Forensic Science Internutti,
Elsevier Scientific Publishers
49 (1991) 185-192 Ireland Ltd.
INTERACTION OF BUTORPHANOL, INHIBITOR, TRANYLCYPROMINE
185
WITH MONOAMINE OXIDASE
ADEL A. GOMAA, LAILA H. MOHAMMEDB, HAMDY N. AHMEDb and AFAF M.A. FARGHALYc Departments of Phurmmology aAnesthmiolagy, Faculty of Medicine, Ass&t University (Egypt)
bNeurobgy,
%orensic
Medicine and Toxicology,
(Received July 13th, 1990) (Revision received December 27th, 1990) (Accepted January 17th, 1991)
Summary This investigation examines the possibility of interaction between tranylcypromine and butorphanol in comparison to pethidine. The LD,, of pethidine and butorphanol were determined in mice pretreated with the non-selective monoamine oxidaae (MAO) inhibitor, tranylcypromine orally for 8 days or with oral saline solution. Tranylcypromine decreased the LD, of both pethidine and butorphanol by 78% and 41%, respectively. Anesthetized rabbits with halothane pretreated with tranylcypromine or saline were given pethidine (5 mg/kg iv.) or butorphanol(O.5,l and 2 mg/kg i.v.). Pethidine produced a marked increase in blood pressure in rabbits pretreated with tranylcypromine and did not affect significantly the heart rate. Butorphanol did not affect either blood pressure or heart rate at doses of 0.5 or 1 mg/kg. However, the largest dose of butorphanol(2 mg/kg) produced hypotension and tachycardia in rabbits pretreated with tranylcypromine. Neither pethidine nor butorphanol affected the temperature of anesthetized rabbits pretreated with tranylcypromine or saline. Key words: Butorphanol;
Tranylcypromine;
Monoamine oxidase inhibitor; Interaction
Introduction The popular use of monoamine oxidase (MAO) inhibitors in comparison to other methods of treatment for depression and phobias led many investigators to study their interaction with the commonly used narcotics. Butorphanol tartarate (L-N-cyclobutyl-methyl-3-14-P dihydroxymorphinan) is one of the narcotic analgesics widely used nowadays [l]. In balanced anesthesia, butorphanol satisfies all requirements of the analgesic components and therefore, may prove to be a valuable addition to presently available drugs employed for pain relief during surgery [2]. Severe toxic interaction occurs when patients treated with MAO inhibitors are given the narcotic analgesic pethidine [3,4]. Some investigators recommended the discontinuation of MAO inhibitors 2 weeks prior to anesthesia because of the potential for serious adverse drug interactions [5,6], whereas others reported that discontinuing chronic MAO inhibitors therapy prior to anesthesia and surgery is not Printed and Published in Ireland
186
necessary [7]. The aim of this study is to clarify if there are serious interactions between the narcotic analgesic drug “butorphanol” and the non-selective MAO inhibitor, tranylcypromine in anesthetized animals. Materials
and Methods
Toxicity study: effect of tranylcyprmine on the LD, of butorphanol and pethidine Two groups of 36 mice were pretreated for 10 days. Group I (36 mice) received the non-selective MAO inhibitor drug, tranylcypromine sulphate (parnate), dissolved in 0.9% saline solution and given in a dose of 15 mg/kg body weight orally. Group II (36 mice) received physiological saline (the same volume as tranylcypromine solution) orally and served as a control group. Pethidine and butorphanol were injected intraperitonealy in each group (18 mice for each drug), 4 h after the last dose of tranylcypromine. Mortality was assessed 12 h after administration of pethidine or butorphanol. Median lethal dose (LD,,) values for both drugs were measured according to the method of Litchfield and Wilcoxon [8]. Effect of MAO inhibitors on the pattern of action of butorphanol on cardiovascular system Six groups of rabbits, each consisting of six rabbits of either sex (weight, 1.5-2 kg), were pretreated with either physiological saline (two groups) or tranylcypromine sulphate (four groups), for 10 days. On the day of the experiment (11th day), the rabbits were anesthetized lightly with halothane. Body temperature, arterial blood pressure and heart rate were monitored for 15 min before the beginning of recording until stability occurs. Recorditig continued every 10 min up to 70 min. The rabbits pretreated with tranylcypromine were classified into four groups, each one containing 6 rabbits. Butorphanol was injected i.v. in an ear vein at three doses: 0.5 mg/kg, 1 mg/kg and 2 mg/kg in three groups of rabbits. Pethidine was injected in the same way in a dose of 5 mglkg in the fourth group. The remaining two groups served as control groups (pretreated with physiological saline). Butorphanol was injected in a dose of 2 mg/kg in one group and pethidine was injected in a dose of 5 mglkg in the second group. Statistical analysis Students t-test was used for statistical significant. Data represent mean f S.E.
