrations:
c = Σ ici,
where
i is as defined above, and ci is the molar concentration of the ith
solute in solution. For example, the osmolarity of a solution prepared by
dissolving 1 g of vancomycin in 100 ml of 0.9% sodium chloride solution can
be calculated as follows:
[3 × 10 g/L/1468 (mol. wt. of vancomycin) + 2 × 9 g/L/58.5 (mol. wt. of sodium
chloride)] × 1000 = 328 mOsmol/L.
The results suggest that the solution is slightly hyperosmotic since the
osmolality of blood ranges between 285 and 310 mOsmol per kg. However,
the solution is found to be hypo-osmotic and has an experimentally
determined osmolality of 255 mOsmol per kg.1 The example illustrates that
osmolarity values calculated theoretically from the concentration of a solution
should be interpreted cautiously and may not represent the osmotic properties
of infusion solutions.
The discrepancy between theoretical (osmolarity) and experimental
(osmolality) results is, in part, due to the fact that osmotic pressure is related
to osmolality and not osmolarity. More significantly, the discrepancy between
experimental results and the theoretical calculation is due to the fact that the
osmotic pressure of a real solution is less than that of an ideal solution
because of interactions between solute molecules or between solute and
solvent molecules in a solution. Such interactions reduce the pressure exerted
by solute molecules on a semipermeable membrane, reducing experimental
values of osmolality compared to theoretical values. This difference is related
to the molal osmotic coefficient (Φm,i). The example also illustrates the
importance of determining the osmolality of a solution experimentally, rather
than calculating the value theoretically.
MEASUREMENT OF OSMOLALITY
The osmolality of a solution is commonly determined by the measurement of
the freezing point depression of the solution.
Apparatus— The apparatus, an osmometer for freezing point depression
measurement, consists of the following: a means of cooling the container
used for the measurement; a resistor sensitive to temperature (thermistor),
with an appropriate current- or potential-difference measurement device that
may be graduated in temperature change or in osmolality; and a means of
mixing the sample.
Osmometers that measure the vapor pressures of solutions are less
frequently employed. They require a smaller volume of specimen (generally
about 5 µL), but the accuracy and precision of the resulting osmolality
determination are comparable to those obtained by the use of osmometers
that depend upon the observed freezing points of solutions.
Standard Solutions— Prepare Standard Solutions as specified in Table 1, as
necessary.
Table 1. Standard Solutions for Osmometer Calibration2
Standard Solutions
Osmolality
(Weight in g of sodium chloride per kg (mOsmol/kg)
of water)
( m)
Molal
Osmotic
Coefficient
(Φm, NaCl)
Freezing
Point
Depression
( )
∆Tf
3.087
100
0.9463
0.186
6.260
200
0.9337
0.372
9.463
300
0.9264
0.558
12.684
400
0.9215
0.744
15.916
500
0.9180
0.930
19.147
600
0.9157
1.116
22.380
700
0.9140
1.302
2 Adapted from the European Pharmacopoeia, 4th Edition, 2002, p. 50.
Test Solution— For a solid for injection, constitute with the appropriate diluent
as specified in the instructions on the labeling. For solutions, use the sample
as is. [NOTE—A solution can be diluted to bring it within the range of
measurement of the osmometer, if necessary, but the results must be
expressed as that of the diluted solution and must NOT be multiplied by a
dilution factor to calculate the osmolality of the original solution. The molal
osmotic coefficient is a function of concentration. Therefore, it changes with
dilution.]
Procedure— Set the zero of the apparatus using water. To calibrate the
apparatus, choose at least two solutions from Table 1 such that the
osmolalities of the Standard Solutions span the expected range of osmolality
of the Test Solution. Introduce an appropriate volume of each Standard
Solution into the measurement cell as per the manufacturer's instructions, and
start the cooling system. Usually, the mixing device is programmed to operate
at a temperature below the lowest temperature expected from the freezing
point depression. The apparatus indicates when the equilibrium is attained.
