ADONIS01407783910003C)K

J. vet. Ph;irm;icol. Therap. 14, 3 17-325, 1991.

The pharmacokinetics and locomotor activity of alfentanil in the horse P. J . PASCOE, W. D. BLACK,* J. M. C L A X T O N * 8c R. E. SANSOM Departments of Clinical Studies and *Biomedical Sciences, Ontario Veterinary College, University ofcuelph, Guelph, Ontario, Canada Pascoe, P.J., Black, W.D., Claxton, J.M., Sansom. R.E. T h e pharmacokinetics and locomotor activity of alfentanil in the h0rse.J. vet. Phurmucol. Therap. 14, 3 17-325. T h e pharmacokinetics of alfentanil were investigated in the horse. Four doses of alfentanil (4, 10, 20 and 40 pg/kg) were given to four horses at different times and their locomotor activity monitored. Doses of 20 and 40 pg/kg produced a significant increase in locomotor activity. T h e plasma concentrations of alfentanil were measured in six standing horses and the pharmacokinetics calculated. It was found that the decay curves were best described by a biexponential equation. T h e elimination half-life (@ was 2 1.65 f 3.99 min and the clearance (CI) was 14.1 zk 0.7 ml/kg/min. T h e same horses were anaesthetized with xylazine-ketamine and maintained with halothane in oxygen for the first experiment and isoflurane in oxygen for the second experiment. T h e pharmacokinetics were again calculated from measured plasma alfentanil concentrations. There were significant differences between the kinetics in the conscious and the anaesthetized animals but there were no significant differences in alfentanil kinetics between the two anaesthetic agents. T h e t,/,p for alfentanil under halothane and isoflurane anaesthesia were 55.95 f 20.77 and 68.03 k 23.22 min, respectively, and the C1 values were 14 k 1.7 and 13.6 f 1.32 ml/kg/min. P . J . Pascoe, Department of Surgery, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. .

INTRODUCTION Opioids have been used for many years in equine practice. They have been shown to be of particular benefit when used as analgesics in equine colic (e.g. meperidine, morphine, butorphanol) (Hackett, 1976; Muir & Robertson, 1985). Opioids have been used in conjunction with sedatives to produce more effective chemical restraint (e.g. xylazinemorphine, xylazine-butorphanol) (Muir et al., 1979; Kalpravidh et al., 1984). They have also been used to produce a neuroleptanalgesic state for surgical procedures in the recumbent horse (e.g. etorphine-acepromazine) (Dobbs

& Ling, 1972). One effect of the potent opioids with preceptor activity is to produce increased locomotor activity which some people have attempted to use to influence horse races (Tobin et al., 1979). T h e doseresponse curves for locomotor activity were defined by Tobin et al. (1979). They showed that the p-opioid agonists produced increasing locomotor stimulation up to the point where the agent began producing narcosis causing the animal to become recumbent. Alfentanil is a member of the 4-anilinopiperidine series of which fentanyl is the prototype. In comparison to fentanyl, alfentanil is less potent, has a higher degree of

317

318 P . J. Pascoe et al: protein binding, lower lipid solubility and is less ionized at physiological pH. These physicochemical properties help to determine its rapid onset of action (89% of the drug is in the unionized form at pH 7.4 so it readily crosses lipid membranes) and its smaller volume of distribution compared with fentanyl (higher protein binding and lower lipid solubility) (Cookson et al., 1983). Alfentanil was developed specifically to fill the need for a shortacting opioid in human anaesthesia (Mather, 1983). T h e potential advantages of alfentanil over fentanyl and many other opioids are its rapid onset of action and its short duration of effect. This would permit its use as an analgesic with short-acting sedatives and anaesthetics without the danger of excitation (Dyson el al., 1987) and respiratory depression following the procedure. This present investigation was undertaken to determine the pharmacokinetic parameters of alfentanil in the horse. METHODS Six Standardbred horses, determined to be healthy by physical examination, a complete blood count and a biochemical profile, were used in the study. The mean body weight was 422 kg with a range of 390-466 kg. There were two geldings and four mares ranging in age from 3 to 10 years. The experiment was divided into three parts.

