Original Researcll ArtIcle
Oin, Pha. maookinel. 19
(~):
416-422,1990
0312-5963/90/00 10-0416/S03.SOro
CAd;! lnln'Mlion31 Limned All ri&hIS reserved. CPKOO3375
Influence of Age on the Pharmacokinetics of Alfentani! Gender Dependence
Harry 1.M. Lemmens. Anton G.L. BUrin, Pim J. Hennis, Marina P.P.R. Gladines and James G. Bovill Depal1ment of An esthesiology, University Hospital Leiden, Leiden. The Netherlands
Studies on the effects of age on the pharmacokinetics of alfentanil are inconclusive. A possible factor in explaining the differences be tween various studies could be the effect of gcnder. The authors studied the effecls of age on the pharmacokinetics of alfentanil in female (n ., 2 1) and male (n - 15) patients undergoing lower abdominal surgery under nitrous oxide alfcntani! anaesthesia. There was a Significant negative correlation (r ,. -0.79, p < 0.00]) between plasma alfentanil clearance (Cl) and age in women «SOy, median Cl 24.84 L/ h: >SOy. median CL 14.S2 L/h). but not in men «SOy. med ian CL 19.44 l / h: >SOy, median CL 16.2 L/h). The conclusion is drawn that the effects of age on the pharmacokinetics of alfentani] are gender-dependenl.
Alfentanil is a synthetic opioid whose action is of rapid onset and short duration. It has a small volume of distribution at steady-state and a short elimination half-life (Bovill et at 1982), which make it more suitable than other opioids for use by continuous infusion. A variable rate infusion of alfentanil, titrated to responses of the patient during surgery, resu lts in greater haemodynamic stability and a more rapid recovery than achieved with intermittent bolus admin istration (Ausems et al. 1988). These advantages of conti nuous infusion are particularly important in elderly patients, who are more prone than the young to complications during and after anaesthesia and surgery. The pharmacokinetics of alfen tanil in elderly patients have been studied and compared with those in young patients by Helmers et al. ( 984), 1 Maitre et al. (1987) and Scott and Stanski (1987).
A dC(;reased plasma clearance was found by Helmers et a1. (1984) but not by Scott and Stanski (1987), possibly due to differences in the populations studied; the former ~tudied patients of both sexes, whereas the latter studied only men. Other factors that may have contributed to the differences could be the type of surgery and concomitantly administered drugs. This study was made to evaluate the role of gen· der in the effC(;ts of age on the pharmacokinetics of alfentanil in patients undergoing lower abdominal surgery.
Patients and Methodl After approval by the local medical ethics committee and the obtaining of informed consent, 36 patients ( 15 men aged 24 to 78 and 21 women aged
4 17
Age and the KLnellcs of AlfenlanLl
25 to 79) undergoing elective lower abdominal surgery were studied. Only those with normal cardiac. hepatic. renal and pulmonary function were enrolled. Patients who were malnourished or grossly obese. had a history of alcohol or drug abuse. or wcre on preoperative medication were excluded. PremedLcalLon was with oral temazepam 10 to 20mg and mtramuscula r atropi ne 0.25 to O.5mg, administered at 1 and 0.5 hour, respectively. before surgery. ECG electrodes were put in place on arri val in the operating theatre. A 20-gauge can nula was inserted In a radial artery for continuous measurement of blood pressure and collection of blood samples. Before induction of anaesthesia. 300 to 500ml NaCI 0.9% was infused; pancuronium 0.02 mg/kg was given to prevent muscle rigidity, and atropine O.5mg to prevent brad ycardia. After 3 minutes breathing 100% oxygen the fresh gas flow was changed to 66% nitrous oxide in oxygen. Simultaneously. an alfentanil infusion following a Wagner infusion scheme (Wagner 1974) was staned using a 'Harvard model 945' mfusion pump (Harvard Apparatus. South Natick. Mass.. USA). The initial mfusion rate was 15.5 .ug/kg/min. When consciousness was lost suxamethonium I mg/kg was administered and the trachea intubated. VenIllation of the lungs was adjusted to maintain endtidal carbon dioxide concentration between 4 and 5 vol%. Fifteen minutes after the stan of the alfentani l Infusion. thc infusion rate was decreased to 1.21 .I'&fkg/min and this rate was maintained during surgery until the peritoneum was closed. Pancuroni um was given for neuromuscular blockade. Sufentanil 25.ug was administered if anaesthesia was inadequate as defined by the following criteria: I.