Calibrate the osmometer using an appropriate adjustment device such that
the reading corresponds to either the osmolality or freezing point depression
value of the Standard Solution shown in Table 1. [NOTE—Some instruments
indicate osmolality and some others show freezing point depression.] Before
each measurement, rinse the measurement cell at least twice with the
solution to be tested. Repeat the procedure with each Test Solution. Read the
osmolality of the Test Solution directly, or calculate it from the measured
freezing point depression.
Assuming that the value of the osmotic coefficient is essentially the same
whether the concentration is expressed in molality or molarity, the
experimentally determined osmolality of a solution can be converted to
osmolarity in the same manner in which the concentration of a solution is
converted from molality to molarity. Unless a solution is very concentrated, the
osmolarity of a solution ( c) can be calculated from its experimentally
determined osmolality ( m):
c = 1000 m / (1000 /
where wi is the weight in g; and
+ Σwi i),
i is the partial specific volume, in mL per g,
of the ith solute. The partial specific volume of a solute is the change in
volume of a solution when an additional 1 g of solute is dissolved in the
solution. This volume can be determined by the measurement of densities of
the solution before and after the addition of the solute. The partial specific
volumes of salts are generally very small, around 0.1 mL per g. However,
those of other solutes are generally higher. For example, the partial specific
volumes of amino acids are in the range of 0.6–0.9 mL per g.
1 Kastango, E.S. and Hadaway, L. International Journal of Pharmaceutical
Compounding 5, (2001) 465-469.
Auxiliary Information— Staff Liaison : Horacio Pappa, Ph.D.
Expert Committee : (GC05) General Chapters 05
USP29–NF24 Page 2718
Pharmacopeial Forum : Volume No. 31(3) Page 845
Phone Number : 1-301-816-8319
Osmometer
From Wikipedia, the free encyclopedia
Jump to: navigation, search
An osmometer is a device for measuring the osmotic strength of a solution, colloid,
or compound.
There are several different techniques employed in osmometry:
•
•
•
Vapor pressure depression osmometers determine the concentration of
osmotically active particles that reduce the vapor pressure of a solution.
Membrane osmometers measure the osmotic pressure of a solution separated
from pure solvent by a semipermeable membrane.
Freezing point depression osmometer may also be used to determine the
osmotic strength of a solution, as osmotically active compounds depress the
freezing point of a solution.
Osmometers are useful for determining the concentration of dissolved salts or sugars
in blood or urine samples. Osmometry is also useful in determining the molecular
weight of unknown compounds and polymers.
Osmometry is the measurement of the osmotic strength of a substance [1]. This is
often used by chemists for the determination of average molecular weight
Pharmacokinetics and anaesthesia
Fred Roberts MB ChB FRCA
Dan Freshwater-Turner MA MB BChir MRCP
Key points
General principles
Membrane transfer
Drugs need to cross cell membranes in order to
produce their effects (e.g. gastro-intestinal
absorption, reaching intracellular sites of action).
Such transfer occurs more readily with a:
†
†
†
†
low degree of ionization
low molecular weight
high lipid solubility
high concentration gradient
The extent of ionization is influenced substantially by environmental pH, an effect that is
used to prepare highly ionized, aqueous solutions of acidic drugs such as thiopental (solution pH 10.5) or basic ones such as lidocaine
(solution pH 5.2), as shown in Fig. 1.
In the more neutral pH of the body, much
of the drug reverts to the unionized form
enabling membrane transfer to reach its site of
action. If this change in pH does not occur, the
drug cannot become unionized and will be
ineffective (e.g. lidocaine in the acidic environment of infected tissue).
Partial pressure and solubility
For an inhaled drug, it is the partial pressure
that largely determines its behaviour, both for
moving between phases and producing pharmacodynamic effects at the site of action. In a gas
mixture at sea level, because atmospheric
pressure is 101.3 kPa, partial pressure (kPa) is
often used interchangeably with fractional concentration (%). However, in solution, partial
pressure cannot be equated to blood concentration because of wide variation in solubility.