Part I The locomotor activity of the horses in response to alfentanil was quantified using the method of Tobin et al. (1979). The horses were placed in an 11.6-m2 isolation stall with solid concrete block walls and two observation windows at least 12 h before the experiment. On the morning of the experiment a 14-gauge 13-cm catheter was placed in one jugular vein and the left forefoot was marked with white zinc tape. The horse was then watched for 20 min and the number of times it lifted its left forefoot recorded for each 2-min period. After this 20-min control period the horses were given saline (in a volume equivalent to

40-~g/kgalfentanil) or alfentanil at a dose of 4, 10, 20 or 40 Fg/kg intravenously over 45 s. A minimum of 1 week was allowed between treatments. The number of steps per 2-min period was recorded for 60 min after drug administration. The order in which each horse received the drug was randomized; however, at the end of the experiment each animai had received all treatments. Two of the horses were very excitable and demonstrated markedly increased activity during the control periods and were eliminated from the data analysis. The data were analysed using an analysis of variance for each time period and least significant differences calculated to determine which doses produced significant differences from the saline control. Par1 I I The horses were restrained in a standing stock and a 14-gauge, 13-cm catheter was inserted in each jugular vein. A short piece of narrow bore tubing was attached to one catheter to assist in drawing venous samples (the internal volume of the catheter and the tubing was 1 mi). Alfentanil (40 pg/kg) was injected into the horse over a 455 period. Time zero was considered as the end of the injection period and blood samples were taken before the injection and at 1 , 2, 3, 4, 5, 10, 20, 40, 60 and 90 rnin after the alfentanil was given. At least 10 ml of blood were withdrawn through the catheter and tcbing before each sample was taken. The samples were collected into EDTA tubes, the blood was centrifuged for 15 niin at 1250 g,and the plasma was removed and stored at -20°C until assayed. Analysis of plasma for alfentanil was carried out using a commercial radio-immunoassay kit (Alfentanil RIA kit, Intermedico, Willowdale, Ontario, Canada) (Michiels et al., 1983). All samples collected during the first 20-min period were diluted 1:lO prior to analysis, whereas the others were analysed without dilution or concentration. Fentanyl is metabolized to produce a different first metabolite in the horse when compared to people (Frincke & Henderson, 1980) and it is likely that this metabolite is also detected using the radio-immunoassay specific for fentanyl.

Aljknlanil in the horse

Since alfentanil has a similar structure it was assumed that similar cross-reactivity existed for the parent compound and a major metabolite SO an analysis was carried out using a subset of samplesto determine whether such a metabolite wiould interfere with this assay. This was ddne by carrying out a comparison of estiacted and non-extracted sera from the sawe 12 samples. T h e method used was the onqdescribed in the assay kit for the extraction of 'alfintanil from samples with low concenttations of alfentanil. T h e method was modified ,so that 'the final dilution of the sample was the ,same as the original. T h e samples were chosen with a wide range of measured plasma alfentanil levels and there were no statistical differences between the extracted and non-extracted sera using a paired f-test (Table I). This implies that there is no polar metabolite interfering with this assay and hence the measured values will be referred to as alfentanil concentrations instead of alfentanil equivalents (Soma el al., 1984; Carr, 1988; Delbeke & Debackere, 1989). Pharmacokinetic parameters (Table I) were determined on alfentanil plasma concentrations using a two-compartment open model according to methods previously described (Gibaldi & Perrier, 1982). T h e data were

-

T A B L E 1. Alfentanil concentrations measured on a subset of 12 plasma samples. T h e samples were split and the assay was carried out o n plasma (nonextracted) and o n plasma following a n extraction process designed to concentrate the lipid-soluble alfentanil (extracted) Alfentanil concentration (ngW Sample time (min from injection) Non-extracted 4 5 5 5 10 60 60 90 90 90 120

