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Acta Anaesthesiologica Scandinavica

fSSN OO(JI·5f72

Reinduction of the hypnotic effects of thiopental with NSAIDs by decreasing thiopental plasma protein binding in humans

O. Y-P. Hul, K. M. CHUI, H_ s. L1l!2, s. F. Cl-llAOJ, w Hol and S. T. Has

'School of Pharmacy, 'Department of Gynecology, 'Department of Hospiral and Clinical Pharmacy, and 'Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei and "Far-Eastern Memorial Hospital, Taipei, Taiwan, Republic of China

The effects of 14 non-steroidal arui-inflamrnatory drugs (NSAIDs) - naproxcn, ibuprofen, mefenamic acid, keroprofcn, indomethacin, fenoprofen, diclofcnac sodium, aspirin, salicylic acid, piroxicam, sulindac, [enbufen, flurbiprofen and bcnzvdarnine, on rhe olasma protein binding of thiopental and the clinical consequences of such interactions were studied. Four of them, naproxen, ibuprofen, salicylic acid and aspirin, very significantly decreased the protein binding of thiopental in nitro in human plasma (P< O.OOS). Structurally, they were salicyiares and propionic acid derivatives among the six classes of NSAIDs studied. The aspirin study demonstrated that the protein-displacing phenomenon was temperature-dependent, and concentration. dependent. Clinically, aspirin administered intravenously resulted in a significant increase in the percentage of plasma free thiopental from 16.01:t 3.59% 10 22.27 ± 3.96% (P<O.OOI, n = 10) in patients undergoing surgery, and resulted in three of seven patients sleeping again during recovery from thiopental-induced anesthesia. Alrbough the effect of chronic use of NSAIDs before anesthesia is uncertain, studies should be carried OUI 10 find our if naproxen, ibuprofen, and aspirin influence the depth of anesthesia, time of recovery and duration of ,KI iOI1 of I h iopemal.

Rw;",d 9 ,lallum_!, acceptrd for publication 3 Au.gusl 1992

KI!)" words. I nducuon time; NSAID,; plasma protein binding; thiopental.

Plasma protein binding is a vital part of the studies of pharmacokinetics and pharmacodynamics. The binding of drugs to plasma proteins is a complex, dynamic process. Plasma albumin is the primary determinant of the binding of acidic drugs, whereas, other substances in plasma, particularly highly pro· rein-bound drugs, may compete for binding sires, leading to the displacement of the protein-drug complex -and- an increase in the concentration of free drug. The consequences of such displacement are variable: in most cases, the kinetic changes are transient and a new eq uilibrium with restored conccntrations of free drug in plasma is readily achieved (I). However, even the rernpora rv mer case ill the concentration of free drug in plasma may result in an increase in a pharmacological effect which may be of clinical significance (2).

Thiopental is an acidic, highly protein-bound drug (3). Many factors such as age, disease. and 1l1'1l1:' other drugs could affect the extent olplasma pro tern lJinding or thiopental (3-6). Alterations in d1l' ph.umacokinctirs of thiopental have been deSCribed ill r:t!s prctr.:.u cd

with sulphadimethoxine (7). A decrease in the anesthetic dose of thiopental as well as an increase in the rapidity of induction of anesthesia with rnidazolarn have been reported in patients treated with displacing agents (8, 9).

Most of the nonsteroidal an ti-inflarnmatory drugs i.NSAIDs) are also highly protein bound. Chaplin et al. (10) have shown that the plasma protein binding of thiopental was significantly decreased in rabbit plasma by aspirin, phenylbutazone, Indomethacin, mefenamic acid and naproxen. The pharmacodynamics of thiopental was also affected by concomitant administration of I'>iSA1Ds.

The present study determined the effects of 14 ;\ SA IDs - na proxen, ibuprofen, mefena m ic ac i d, ketoprofen, indomethacin, fenoprofen, didofenac sodium, aspirin, salicylic acid, piroxicarn, sulindac, fcnbufcn, llurbiprofen and bcnzydamine, on the ill vitro protein hinding of thiopental in human plasma. The pharmar okj nrt ics and pharmacodynamics of thiopental, afIccrcd by the presence of aspirin, were also studied in .>\1 rgical patients.