analysis. P < 0.05 was considered
Results Effect of tranylcyprmine on the toxicity of pethidine and butorphanol Table 1 showed that LD,, values for pethidine were decreased significantly (P c 0.001) from 112 (90-140) mg/kg in control group to 25 (18-35) mg/kg in mice pretreated with tranylcypromine. This represents an increase in percentage
187 TABLE 1 EFFECT OF TRANYLCYPROMINE ON LD, OF PETHIDINE AND BUTORPHANOL IN MICE The 95% confidence limits for LD,, of both pethidine and butorphanol are shown in parantheses. Pretreatment
Pethidine F50 (mglkg) I.P.
Butorphanol Percentage increase in
LD,O (mglkg) I. P.
toxicity
toxicity
Saline (control) Tranylcypromine (15 mg&) per day for 10 days
112 (140-90) 25 (35-18)
78
Percentage increase in
185 (222-154)
-
109 (74-142)
41
of toxicity equal to 78%. Meanwhile, the LD,, of butorphanol was diminished significantly (P < 0.001) from 185 (154-222) mg/kg in control group to 109 (84-142) mg/kg in mice pretreated with tranylcypromine, representing an increase in percentage of toxicity equal to 41% (Table 1). Effects of butorphanol or pethidine on the bloodpressure and heart rate in rabbits pretreated by tranylcypromine In rabbits pretreated with saline, the administration of butorphanol in doses of 0.5,l and 2 mg/kg produced a non-significant change in blood pressure. Also, in animals pretreated with tranylcypromine, a non-significant change in blood pressure was observed with butorphanol in 0.5 mg and 1 mg/kg doses. Butorphanol in a very high dose (2 mg/kg), produced a significant drop in mean blood pressure (P < 0.05) in rabbits pretreated with tranylcypromine, Fig. 1 (A,B and C). In rabbits pretreated with saline, the administration of pethidine 5 mg/kg i.v. resulted in a small non-significant decrease of blood pressure in the first 50 min, and then a slight non-significant increase in blood pressure in the last 20 min. However, the increase in arterial pressure produced by pethidine in the tranylcypromine-treated group was significant after 20 min of pethidine administration and up to the end of the experiment (P < O.Ol), Fig. 1D. The administration of butorphanol in doses of 0.5, 1 and 2 mg/kg in saline pretreated animals resulted in a non-significant decrease of heart rate; similarly, in tranylcypromine-treated animals, it produced a non-significant bradycardia when used in doses of 0.5 mg and 1 mg/kg, while a significant tachycardia (P < 0.05) was observed when used in a very high dose (2 mg/kg), Fig. 2 (A,B and C). The results of this experiment also demonstrated that the administration of pethidine in saline-pretreated animals resulted in non-significant change in heart. rate. Also, in tranylcypromine-treated animals, it produced a non-significant increase in heart rate, Fig. 2D.
-_
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Fig. 1. Effect of narcotic analgesics (butorphanol and pethidine) on blood pressure of animals pretreated with tranylcypromine; A - butorphano10.5 mgkg; B - butorphanol 1 mg/kg; C - butorphanol 2 mglkg; D - pethidine 5 mg/kg.