,

150.0 100.0 1 16.0 84.0 58.0 11.8 9.1 7.6 10.8 11.8 4.1

Extracted 150.8 100.0 112.8 112.8 58.0 18.2 5.8 8.0 10.8 11.0 3.5

3 19

plotted in a semi-log fashion and the components of the curve selected from the linear portions of the curve (Gibaldi & Perrier, 1982). T h e pharmacokinetic parameters of the treatment groups were compared using one-way analysis of variance, and F values. Least significant difference parameters were calculated at the 95% confidence level.

PAt III Alfentanil pharmacokinetic parameters were also determined in the anaesthetized horse. T h e same six horses as before were used and a minimum .of 2 weeks was allowed between experiments. Each horse was first anaesthetized with intravenous xylazine (1.1 mg/kg) and ketamine (2.2 mglkg), intubated and connected to a circle system which delivered oxygen and either halothane (the first experiment) or isoflurane (the second experiment) to the animal. Intermittent positive pressure ventilation was started, and eucapnia was maintained (PaCo2 = 3 5 4 5 mmHg). Three jugular catheters were placed, and one catheter was inserted into the facial artery for direct systemic blood pressure monitoring. An intravenous infusion of dobutamine was administered (2 pg/kg/min during halothane and 1 pg/kg/min during isoflurane anaesthesia) to maintain a mean blood pressure of 87 & 15 and 75 f 10 mmHg for halothane and isoflurane, respectively. Oxygen flow was set at 10 Vmin, and the vaporizer setting to 1.752% for halothane and 2 4 . 2 5 % for isoflurane. The horses were maintained in a light plane of anaesthesia prior to the injection of the alfentanil. T h e anaesthetic depth was confirmed by the presence of a brisk palpebral reflex, occasionally nystagmus and spontaneous movement in some animals. If movement occurred the concentration of the inhalant was increased and maintained at the new concentration. Once blood pressure and end tidal concentrations were stable for 20 min, alfentanil was injected intravenously at 40 pg/kg over 45 s. Blood was taken at 1, 2, 3, 4, 5, 10, 20, 40, 60 and 90 min after the injection. T h e anaesthetic was then turned off and the horse moved to a recovery stall. Blood samples, alfentanil analysis as well as pharmacokinetic determinations were handled as described above.

320 P. J. Pmcoe et al. RESULTS Part I

Following injection of the higher doses of alfentanil (20 and 40 pg/kg) the horses initially became quite rigid then briefly ataxic. One horse fell about 1 min after the injection; however, it stood up 3.3 min later. Next the animals started walking around the stall and would snatch at hay and chew it but did not appear to swallow. As locomotor activity decreased they would eat hay while continuing to move around the stall. Some horses exhibited stereotypic behaviour such as head tossing and shaking. Examination of the responses of the horses to alfentanil as measured by the number of steps per 2-min period revealed a great deal of variability. Indeed, two of the six horses studied were omitted from the data analysis. These animals were quite nervous and responded to virtually all handling and noise

by greatly increased locomotor activity (i.e. pre-saline counts for one animal ranged from 51 to 65 per 2-min period and this compares with ranges of 0-8 per 2-min period for the results presented in Fig. 1). An increase in the number of steps was observed with these two horses only at the highest alfentanil dose (40 pgkg). This response lasted for the whole 60-min observation period (after injection) rather than the 20-25 min seen in the other animals. The data in Fig. 1 reveal a dose-response relationship between the steps per 2-min response and the dose of alfentanil. The shaded area indicates the range of responses to saline and the control (20 min preinjection) responses. No response was seen to the low dosage (4 pg/kg), and the 10-pg/kg dosage produced maximum activity at 4 min (28.7 k 12.7) after injection, but it was not significantly different from the saline control. Maximum responses to alfentanil (20 pg/kg) occurred 2 and 4 min after administration.