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. NSAlDS DECREASE PROTEIN-BOUND THIOPENTAL

259

:-'IATERIAL AND METHODS

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Thiopental, thiopental injection (500 mg, Veteran Pharmaceutical Plant, Taipei, Taiwan, R. O. C.j, 1,1 NSAIDs and lysine aspirin

. injection (eq. I g aspirin, China Chern. Co., Taiwan, R.O.C.) were llurchased from or kindly supplied by their manufacturers. All other soh·ents and chemicals were of reagent grade.

Til iopental aw!)'

Plasma samples containing 52.5 ng of phenolphthalein (internal standard) were extracted by acetonitrile and assayed by the high performance liquid-chromatography assay (3). The low detection limit was 50 ng of thiopental.

In I,i IrQ study

Ultrafiltration technique (3) was used to study plasma protein bindiltg of thiopental in the presence or absence of various NSAJDs. The effect of temperature (4, 25, 37"C) and concentration of aspirin (100 TO 1000 ~gfml) on the protein binding of thiopental were evaluated as well.

Clinical study

Eleven female patients (21-64 years) undergoing exploratory laporo- 10m y under general anesthesia for gynecological diseases were selected after written informed consent was obtained. This study was approved by the Institutional Review Board of the National Defense Medical Center.

Patients were fasting for 12 h and not taking any medication known to interfere with the plasma protein binding of thiopental. After insertion of intravenous, intra-arteria 1 catheters and the dra wi <lg of 20 ml of arterial blood, anesthesia was induced by a!, i.v. injection of'thiopental, 4 mg/kg within 30 s, The patien t 's consciousness was eval uatcd mainly by eyelash reflex test and aided by verbal stimulation. Eyelash reflex was checked every 5 s by briskly sweeping the patient's right eyel ash, Blinking of the eyes while sweeping was considered as presence of the reflex. The time from the injection of thiopentai to the initial loss and recovery of reflex was recorded. I rnmediately after recovery of the eyelash reflex, 20 ml of arterial blood was collected and lysine aspirin icontaining 500 mg of aspirin for case I and 750 mg for the other cases) was injected intravenously within 5 s, Eyelash reflex was checked again for the second loss of reflex. A blood sample was collected again at the second loss of reflex Or 90 s after the injection of aspirin in cases of no loss or reflex. Patients' trachea, were then intubated, and anesthetized for operation.

Wil h this longuud inal stud Y design every pal ient ac led as his Or her own control, not only in pharmacokineuc but also in pharmacodynamic aspects.

Bleeding t.ime was evaluated \Isi.ng the lvvmcthod .in cases 8 to ·'11 before and··;fter operation to understand the possible effect of asp; ri 11 or sal icylaies on plate k t [u nction.

Statistical analysis

Va I u ('S are expressed i" me" n ± stand a rd deviation. The in tntro experirnen ts were done in diflereiu hatches. Analyses of variance with Dunnell's test were used to comp""~ several sample; (with NSAll)s) with a common control. The paired r-rest was used in rhe comparison of thiopental concentrations before and after the administration of aspirin: Probability v "1<.1<,, less then 11.0.'i wen: accepted as signiflcanL

RESULTS

III vitro J 111l!}"

Fnur of the 1·+ NS:\JDs. naproxcn is.5 pgfml), ibupro-

fen (41.4 Ilg/ml), aspirin (243.6 Ilg/ml) and salicylic acid (80 Ilg/ml), very significa n tly decreased (P < 0.005) the protein binding of thiopental. Aspirin caused the highest extent of increase in pereen t unbound thiopental from 20,42 ± 0.48% to 26.99 ± 0..46% (Table 1)_ The increase between aspirin and salicylic acid was similar.

