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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' cl '/~ 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~ ;~ t.}",t. Q~""m ,.~n~trations m ave no co el tion' . 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 ~ 100 A 90 ) B c: ~~ ~ 80 , .Q ~'- -J cQ) c (J c: o (.) .~ o ;Q c <{ E 2 Q) (/) 1 ~E 70 c: 60 c: Q) 50 o .~ '- "' 1 1 1 1 1 1 1 1 1 u c: o D (.) 30 I I I I I I I 11 1 1 40 ,2_1 20 I 10 I 2 Time 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 90 -J "O 80 E 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 ¿ 02 70 "@ "E 60 ~ c o 50 (.) "O oS LC "O c :J 40 30 o :s: 20 10 Incision <1 1-1.5 1.5-2 2-2.5 >2.5 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 ;r terval 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. 1~ ~Ineral rat fc: ~ 1~ In Other AMA Journals 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 Al Surg-VoI125, November 1990 Antibiotic Pharmacokinetics-Fry & Pitcher ~