1

I

1 0

20

Time (min)

FIG. 1 . Step counts per 2-min period for four horses given either saline or alfenranil at 4 pg/kg (--), 10 pgkg (-), 20 CIglkg (- -) or 40 pgkg (-) intravenously. The bars are SEM and the asterisks indicate significant differences from the saline control (P < 0.05). The shaded area indicates the average range of values for the saline controls and the pre-treatment controls.

Alfentanil in the horse 321

The responses to this dosage were significant 2-8 min after drug administration. T h e 40-pg/kg alfentanil dosage produced a peak response 8 rnin after administration (70.6 k 3.612 rnin), and the responses were significantly different from saline control from 4 to 22 min (19.8 f 5.5 steps/:! min) after administration. At this dosage some skeletal muscle rigidity was observed immediately after injection accounting for a somewhat reduced step count immediately after drug administration.

Part II

The lines described by the pharmacokinetic parameters (Table I) for a two-compartment model closely fit the mean plasma alfentanil concentration data after intravenous administration (Fig. 2) (r = 0.9552 f 0.0127 for the a curve and r = 0.9926 f O.OG26 for the 6 curve). T h e rate constant of disappearance of drug from the plasma (6)was 0.032 min-l and the 6 intercept was 65.2 ng/ml giving a harmonic mean for the elimination half-life of 21.65 rnin (Lam et al., 1985). T h e volume of the central compartment (Vc) was 187.7 f 22.0 ml/kg and the volumes of distribution, VCicdrea)and Vd(rr) were 445 f 2 1.4 and 343.2 f 52.7 ml/kg, respectively. Average total body clearance (CI)was 14.1 f 0.7 ml/kg/min.

I

I

I

I

20

40

60

80

I 100

Time ( m i d

Part III

FIG. 2. Plasma elimination curves for alfentanil concentrations in six horses when conscious ( 0 )and when anaesthetized with halothane ( A ) or isoflurane (m). The slope of the initial elimination (a)is more rapid but the slope of the secondary elimination (fl)is slower in the anaesthetized animals. There-is no statistical difference between the curves for the two anaesthetic agents.

T h e effects of halothane and isoflurane anaesthesia on alfentanil pharmacokinetics are presented in Table I1 and Fig. 2 ( r = 0.9855 k 0.0048 and r = 0.9729 f 0.0104 for the a curves and r = 0.9792 k 0.0105 and r = 0.9723 k 0.0185 for the 6 curves for halothane and isoflurane, respectively). N o statistical differences were detected between the two inhalants in their effects on the kinetic parameters. Numerous differences were found between the results from the conscious and anaesthetized animals. The rate constant of disappearance of drug from the plasma (6) was reduced as well as the b intercept on theyaxis. Anaesthesia also increased the distribution microconstant k12 (central to peripheral

compartments) and decreased movement in the other direction (k21). T h e volume of distribution of alfentanil, as expressed by the Vdcdred) and Vd(rr)were both increased dramatically by anaesthesia. Also the volume of the peripheral compartment (V,), defined with respect to the drug concentration in the plasma of the central compartment (VJ, was increased by approximately fivefold in the anaesthetized horses. Anaesthesia also decreased V , but this only reached statistical significance during isoflurane anaesthesia. T h e half-lives of distribution and elimination appeared to be decreased and increased,

322 P. J. Pascoe et al. T A B L E I I. Pharmacokinetic parameters for alfentanil following intravenous alfentanil (40 pg/kg) in the conscious and anaesthetized horse (n = 6). The results are expressed as the mean f SEM. Statistically significant differences between the three treatments are indicated where a is different from ( P C 0.05)

Parameter

Conscious 174.5" f 0.22" f 65.2" f 0.032" f 423.5 f 242.7 k 187.7" f 3.11 f 21.65 f 0.085" f 0.086" f 0.084 f 2.87 f 445.7" f 343.2" f 156.5" f .14.1 f

