PANCURONIUM BROMIDE: AN INDIRECT SYMPATHOMIMETIC AGENT

Br.J. Anaesth. (1976), 48, 1143

PANCURONIUM BROMIDE: AN INDIRECT SYMPATHOMIMETIC AGENT J. SEGARRA DOMENECH, R. CARLOS GARCIA, J. M. RODRIGUEZ SASIAIN, A. QUINTANA LOYOLA AND J. SANTAFE OROZ SUMMARY

In clinical practice the choice of neuromuscular blocking drug is usually determined by the duration and type of block required. However, other actions of the drugs may be important, especially effects on the circulation. Pancuronium bromide is the only drug which increases arterial pressure in both animals (Buckett and Bonta, 1966; Buckett, 1968; Smith, Proctor and Spence, 1970) and man (KomesarofF, 1970; Loh, 1970; Levin and Dillon, 1971; Lubke and Dannemann, 1971; Saini and Sharma, 1971; Harrison, 1972; Nightingale and Bush, 1973). Several mechanisms have been proposed to account for this action. Saxena and Bonta (1970) described an antimuscarinic action, whilst Nana, Cardan and Domokos (1973) found that pancuronium increased plasma catecholamine concentrations, and they suggested that increased sympathetic activity was involved. Plasma noradrenaline concentrations increased to the greatest extent and this suggests that the action of pancuronium may be on the adrenergic nerve presynaptic membrane, causing a release of neurotransmitter. The demonstration of a presynaptic site of action involves both the induction of tachyphylaxis and the use of specific agents to modify the pressor response. We describe the results of such experiments in dogs.

1 g/kg. The dogs were ventilated artificially (Respirator B. Type 87 40-45. Braun-Melsungen). The following pressures were measured using appropriate catheters and transducers (Statham P-23 R and Recorder R411 Dynograph, Beckman): left ventricular, aortic arterial and central venous. The rate of change of left ventricular pressure (LV dp/dt) was recorded on occasions. Pancuronium 0.2 mg/kg i.v. was given at approximately 15-min intervals, at the end of which time any cardiovascular changes had disappeared. Immediately following the first injection of pancuronium, which did not cause an increase in arterial pressure, noradrenaline was infused i.v. for 25 min at a rate of 7 [i.g/min. When the arterial pressure was stable after this infusion, further doses of pancuronium were given. Two dogs received guanethidine 0.5 mg/kg i.v. following infusion of noradrenaline, and, when cardiovascular measurements were stable (60-120 min), pancuronium bromide 0.2 mg/kg was injected. Another two dogs received reserpine 0.01 mg/kg i.v., before the administration of pancuronium. In addition, two dogs were treated with desipramine 0.3 mg/kg i.v. before the infusion of noradrenaline.

METHODS

The initial injection of pancuronium caused increases in left ventricular systolic and aortic systolic and diastolic pressures, but did not alter central venous pressure. A second dose, given 15 min after the first, caused smaller changes, and a third dose, 15 min later, no change in arterial pressure or ventricular systolic pressure (fig. 1 and table I).

RESULTS

Ten mongrel dogs (weight range 8-12 kg) were anaesthetized with morphine 2-4 mg/kg and urethane J. SEGARRA DOMENECH, R. CARLOS GARCIA, J. M. RODRIGUEZ SASIAIN, A. QUINTANA LOYOLA, J. SANTAFE

OROZ, Department of Pharmacology, The School of Medicine, The University of Bilbao, Spain.

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In the dog, pancuronium 0.2 mg/kg increased left ventricular systolic pressure and systemic arterial pressure, but did not change central venous pressure. Repeated doses produced diminishing responses and eventually no change in arterial pressure. After tachyphylaxis was established, a pressor response to pancuronium could be induced by an i.v. infusion of noradrenaline. Desipramine, a noradrenaline blocking agent, prevented the restoration of the pressor effect of noradrenaline. Guanethidine and reserpine abolished the restoration of the pressor response to pancuronium by noradrenaline. These findings are consistent with the hypothesis that pancuronium acts on the postganglionic nerve endings and causes release of noradrenaline.