Temperature affected the thiopental plasma protein binding. The higher the temperature, the lower the binding. At a concentration of 10 j..Lg/ml of thiopental, the percent unbound increased significantly from 2L66 ± 1.00 (4°C), to 22.57 ± 0.41 (25°C) and 24,03 ± 0,48 (37°C) (P<O.005). When the concentration of thiopental was 20 Ilgjml, the percent unbound also significantly increased from 22.28 ± 0.20 (4cC), to 24_82 ± 0.55 (25°C) and 25.24 ± 0.34 (37°C) (P < 0.00 I). In the present study, every comparison had its own control under the same temperature. Therefore, no temperature effect could affect the comparison result itself. The extent of decrease in plasma protein binding of thiopental was aspirin concentration dependent. The higher the aspirin concentration, the higher the displacement of the extent of thiopental plasma protein binding.

In vivo study

Ten of eleven patients completed the kinetic study, and seven successfully completed the dynamic study. The

Table I

Comparisons of the percentage of unbound thiopental (I-Iean ± s.d.) in the presence or absence orNSAIDs at 25 ± I '·C in human plasma containing ).0 !1g/ml of total thiopental.

Percentage or u nbou nd Statistics
Cone. or thiopental (AxOVA &
NSAID,' Without Widl Dunnett's
NSAlDs (Ilg/ml) NSAlDs NSAIDs test)
Naproxen 55 20.2 ± 0.07 26.6+ ± 0.22 5
J buprofen 4Ll 20.2 ± 0_07 22.45 ± 0.54 S
Mefenamic acid 9.6 20.2 ± 0.07 20.59 ± 0.46 X.S
Kctoprofen 5 . .0 20.2 ± 0 . .07 2.0.52 ± .0.16 .V·.S.
Indomethacin 3.0 2.0.2 ± 0.07 19.76 ± 0.53 .,\-,S,
Fenoprolcn 35 20.2 ± 0.07 19 ... 72± 1.01 .Y.S.
Diclofcna( sod. 0.3 20.2 ± 0.07 1<1.12±.o_12 . .\'.5.
Aspirin 243.6 20.42 ± OA8 26.99 ± 0.16 S
Salicylic :tcid 80 20.42 + .0.48 26.88 ± 0.91 5
Piroxicarn 9.6 20,42 ± 0.18 1970! 0.44 . \·.S.
Sulindac 5.7 26.31 ± 0,27 25.79 ± 0.23 .\".5".
Flurbiprofen 50 rs.s: ± 0.65 18_66 ± 0,07 ,\-.S
Feubufen" 3.69 27.04 ± 0.58 26.90rO.91 .\"S.
Bcnzydarnine" 6.25 22.33 ± 0.78 21.52 ± 0.41 .\".S. a: The selecred concentrations of NSAIDs were within rheir t her a-

peutic ranges.

b: Ternpcrarure was 37 ± 0_5"C .

.1'; Suuistirally significant , P< 0.005; :\".8.: not significun t ,

The replicauon of the study was three .. -\:"'OV,\ ,H)(J Dunnett's lest WITC applied on muhiple group comparisons.

260

O. Y-P. HU ET AL.

incomplete studies in three patients were due to Inadequate sampling of blood or indeterminate changes in eyelash reflex.

Patients lost the eyelash reflex within 150 to 470 s (mean 244 s) after the injection of thiopental. Total and free concentrations of thiopental, determined in the plasma drawn at the time of recovery, were 12.25 ± 3.07 J.Lg/ml and 1.95 ± 0.94 J1g/ml, respectively (Table 2). Within 85 s after the injection of aspirin, the total concentration of thiopental fell insignificantly down to 10.31 ± 3.38 J1g/ml, whereas the free concentration of thiopental increased insignificantly to 2.32 ± 0.95 Ilg/ ml. The percent unbound thiopental increased significantly _from 16.0l ± 3.59% to 22.27 ± 3.96% (P<O.OOI, n= 10). Regardless of the rapidly decreasing blood level of thiopental, from 12.25 ± 3.07 Ilg/ml to 10.31 ± 3.38 J.Lgfml, three out of seven patients fell asleep again within 85 s (30, 85, and 77 s in cases 2, 3, and II) after the injection of aspirin. Bleeding time in patients before and' after operation showed no change.