Gas solubility in blood is usually expressed as
the blood– gas partition coefficient (BGPC),
defined as the volume of gas dissolved in a unit
volume of blood when at equilibrium with the
gas alone. A more soluble drug (high BGPC)
requires a greater number of molecules to be
dissolved to exert a given partial pressure than
a less-soluble one (low BGPC).
Recommended drug doses are
derived from average values in
population studies and provide
no certainty of response in a
specific individual.
Elimination half-life at steady
state is of limited value in
describing the recovery profile
of a drug administered for a
short period only. Contextsensitive half-time provides
more useful information under
these circumstances.
If a drug is given as a constant
rate infusion, steady-state
concentration will only be
achieved after four to five halflives.
Partial pressure largely
determines the behaviour of
an inhaled drug.
For maintenance of
anaesthesia, a predictable
steady state is easier to
achieve with an inhalational
agent than an i.v. one.
Exponential processes
Pharmacokinetic processes usually occur at a
rate proportional to the concentration gradient
at the time. As the process continues, the concentration gradient falls, thus progressively
slowing the rate of change. This results in an
exponential relationship between concentration
and time and applies to most drug elimination
and transfer between tissues.
There are two ways in which an exponential
function can be described (Fig. 2). If a specified time period is set, the decline is defined by
the fraction by which the concentration has
been reduced during this interval. This is the
elimination rate constant (k), expressed as
time21. Alternatively, a given fractional
reduction in concentration is set, and the time
doi:10.1093/bjaceaccp/mkl058
Continuing Education in Anaesthesia, Critical Care & Pain | Volume 7 Number 1 2007
& The Board of Management and Trustees of the British Journal of Anaesthesia [2007].
All rights reserved. For Permissions, please email: [email protected]
Fred Roberts MB ChB FRCA
Consultant Anaesthetist and Honorary
Clinical Lecturer
Department of Anaesthesia
Royal Devon and Exeter Hospital
(Wonford)
Barrack Road, Exeter EX2 5DW
UK
Tel: þ 44 01392 402474
E-mail: [email protected]
(for correspondence)
Dan Freshwater-Turner MA MB BChir
MRCP
Associate Lecturer
University of Queensland and Senior
Registrar in Intensive Care Medicine
Royal Brisbane and Women’s Hospital
Brisbane
Australia
25
Downloaded from ceaccp.oxfordjournals.org by Richard Hodgson on October 3, 2010
Pharmacokinetics explains what happens to a
drug in the body, whereas pharmacodynamics
describes the actions produced by the drug on
the body. Therefore, the effects of a drug result
from a combination of its pharmacokinetic and
pharmacodynamic characteristics in that individual. Wherever possible, drug administration
should be based on a measured patient
response, which will incorporate both of these
aspects of its pharmacology.
However, such an approach may not always
be possible. The response may be masked by
other factors (e.g. neuromuscular blockers
masking signs of anaesthetic depth) or difficult
to quantify precisely (e.g. action of antibiotics
or anti-emetics). Under these circumstances,
previously established pharmacokinetic and
pharmacodynamic data are used to guide
administration. This article aims to explain and
simplify the principles of pharmacokinetics so
that their application to clinical practice can be
better understood.
Pharmacokinetics and anaesthesia
taken to achieve this level is found. If a 50% reduction in concentration is used, the time taken is the half-life (t1/2); this will be
constant whatever starting drug concentration is used. Another
time period that can be used to describe the curve is the time constant (t). This is the point at which the elimination of drug would
have been completed if the process had continued at its initial rate;
it corresponds with a reduction in concentration to 37% of the
original value.
Pharmacological compartments
Drugs are not distributed uniformly throughout the body. The
speed with which a drug reaches a particular tissue is largely
dependent on its local blood flow, and for analytical convenience,
similar tissue types are often grouped together into various ‘compartments’ depending on their blood supply.
The capacity of each compartment to act as a reservoir for the
drug is determined by a combination of its size and affinity for the
drug. It is important to note that pharmacokinetic compartments
are mathematical models and do not correspond to actual tissues;
Fig. 3 Illustration of a three-compartment model for a lipid-soluble drug.