Effect of butorphanol or pethidine on temperature of animals pretreated with tranykypromine Pethidine (5 mg/kg iv.) caused no change in body temperature in rabbits pretreated with saline. Meanwhile, pethidine (5 mglkg i.v.) caused a slight nonsignificant increase in body temperature in anesthetized rabbits pretreated with tranylcypromine Fig. 3D. In the second experiment, butorphanol in doses of 0.5, 1 and 2 mglkg intravenously did not cause any change in the body temperature of anesthetized rabbits pretreated with either tranylcypromine or saline, Fig. 3 (A,B and C).
189
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_
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with 320
320
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300 280 260 240 220 200
ISOl 0’
1
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20
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30
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40
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80
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Time (min.)
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Fig. 2. Effect of narcotic analgesics (butorphanol and pethidine) on heart rate of animals pretreated with tranylcypromine; A - hutorphanol 0.5 mg/kg; B - butorphanol 1 mg/kg; C - butorphanol 2 mgkg and D - pethidine 5 mgkg.
Discussion This study showed that butorphanol is safer than pethidine in animals pretreated by a non-selective MAO inhibitor, tranylcypromine. The percentage of toxicity of butorphanol and pethidine increased by about 41% and 78%, respectively in animals pretreated with tranylcypromine. The median lethal dose (LD,,) of butorphanol was 109 (84-142) mg/kg, while the LD,, was 25 (18-35) mglkg with pethidine in the group of animals pretreated with tranylcypromine. It was reported that the LD, of pethidine decreased in animals pretreated with a non-selective MAO inhibitor, phenelzine or combined clorgylin (MAO inhibitor A) and deprenyl (MAO inhibitor B) [9]. The same toxicity was observed in animals pretreated with a non-selective MAO inhibitor, tranylcypromine [lo]. It was surprising in this study to observe that injection of pethidine (5 mg/kg)
190
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Fig. 3. Effect of narcotic analgesics (butorphanol and pethidine) of animals pretreated with tranylcypromine; A - butorphano10.5 mg/kg; B - butorphanol 1 mg/kg; C - butorphanol2 mgkg and D - pethidine 5 mg/kg.
in anesthetized rabbits pretreated by the non-selective MAO inhibitor, tranylcypromine, did not produce hyperthermia. This is in contrast with other studies [ll], where pethidine (5 mg/kg i.v.) caused significant hyperthermia (P < 0.001) in animals pretreated with the non-selective MAO inhibitor, phenelzine. Moreover, an increase in temperature by 23°C after injection of pethidine was reported in animals pretreated with the MAO inhibitor, phenelzine in comparison to elevation of only 0.5% in the control group (pretreated with saline) [12]. The mechanism of hyperthermia was explained on the basis of the rise of brain 5-hydroxytryptamine (5-HT) [13]. Pretreatment with p-chlorophenylalanine (PCPA) which depletes brain 5-HT, protected the rabbits against the otherwise fatal hyperpyrexia resulting from pargyline-pethidine interaction. On the other hand, lithium and yohimbine, which increase 5-HT concentration in the brain, caused pethidine to provoke a hyperpyrexic response. Butorphanol at different doses: 0.5, 1 and 2 mg/kg also caused no significant change in the temperature of animals pretreated with tranylcypromine. This discrepancy between our results and results of others may be attributed to changes in experimental conditions adopted and change in the type of drugs
191