Increase in systolic blood pressure by more than 15mm Hg above normal for that patient. Normal was defined as the ol west pressure measured in the time from admission to the hospital until just before premedication. 2. A heart rate higher than 90 beats/ min in the absence of hypovolaem ia. 3. Other autonomic signs such as sw~ting. flushing or lacrimation.
4. Somatic responses such as movements, swallowing, coughing, grimacing or eye movement. During surgery, each patient received a maintenance infusion of 300-500 ml/ h NaO 0.9% supplemented by a volume equal to the blood loss. After surgery, the NaO infusion was continued at a rate of80 to 125 mlfh. Intramuscular methadone 0.1 mg/kg was given for postoperative analgesia. If indicated. antibiotics (clindamycin together with kanamycin, pipcraeillin or doxycycline) were administered during the study, although no patient received erythromycin since this is known to reduce the clearance of alfentanil (Bankowski et al.
1989). Before starting Ihe administration of alfentanil an anerial blood sample was collected for determination of alfentanil plasma protein binding. Arterial blood samples for determination of the plasma alfentanil concentration were obtained 1, 2. 5, 7, 10, 15, 17, 20. 25. 30, 45, 60, 75 and 90 minutes after alfentanil infusion was started and then every 30 minutes until the infusion was slOpped. After stopping the infusion. arterial blood samples were laken at 0, 5, 10, 15.30,45,60,90, 120, 180 and 240 minutes, and venous blood samples at 240, 360, 480 and 600 minutes.
Assa)'s and Data Anal)'sis The plasma protein binding of alfentani l was detennined by equilibrium dialysis with a 'Oianorm' dialysis system, equi pped with 20 'Teflon' dialysis cells (Oiachcma, Ruschlikon, Switzerland). The cell membranes had a molecular weight cutoff of 10 000 Oaltons. One millilitre plasma samples werespiked with alfentaml SOOng and dialysed against 2ml of an isotonic (.I' '" 0.345 mol/ L; pH '" 7.4) phosphate buffer solution. consisting of Na2HP04 (107 mmol/ L) and KH 2P04 (24 mmoll L). The dialysis was eamed out in a temperaturecontrolled .....ater bath at 3T'C for 4 houn at 20 rpm. Under these condi tions, binding ofalfentanil to the membrane or cell walls was minimal «5%). Concentrations of alfentanil in plasma and dialysate were determLned by capillary gas chroma-
Clm. Phafmacokmf'f. 19 ($) 1990
418
tography. R 38527 (Janssen Phannaceutica, Beerse. Belgium) as internal standard was added to O.2ml plasma o r O.3ml dialysate and, after mixing, the sample was extracted for 30 seconds with Sml or redistilled reagent grade n-pentane (Merck, Darmstadt. West Germany) on a whirl mixer. After centrifugation the organic phase was transferred to a conical centrifuge lube and evaporated to dryness in a stream of dry nitTosen on a water bath at 4O"c. The residue was dissolved in 50 to IOO~1 analytical grade absolute alcohol (Merck, Darm stadt, West Gennany), and '-41 was introduced into the gas chromatograph via a falling needle solid injection system (Ch rompack, Middelburg, The Nether-
CP·SiI·5·CB (Chrompack. Middelburg, The Neth· erlands) as the stationary phase. The operating temperatures of the injection port, column oven and detector were 300"C, 23O"C and 300"C. re· spectively. Helium was used as the carrier gas (flow rate 4 ml/ min) and an auxiliary flow of heli um (26 ml/ min) was fed into the detector. The coefficient of variation of the gas chromatogrnphic method did no t exceed 5% in the alfentanil concentration range encou ntered in this study. Free fractions ofalfentanil (fu) were determined from the concentrations of drug in plasma before dialysis (C p) and the concentration in dialysate after dialysis {Cd}, using the following equation:
lands).