Pipe size represents blood flow and tank size the capacity as a drug
reservoir.
they are a concepts enabling the prediction of the pharmacokinetic
behaviour of drugs. When performing mathematical modelling, it
is likely that a lipid-soluble drug that is widely distributed is likely
to have several compartments; a highly ionized drug that remains
in the extracellular space is likely to be best described by assuming
a one-compartment model. An example of a three-compartment
model is shown in Fig. 3; these correspond to vessel-rich, intermediate, and vessel-poor tissues, with a central compartment
(blood), through which drugs must pass during uptake or
elimination.
Because movement between compartments is dependent on the
concentration difference between them, the process is exponential
and the rate of transfer to the slower tissues decreases as they
accumulate more drug.
Volume of distribution
When a drug has been fully distributed throughout the body and
the system is at equilibrium, the volume within which the drug is
contained is called the volume of distribution at steady state (Vss
d ).
It is a theoretical value expressed as the volume of blood which
would be necessary to contain the entire drug present in the body,
at the equilibrium concentration (units litre kg21).
For a lipid-soluble drug (e.g. fentanyl) a litre of fat will hold
many times more drug than a litre of blood, and thus its Vss
d
(4 litre kg21) will be much greater than the total body volume. In
contrast, a highly ionized drug (e.g. glycopyrrolate) that does not
21
readily cross lipid membranes has a Vss
.
d of only 0.16 litre kg
Clearance
Fig. 2 Exponential decline. C0 initial concentration; t12 half-life; t, time
constant
26
Although a drug may be widely distributed throughout the body, it
is usually removed only from the blood. Clearance (Cl) is a
concept used to describe this, and it represents the volume of
blood from which the drug is completely eliminated in unit time.
For example, if the concentration in blood is reduced by 20% in an
hour, the result is equivalent to removing the entire drug from 20%
Continuing Education in Anaesthesia, Critical Care & Pain j Volume 7 Number 1 2007
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Fig. 1 Ionization and environmental pH. Red arrows indicate the pH at
which lidocaine (a weak base) and thiopental (a weak acid) are prepared in
solution. At body pH, much of the drug becomes unionized and can cross
membranes.
Pharmacokinetics and anaesthesia
of the blood volume (1000 ml), corresponding to a clearance of
1000 ml h21 or 16.7 ml min21; it is stated that clearance is also
often adjusted for body weight.
A large elimination rate constant (k) produces a short elimination half-life (t12); this will result from a high (Cl) or a small
volume of distribution (Vss
d ).
Pharmacokinetic pathway
In general, the passage of a drug through the body can be separated into three distinct phases: uptake, distribution, and
elimination.
Different routes of administration produce variability in the rate of
drug uptake and amount of drug delivered effectively to the body.
I.V. administration of a drug results in the entire dose entering the
plasma immediately, although it must pass initially through the
pulmonary circulation and some drugs (e.g. fentanyl) have significant take-up by the lungs.
Gastrointestinal (GI) administration requires the drug to cross
the intestinal wall. The rate of absorption depends on surface area,
pH, and, in some drugs, active systems. In general, unionized
drugs (e.g. ethanol) are well absorbed throughout the intestine;
absorption of weak acids (e.g. aspirin) is facilitated by a low pH
and weak bases (e.g. morphine) by a high pH. For drugs that
remain completely ionized throughout the gut (e.g. glycopyrrolate),
passive GI absorption is negligible.
Even after GI absorption, a drug may not reach the systemic circulation. Metabolism can occur in the gut mucosa (e.g. dopamine) or
in the liver during its first pass via the portal vein (e.g. propranolol).
This problem can be circumvented by administration at a site that
avoids the portal circulation such as sublingual or, to some extent,
rectal. The degree to which an administered drug reaches the systemic bloodstream is termed its bioavailability (Fig. 4).
Uptake after intramuscular or subcutaneous administration is
largely dependent on local blood flow rather than ionization or
lipid solubility. The transdermal route can be used for highly
Fig. 4 Oral bioavailability. Same dose administered i.v. and orally on
separate occasions. Oral bioavailability ¼ area under curveoral/area under
curvei.v..
