In vitro and in vivo neuromuscular effects of atracurium and rocuronium in rats treated with carbamazepine for seven days

Abstracts

JUSTIFICATIVA E OBJETIVOS: Trata-se de um estudo experimental que investigou in vitro e in vivo o bloqueio neuromuscular produzido pelo rocurônio e atracúrio em ratos tratados com carbamazepina e determinou as concentrações de citocromo P450 e b5 redutase em microssomos hepáticos. MÉTODO: Ratos foram tratados por sete dias com carbamazepina (CBZ) - 40 mg.kg-1 pelo método de gavagem e sacrificados no oitavo dia sob anestesia com uretana. As preparações in vitro e in vivo foram montadas de acordo com as técnicas de Bulbring e de Leeuwin e Wolters, respectivamente. As concentrações e doses utilizadas dos bloqueadores nas preparações in vitro e in vivo foram, respectivamente, 20 µg.mL-1 e 0,5 mg.kg-1 para atracúrio (ATC); 4 µg.mL-1 e 0,6 mg.kg-1 para rocurônio (ROC). Cada protocolo teve um n = 5 e as respostas foram observadas por 60 minutos. Os efeitos do ATC e ROC foram avaliados nas preparações de ratos tratados (Cbz t) e comparados com os observados nas de ratos não-tratados (CBZst). As concentrações de citocromo P450 e b5 redutase foram determinadas em microssomos isolados de fígados de ratos tratados (CBZt) e comparadas com as obtidas em ratos não tratados (CBZst). RESULTADOS: A carbamazepina não alterou a amplitude das respostas musculares; in vitro e in vivo, não houve diferença entre o bloqueio neuromuscular produzido pelo atracúrio nas preparações CBZt versus CBZst; o bloqueio neuromuscular produzido pelo rocurônio nas preparações CBZt foi potencializado in vitro. A carbamazepina não alterou as concentrações de citocromo P450 e b5. CONCLUSÕES: O tratamento por sete dias com carbamazepina não influenciou no bloqueio produzido pelo atracúrio, e alterou in vitro os efeitos do rocurônio. O tempo de tratamento não foi suficiente para causar indução enzimática e diminuir a sensibilidade ao rocurônio.

ANIMAIS: ratos; ANTICONVULSIVANTE: carbamazepina; BLOQUEADORES NEUROMUSCULARES, adespolarizante

SCIENTIFIC ARTICLE

In vitro and in vivo neuromuscular effects of atracurium and rocuronium in rats treated with carbamazepine for seven days

Efectos neuromusculares in vitro e in vivo del atracurio y del rocuronio en ratones sometidos a tratamiento de siete días con carbamazepina

Caroline Coutinho de Barcelos^I; Angélica de Fátima de Assunção Braga, TSA^II; Franklin Sarmento da Silva Braga^III; Gloria Braga Potério, TSA^II; Samanta Cristina Antoniassi Fernandes^I; Yoko Oshima Franco^IV; Léa Rodrigues Simioni^V

^IMestra em Farmacologia pelo Curso de Pós-Graduação do Departamento de Farmacologia da FCM-UNICAMP

^IIProfessora-Associada do Departamento de Anestesiologia da FCM-UNICAMP

^IIIProfessor-Doutor do Departamento de Anestesiologia da FCM-UNICAMP

^IVPesquisadora Colaboradora Voluntária do Departamento de Farmacologia da FCM-UNICAMP

^VProfessora-Associada do Departamento de Farmacologia da FCM-UNICAMP

^{Correspondence to}

SUMMARY

BACKGROUND AND OBJECTIVES: This experimental study investigated the in vitro and in vivo neuromuscular blockade of rocuronium and atracurium in rats treated with carbamazepine and determined the concentration of cytochrome P450 and b5 reductase in hepatic microsomes.

METHODS: Rats were treated with carbamazepine (CBZ) – 40 mg.kg^-1 by gavage and sacrificed on the eighth day under anesthesia with urethane. In vitro and in vivo preparations followed the techniques of Bulbring and Leeuwin and Wolters, respectively. Concentrations and doses of the neuromuscular blockers used in in vitro and in vivo preparations were, respectively, 20 µg.mL^-1 and 0.5 mg.kg^-1 for atracurium (ATC); and 4 µg.kg^-1 and 0.6 mg.kg^-1 for rocuronium (ROC). Each protocol had an n = 5 and the response was observed for 60 minutes. The effects of ATC and ROC were evaluated in the preparations of rats treated with carbamazepine (CBZ_t) and compared to those of non-treated rats (CBZ_st). The concentration of cytochrome P450 and b5 reductase were determined in hepatic chromosomes of rats treated with carbamazepine (CBZ_t) and non-treated rats (CBZ_st).