'. -
Analyses were carried OUI with a ' Hewlett Pack· ard 5890A' gas chro matograph, equipped with a nitrogen detecto r and a capillary fused silica column (length 10m, internal d iameter O. 32mm) with TlbM I. Pilleni deUII, lod phltmicolllrletic parlmeler, In
.... " • 2 3
,•
• 7
••
10
"
.." 13
."
17
18
"
20
"
Ago
0'
..
CL Ill"
32
85 78 80
33 39
72 50
Of
85
27.3 2&.86 16.& 27.6 25.26 20.2& 31 .62
70 60
24.42
25
'"'"
... " ""
. 85
"
87 71
"""
"
87 70
" ,."
.
63
70 60
" "
22.'
20." 18.& 12.96 12.42
..
14.52 13.92 18.62 15.38 10.98
' .38
women I.
""
7.' 10 3.3 ' .3
,.,
•••
12.5 U 10.1 12.4
' .1 10.1
7.' 10 12.1
' .7 8 23.2
•• • ' .2
15.24
8
- 0.79 '
0.20
'-I"""
. 93 99
... .".. 93
102 "0
.
132
". ." ...
... 170
.,.
Vo
IL, ' .3 ' .7 ' .0 3.' 3.7 3.' ' .0
... 3.'
•• • ' .3
,.• 3.0
3.' 3.' 3.'
' .1
130
2.' ' .2
2"
1.8
..
Va
IL,
27
40
.,"
..,. . .. . 32
27 33 32
33 36
35
26
"
32'
2.0
87
0.74'
- 0.49'
- 0.2 1
• totll bocIy cIe.,lnce: lu • ,," frICtion (II 1111ntanif: 1'1 • t~ hllI-~I.: lie • \'OIumoe 01 centrl' VI •• \'OIumoe 01 dbtribullon II slIl
Oin, Pha. maookinel. 19
(~):
416-422,1990
0312-5963/90/00 10-0416/S03.SOro
CAd;! lnln'Mlion31 Limned All ri&hIS reserved. CPKOO3375
Influence of Age on the Pharmacokinetics of Alfentani! Gender Dependence
Harry 1.M. Lemmens. Anton G.L. BUrin, Pim J. Hennis, Marina P.P.R. Gladines and James G. Bovill Depal1ment of An esthesiology, University Hospital Leiden, Leiden. The Netherlands
Studies on the effects of age on the pharmacokinetics of alfentanil are inconclusive. A possible factor in explaining the differences be tween various studies could be the effect of gcnder. The authors studied the effecls of age on the pharmacokinetics of alfentanil in female (n ., 2 1) and male (n - 15) patients undergoing lower abdominal surgery under nitrous oxide alfcntani! anaesthesia. There was a Significant negative correlation (r ,. -0.79, p < 0.00]) between plasma alfentanil clearance (Cl) and age in women «SOy, median Cl 24.84 L/ h: >SOy. median CL 14.S2 L/h). but not in men «SOy. med ian CL 19.44 l / h: >SOy, median CL 16.2 L/h). The conclusion is drawn that the effects of age on the pharmacokinetics of alfentani] are gender-dependenl.
Alfentanil is a synthetic opioid whose action is of rapid onset and short duration. It has a small volume of distribution at steady-state and a short elimination half-life (Bovill et at 1982), which make it more suitable than other opioids for use by continuous infusion. A variable rate infusion of alfentanil, titrated to responses of the patient during surgery, resu lts in greater haemodynamic stability and a more rapid recovery than achieved with intermittent bolus admin istration (Ausems et al. 1988). These advantages of conti nuous infusion are particularly important in elderly patients, who are more prone than the young to complications during and after anaesthesia and surgery. The pharmacokinetics of alfen tanil in elderly patients have been studied and compared with those in young patients by Helmers et al. ( 984), 1 Maitre et al. (1987) and Scott and Stanski (1987).