† high fractional concentration of inhaled drug
† high minute ventilation
† low BGPC
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Uptake
lipid-soluble drugs (e.g. GTN, fentanyl), where slow absorption
eventually produces sustained blood concentrations.
A fundamentally different pattern of uptake is seen for an
inhaled drug in that it crosses the alveolar membrane into the blood
along its partial pressure gradient. This produces an exponential
wash-in, until at equilibrium (i.e. the partial pressure in blood equals
that in the inspired and expired gas) no further net uptake occurs.
A clinical effect requires sufficient uptake to exert an adequate
partial pressure in the body tissues; it is achieved most rapidly by a:
The faster speed of onset produced by a low BGPC reflects the
smaller number of molecules needed in solution to exert a partial
pressure. A low cardiac output can also accelerate the uptake somewhat, with reduced perfusion to areas outside the vessel-rich group
resulting in less drug needed to be taken up from the alveoli.
Alveolar partial pressure, measurable from end-tidal exhaled
gas, closely reflects that of arterial blood and, in turn, that of the
brain, enabling continuous monitoring of an indirect measure of
drug delivery to the target site.
Distribution
After i.v. administration of a drug, the peak blood concentration is
determined by the dose, the rate of administration, and the cardiac
output. With a high cardiac output, the effective volume of blood
in which the drug is initially diluted is larger, leading to a lower
peak concentration. However, the high cardiac output transports
the drug quickly to the vessel-rich tissues (including brain), and
for highly lipid-soluble drugs, rapid equilibration occurs, leading
to a fast onset of action. It is the high blood supply more than the
lipid solubility that explains this.
Conversely, a low cardiac output leads to a higher initial peak
concentration, because the drug is mixed with a smaller volume of
blood during injection, though it will take longer to reach its target
site. This explains why a smaller dose of induction agent is
required in an elderly or shocked patient but may have a slower
onset of action, while a young patient may require a much larger
dose, yet will start to feel the effects more quickly.
Other tissues may also have a high affinity for the drug, but can
only take up the drug slowly as they receive a lower proportion of the
cardiac output. As they do so, however, the blood concentration
decreases, soon falling below the brain concentration, whereupon the
drug leaves the brain to be redistributed to other tissues. This redistribution is referred to as the a phase and explains the rapid termination
of effect of lipid-soluble drugs such as propofol or thiopental following a bolus dose. As the less well-perfused tissues accumulate more
drug, the concentration difference between compartments falls and
the rate of redistribution slows in a declining exponential fashion.
This also acts to slow down the redistribution if further drug is given,
and subsequent doses should therefore be amended accordingly.
Continuing Education in Anaesthesia, Critical Care & Pain j Volume 7 Number 1 2007
27
Pharmacokinetics and anaesthesia
For inhalational agents, the pharmacokinetic model for distribution is similar; however, because the rate of administration is
slower, the various compartments fill simultaneously, although at
different rates depending on their blood supplies. Because there is
never a rapid loading dose to any one compartment, redistribution
between compartments is minimal. As administration continues,
the vessel-poor and intermediate compartments become progressively saturated, delaying subsequent recovery, particularly for
agents with a high lipid solubility.1 Regardless of the period of
administration, however, the partial pressure in any tissue will
never exceed that administered.
Although the initial effects of a drug may wear off because of redistribution, full recovery depends upon the removal of the drug from
the body. Such elimination may result from excretion, metabolism,
or a combination of both. Large molecular weight drugs are often
excreted in the bile, but most drugs are renally excreted. In order for
the kidneys to handle lipid-soluble drugs, they need to be metabolized into a polar, water-soluble form. Most of this metabolism
occurs in the liver and can be divided into Phase 1 and Phase 2 reactions. Phase 1 reactions include oxidation, reduction, and hydrolysis;
in Phase 2 reactions, the resulting metabolites are conjugated with
sulphate, glucuronide, or other groups.