47.5 0.04 5.0 0.002 10.3 47.4 22.0 1.32 3.99 0.056 0.011 0.015 0.13 21.4 52.7 63.2 0.7

Halothane 245.4"h f 0.40h & 26.7h f 0.012h f 421.8 f 272.0 f 152.Wh f 1.72 f 55.95 f 0.264h k 0.055h f 0.097 f 3.15 f 1197.5h f 921.3h k 769.4h k 14.0 f

Isoflurane

348.P f 0.36"' f 20.gh f 2.9 . 0.002 0.010h f 421.2 f 10.4 369.6 rf: 21.6 115.3' rf: 12.5 1.94 k 0.83 68.03 f 20.77 0.220h f 0.057 0.030" f 0.014 0.1 18 f 0.014 3.22 f 0.51 137.5 1371.7" f 954.3h rt 114.8 839.0" f 258.1 13.6 f 1.7 21.6

0.07

'

44 0.03 ' 2.0 ' . 0.001 8.0 45.3 12.1 0.37 23.22 0.025 0.004 0.009 0.48 144.4 I 1 1.8 256.5 1.32

*Harmonic mean 2 pseudo-standard deviation.

respectively, by anaesthesia. This is a reflection of the significant increase in the rate constant of distribution (a)and decrease in the rate constant of disappearance from the plasma (p). The rates of clearance of alfentanil in the anaesthetized animals, 14.00 2 1.64 and 13.57 f 1.32 ml/kg/min, were not statistically different from the clearance in conscious animals.

DISCUSSION Administration of alfentanil to horses at doses of 4 4 0 pg/kg produced profound behavioural changes similar to those reported by Tobin et al. (1979) for fentanyl. At 40-pg/kg fentanyl, Tobin et al. reported that all horses fell during.the first few minutes after administration. On the premise that alfentanil has one quarter the potency of fentanyl (Cookson et al., 1983) a dose of 160 pg/kg was given to one horse in a pilot study. T h e horse feJ1, showing signs of muscular rigidity and hyper-

aesthesia typical of high-dose opioids in this species (Tobin et al., 1979). In this study we did not attempt to produce a maximal alfentanil response, and we did not wish to have the horses fall. One horse did, however, become recumbent even at the 40-pg/kg dose, and it was thought that further increases would be a hazard to the animals. It was also evident, in this study, that there was considerable individual variability in the locomotor response. The two horses which were removed from the data analysis did show a response to the alfentanil but had resting step counts which were totally abnormal. Although the horses were placed in the stalls at least 12 h ahead of the study period these two. animals were clearly agitated. T h e stalls used for the study were part of the veterinary teaching hospital, and it was impossible to remove all extraneous noise and movement from the area. Although the conditions were controlled as much as possible, this limitation may account for the greater individual variability in this study in comparison with that reported by Tobin et al. (1979).

Alfenfanil in the horse 323

Figure 1 shows the dose-response relationship (step response vs. alfentanil dosage) observed in the horses (n = 4). At the lower doses (4 and 10 pg/kg) no significant response was noted. At the two higher doses (20 and 40 pg/kg) the locomotor response was significant, but there was a difference in the time taken to reach a maximum step count (2 vs. 8 min after drug administration). This is a reflection of the tendency for the horse to show muscular rigidity at the onset of action of the drug. At the higher dose this rigidity lasted longer and delayed the onset of rapid stall walking. T h e radio-immunoassay used in this experiment was designed for use on human plasma. T h e expectation for this assay is that the metabolites would not interfere with the test. In previous studies it has been shown that fentanyl is metabolized to a polar carboxy compound in the horse and that this metabolite is close enough to the original molecule that it cauld interfere with the assay. We have established, by analysing the extracted vs. non-extracted plasma that a polar metabolite is unlikely to be present in significant quantities. However, this does not establish how the alfentanil is metabolized in the horse and it is possible that a non-polar metabolite could be present which would show up in both the extracted and non-extracted samples. Although the above evidence is fairly sound it is indirect and further analysis will have to be carried out before this question can be answered. The model used to describe alfentanil pharmacokinetics in this publication is the two-compartment open model (Gibaldi & Perrier, 1982). Studies in man suggest that either two- or tht-ee-compartment models may be appropriate. Maitre el al. (1987) compared two- and three-compartment models and found, somewhat predictably, that the threecompartment model was mathematically a better predictor of alfentanil concentrations when a population of humans was studied. Other studies on alfentanil pharmacokinetics in people have used a two-compartment model (Meistelman ef al., 1987; Persson el al., 1988; Van Beem et al., 1989). Both models appear to be appropriate considering the inherent variability in individual patient plasma concentrations (Bovill et al., 1982;