A dC(;reased plasma clearance was found by Helmers et a1. (1984) but not by Scott and Stanski (1987), possibly due to differences in the populations studied; the former ~tudied patients of both sexes, whereas the latter studied only men. Other factors that may have contributed to the differences could be the type of surgery and concomitantly administered drugs. This study was made to evaluate the role of gen· der in the effC(;ts of age on the pharmacokinetics of alfentanil in patients undergoing lower abdominal surgery.
Patients and Methodl After approval by the local medical ethics committee and the obtaining of informed consent, 36 patients ( 15 men aged 24 to 78 and 21 women aged
4 17
Age and the KLnellcs of AlfenlanLl
25 to 79) undergoing elective lower abdominal surgery were studied. Only those with normal cardiac. hepatic. renal and pulmonary function were enrolled. Patients who were malnourished or grossly obese. had a history of alcohol or drug abuse. or wcre on preoperative medication were excluded. PremedLcalLon was with oral temazepam 10 to 20mg and mtramuscula r atropi ne 0.25 to O.5mg, administered at 1 and 0.5 hour, respectively. before surgery. ECG electrodes were put in place on arri val in the operating theatre. A 20-gauge can nula was inserted In a radial artery for continuous measurement of blood pressure and collection of blood samples. Before induction of anaesthesia. 300 to 500ml NaCI 0.9% was infused; pancuronium 0.02 mg/kg was given to prevent muscle rigidity, and atropine O.5mg to prevent brad ycardia. After 3 minutes breathing 100% oxygen the fresh gas flow was changed to 66% nitrous oxide in oxygen. Simultaneously. an alfentanil infusion following a Wagner infusion scheme (Wagner 1974) was staned using a 'Harvard model 945' mfusion pump (Harvard Apparatus. South Natick. Mass.. USA). The initial mfusion rate was 15.5 .ug/kg/min. When consciousness was lost suxamethonium I mg/kg was administered and the trachea intubated. VenIllation of the lungs was adjusted to maintain endtidal carbon dioxide concentration between 4 and 5 vol%. Fifteen minutes after the stan of the alfentani l Infusion. thc infusion rate was decreased to 1.21 .I'&fkg/min and this rate was maintained during surgery until the peritoneum was closed. Pancuroni um was given for neuromuscular blockade. Sufentanil 25.ug was administered if anaesthesia was inadequate as defined by the following criteria: I.
Increase in systolic blood pressure by more than 15mm Hg above normal for that patient. Normal was defined as the ol west pressure measured in the time from admission to the hospital until just before premedication. 2. A heart rate higher than 90 beats/ min in the absence of hypovolaem ia. 3. Other autonomic signs such as sw~ting. flushing or lacrimation.
4. Somatic responses such as movements, swallowing, coughing, grimacing or eye movement. During surgery, each patient received a maintenance infusion of 300-500 ml/ h NaO 0.9% supplemented by a volume equal to the blood loss. After surgery, the NaO infusion was continued at a rate of80 to 125 mlfh. Intramuscular methadone 0.1 mg/kg was given for postoperative analgesia. If indicated. antibiotics (clindamycin together with kanamycin, pipcraeillin or doxycycline) were administered during the study, although no patient received erythromycin since this is known to reduce the clearance of alfentanil (Bankowski et al.
1989). Before starting Ihe administration of alfentanil an anerial blood sample was collected for determination of alfentanil plasma protein binding. Arterial blood samples for determination of the plasma alfentanil concentration were obtained 1, 2. 5, 7, 10, 15, 17, 20. 25. 30, 45, 60, 75 and 90 minutes after alfentanil infusion was started and then every 30 minutes until the infusion was slOpped. After stopping the infusion. arterial blood samples were laken at 0, 5, 10, 15.30,45,60,90, 120, 180 and 240 minutes, and venous blood samples at 240, 360, 480 and 600 minutes.