used. In the previous studies, hyperthermia was observed in conscious animals, while in our study, the animals used were anesthetized by halothane which could produce peripheral vasodilation and favor hypothermia rather than hyperthermia. Previous studies demonstrated cardiovascular toxic reactions when pethidine and MAO inhibitors were administered simultaneously. It was reported that the administration of pethidine in animals pretreated with the MAO inhibitor phenelzine, resulted in tachycardia and an increase in mean arterial pressure [l l] . However, in our study hypertension resulted only from the interaction of pethidine and tranylcypromine. Also, it was previously demonstrated that hypertension without tachycardia occurs in animals administered MAO inhibitor and pethidine 1141. In our study, butorphanol did not produce hypertension in animals pretreated with tranylcypromine. However, at very high doses (2 mg/kg), hypotension and most probably reflex tachycardia occured in anesthetized animals pretreated with tranylcypromine. Hypotension most probably is due to depression of higher centers (medullary centers). Therefore, it is clear from the present data that butorphanol at doses equivalent to very high therapeutic doses did not produce adverse toxic interaction with tranylcypromine. Buprenorphine is similarly without toxic interaction when administered concurrently with MAO inhibitor [ll]. Additionally, there are no reports of clinical observations of a toxic interaction between morphine or pentazocine with MAO inhibitors [15-171. In conclusion, our results demonstrated that although the toxicity study revealed that there was an increase in toxicity of butorphanol due to interaction with tranylcypromine, there was no adverse toxic reaction due to interaction of tranylcypromine with butorphanol at doses equivalent to about 25 times the recommended therapeutic dose. References 1
2 3 4 5 6
8 9
C.E. Rosow, The pharmacology of butorphanol tartrate; the international symposium on butorphanol tartrate, Seventh World Congress of Anaesthesiology Hamburg, Germany, September 14-21, 1980. G. Corrsen, Introduction; The international symposium on butorphanol tartrate, Seventh World Congress of Anaesthesiology, Hamburg, Germany, September 14-21, 1980. J.C. Shee, Dangerous potentiation of pethidine by iproniazid, and its treatment. Br. Med. J., 2 (1960) 507-508. DC. Taylor, Alarming reaction to pethidine in patients on phenelzine. Lance& 2 (1962) 401-402. E.R. Perks, Monoamine oxidase inhibitors. Anuesthesia, 19 (1964) 376-86. O.J. Viegos, Psychiatric illness. In R.K. Stoeling and S.F. Deerdort (eds.), Anaesthesia and Coexisting Disease, Churchill Livingstone, New York, 1983, pp. 633-71. A.R. El-Gansouri, A.D. Ivankovich, B. Braberman and R. McCarthy, Monoamine oxidase inhibitors: should they be discontinued preoperatively? Am&h. An&g., 64 (1985) 592-6. J.T. Litchfield and F. Wilcoxon, A simplified method of evaluating dose effect experiments. J. Pharmmol. Exp. Thm., 96 (1949) 99-113. R. Boden, R. Botting, P. CouIson and G. Spanswick, Effect on non-selective and selective inhibitors of monoamine oxidases A and B on pethidine toxicity in mice. Br. J. Phamacol., 82 (1984) 151-154.
192
10 11
12 13
14 15
16 17
B. Tabakoff, F. Moses, S.R. Philips and A.A. Boluton, Effects of tranylcypromine and pargyline on brain tryptamine. Ezptitia, 33 (1977) 380-381. J.E. Mackenzie and Frank, Influence of pretreatment with a monoamine oxidase inhibitors (phenelsine) on the effects of buprenorphine and pethidine in the conscious rabbits. Br. J. Anaesth., 60 (1988) 216-221. A.J. Jounela, M.J. Mattila and J. Knoll, Interaction of selective inhibitors of monoamine oxidase with pethidine in rabbit. Biochem. Pharmacol., 26 (1977) 806-808. J. Fahim, M. Ismail and O.H. Osman, The role of 5-hydroxytryptamine and noradrenaline in the hyperthermic reaction induced by pethidine in rabbits pretreated with pargyline. Br. J. Pharmol., 46 (1972) 416-422. A.J. Jounela, Influence of phenelzine on the toxicity of some analgesics in mice. Ann. Med. Exp. Fenn, 48 (1970) 261-265. R. Botting, S., C.T. Eason, P.H. Hutson and L. Wells, Modification of monoamine oxidase inhibitors of the analgesic, hypothermic and toxic actions of morphine and pethidine in mice. J. Phurm. Pharmucol., 30 (1978) 36-40. J.C. Sinclair, The effects of meperidine and morphine in rabbits pretreated with phenelzine. T&ol. A&. Pharmaeol., 22 (1972) 231-227. R.G. Penn and K.J. Rogers, Comparison of the effects of morphine, pethidine and pentazocine in rabbits pretreated with monoamine oxidase inhibitor. Br. J. Pharmacol., 42 (1971) 485-492.
Elsevier Scientific Publishers
49 (1991) 185-192 Ireland Ltd.