Camu e f al., 1982; Fragen e f al., 1983; Goresky et al., 1987). In the study reported here, plasma concentrations were measured over a 90-min time period. A two-compartment open model appeared to fit the data well (Fig. 2). Had the samples k e n collected for a longer time (e.g. for 360 rnin as in some human studies) the need for a third compartment might have been evident. The drug appears to have an even more rapid clearance in the horse compared with man (average clearance from five studies in man = 5.57 mVkg/min when V, is corrected for body weight) (Maitre et al., 1987). T h e elimination half-life was also considerably shorter (95 min in adult healthy volunteers vs. 21.65 min in this study) (Bower & Hull, 1982). T h e Vd(ss) in the conscious horse (343.2 ml/kg) was similar to the v d ( s ) reported in people (387.3 and 495.7 mVkg calculated from two human studies) (Bower & Hull, 1982). Anaesthesia with halothane had a great impact on the pharmacokinetics of alfentanil. T h e rate constant of distribution, a, after intravenous administration was approximately twice as great in the anaesthetized animals. This is further reflected in the transfer microconstants; k12 (central to peripheral) which was increased, and kP1 (peripheral to central) which was decreased (Table I), both suggestive of a movement of drug from the central to the peripheral compartment. This change in the distribution kinetics of drug may reflect an expansion of the peripheral vascular beds in the anaesthetized hypotensive horse, compared with the conscious, excited animal. Despite our efforts to maintain normal blood pressure and cardiac output a significant fall normally occurs in the anaesthetized, ventilated horse (Hodgson et al., 1977; Steffey et al., 1987). Greater access of the drug to peripheral vascular beds and to sites of storage in the peripheral compartment would be reflected in expansion of the Vd(area) and vd(ss) parameters. In fact an increase of two- to threefold in these parameters is evident in our data (Table I) for the anaesthetized horses. In addition, expansion of the peripheral compartment (V,) is in the order of five- to sixfold. T h e significant decrease in the rate constant of disappearance of drug from plasma (fi; Table I and Fig. 2) in

324 P. J. Puscoe et al. anaesthetized horses does not appear to be caused by a decrease in the rate of elimination of d r u g from the central compartment as might be expected if the anaesthetic were decreasing the rate of drug metabolism in the liver. It may, however, reflect the combined effects of a larger proportion of the drug dosage being sequestered in storage sites in the peripheral compartment as well as the slow release from this area, as reflected in the significantly reduced kpl parameter. T h e lack of differences between the anaesthetics in the pharmacokinetics of alfentanil in the horse may indicate that the changes we report are due to anaesthesia itself, ratherthan the specific agent used. An attempt was made to maintain a stable light plane of anaesthesia with a constant input into the circuit. T h e vaporizer settings used in this study would produce an anaesthetic level of the order of 1.5 MAC for both agents but it is recognized that there would be some individual variation due to b o d y size, tissue solubility and individual anaesthetic requirements. In ocher experiments which have compared the effects of different inhalant agents the comparison is made on the basis of a constant end-tidal level of the inhalant. By doing this one can compare one study with another but the use of statistically derived MAC values does not account for the individual variation associated with the animals involved in each experiment. In the current experiment, an attempt was made to combine a method which would give a relatively constant input into the animal (high-flow oxygen with a narrow range of settings on the vaporizer), while still allowing for some individual variation (using clinical signs of anaesthesia). In a pilot study it was found that under the described anaesthetic conditions, blood pressure could not be maintained without dobutamine. Indeed one horse went into cardiac arrest following alfentanil administration. This animal was in a very light plane of anaesthesia but its mean blood pressure would not rise above 40-50 mmHg. It became profoundly hypotensive after the alfentanil and went into cardiac arrest. It was successfully resuscitated and behaved normally after recovery. T h e different doses of dobutamine under halothane and isoflurane were based on initial studies which suggested that horses