RESULTS: Carbamazepine did not change the amplitude of neuromuscular response; differences in the neuromuscular blockade produced by atracurium in CBZ₁ preparations were not observed, in vitro or in vivo, when compared with CBZ_st; the neuromuscular blockade produced by rocuronium in CBZ_t preparations was potentiated in vitro. Carbamazepine did not change the concentrations of cytochrome P450 and b5.

CONCLUSIONS: Seven-day treatment with carbamazepine did not change the neuromuscular blockade produce by atracurium, but altered the in vitro effects of rocuronium. The duration of the treatment was not enough to cause enzymatic induction and decrease the sensitivity to rocuronium.

Key Words: ANIMALS, rats; ANTICONVULSANTS, carbamazepine; NEUROMUSCULAR BLOCKERS, non-depolarizing: atracurium, rocuronium.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Se trata de un estudio experimental que investigó in vitro e in vivo el bloqueo neuromuscular producido por el rocuronio y atracurio en ratones tratados con carbamazepina y determinó las concentraciones de citocromo P450 y b5 reductasis en microsomas hepáticos.

MÉTODO: Ratones fueron tratados por siete días con carbamazepina (CBZ) – 40 mg.kg^-1 a través de una sonda y sacrificados al octavo día bajo anestesia con uretana. Las preparaciones in vitro e in vivo fueron montadas de acuerdo con las técnicas de Bulbring y de Leeuwin y Wolters, respectivamente. Las concentraciones y dosis utilizadas de los bloqueadores en las preparaciones in vitro e in vivo fueron, respectivamente, 20 µg.mL^-1 y 0,5 mg.kg^-1 para atracurio (ATC); 4 µg.mL^-1 y 0,6 mg.kg^-1 para rocuronio (ROC). Cada protocolo tuvo un n = 5 y las respuestas fueron observadas por 60 minutos. Los efectos del ATC y ROC fueron evaluados en las preparaciones de ratones tratados (Cbz_t) y comparados a los observados en los de ratones no tratados (CBZ_st). Las concentraciones de citocromo P450 y b5 reductasis fueron determinadas en microsomas aislados de hígados de ratones tratados (CBZ_t) y comparadas con las obtenidas en ratones no tratados (CBZ_st)

RESULTADOS: La carbamazepina no alteró la amplitud de las respuestas musculares; in vitro y in vivo, no hubo diferencia entre el bloqueo neuromuscular producido por el atracurio en las preparaciones CBZ_t versus CBZ_st; el bloqueo neuromuscular producido por el Rocuronio en las preparaciones CBZ_t fue potenciado in vitro. La carbamazepina no alteró las concentraciones de citocromo P450 y b5.

CONCLUSIONES: El tratamiento por siete días con carbamazepina, no influenció en el bloqueo producido por el atracurio, y alteró in vitro los efectos del rocuronio. El tiempo de tratamiento no fue suficiente para causar la inducción enzimática y disminuir la sensibilidad al rocuronio.

INTRODUCTION

Several drugs used in the pre or perioperative period can interfere with the neuromuscular transmission or with the pharmacokinetic and pharmacodynamic characteristics of neuromuscular blockers, decreasing or potentiating their effects. Among the drugs that could alter the effects of neuromuscular blockers are local anesthetics, inhalational anesthetics, aminoglycosides, anticonvulsants, antiarrhythmic agents, magnesium, lithium, calcium channel blockers and others ^1-7.

Anticonvulsants are widely used in the treatment of seizures, bipolar disorder and different forms of neuropathy and among those used more often are phenytoin, vigabatrin, carbamazepine, valproates, phenobarbital and lamotrigine ^8-12. The blockade of voltage-gated sodium channels represents the primary action of those agents. It reduces the electrical excitability of cell membranes necessary to generate an action potential ¹⁰. Additionally, due to the inhibition of GABA transaminase, they potentiate the synaptic inhibition mediated by GABA ^8-10. It seems that the action of some of those drugs occurs via a third mechanism, the inhibition of type L calcium channels and other subtypes of voltage-gated calcium channels ^8,10.