INTERACTION OF BUTORPHANOL, INHIBITOR, TRANYLCYPROMINE
185
WITH MONOAMINE OXIDASE
ADEL A. GOMAA, LAILA H. MOHAMMEDB, HAMDY N. AHMEDb and AFAF M.A. FARGHALYc Departments of Phurmmology aAnesthmiolagy, Faculty of Medicine, Ass&t University (Egypt)
bNeurobgy,
%orensic
Medicine and Toxicology,
(Received July 13th, 1990) (Revision received December 27th, 1990) (Accepted January 17th, 1991)
Summary This investigation examines the possibility of interaction between tranylcypromine and butorphanol in comparison to pethidine. The LD,, of pethidine and butorphanol were determined in mice pretreated with the non-selective monoamine oxidaae (MAO) inhibitor, tranylcypromine orally for 8 days or with oral saline solution. Tranylcypromine decreased the LD, of both pethidine and butorphanol by 78% and 41%, respectively. Anesthetized rabbits with halothane pretreated with tranylcypromine or saline were given pethidine (5 mg/kg iv.) or butorphanol(O.5,l and 2 mg/kg i.v.). Pethidine produced a marked increase in blood pressure in rabbits pretreated with tranylcypromine and did not affect significantly the heart rate. Butorphanol did not affect either blood pressure or heart rate at doses of 0.5 or 1 mg/kg. However, the largest dose of butorphanol(2 mg/kg) produced hypotension and tachycardia in rabbits pretreated with tranylcypromine. Neither pethidine nor butorphanol affected the temperature of anesthetized rabbits pretreated with tranylcypromine or saline. Key words: Butorphanol;
Tranylcypromine;
Monoamine oxidase inhibitor; Interaction
Introduction The popular use of monoamine oxidase (MAO) inhibitors in comparison to other methods of treatment for depression and phobias led many investigators to study their interaction with the commonly used narcotics. Butorphanol tartarate (L-N-cyclobutyl-methyl-3-14-P dihydroxymorphinan) is one of the narcotic analgesics widely used nowadays [l]. In balanced anesthesia, butorphanol satisfies all requirements of the analgesic components and therefore, may prove to be a valuable addition to presently available drugs employed for pain relief during surgery [2]. Severe toxic interaction occurs when patients treated with MAO inhibitors are given the narcotic analgesic pethidine [3,4]. Some investigators recommended the discontinuation of MAO inhibitors 2 weeks prior to anesthesia because of the potential for serious adverse drug interactions [5,6], whereas others reported that discontinuing chronic MAO inhibitors therapy prior to anesthesia and surgery is not Printed and Published in Ireland
186
necessary [7]. The aim of this study is to clarify if there are serious interactions between the narcotic analgesic drug “butorphanol” and the non-selective MAO inhibitor, tranylcypromine in anesthetized animals. Materials
and Methods
Toxicity study: effect of tranylcyprmine on the LD, of butorphanol and pethidine Two groups of 36 mice were pretreated for 10 days. Group I (36 mice) received the non-selective MAO inhibitor drug, tranylcypromine sulphate (parnate), dissolved in 0.9% saline solution and given in a dose of 15 mg/kg body weight orally. Group II (36 mice) received physiological saline (the same volume as tranylcypromine solution) orally and served as a control group. Pethidine and butorphanol were injected intraperitonealy in each group (18 mice for each drug), 4 h after the last dose of tranylcypromine. Mortality was assessed 12 h after administration of pethidine or butorphanol. Median lethal dose (LD,,) values for both drugs were measured according to the method of Litchfield and Wilcoxon [8]. Effect of MAO inhibitors on the pattern of action of butorphanol on cardiovascular system Six groups of rabbits, each consisting of six rabbits of either sex (weight, 1.5-2 kg), were pretreated with either physiological saline (two groups) or tranylcypromine sulphate (four groups), for 10 days. On the day of the experiment (11th day), the rabbits were anesthetized lightly with halothane. Body temperature, arterial blood pressure and heart rate were monitored for 15 min before the beginning of recording until stability occurs. Recorditig continued every 10 min up to 70 min. The rabbits pretreated with tranylcypromine were classified into four groups, each one containing 6 rabbits. Butorphanol was injected i.v. in an ear vein at three doses: 0.5 mg/kg, 1 mg/kg and 2 mg/kg in three groups of rabbits. Pethidine was injected in the same way in a dose of 5 mglkg in the fourth group. The remaining two groups served as control groups (pretreated with physiological saline). Butorphanol was injected in a dose of 2 mg/kg in one group and pethidine was injected in a dose of 5 mglkg in the second group. Statistical analysis Students t-test was used for statistical significant. Data represent mean f S.E.