under isoflurane showed a greater rise in heart rate with the 2-~g/kg/mindose. While it was evident that the higher dose of dobutamine produced a better blood-pressure response and circulatory status, the pharmacokinetic data of both anaesthetized groups were essentially similar. In retrospect it may have been better to have used a variable dose of dobutamine to achieve a narrower range of blood-pressure values. It is therefore possible that the pharmacokinetics of alfentanil between the halothane- and isofluraneanaesthetized horses are not the same and that the differences in cardiovascular status between the two groups may have masked this difference. In conclusion, alfentanil appears to be similar to other preceptor agonists in producing excitatory effects in horses at high doses. Increasing doses of alfentanil caused increases in steps per 2-min period, but at the 40-pg/kg dose a period of rigidity occurred before the increase in locomotor activity. A two-compartment open model fits the plasma concentration-time data. Comparison of the pharmacokinetics of the alfentanil data indicates that anaesthesia caused an expansion of the volume of distribution while slowing the rate of disappearance of the drug from the blood after equilibration.

ACKNOWLEDGMENTS T h e authors are grateful to the Canadian Veterinary Research Trust Fund and Janssen Pharmaceutica for funding this project.

REFERENCES Bovill, J.G., Sebel, P.S., Blackburn, C.L. & Heykants, J. (1982) The pharmacokinetics of Alfentanil (R39209): A new opioid analgesic. Anesthesiolog?, 57, 43-43.

Bower, S. & Hull, C.J. (1982) The comparative pharmacokinetics of fentanyl and alfentanil. En'tkh

J O U Tof~ A ~ ~ L h o s i 54, a , 871-877.

Carr, D.B. (1988) Opioids. IntemfiunufAnesthesiology Clinics, 26, 273-287. Camu, F., Gepts, E., Rucquoi, M. & Heykants, J . (1982) Pharmacokinetics of alfentanil in man. Anesrhesia and Analgesia, 61, 657-66 1.

Alfentanil in the horse Cookson, R.F., Niemegeers, C.J.E. & Vanden Bussche, G. (1983) The development of alfentamil. British Journal of Anaesfhesia, 55, 147% 155s. Delbeke, F.T. & Debackere, M. (1989) Elisa detection of fentanyl in horse urine and plasma. Journal of VeferinatyPharmqcology and Therapeufics, 12, 1 4 .

