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Basic Science Review
DonaldE. Fry,MD, DavidE. Pitcher,MD
.Pharmacokinetics
is'the study of varIables that affect drug
concentratlons at the effector site. The descriptive terms peak
concentration, ellmínation ha/f-/ífe, vo/ume of dístríbut/on, and
bioavailabí/íty are commoniy used to express pharmacokinetlc
variabillty among drugs used in patient careoThe pharmacokinE'tIc characteristics of drugs are Important for surgeons to undEirstand because they represent differences that mar assume clirllcal slgnificance when seiecting antiblotics for preoperati\/e
preventive indications. in addition, the changing hemodynamic
pattern of the stressed and septic patient mar result in changlrlg
pharmacokinetic patterns for an antibiotic, whlch, in turn, mar
requlre changes in the dosing reglmen during the course of
treatment.
(ArchSurg.1990;125:149G-1492)
T
he pharmacokinetics of antibiotics (and other drugs) is
commonly discussed by pharmacologists in unfamiliar
descriptive tenns that are poorly understood by surgeons.
Becausesurgeons use antibiotics in many areas oftheir practice, a greater awarenessofpharmacokinetics and its clinical
significance is important.
PHARMACOKINETIC PRINCIPLES
Pharmacoldnetics is the study of variables that govern the
concentration of a drug at its effector Bite. The drug is administered and absorbed into the central pool, or serum, of the
patient. Oral drugs are absorbed over variable lengths of
time, while intramuscularly administered antibiotics are absorbed more rapidly and with less variability than oral1y
administered drugs. Both oral and intramuscular administration have a sustained-release profile, which means that drug
metabolism or excretion wiIl begin prior to complete absorption of a given dose. Thus, concentrations in the central pool
are influenced by both rates of drug uptake from the gut or
intramuscular reservoir, and the rates of drug metabolism or
excretion. With intravenous administration, drug absorption
is virtual1y immediate so that the central pool concentration
becomesa consequenceof drug elimination alone.
As the drug concentration in the central pool riges, gradients for diffusion into the various tissues occur. The equilibriAcceptedíor publicationAugust11,1990.
From tbe Departmentoí Surgery,University oí New MexicoSchooloí
Medicine,AIbuquerque.
Reprint requeststo Departmentoí Surgery,University oí New Mexico
SchooloíMedicine,
2211LomasBlvdNE, Albuquerque,
NM87131(DrFry).
1490
12'
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Arch Surg -Vol
125, November 1990
um state between the central pool and any tissue is governed
by multiple variables. The total blood supply, the lipid content
ofthe tissue, the lipophilic or lipophobic character ofthe drug,
and the protein-binding characteristics of the drug will each
affect the rapidity of drug delivery at the tissue Bite. Thus,
drug concentration wil1 rige more quickly in well-vascularized
muscle as opposed to relatively a\"RScular fat tissue. If the
drug is lipophilic, fat tissue concentrations wil1 steadily rige as
long as the central pool concentration exceeds the fat tissue
concentration, but wil1 then have sustained tissue concentrations even though serum concentrations will subsequently
become negligible. Highly protein-bound drugs wil1 diffuse
less rapidly into the interstitial space than non-protein bound
drugs, and willlargely be excluded from intracellular water.
~~ }mnnrtAn~. Doint nf t.h;Q_t'l;~"11QQ;.n~
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e
(PC) of any drug in serum alter intravenous administration is illustrated at point A in Fig 1. Peak
concentration is the greatest concentration of drug in serum
following a single dose. Peak concentration occurs very rapidly alter intravenous administration, is somewhat delayed (12
to 15 minutes) alter intramuscular administration, and may
not occur until much later with oral administration. Point C in
Fig 1 represents the eauilibrated m~um
concentration of
the antibiotic. This reduced concentratlon when compared
with point A occurs as a consequence of equilibration between
the tissues and the central pool.
The time required for the drug serum concentration to
decline by one haIfis then defined as the eliminn.tinn. h.n.lf-z,:fe
(tvJ. When declining drug concentrations ¡rom metabolism or
excretion are recorded on a semilogarithmic plot, the rate of
drug elimination becomes linear and reflects the slope of the
line. The tll2remains constant ayer a broad range of concentrations, such that the duration of drug presence in serum can be
described as multiples of that tll2' Thus, changes in the function or perfusion of organs responsible for drug elimination
will have an impact on tll2and the necessary dosing interval for
the antibiotic being used.