analysis. P < 0.05 was considered
Results Effect of tranylcyprmine on the toxicity of pethidine and butorphanol Table 1 showed that LD,, values for pethidine were decreased significantly (P c 0.001) from 112 (90-140) mg/kg in control group to 25 (18-35) mg/kg in mice pretreated with tranylcypromine. This represents an increase in percentage
187 TABLE 1 EFFECT OF TRANYLCYPROMINE ON LD, OF PETHIDINE AND BUTORPHANOL IN MICE The 95% confidence limits for LD,, of both pethidine and butorphanol are shown in parantheses. Pretreatment
Pethidine F50 (mglkg) I.P.
Butorphanol Percentage increase in
LD,O (mglkg) I. P.
toxicity
toxicity
Saline (control) Tranylcypromine (15 mg&) per day for 10 days
112 (140-90) 25 (35-18)
78
Percentage increase in
185 (222-154)
-
109 (74-142)
41
of toxicity equal to 78%. Meanwhile, the LD,, of butorphanol was diminished significantly (P < 0.001) from 185 (154-222) mg/kg in control group to 109 (84-142) mg/kg in mice pretreated with tranylcypromine, representing an increase in percentage of toxicity equal to 41% (Table 1). Effects of butorphanol or pethidine on the bloodpressure and heart rate in rabbits pretreated by tranylcypromine In rabbits pretreated with saline, the administration of butorphanol in doses of 0.5,l and 2 mg/kg produced a non-significant change in blood pressure. Also, in animals pretreated with tranylcypromine, a non-significant change in blood pressure was observed with butorphanol in 0.5 mg and 1 mg/kg doses. Butorphanol in a very high dose (2 mg/kg), produced a significant drop in mean blood pressure (P < 0.05) in rabbits pretreated with tranylcypromine, Fig. 1 (A,B and C). In rabbits pretreated with saline, the administration of pethidine 5 mg/kg i.v. resulted in a small non-significant decrease of blood pressure in the first 50 min, and then a slight non-significant increase in blood pressure in the last 20 min. However, the increase in arterial pressure produced by pethidine in the tranylcypromine-treated group was significant after 20 min of pethidine administration and up to the end of the experiment (P < O.Ol), Fig. 1D. The administration of butorphanol in doses of 0.5, 1 and 2 mg/kg in saline pretreated animals resulted in a non-significant decrease of heart rate; similarly, in tranylcypromine-treated animals, it produced a non-significant bradycardia when used in doses of 0.5 mg and 1 mg/kg, while a significant tachycardia (P < 0.05) was observed when used in a very high dose (2 mg/kg), Fig. 2 (A,B and C). The results of this experiment also demonstrated that the administration of pethidine in saline-pretreated animals resulted in non-significant change in heart. rate. Also, in tranylcypromine-treated animals, it produced a non-significant increase in heart rate, Fig. 2D.
-_
-
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with saline
Pretreated
with
B
A -
tranvlcypromine z!
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-
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Fig. 1. Effect of narcotic analgesics (butorphanol and pethidine) on blood pressure of animals pretreated with tranylcypromine; A - butorphano10.5 mgkg; B - butorphanol 1 mg/kg; C - butorphanol 2 mglkg; D - pethidine 5 mg/kg.