Carbamazepine, a derivative of tricyclic antidepressants, is effective in the treatment of partial complex seizures and it is also used in the treatment of different types of neuropathic pain including diabetic neuropathic pain ^11,12. Currently, it is one of the most used anticonvulsant agent and occasionally it is also useful in the treatment of manic-depressive disorder ⁸.

Although several studies have investigated the effects of anticonvulsants in the neuromuscular response and their interaction with neuromuscular blockers, the results are conflicting. Some studies have demonstrated that anticonvulsants modify the response to neuromuscular blockers, potentiating, decreasing, or not interfering with it ^13-19. Therefore, the study of those interactions can be interesting in the anesthetic practice or in critical patients. The present study was done in rats treated with carbamazepine for seven days (CBZ_t) and non-treated (CBZ_st) rats and its objective was to evaluate, in vitro and in vivo: the effects of carbamazepine on the neuromuscular transmission and its influence on the neuromuscular blockade produced by atracurium and rocuronium; and determine the concentrations of cytochrome P450 and b5 reductase in hepatic microsomes.

METHODS

This is an in vitro and in vivo experimental study and the procedures are in accordance with the ethical principles for animal experiments of the Colégio Brasileiro de Experimentação Animal (COBEA) and were approved by the Ethics Commission on Animal Experiments of the Instituto de Biologia of the Universidade Estadual de Campinas. Male Wistar rats weighing 180 to 250 g, provided by the Biotério Central da Unicamp, Campinas (SP) were used in this study. Animals were treated with carbamazepine by gavage for seven days, they were kept in cages with controlled temperature and illumination (12 hours light and 12 hours darkness) and received water and food ad libitum.

Study of the neuromuscular response

For the in vitro study, the rat phrenic nerve-hemidiaphragm (FND) was used. Animals (n = 5) were sacrificed under anesthesia with urethane (1.2 mg.kg^-1, intraperitoneal) on the eighth day and prepared according to the technique described by Bulbring ²¹. The hemidiaphragms, along with the corresponding phrenic nerves, were removed and preserved in a bowl containing 40 mL of Tyrode's solution with the following in mM composition: NaCl 137; KCl 2.7; CaCl₂ 1.8; NaHCO₃ 11.9; MgCl₂ 0.25; NaH₂PO₄ 0.3; and glucose 11. The preparation was constantly aired with carbogen (95% O₂ + 5% CO₂) and maintained at 37° C. The nerve was placed on platinum electrodes connected to a Grass 548 stimulator. The diaphragm was under constant tension (5 g), with its tendinous connected to a wire and that to an isometric Load Cell BG50 GMS transducer and subjected to indirect stimulation of 0.1 Hz for 0.2 msec, and muscular responses were recorded in a Gould RS 3400 physiographer.

The technique proposed by Leeuwin and Wolters ²² was used for the in vitro study. Rats were anesthetized with urethane (1.2 mg.kg^-1), a tracheostomy was done and they were maintained in mechanical ventilation with a Hugo Basile respirator (mod. 7025) set to maintain a tidal volume of 1.2 mL.kg^-1 of body weight and respiratory rate of 70 bpm. After dissection and section of the tendon of the anterior tibialis muscle and the sciatic nerve, trepanation of the tibia was done in order to fix the inferior member to a cork base. The tendon of the anterior tibialis muscle was connected to an isometric transducer (BG 50g) and the transducer was connected to the physiographer (Gould RS 4300). The distal stump of the sciatic nerve was stimulated (Grass S48 stimulator) through electrodes connected to it, using supramaximal stimuli of 0.2 ms and 0.5 Hz. After recording the control response and the perfect status of the preparation was verified, atracurium and rocuronium were injected through the penial vein.

In the in vitro studies, the concentrations of atracurium and rocuronium used were 20 µg.mL^-1 and 4 µg.mL^-1, respectively; in vivo, 0.5 mg.kg^-1 and 0.6 mg.kg^-1, respectively. The concentrations used were based on the degree of blockade produced by the drugs after obtaining the dose-response curve (not shown). Muscular responses were recorded before and every 15 minutes for 60 minutes after the administration of the study drug.

In vitro and in vivo the following parameters were evaluated: 1) amplitude of the muscular response in preparations of rats treated with carbamazepine; 2) the effect of atracurium and rocuronium on the muscular response in preparations of rats treated with carbamazepine (CBZ_t) and not treated (CBZ_st).