Valume of distribution
(VD) represents the theoretical
volume ofoody water necessary to dissolve a given dose of a
drug, assuming no elimination. This is calculated by extrapolation ofthe equilibrated elimination slope to point B, or tÍmezero concentration on the ordinate (Fig 1). Point B is the
extrapolated concentration of the drug in serum alter fuII
equilibration among aI1 tissues, but without any elimination.
Antibiotic Pharmacokinetics-Fry & Pitcher
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Fig 1. -The serum concentrations of a theoretical antibiotic given to a
palien!. Point A is the peak serum concentration; B, the extrapolated,
time.zero concentration that is useful in the calculation of the volume
of distribution; C, the maximum equilibrated serum concentration; and
D, !he concentration of the antibiotic in serum that is one half of point C
and thus defines the elimination half-life (t'l2) of!he an!ibiotic. The area
under the curve represents the bioavailability of !he drug. The time
interval from administration until the drug concentration dropped be.
low the minimum acceptable therapeutic concentration represents the
therapeutic availability. The plot is given a linear configuration because the drug concentrations are expressed as the logarithm of the
actual values.
Time, h
Fig 2. -The serum concentrations in milligrams per liter after preoperative administration of cephalothin (2 9 given intravenously) and cefazolin (1 9 given intravenously) in patients undergoing cholecystectomy. Shaded bars represent cephalothin; closed bars, cefazolin.
100
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Thus, a l-g (1000-mg)-dose that results in an extrapolated
time-zero concentration of 50 mg/L would havea VD equal to
dose/time-zero concentration, or 1000mg/(50 mg/L) = 20 L.
Knowing that a patient weighing 70 kg has an extraceIlular
water volume of 14 L means that this drug most likely penetrates the intraceIlular water volume to have a VD of 20 L.
The determination of the VD assumessignificance by virtue
of dictating the maximum PC in serum for a drug with a
given t~.
Another common term used in pharmacokinetics is .Q:iQ.:..
a~ailabilitu-Bioavailability represents the area rinder1Ji'e'"
~e
of the serum concentration plato Drugs with high PC,
small VD, and longer t~ will have greater bioavailability than
drugs with low PC, large VD, and short t~. Differences in
bioavailability explain why drugs with similar elimination t~
may actually have different redosing intervals.
Therapeutic availability is our term, chosenbecauseit is
more clinically applicable. Therapeutic availability is the duration of time by which the antibiotic concentration exceeds
the targeted therapeutic concentration that is desired for
treatment objectives. Antibiotics with high PCbut very short
t~ have a large calculated bioavailability but with a short
redosing intervalo The actual duration of antibiotic concentration or therapeutic availability that is greater than or equal to
the minimum inhibitory concentration for the bacteria likely
to be encountered is relatively short. Drugs with lower PC,
but long t~, may have a smaller bioavailability but a longer
therapeutic availability by virtue of a longer period of time
Arch Surg -Vol 125, November 1990
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Time, h
Fig 3.- The
preoperative
and celazolin
cystectomy.
wound fluid concentrations in milligrams per liter alter
administration 01 cephalothin (2 9 given intravenously)
(1 9 given intravenously) in patients undergoing choleShaded bars represent cephalothin;
closed bars,
celazolin.
abovethe minimum inhibitory concentration. Because of differences in target tissue pharmacokinetics, an ideal design
would be to know the therapeutic availability at the tissue site
rather thaninserum.