Effect of butorphanol or pethidine on temperature of animals pretreated with tranykypromine Pethidine (5 mg/kg iv.) caused no change in body temperature in rabbits pretreated with saline. Meanwhile, pethidine (5 mglkg i.v.) caused a slight nonsignificant increase in body temperature in anesthetized rabbits pretreated with tranylcypromine Fig. 3D. In the second experiment, butorphanol in doses of 0.5, 1 and 2 mglkg intravenously did not cause any change in the body temperature of anesthetized rabbits pretreated with either tranylcypromine or saline, Fig. 3 (A,B and C).
189
340
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Pretreated
with salme
_
Pretreated
with 320
320
t
300 280 260 240 220 200
ISOl 0’
1
IO
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20
B
30
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40
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50
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Time (min.1
Time (min.)
leol Time hnin.l
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Fig. 2. Effect of narcotic analgesics (butorphanol and pethidine) on heart rate of animals pretreated with tranylcypromine; A - hutorphanol 0.5 mg/kg; B - butorphanol 1 mg/kg; C - butorphanol 2 mgkg and D - pethidine 5 mgkg.
Discussion This study showed that butorphanol is safer than pethidine in animals pretreated by a non-selective MAO inhibitor, tranylcypromine. The percentage of toxicity of butorphanol and pethidine increased by about 41% and 78%, respectively in animals pretreated with tranylcypromine. The median lethal dose (LD,,) of butorphanol was 109 (84-142) mg/kg, while the LD,, was 25 (18-35) mglkg with pethidine in the group of animals pretreated with tranylcypromine. It was reported that the LD, of pethidine decreased in animals pretreated with a non-selective MAO inhibitor, phenelzine or combined clorgylin (MAO inhibitor A) and deprenyl (MAO inhibitor B) [9]. The same toxicity was observed in animals pretreated with a non-selective MAO inhibitor, tranylcypromine [lo]. It was surprising in this study to observe that injection of pethidine (5 mg/kg)
190
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’ 40
Time (min.)
Fig. 3. Effect of narcotic analgesics (butorphanol and pethidine) of animals pretreated with tranylcypromine; A - butorphano10.5 mg/kg; B - butorphanol 1 mg/kg; C - butorphanol2 mgkg and D - pethidine 5 mg/kg.
in anesthetized rabbits pretreated by the non-selective MAO inhibitor, tranylcypromine, did not produce hyperthermia. This is in contrast with other studies [ll], where pethidine (5 mg/kg i.v.) caused significant hyperthermia (P < 0.001) in animals pretreated with the non-selective MAO inhibitor, phenelzine. Moreover, an increase in temperature by 23°C after injection of pethidine was reported in animals pretreated with the MAO inhibitor, phenelzine in comparison to elevation of only 0.5% in the control group (pretreated with saline) [12]. The mechanism of hyperthermia was explained on the basis of the rise of brain 5-hydroxytryptamine (5-HT) [13]. Pretreatment with p-chlorophenylalanine (PCPA) which depletes brain 5-HT, protected the rabbits against the otherwise fatal hyperpyrexia resulting from pargyline-pethidine interaction. On the other hand, lithium and yohimbine, which increase 5-HT concentration in the brain, caused pethidine to provoke a hyperpyrexic response. Butorphanol at different doses: 0.5, 1 and 2 mg/kg also caused no significant change in the temperature of animals pretreated with tranylcypromine. This discrepancy between our results and results of others may be attributed to changes in experimental conditions adopted and change in the type of drugs