Determination of the concentration of cytochrome P450 and b5 reductase

To determine the concentration of cytochrome P450 and b5 reductase on hepatic microsomes, the livers of CBZ_t rats (G2) used in in vitro and in vivo study of the muscular response were used. A control group – G1 (CBZ_st, n = 5), was composed by rats that received only normal saline for seven days. The following procedure was undertaken: exposure of the liver through a ventral incision; with the aid of a catheter, 50 mL of normal saline without heparin were injected in the cardiac ventricle, until the liver became whitish, at which time it was removed and frozen in liquid nitrogen. Hepatic microsomes were isolated from individual livers. Tissues were homogenized by hand with a potassium phosphate buffer and centrifuged at 10,000 x g for 20 minutes (Beckman Avanti J-20 XPI centrifuge). The supernatant was separated and ultracentrifuged at 100,000 x g for 1 hour. Microsomes were stored in a freezer at -80°C for posterior determination of total proteins, in which the Bradford colorimetric method (1976) was used with BSA as the standard. The specific concentrations of cytochrome P450 and b5 were determined using the concentration of b5 reduced by NADH (1 mM), and the concentration of P450 reduced by DTN (2 mM) and CO (carbon monoxide) as a ligand. A plate spectrophotometer (Biotek Powerwave 2) was used for the analysis. The concentration of cytochromes was calculated according to the Lambert-Beer formula (A/C.L.e) and related to the concentration of total proteins in the microsome sample, in which:

A = delta absorbance

e = specific absorbance: P450 = 91 / mM cm and b5 = 112 / mM cm;

L = optical path of the small vat, cm;

C = concentration of microsomal proteins (mg protein.mL^-1).

Results are expressed as mean and standard deviation. The amplitude of the muscular response was compared before and 60 minutes after the administration of the drugs. The concentrations of P450 and b5 reductase obtained in liver rats treated with carbamazepine (CBZ_t) were compared with those of the control group (normal saline, CBZ_st). The Student's t test was used assuming a level of significance of 5% (a = 5%). The test power was calculated, obtaining b > 20% (power > 80%).

RESULTS

Muscular response

In the in vitro (rat phrenic nerve-hemidiaphragm) and in vivo (external sciatic-popliteal nerve - anterior tibialis muscle) preparations of rats exposed to carbamazepine (40 mg.kg^-1) there were no significant changes in the amplitude of the muscular response to indirect stimulation (Figures 1 and 2).

In vitro, the neuromuscular blockade produced by atracurium in preparations of treated rats (CBZ_t) was 70.0 ± 8.16%, which was not statistically different from that obtained (74.7 ± 5.05%) in preparations of untreated rats (CBZ_st) (Figure 3).

As for rocuronium, in CBZ_t rats the neuromuscular blockade was of 85.3 ± 17.52% versus 59.7 ± 20.1% in CBZ_st rats and this difference was statistically significant (p = 0.0003) (Figure 4).

Figure 5

In in vivo experiments, the neuromuscular blockade produced by atracurium in CBZ_t rats was of 56.87 ± 9.73%, which was not statistically different than that produced in CBZ_st rats (56.5 ± 12.0) (Figure 6).

In CBZ_st rats, the neuromuscular blockade induced by rocuronium was 78.9 ± 18.39%, which was not statistically different than CBZ_t rats (65.8 ± 6.92) (Figure 6).

Concentration of cytochrome P450 and b5 reductase

The concentration of cytochrome P450 and b5 reductase in hepatic microsomes in both groups (CBZ_t and CBZ_st) was: CBZ_st (0.43 and 0.45 nmol/mg of protein, respectively); CBZ_t (0.39 and 0.37 nmol.mg^-1, respectively), but this difference was not statistically significant (Figure 7).

DISCUSSION

There is evidence that the pharmacokinetic and pharmacodynamic properties of neuromuscular blockers can be modified by factors such as age, acid-basic status, temperature, different pathologies (burns, disorders of the upper and inferior neurons), and drugs ^1,6,7. Among the drugs used in the pre or perioperative period, some can interfere, or not, in neuromuscular transmission potentiating or attenuating the effects of neuromuscular blockers.