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1144

CVP (cmH 2 O) 7

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Pancuronium 0.2 mg/kg

Pancuronium 0.2 mg/kg

Pancuronium 0.2 mg/kg

FIG. 1. Acute tolerance following three consecutive doses of pancuronium bromide 0.2 mg/kg. LVP = left ventricular pressurej CVP = central venous pressure; ACP = central aortic pressure. TABLE I. Heart rate (HR; beat/min), arterial systolic (SP; mm Hg) and diastolic pressure (DP; mm Hg) in dogs, following three consecutive doses of pancuronium 0.2 mgjkg at 15-min intervals Pancuronium (first dose)

Control

Dog

HR

SP

DP

HPI

1 2 3 4 5 6 7 8 9 10

110 120 118 127 122 130 125 133 144 132

100 130 127 144 139 154 141 148 168 144

80 90 88 97 87 99 89 79 95 80

130 145 129 139 141 151 137 154 169 147

126 139 9.4 18

88 7

Mean

SD

Pancuronium (second dose)

Pancuronium (third dose)

SP

DP

HR

SP

DP

HR

SP

DP

130 148 141 152 149 166 154 159 180 156

100 100 98 112 96 118 100 98 120 97

115 132 120 122 130 141 130 144 150 140

118 138 129 149 145 160 149 156 177 143

92 97 92 101 92 109 96 84 110 83

113 120 118 126 123 128 123 133 140 135

113 131 125 142 137 156 140 147 166 140

83 91 86 95 82 93 86 75 92 75

144 153 11..9 13

104 9

132 146 11.3 16

95 9

125 139 8.2 15

86 7

Following the production of tachyphylaxis, the subsequent infusion of noradrenaline restored the pressor response to pancuronium (fig. 2). Tachyphylaxis to pancuronium could be demonstrated again after noradrenaline. Following the noradrenaline infusion, a third injection of pancuronium did not increase arterial pressure. After the production of

tachyphylaxis and infusion of noradrenaline, guanethidine 0.05 mg/kg or reserpine 0.01 mg/kg was given to deplete the nerve terminals of noradrenaline in two animals. The subsequent injection of pancuronium had no pressor effect (figs 3 and 4). In two dogs tachyphylaxis to pancuronium was produced and desipramine 0.3 mg/kg was given. This drug acts

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ACP (mmHg) 120

SYMPATHOMIMETIC EFFECT OF PANCURONIUM LVP (mm Hg)

1145

180

120 60 0 CVP (cm H2O)

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Pancuronium bromide 0.2 mg/kg 1 min

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Noradrenaline infusion 7 //g/min

Pancuronium bromide 0.2 mg/kg

FIG. 2. Restoration of a pressor response to pancuronium following the infusion of noradrenaline. LVP (mm Hg) 180 120

60 0 CVP (cmH 2 O)

ACP (mm Hg)

Noradrenaline infusion 7 /ig/ml/min

CONTROL 1 min

Guanethidine 0.05 mg/kg

Pancuronium bromide 0.2 mg/kg

i

FIG. 3. Guanethidine administered 2 h before the injection of pancuronium after noradrenaline infusion. No pressor response.

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ACP (mm Hg)

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1146 dp/dt (mm Hg/s) 1600r

LVP 150 (mmHg) 100 50 0

12

5

50

CVP (cm H2O) 1 min

Control

Noradrenaline Reserpine 0.01 mg/kg Pancuronium infusion 7 /*g/min (60 min after infection) 0.2 mg/kg

FIG. 4. Reserpine 0.01 mg/kg, 60 min after noradrenaline infusion and 90 min before the injection of pancuronium. No pressor response.

at the adrenergic nerve ending to block the uptake of noradrenaline. Following the infusion of noradrenaline, a further injection of pancuronium did not produce a pressor response (fig. 5). DISCUSSION