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used. In the previous studies, hyperthermia was observed in conscious animals, while in our study, the animals used were anesthetized by halothane which could produce peripheral vasodilation and favor hypothermia rather than hyperthermia. Previous studies demonstrated cardiovascular toxic reactions when pethidine and MAO inhibitors were administered simultaneously. It was reported that the administration of pethidine in animals pretreated with the MAO inhibitor phenelzine, resulted in tachycardia and an increase in mean arterial pressure [l l] . However, in our study hypertension resulted only from the interaction of pethidine and tranylcypromine. Also, it was previously demonstrated that hypertension without tachycardia occurs in animals administered MAO inhibitor and pethidine 1141. In our study, butorphanol did not produce hypertension in animals pretreated with tranylcypromine. However, at very high doses (2 mg/kg), hypotension and most probably reflex tachycardia occured in anesthetized animals pretreated with tranylcypromine. Hypotension most probably is due to depression of higher centers (medullary centers). Therefore, it is clear from the present data that butorphanol at doses equivalent to very high therapeutic doses did not produce adverse toxic interaction with tranylcypromine. Buprenorphine is similarly without toxic interaction when administered concurrently with MAO inhibitor [ll]. Additionally, there are no reports of clinical observations of a toxic interaction between morphine or pentazocine with MAO inhibitors [15-171. In conclusion, our results demonstrated that although the toxicity study revealed that there was an increase in toxicity of butorphanol due to interaction with tranylcypromine, there was no adverse toxic reaction due to interaction of tranylcypromine with butorphanol at doses equivalent to about 25 times the recommended therapeutic dose. References 1
2 3 4 5 6
8 9
C.E. Rosow, The pharmacology of butorphanol tartrate; the international symposium on butorphanol tartrate, Seventh World Congress of Anaesthesiology Hamburg, Germany, September 14-21, 1980. G. Corrsen, Introduction; The international symposium on butorphanol tartrate, Seventh World Congress of Anaesthesiology, Hamburg, Germany, September 14-21, 1980. J.C. Shee, Dangerous potentiation of pethidine by iproniazid, and its treatment. Br. Med. J., 2 (1960) 507-508. DC. Taylor, Alarming reaction to pethidine in patients on phenelzine. Lance& 2 (1962) 401-402. E.R. Perks, Monoamine oxidase inhibitors. Anuesthesia, 19 (1964) 376-86. O.J. Viegos, Psychiatric illness. In R.K. Stoeling and S.F. Deerdort (eds.), Anaesthesia and Coexisting Disease, Churchill Livingstone, New York, 1983, pp. 633-71. A.R. El-Gansouri, A.D. Ivankovich, B. Braberman and R. McCarthy, Monoamine oxidase inhibitors: should they be discontinued preoperatively? Am&h. An&g., 64 (1985) 592-6. J.T. Litchfield and F. Wilcoxon, A simplified method of evaluating dose effect experiments. J. Pharmmol. Exp. Thm., 96 (1949) 99-113. R. Boden, R. Botting, P. CouIson and G. Spanswick, Effect on non-selective and selective inhibitors of monoamine oxidases A and B on pethidine toxicity in mice. Br. J. Phamacol., 82 (1984) 151-154.
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B. Tabakoff, F. Moses, S.R. Philips and A.A. Boluton, Effects of tranylcypromine and pargyline on brain tryptamine. Ezptitia, 33 (1977) 380-381. J.E. Mackenzie and Frank, Influence of pretreatment with a monoamine oxidase inhibitors (phenelsine) on the effects of buprenorphine and pethidine in the conscious rabbits. Br. J. Anaesth., 60 (1988) 216-221. A.J. Jounela, M.J. Mattila and J. Knoll, Interaction of selective inhibitors of monoamine oxidase with pethidine in rabbit. Biochem. Pharmacol., 26 (1977) 806-808. J. Fahim, M. Ismail and O.H. Osman, The role of 5-hydroxytryptamine and noradrenaline in the hyperthermic reaction induced by pethidine in rabbits pretreated with pargyline. Br. J. Pharmol., 46 (1972) 416-422. A.J. Jounela, Influence of phenelzine on the toxicity of some analgesics in mice. Ann. Med. Exp. Fenn, 48 (1970) 261-265. R. Botting, S., C.T. Eason, P.H. Hutson and L. Wells, Modification of monoamine oxidase inhibitors of the analgesic, hypothermic and toxic actions of morphine and pethidine in mice. J. Phurm. Pharmucol., 30 (1978) 36-40. J.C. Sinclair, The effects of meperidine and morphine in rabbits pretreated with phenelzine. T&ol. A&. Pharmaeol., 22 (1972) 231-227. R.G. Penn and K.J. Rogers, Comparison of the effects of morphine, pethidine and pentazocine in rabbits pretreated with monoamine oxidase inhibitor. Br. J. Pharmacol., 42 (1971) 485-492.