DISCUSSION

Naproxcn, ibuprofen, fenoprofen, keioprofen, llurbiprofen and fenbufen were ~SAIDs with propionic acid derivative; naproxcn and ibuprofen had a significant effect on plasma protein binding of thiopental; whereas, with similar structures, fenbufen, fenoprofen, flurbiprofen and ketoprofen had no effect on thiopental plasma protein binding. Among six classes of NSAIDs studied, only salicylates and propionic acid derivatives could significantly reduce thiopental plasma protein binding.

Three out of seven patients fell asleep again within 85 s after the injection of aspirin. Apparently, aspirin has no anesthetic effect. It is also not likely that aspirin can interfere with the dose-response relationship, i.e. pharmacodynamics, of thiopental. The most probable mechanism of this "re-induction" effect of aspirin is kinetic displacement of the protein binding sites of thiopental. It is generally believed that the plasma free thiopent al distributes to the central nervous system

Table 2

The changes in plasma concentrations and percent unbound of thiopental afrer an i.v, injection of 500 mg (case I) or 7;,0 mg (cases 2 10 10) of aspirin during the induction of anesthesia with an i.v, bolus injection of -1 m.~.'kg of thiopental.

Thiopental cone. (l1g/mll % unbo~nd Salicvlares
Case no. Condition Free (n = 3) Total (n=3; thiopental cone. il1gjml)
before' 115±0.01 9.37 ± 0.3 i 12.29 ± 0.23
afterb 1.19 ± 0.00 6.44 ± 0.20 18.48 ± 0.65 65.38
2 before j 10 ± 0.04 11.68.i 107 H.66 ± 1.32
after 3.13 ± 0.04 16.51 ± 1.73 19.14 ± 2.31 15+.88
3 before 1.31 ± 0.01 9.46± 1.57 13.87 ±o.:n
after 1.89 ± 0.06 8.61 ± 0.36 21.94 ± 0.87 113.42 ± 9.42
4 before 1.30 ± 0.04 7.95 ± 1.20 16.59 ± 1.87
after 1.67:!: 0.02 1.30 ± 0.50 '22.91 ± 1.27 I 10.66 ± I 1.88
5 before I .... , ± 0.05 9.89 ± 2.16 15.26 ± 3.06
after 1.53 ± 0.02 797",031 19.22~O73 130.22 ± 13.6ll
6 before 1.49 ± 0.01 12.46 ± 051 11.98±0:'4
. after +:65± 0.02 8.57± 9.61 19.47 ± 1025 104.21 ±20.26
7 before 210 ± 0.02 1:l.56 ± 1..)6 13.67±098
after 1.80 ±0.06 8.40:c055 '2163 ± 2.27 j 23.29 ± 10.07
8 before 3.33 ± 0.07 lb .. 12 ± 0.3/ 2067±0.71
aftn ,Uil ±0.21 13.ni 1.26 26.57.~ 3.77 68.1 i ± 2.73
9 bcfor« 3.70 ± 0.10 IG.2lJ ± 1.11) 2280 ±. 1.65
after 3.76 ± 0.18 12.0:'>;!: O.4~ 31.24 ± 0.6:'> 98.22±5.17
10 before 2.:'1 ± 0.07 13.73:,: 023 18.30±0.81
after 2.99±0.13 13.55 ± O.H nl2± 1,48 71.81±6.i5
Mean ± s.d. before 1.95 ± 094 122:: ± 3.0i 16.01 ±. 3.:'>9
~fttr 1.32 ±. 0.95'" 10.31 :!: .nS'·· 22.27 ± 3.96· 108.3~ ± 27.31' a: Before II. r injecuon or aspirin. Eadl plasmn -amp!e was divided into th r ee pOri in'!; after v irhdrawing , rhcn a Il"ly,cd "·par;",,lv. b: Aftn ,he injcctio» of aspirin.

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NSt\lDS DECREASE PROTEIN·BOUND THIOPENTAL

261

and prociuces the anesthetic effect. Presurna bly, a.bou t 30% Jess of an amount (estimated by 1 - (16.01! 22.27) of thiopental is thus needed for the induction of anesthesia providing the patient is taking aspirin In the concentration of 108.32 ± 27.31 pg/rnl before anesthesia, as seen in our study (Table 2). Whether the dose of thiopental should be adjusted 'according to the dose of aspirin or other NSAIDs needs further evaluation .