The development of tachyphylaxis to pancuronium can be explained by assuming that the drug acts at the postgangUonic adrenergic nerve terminals to release noradrenaline in a manner similar to tyramine and ephedrine. The absence of a response to a third injection may be explained on the basis of depletion of the noradrenaline stores by the previous injections. In this situation, a noradrenaline infusion would replenish the stores as this agent is readily taken up by the presynaptic nerve ending. Desipramine blocks this mechanism (Axelrod, Whitby and Herring, 1961) and thus prevents the restoration by noradrenaline of the pressor response to pancuronium. Reserpine and guanethidine act at the nerve terminals to reduce the size of the noradrenaline stores and their use following the noradrenaline infusion, by depleting the stores, prevents the restoration of a pressor response

to pancuronium. When given before pancuronium, desipramine may enhance the pressor response by blocking the usual uptake of noradrenaline following the first injection of pancuronium. Uptake back into the nerve endings is the major mechanism terminating the action of adrenergic nerve activity (Axelrod, 1963). The results reported here are consistent, therefore, with the interpretation that the pressor response to pancuronium results from an indirect action on the nerve terminals. If the mechanism were that of a general increase in sympathetic nerve activity, as suggested by Nana, Cardan and Domokos (1973), it is unlikely that tachyphylaxis would be seen or that the response would be modified by drugs known to act at the adrenergic nerve terminals. The phenomena described here may have practical clinical consequences. If tachyphylaxis develops in man it may be that only the first injection of pancuronium will produce undesirable increases in arterial pressure. If the avoidance of the hypertension were desirable, the pressor response might be blocked by pretreatment with drugs such as guanethidine or reserpine which act directly on the adrenergic receptors. Dangerous drug

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ACP (mm Hg)

SYMPATHOMIMETIC EFFECT OF PANCURONIUM

1147

dp 'di (mmHg'i)1600f i

LVP (mm Hg) 100 50 0

CVP (cmH2O)

J20

7

[ 1 min Control

Dimethylimipramine 0.3 mg/kg

Noradrenaline Pancuronium bromide Infusion 7 /ig/ml/min 0.2 mg/kg

FIG. 5. Dimethylimipramine (Desipramine) 0.3 mg/kg administered before the infusion of noradrenaline. No pressor response to pancuronium 90 min later. Buckett, W. R., and Bonta, I. L. (1966). Pharmacological studies with NA97 (2|3,16p-dipiperidino-5a-androstane3a,17p-diol diacetate dimethobromide). Fed. Proc, 25 218. Harrison, G. A. (1972). The cardiovascular effects and some relaxant properties of four relaxants in patients about to undergo cardiac surgery. Br. J. Anaesth., 44, 485. Komesaroff, D. (1970). Further clinical studies on pancuronium bromide. I I : A study of the effects on the blood pressure and pulse rate. Med. J. Aust., 11, 497. Levin, N., and Dillon, J. B. (1971). Cardiovascular effects of pancuronium bromide. Anesth. Analg. (Cleve.), 50,508. Loh, L. (1970). The cardiovascular effects of pancuronium bromide. Anaesthesia, 25, 356. Lubke, P. and Dannemann, H. J. (1971). Uber den Einfluss von Pancuroniumbromid auf das Herz-Kreislauf REFERENCES verhalten in Neuroleptanalgesie. Anaeslhesist, 20, 402. Axelrod, J. (1963). The formation, metabolism, uptake, Nana, A., Cardan, E., and Domokos, M. (1973). Blood and release of noradrenaline and adrenaline j in The catecholamine changes after pancuronium. Ada AnaesClinical Chemistry of Monoamines, 1st edn, p. 5, Amsterthesiol. Scand., 17, 83. dam: Elsevier Publishing Co. Nightingale D. A., and Bush, G. H. (1973). A clinical Whitby, L. G., and Herring, G. (1961). Effect of comparison between tubocurarine and pancuronium in psychotropic drugs on the uptake of 3H-noradrenaline children. Br. J. Anaesth., 45, 63. by tissues. Science, 133, 383. Saini, R. K., and Sharma, P. L. (1971). Effect of some adrenergic betareceptor antagonists of the action of Buckett, W. R. (1968). The pharmacology of pancuronium d-tubocurarine and pancuronium bromide. Ind J. Med. bromide a new non-depolarising neuromuscular blocking Res., 59, 1104. agent. Irish J. Med. Sci., 12, 565.

interactions may occur in patients treated with desipramine, which enhances the pressor effect of pancuronium. Similar problems might occur in patients treated with monoamine oxidase inhibitors which increase the noradrenaline stores in the nerve terminals. Patients anaesthetized with ether, in whom there is increased sympathetic activity, and patients anaesthetized with agents which sensitize the heart to catecholamines, may pose a problem also. Finally, the patient with a phaeochromocytoma may exhibit a profound pressor response to pancuronium.