For most drugs, elimination occurs in an exponentially declining manner, the rate of elimination being proportional to the
plasma concentration, as the downstream end of the gradient
remains at zero. This system (i.e. the amount of drug being
removed is a constant fraction in unit time rather than a constant
amount) is known as first-order kinetics.
For some drugs, elimination may depend on the action of an
enzyme or transporters which can become saturated. Once the
relevant blood concentration is reached, elimination becomes constant, limited to a maximum amount in unit time. This is referred
to as zero-order kinetics and can result in dangerously high
concentrations with continued, unmonitored drug administration.
It may be encountered at high concentrations with aspirin, ethanol,
phenytoin, or thiopental.
With inhalational agents (halothane excepted), metabolism
occurs and elimination is via the reverse process to uptake.
Recovery is reliant on adequate ventilation, but its duration is
usually more dependent on the extent of tissue saturation.
Practical applications
Establishing steady state
If a drug is given as a constant infusion, it will eventually reach a
steady state (i.e. with the whole V ss
d containing the drug at a stable
concentration, and elimination occurring at the same rate as administration). It takes four to five elimination half-lives to achieve this.
The target concentration can be attained far more rapidly using
an initial loading dose followed by further additional drug in a
28
Fig. 5 Context-sensitive half-times of fentanyl, alfentanil, and remifentanil.
declining exponential fashion as redistribution to other tissues
occurs. Computer-driven target-controlled infusion (TCI) systems
deliver this pattern automatically,2 adjusted for patient age, weight,
and target concentration. Alternatively, this can be approximated
closely using a stepped manual infusion scheme.3
Context-sensitive half-time
Elimination half-life relates to the decline in plasma drug concentration from steady state following distribution throughout the
whole V ss
d . It provides a useful guide to dosage intervals for longterm drug maintenance. However, in anaesthetic practice, few
drugs are administered long enough to reach the steady state. The
context-sensitive half-time (CST) then becomes a more useful
descriptor,4 detailing the plasma half-life after an infusion of a
specified duration (Fig. 5).
For drugs such as fentanyl, in which redistribution is the main
mechanism responsible for the decline in plasma concentration
after a brief infusion or bolus, the CST will initially be short. As
the duration of infusion continues, redistribution becomes progressively less important and the CST increases, until ultimately it
equals the elimination half-life. For a drug with a small volume of
distribution, such as remifentanil, redistribution is very limited and
the CST changes little even with prolonged infusion.
Predictability
Established pharmacokinetic and pharmacodynamic data are
derived from averaged population studies. When based on these,
even the most sophisticated dosage schemes for i.v. drugs will
produce substantial variation in response between individuals, in
both the blood/brain concentration ( pharmacokinetics) and the subsequent effects ( pharmacodynamics).5
In contrast, for inhalational anaesthetic agents, although pharmacodynamic variability will still occur, pharmacokinetic behaviour will be far more predictable, because of the physics of gas/
vapour solution in a liquid. Indeed, at equilibrium the partial
pressure of an inhalational agent in blood (and other tissues)
will precisely equal that in the inhaled gas mixture. Furthermore,
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Elimination
Pharmacokinetics and anaesthesia
the end-tidal partial pressure of an inhalational agent can be
measured in real-time, providing a value very close to that in
arterial blood.
References
3. Roberts FL, Dixon J, Lewis GT, Tackley RM, Prys-Roberts C. Induction
and maintenance of propofol anaesthesia. A manual infusion scheme.
Anaesthesia 1988; 43(Suppl.): 14– 7
4. Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs.