Thiopental plasma protein binding decreased highly significantly after the injection of aspirin in all patients, but resulted in three out of seven patients falling asleep again. The discrepancy between the kinetic and dynamic effects might be caused by delayed injection of aspirin in the rapid distribution phase of plasma thiopental.

It is well known that for a poorly extracted drug, an increase in the unbound fraction in the blood at a steady state can markedly alTecr systemic clearance and total drug levels but has little effect on free drug concentration (11)- However, this rule will not apply to prediction of the effect of thiopental, since thiopental usually has its effect on the brain at the peak concentration or in the rapid distribution phase. The increase in the unbound fraction in blood may result in an increase in partition of the drug in the rargc; organ, an increase in active moiety to bind with the receptor site and the subsequent reinduction of sleepiness.

In summary, among 6 classes of 14 NSAIDs, naproxcn, ibuprofen, salicylic acid and aspirin significantly increased the unbound fraction of thiopental in plasma. In an aspirin study, this phenomenon was concentration-dependent. In addition, the unbound fraction of thiopental was positively dependent on (he temperature. In clinical study, aspirin resulted in a significant displacement of protein-bound thiopental, which may contribute to the patients' falling asleep again after recovery from thinpental-ind uccd anesthesia. Although the effect of chronic usc of NSAIDs before anesthesia is uncertain, studies should be carried out to findvout if naproxen, ibuprofen' and aspirin

influence the depth of anesthesia, time of recoverv, and duration of action of thiopental,

ACKNOWLEDGEMENT

This work was partially supported by the National Science Council (NSC78-0412-BOI6-63).

REFERENCES

I, Sellers EM. Plasma protein displacement interactions are rarely of clinical significance. Pharmacology 1979: 18: 225-22/.

2. /l1o£lnay J C, D'Arcy P r. Protein binding displacement interactions and their clinical importance. Drugs 1983: 25: 495-513.

3. Ho S T, Hu 0 Y P_ The mechanism of reducing thiopentone dose in elder! y patients undergoing surgery. Proc Nail Sci Counc ROC 1988: 12: 1-8.

4, Christcnsen ] H, Anderson F,JansenJ A. Influence of age and sex on tile pharmacokinetics of thiopentone. Br ] Anaesth 1981: 53: ]]89-1194,

5. Christensen J H, Anderson F, Jans~n J A. Pharmacokinetics and pharmacodynamics of thiopentone, a comparison between young and elderly patients. Anaesthesia t 982: 37: 393-404.

6. Jung D J, Mayersohn M, Perrier D 0, Calkins j, Saunder R, Thiopental disposition in lean and obese patients undergoing surgery. A ncsthlJio/v,V' 1982: 56: 269-274. ,

7. Ghoneirn M M, Pandya H B, Kelley S E, Fischer LJ. Corry R J Binding of thiopental to plasma proteins: effects on distribution in the brain and heart, Anesthesiology 1976: 45: 635-£39_

8. Csogor S J, Kcrez SF Enhancement of thiopentone anaesthesia b)' sulphalurazole. B, .7 Anaesth 1970: 42: 938-990.

9, Halliday NJ, DundeeJ W, Loughran P G, Harper K \\'. Age and plasma proteins influence the action of midazolarn. AneslheJi%g)' 1934: 61: 1\357

10, Chaplin M D, Roszkowski, Richards R K. Displacement of thiopental from plasma proteins by nonsteroidal anri-inflammawry agents. PTOC Soc Exp B,o/ Med 1973: 143: 667-671.

II. Wilkinson G R, Shand D G. A physiological approach to hepatic drug clearance. Cli» Pharmacol Til" 1975: 18: 377-390.

Address:

O/im Ioa-Pu'Hu, Phf), School or Pharmacy

National Defense t\lrdical Center P.O. Box 900-18·5011

Taipei

Taiwan

R.O.C

INSTlTlJT-:] r.;::/(ICHlO DEl SE::URO SOC!

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