Antibiotic Pharmacokinetics-Fry
& Pitcher
1491
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CLINICAL SIGNIFICANCE OF PHARMACOKINETlCS
A first example that underscores the significance of pharmacokinetics can be seen in the use of antibiotics for preventive indications. Early studies in antibiotic prevention of
infection for elective gastrointestinal resections demon'strated significant benefits from preoperative use of cephaloridine1 or cefazolin sodium.2 Subsequent studies using ce'pha1othin sodiums.4showed no benefit, despite the similar
antimicrobial spectrum of this cephalosporincompared with
cephaloridine and cefazolin. However, measurement of serum (Fig 2) and tissue (Fig 3) concentrations of cefazolinand
cephalothin demonstrated lower cephalothin concentrations
at eachtime period.6 Cefazolinhas a greater PC, a lesser VD
(it is highly protein bound), a tm of2 hours, and a therap~utic
availability of 4 hours. Cephalothin has a lesserPC, a greater
VD, a tm of 35 to'40 minutes, and only a 75- to 9O-minute
therapeutic availability. The failure of cephalothin, and the
successof cephaloridine and cefazolin,as preventive antibiot-
ics emphasizethe importance oí therapeutic availability in
covering the period oíbacterial contamination.
.An additional example can be identified in the use oí aminoglycosides íor therapeutic indications. Septic and stressed
patients generally demonstrate a hyperdynamic circulation,
which, in patients with normal kidney function, will result in
accelerated excretion oí the drug.6,1Pharmacokinetic dosing,
while initially advocated to prevent toxic effects oí aminoglycoside antibiotics, is now cornmonlyused to ensure adequacy
oí drug administration. Up to five times the daily recommended clase oí aminoglycosides may now be required in
these patients with very elevated cardiac outputs. One can
only speculate about the underdosing oí other antibiotics or
drugs that occur in the hyperdynamic setting.
In
surnmary,
surgeons.
drug
An
pharmacokinetics
understanding
has
oí
been
pharmacokinetics
ignored
by
is
1
neces-
saiy ifwe are to optimize the clinical applications oíantibiotics
í?rthe care oíthe surgical patient.
Refer ences
l. PolkHC Jr, Lopez-Mayor
JR. Postoperative
woundinfection:a prospec5. Fry DE, Trachrenberg L, PoIk HC Jr. The significance oí antibiotic
tive studyofdetenninantfactorsandprevention.Surgery.1969;66:91-103.
acti\'ity in the surgical wound in sysremic antibiotic prophylaxis. Aktuel Probl
2. StoneHH, HooperCA, KolbLO, GeheberCE, OawkinsEJ. Antibiotic
Chir 0riJwp. 1981;19:47-50.
prophylaxiain gastric, biliary, and colonicsurgery. Ann Surg. 19i6;184:
6. Niemiec PW Jr, Allo MD, Miller CF. Effect oí aIrered volume of distribu443-452.
tion on aminoglycosideIeveIsin patients in surgical inrensive careoArch Surg.
3. BurdonJGW,MorrisPJ,HuntP,WattsJM. A trialofcephalothinsodium 1987;122:207-210.
ArchSurg.1911;112:
surge! t,opreventw.
7. Reed RL, Crotchett PM, CrotchetJ, Fischer RP. Pharmacoldnetic mom~, Bartlett J!
ShulteWJ, Gorbacl
toring oí nephrotoxic antibiotics in surgical inrensive care patient.9. Presenred
to controlsepticCOy
Preoperatlve ophylacticce
at the American Association íor the Surgery oí Trauma; October 7, 1988;
colorecta1opo tion: results contr
inicaltrial. Am J SI.
NewportBeach, Calif. Abstract.
68-74.
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ARCHIVES OF INTERNAL MEDICINE
Compliance Declines BetweenClinic Visits
f:
JoyceA. Crarner;RichardD. Scheyer,MD; RichardH. Mattson,MD
Adherence to prescribed drug dosing regirnens declined substantially during th
..isits and drug level tests. Using rnicroelectronic rnonitors to observe pill-taking ha!
8'8%compliance.rhese
oef(~ ~ , n~~
'.ance after the ..isit, but this dropped to 67% I
Jre ano 00'10compiló
19-ierrn "steady-state" d
dataindica that spot drug levels1990;150:1509-1510).
rep
betweenclinic
20patientsaveraged;¡liance
a rnonthlater.
;erurnconcentrations
Arch Intern Me!
Reprint requests Epilepsy Research-12íVA Medical Center, 950 Campbell Ave, West Haven, T 06516(MsCramer).
1492
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Surg-VoI125, November 1990
Antibiotic Pharmacokinetics-Fry & Pitcher
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