Anesthesiology 1992; 76: 334–41
1. Eger E. II, Saidman LJ. Illustrations of inhaled anesthetic uptake, including
intertissue diffusion to and from fat. Anesth Analg 2005; 100: 1020–33
5. Hoymork SC, Raeder J, Grimsmo B, Steen PA. Bispectral index, serum
drug concentrations and emergence associated with individually adjusted
target-controlled infusions of remifentanil and propofol for laparoscopic
surgery. Br J Anaesth 2003; 91: 773–80
2. Gray JM, Kenny GN. Development of the technology for ‘Diprifusor’
TCI systems. Anaesthesia 1998; 53(Suppl. 1): 22– 7
Please see multiple choice questions 22 –25
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Continuing Education in Anaesthesia, Critical Care & Pain j Volume 7 Number 1 2007
29
PHARMACOLOGY REVIEW
From the Cleveland Clinic’s Comprehensive Anesthesiology Review,
presented April 30 to May 5, 2005
Basic Pharmacology for the Anesthesiologist— John E. Tetzlaff, MD, Professor of
Anesthesiology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve
University, and Program Director, Center for Anesthesiology Education, Division of
Anesthesiology and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland
Pharmacokinetics: simple model considers body as single box or compartment; amount
of drug injected defined as dose; concentration of drug in compartment determined by
volume of distribution (physiologic distribution); drug-specific volume of distribution
equals amount of drug in body divided by concentration in blood
Metabolism: half-life—time required for plasma concentration to decrease by
half; first-order elimination—constant fraction of change in clearance per unit time; zeroorder elimination—constant amount of change in clearance per unit time
Central compartment: contains high-volume or high blood flow (BF) organs (eg,
heart, great vessels, lungs); instant peak blood levels attained; with drugs metabolized or
rapidly redistributed, relatively rapid fall in concentration without continuous infusion;
highly related to initial drug action for most anesthetic drugs
Peripheral compartment: includes several compartments; size depends on
peripheral BF and whether tissue in question ionic or lipid-soluble; change much slower,
especially in highly lipid-soluble peripheral compartments; peak levels achieved slowly
and decrease slowly; in general, intial effect of drugs in central compartment and
sustained effects in peripheral compartment
Clearance
Hepatic: major source of drug clearance; main metabolic actions oxidation,
reduction, hydrolysis, and conjugation; cytochrome system capable of oxidation and
reduction; conjugation of large or lipid-soluble molecules occurs by unique enzymes;
elimination of anesthetic drugs directly proportional to hepatic BF; drugs administered
orally pass through liver before redistribution to central compartment
Renal clearance: as primary source of elimination, favors small molecules, and
water-soluble over lipid-soluble molecules; decreases slightly with age; proportional to
renal BF
Tissue clearance: minor component to elimination of majority of anesthetic
agents; may be enzyme-mediated ester hydrolysis; classic examples are succinylcholine
and ester local anesthetics; also some spontaneous ester hydrolysis; amount of clearance
limited and rapidly shifts from first-order to zero-order elimination; subject to BF, but to
lesser extent
Protein binding: contributes to drug clearance to extent that agents protein
affiliated; determined by protein-binding capacity; principal proteins in plasma and serum
involved in protein binding include albumin and α1 -acid glycoprotein; influenced by
nutrition and aging
Factors that alter clearance
Continuous infusion: avoids competition between sudden effect in central
compartment and sustained effect in peripheral compartment; achieve steady state by
determining balance between rate of administration and clearance; steady state achieved
by continuous infusion or infusion as adjunct to loading dose
Route of administration: uptake slower when drug administered into poorly
vascularized area or area with low regional BF; target effect achieved quickly when drug
injected into area with high BF; accelerated redistribution in areas of high BF and slow
redistribution in areas of low BF; ionic substances can have absorbance limited by pH;
ion trapping may cause artificially elevated concentrations
Patient variability: coadministration of other medications may induce enzymes
that accelerate or reduce clearance; renal BF decreases with increasing age; variety of
metabolic enzyme systems dependent on maturity; maternal and fetal α1 -acid
glycoproteins can be reduced; illness or severe comorbidity in mother may cause reduced