Dobbs, H.E. & Ling, C.M. (1972) The use of etorphine/acepromazine in the horse and donkey. Vefm’naty Record, 91, 40-41. Dyson, D.H., Pascoe, P.J., Viel, L., Staempfli, H., Baird, J.D. & Stevenson, E. (1987) Comparison of detomidine hydrochloride, xylazine, and xylazine plus morphine in horses: a double blind study. Equine Veferinaty Science, 7, 211-216. Fragen, R.J., Boo!, L.H.D.J., Braak, G.J.J., Vree, T.B., Heykants, J. & Crul. J.F. (1983) Pharmacokinetics of the infusion of alfentanil in man. British JOUnial Of A w s U U S ~ ~55, , 1077-1081. Frincke, J.M. & Henderson, G.L. (1980) The major metabolite of fentanyl in the horse. Drug Metabolism and Disposifion, 8, 425427. Gibaldi, M. & Perrier, D. (1982) PhannacoCineticr, 2nd edn. Marcel Dekker. Inc., New York. Goresky, G.V., Koren, G., Sabourin. M.A., Sale, J.P. & Strunin, L. (1987) The pharmacokinetics of alfentanil in children. Anesthesiology,67, 654-659. Hackett, R.P. (1976) Analgesics for horses. Veterinaty Anesthesia, 3, 1 1 6 1 19. Hodgson, D.S., Steffey, E.P., Grandy, J.L., Woliner, M.J. (1986) Effects of spontaneous, assisted and controlled ventilatory modes in halothaneanesthetized geldings. AmericanJournal of Veterinary Research, 47, 992-996. Kalpravidh, M.. Lumb, W.V., Wright, M. & Heath, R.B. (1984) Effects of butorphanol, flunixin, levorphanol. morphine and xylazine in ponies. American Journal of Velerinaty Research; 45, 217223. Lam, F.C., Hung, C.T. & Perrier, D.G. (1985) Estimation of variance for harmonic mean halflives. Journal of Pharmaceulual Scknce, 74, 229231. Maitre, P.O., Vozeh, S., Heykants, J., Thomson, D.A. & Stanski, D.R. (1987) Population pharma-

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cokinetics of alfentanil: T h e average dose-plasma concentration relationship and interindividual variability in patients. Anesfheswlogy, 66, 3-12. Mather, L.E. (1983) Clinical pharmacology of fentanyl and its newer derivatives. Clinical Phannacokinefus, 8, 422446. Meistelman, C., Saint-Maurice, C., Lepaul, M., Levron, J.C., Loose, J.P. & MacGee, K. (1987) A comparison of alfentanil pharmacokinetics in children and adults. Anesthesiology, 66, 13-16. Michiels, M., Hendriks, R. & Heykants, J. (1983) Radioimmunoassay of the new opiate analgesics alfentanil and sufentanil. Preliminary pharmacokinetic profile in man. Journal of Pharmocy and Pharmacology, 35, 86-93. Muir, W.W., Skarda, R.T. & Sheehan, W.C. (1979) Hemodynamic and respiratory effects of xylazine-morphine sulfate in horses. American J o u m l of Vefm’taaty Research, 40, 1417-1420. Muir, W.W. & Robertson, J.T. (1985) Visceral analgesia: effects of xylazine, butorphanol, meperidine and pentazocine in horses. American J o u m l of Veterinary Research, 46, 2081-2084. Persson, M.P.,Nilsson, A. & Hartvig, P. (1988) Pharmacokinetics of alfentanil in total i.v. anaesthesia. BrifishJournal of Anaesfhesia,60. 755-761. Soma, L.R., Korber, K., Anderson, T. & Hopkins, J. (1984) Effects of furosemide on the plasma and urinary concentrations and the excretion of fentanyl: model for the study of drug interaction in the horse. American Journal of Veterinary Research, 45, 1743-1749. Steffey, E.P.. Dunlop, C.1., Farver, T.B., Woliner, M.J. & Shultz, L.J. (1987) Cardiovascular and respiratory measurements in awake and isoflurane-anesthetized horses. Amnican Journal of Veferinaty Research, 48, 7-12. Tobin, T., Combie, J., Shults, T. & Dougherty, J. (1979) T h e pharmacology of narcotic analgesics in the horse. 111. Characteristics of the locomotor effects of fentanyl and apomorphine. J o u m l of Equine Medicine and Surgety, 3, 284-288. Van Beem, H., Van Peer, A., Gasparini, R. el a/. (1989) Pharmacokinetics of alfentanil during and, after a fixed rate infusion. B r i h h Journal of Anaesthesia, 62, 610-615.

The pharmacokinetics and locomotor activity of alfentanil in the horse.

The pharmacokinetics of alfentanil were investigated in the horse. Four doses of alfentanil (4, 10, 20 and 40 micrograms/kg) were given to four horses...
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