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ACP (mmHg)

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1148 Saxena, P. R., and Bonta, I. L. (1970). Mechanism of selective cardiac vagolytic action of pancuronium bromide. Specific blockade of cardiac muscarinic receptors. Eur. J. Pharmacol., 3, 332. Smith, G., Proctor, D. W., and Spence, A. A. (1970). A comparison of some cardiovascular effects of tubocurarine and pancuronium in dogs. Br. J. Anaeslh., 42, 923. LE BROMURE DE PANCURONIUM: AGENT SYMPATHICOMIMETIQUE INDIRECT RESUME

PANCURONIUM-BROMID: EIN INDIREKTES SYMPATHOMIMETISCHES MITTEL ZUSAMMENFASSUNG

Bei einem Hund wurde durch eine Dosis von 0,2 mg/kg Pancuronium der systolische Druck im linken Ventrikel

BROMURO DE PANCURONIO: UN AGENTE SIMPATOMIMETICO INDIRECTO SUMARIO

En el perro, pancuronio 0,2 mg/kg aumento la presion sist61ica ventricular izquierda y la presion arterial general, pero no altero la presi6n venosa central. Dosis repetidas produjeron respuestas decrecientes y eventuahnente ningiin cambio en la presi6n arterial. Despues de establecer taquifilaxis podia inducirse una respuesta presora al pancuronio mediante infusion endovenosa de noradrenalina. La desipramina, un agente bloqueante de noradrenalina, impidi6 la restauracion del efecto presor de noradrenalina. Guanetidina y reserpina abolieron la restauracion de la respuesta presora al pancuronio por la noradrenalina. Estos hallazgos se corresponden con la hipotesis de que el pancuronio actua sobre las terminaciones nervales posganglionares y causa la liberation de noradrenalina.

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Sur les chiens, le pancuronium, a raison de 0,2 mg/kg, a fait augmenter la pression systolique ventriculaire gauche et la tension arterielle systemique, mais n'a pas modifie la pression veineuse centrale. Des doses repetees ont provoque des reactions decroissantes, puis eventuellement aucun changement dans le tension arterielle. Apres tachyphylaxie, on a pu provoquer une reaction pressive au pancuronium par une perfusion intraveineuse de noradrenaline. La desipramine, qui est un agent de blocage de la noradrenaline, a empeche le retour de l'effet pressif de la noradrenaline. La guanethidine et la reserpine ont aboli le retour de la reaction pressive au pancuronium par la noradrenaline. Ces resultats sont conformes a l'hypothese que le pancuronium agit sur les terminaisons des nerfs postganglioniques et provoque le degagement de la noradrenaline.

und der systemische arterielle Druck erhSht, nicht aber der zentralvenose Druck. Wiederholte Dosen ergaben verringerte Reaktionen und fuhrten schliesslich zu keiner Anderung des arteriellen Druckes mehr. Nach Entstehen von Tachyphylaxe konnte durch intraven6se Infusion von Noradrenalin eine blutdruckerhOhende Reaktion auf Pancuronium eingeleitet werden. Desipramin, ein Noradrenalin-Blockierungsmittel, verhinderte die Wiederherstellung des blutdruckerhShenden Effekts von Noradrenalin. Durch Guanethidin und Reserpin wurde die Wiederherstellung dieses Effekts auf Pancuronium durch Noradrenalin eliminiert. Diese Ergebnisse entsprechen der Hypothese, dass Pancuronium auf die retroganglionaren Nervenenden einwirkt und die Freigabe von Noradrenalin verursacht.