albumin concentration
Disease: renal clearance proportional to creatinine clearance; liver disease affects
molecules metabolized in liver; also reduces protein binding; causes reduction in
metabolic capacity as hepatic parenchyma damaged; intrahepatic shunting causes
molecules to pass through shunts without exposure to enzyme system, resulting in lower
metabolism; cardiac failure influences elimination (hepatically and renally); causes
diminished hepatic BF, alters regional BF, decreases renal BF, and alters tissue clearance
Postoperative period: absorption from gastrointestinal (GI) tract reduced; metabolic rates
also reduced; in patient with multiple surgical procedures or critical care needs, reduced
drug binding because of catabolism eliminating serum proteins; intra-abdominal or
intrathoracic procedure associated with diminished liver BF
Metabolism: many anesthetic drugs have first-order elimination, but some have high
molecular weight, high lipid solubility, or both; depends on metabolic alteration to be
further metabolized or excreted intact through renal system; involves adding polar
molecules and oxidation, reduction, and hydrolysis steps to allow renal elimination of
smaller molecules; oxidation occurs in smooth endoplasmic reticulum almost exclusively
in liver; oxidation can involve aliphatic substitution, desulfuration, or dehalogenation;
reduction occurs at anaerobic conditions almost completely in liver via cytochrome P450
system; hydrolysis can occur via variety of enzyme systems in liver, lung, and other
tissues; pseudocholinesterase system highly active; phase II reactions modify molecules
to facilitate clearance; most common reactions glucuronic acid conjugation on amine side
or acetylation on hydrophobic side; others include mercapturic acid synthesis for sulfurcontaining molecules, sulfate formation, amide synthesis, and methylation
Pharmacogenetics: ≈6 sites where cytochrome P450 system active; lesions known to
cause specific conditions
Pharmacodynamics: relationship between plasma concentration and designed drug
effects; majority of receptors have balance between agonist and antagonist activity;
receptor activity dependent on concentration and altered by drugs, physiologic
conditions, and disease; receptor structure and function related; complex chemical event
involving G-proteins, ion channels, ion restoration pumps, and second messengers
(including hormones)
Compounding local anesthetics to reduce toxicity: depends on selection of local
anesthetics; ideally, choose short-acting anesthetic from one category and longer-acting
anesthetic from another category to reduce toxicity.
Suggested Reading
Bernards CM et al: Epidural, cerebrospinal fluid, and plasma pharmacokinetics of
epidural opioids (part 1): differences among opioids. Anesthesiology 99:455, 2003;
Egan TD et al: Remifentanil versus alfentanil: comparative pharmacokinetics and
pharmacodynamics in healthy adult male volunteers. Anesthesiology 84:821, 1996;
Elfstrom J: Drug pharmacokinetics in the postoperative period. Clin Pharmacokinet 4:16,
1979;
Greenwood-Van Meerveld B et al: Preclinical studies of opioids and opioid antagonists
on gastrointestinal function. Neurogastroenterol Motil 2:46, 2004;
Hogue CW Jr et al: A multicenter evaluation of total intravenous anesthesia with
remifentanil and propofol for elective inpatient surgery. Anesth Analg 83:279, 1996;
Hug CC Jr: Pharmacokinetics of drugs administered intravenously. Anesth Analg 57:704,
1978; Krejcie TC et al: A recirculatory model of the pulmonary uptake and
pharmacokinetics of lidocaine based on analysis of arterial and mixed venous data from
dogs. J Pharmacokinet Biopharm 25:169, 1997;
Leslie JB: Alvimopan for the management of postoperative ileus. Ann Pharmacother
39:1502, 2005;
Lowenstein E et al: Cardiovascular response to large doses of intravenous morphine in
man. N Engl J Med 281:1389, 1969;
Lowenstein E et al: Narcotic "anesthesia" in the eighties. Anesthesiology 55:195, 1981;
Shand DG et al: Effects of route of administration and blood flow on hepatic drug
elimination. J Pharmacol Exp Ther 195:424, 1975;
Thompson JP et al: Remifentanil--an opioid for the 21st century. Br J Anaesth 76:341,
1996;
Wilkinson GR et al: Commentary: a physiological approach to hepatic drug clearance.
Clin Pharmacol Ther 18:377, 1975;
Wolff BG et al: Alvimopan, a novel, peripherally acting mu opioid antagonist: results of
a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major
abdominal surgery and postoperative ileus. Ann Surg 240:728, 2004;
Yuan CS: Clinical status of methylnaltrexone, a new agent to prevent and manage opioidinduced side effects. J Support Oncol 2:111, 2004.