Assa)'s and Data Anal)'sis The plasma protein binding of alfentani l was detennined by equilibrium dialysis with a 'Oianorm' dialysis system, equi pped with 20 'Teflon' dialysis cells (Oiachcma, Ruschlikon, Switzerland). The cell membranes had a molecular weight cutoff of 10 000 Oaltons. One millilitre plasma samples werespiked with alfentaml SOOng and dialysed against 2ml of an isotonic (.I' '" 0.345 mol/ L; pH '" 7.4) phosphate buffer solution. consisting of Na2HP04 (107 mmol/ L) and KH 2P04 (24 mmoll L). The dialysis was eamed out in a temperaturecontrolled .....ater bath at 3T'C for 4 houn at 20 rpm. Under these condi tions, binding ofalfentanil to the membrane or cell walls was minimal «5%). Concentrations of alfentanil in plasma and dialysate were determLned by capillary gas chroma-
Clm. Phafmacokmf'f. 19 ($) 1990
418
tography. R 38527 (Janssen Phannaceutica, Beerse. Belgium) as internal standard was added to O.2ml plasma o r O.3ml dialysate and, after mixing, the sample was extracted for 30 seconds with Sml or redistilled reagent grade n-pentane (Merck, Darmstadt. West Germany) on a whirl mixer. After centrifugation the organic phase was transferred to a conical centrifuge lube and evaporated to dryness in a stream of dry nitTosen on a water bath at 4O"c. The residue was dissolved in 50 to IOO~1 analytical grade absolute alcohol (Merck, Darm stadt, West Gennany), and '-41 was introduced into the gas chromatograph via a falling needle solid injection system (Ch rompack, Middelburg, The Nether-
CP·SiI·5·CB (Chrompack. Middelburg, The Neth· erlands) as the stationary phase. The operating temperatures of the injection port, column oven and detector were 300"C, 23O"C and 300"C. re· spectively. Helium was used as the carrier gas (flow rate 4 ml/ min) and an auxiliary flow of heli um (26 ml/ min) was fed into the detector. The coefficient of variation of the gas chromatogrnphic method did no t exceed 5% in the alfentanil concentration range encou ntered in this study. Free fractions ofalfentanil (fu) were determined from the concentrations of drug in plasma before dialysis (C p) and the concentration in dialysate after dialysis {Cd}, using the following equation:
lands).
'. -
Analyses were carried OUI with a ' Hewlett Pack· ard 5890A' gas chro matograph, equipped with a nitrogen detecto r and a capillary fused silica column (length 10m, internal d iameter O. 32mm) with TlbM I. Pilleni deUII, lod phltmicolllrletic parlmeler, In
.... " • 2 3
,•
• 7
••
10
"
.." 13
."
17
18
"
20
"
Ago
0'
..
CL Ill"
32
85 78 80
33 39
72 50
Of
85
27.3 2&.86 16.& 27.6 25.26 20.2& 31 .62
70 60
24.42
25
'"'"
... " ""
. 85
"
87 71
"""
"
87 70
" ,."
.
63
70 60
" "
22.'
20." 18.& 12.96 12.42
..
14.52 13.92 18.62 15.38 10.98
' .38
women I.
""
7.' 10 3.3 ' .3
,.,
•••
12.5 U 10.1 12.4
' .1 10.1
7.' 10 12.1
' .7 8 23.2
•• • ' .2
15.24
8
- 0.79 '
0.20
'-I"""
. 93 99
... .".. 93
102 "0
.
132
". ." ...
... 170
.,.
Vo
IL, ' .3 ' .7 ' .0 3.' 3.7 3.' ' .0
... 3.'
•• • ' .3
,.• 3.0
3.' 3.' 3.'
' .1
130
2.' ' .2
2"
1.8
..
Va
IL,
27
40
.,"
..,. . .. . 32
27 33 32
33 36
35
26
"
32'
2.0
87
0.74'
- 0.49'
- 0.2 1
• totll bocIy cIe.,lnce: lu • ,," frICtion (II 1111ntanif: 1'1 • t~ hllI-~I.: lie • \'OIumoe 01 centrl' VI •• \'OIumoe 01 dbtribullon II slIl