Changes in the response to those drugs can be secondary to changes in distribution, metabolism and elimination, as well as at the level of the neuromuscular junction proximal to the central nervous system or in the muscular membrane. In the neuromuscular junction, the interaction can be due to their action on the nerve ending, in the synaptic cleft, or in the post-synaptic membrane, with consequent change in the action potential of the nerve, synthesis, release or enzymatic hydrolysis of acetylcholine, calcium efflux or even due to changes in the number and sensitivity of nicotinic receptors besides being able to cause non-competitive blockade of ion channels. Those factors influence the pharmacology of neuromuscular blockers increasing or decreasing and prolonging or shortening the muscular blockade ^{6,15,20,23-26}.

Among those drugs, anticonvulsants, widely used in the treatment of seizures, bipolar disorder, trigeminal neuralgia and diabetic neuropathy ^8-12 can, by themselves, interfere with the neuromuscular junction, change, or not interfering at all with the pharmacodynamic and pharmacokinetic properties of neuromuscular blockers ^13-19,25-34. Pharmacologic and clinically, carbamazepine is similar to phenytoin, but with fewer undesirable effects and, although effective and useful in the treatment of partial complex seizures, it is also used in the treatment of several types of neuropathic pain. Among the adverse effects, muscular weakness which might result in spontaneous or evoked reduction in the quantal release of acetylcholine ^9,32 is frequent. Additionally, those drugs also affect the membrane of the nerve ending in a manner similar to curare ³⁵. It is a potent inducer of hepatic microsomal enzymes and consequently it has important drug interaction by accelerating the metabolism of several drugs such as oral contraceptives, corticosteroids, phenytoin, warfarin and neuromuscular blockers especially the aminosteroids ^6,9,19,24,25. Although the inhibition of calcium channels and glutamate receptors is involved in the effects of several anticonvulsants the main mechanism of action of carbamazepine seems to be due to changes in membrane excitability through the inhibition of voltage-gated sodium channels that transport the current to the interior of the cell which is necessary for the generation of an action potential ^9,36.

Atracurium, a benzylisoquinoline non-depolarizing neuromuscular blocker is a racemic mixture of ten isomers. It is metabolized in the plasma which includes hydrolysis by specific esterases and a self-degradation known as Hofmann elimination, pH and temperature-dependent, constituting a huge advance because its degradation is not affected by organic dysfunction. Rocuronium is an aminostreroid non-depolarizing neuromuscular blocker and contrary to atracurium the end of its action depends, mainly, on distribution, hepatic uptake and elimination mainly biliary of the unaltered drug ³⁷.

Prior studies ^38-39 using in vitro nerve-muscle preparations, in vivo animal models and clinical assays in humans demonstrated that the neuromuscular blockade produced by different neuromuscular blockers, such as d-tubocurarine, vecuronium and rocuronium is potentiated by the acute administration of several anticonvulsants. Potentiation of pre-existing neuromuscular blockade secondary to the acute administration of anticonvulsants can be attributed to the competition between those drugs and neuromuscular blockers, dislocating them from their binding sites in plasma proteins, with the consequent increase in the active free fraction ³⁹. Other mechanisms have been described in an attempt to explain this potentiation and it was observed that some anticonvulsants have pre and post-junctional blocking effects, stabilize the neuronal membrane, altering the transmembrane flow of sodium, potassium and calcium besides reducing the synthesis and release of acetylcholine ^7,39,40. However, other studies have demonstrated that except for atracurium and mivacurium the potency and duration of action of most neuromuscular blockers are reduced in patients in chronic use of anticonvulsants, such as carbamazepine and phenytoin ^{15,25-27,29,41}.

In the present study it was observed in both experiments that the concentration of carbamazepine used did not cause significant changes in the amplitude of the muscular responses, conflicting with other studies that have reported direct depressor effects of carbamazepine in the neuromuscular junction ³³. Aldernice and Trommer ³³ evaluated the direct effects of different anticonvulsants on the frog neuromuscular junction and observed that contrary to phenobarbital, carbamazepine decreased the releasing of neurotransmitter with the consequent reduction in the amplitude of the end-plate potential.

The effects of atracurium both in vivo and in vitro were not influenced by carbamazepine. The influence of anticonvulsants in the neuromuscular blockade produced by atracurium is controversial. Some authors observed that patients in chronic treatment with phenytoin and carbamazepine did not show resistance to atracurium ^17,25,42 contrary to the results reported by Tempelhoff et al. ¹⁶ who reported a shorter duration of action of atracurium in epileptic patients treated with phenytoin and/or carbamazepine. The opposing results observed can be attributed to the methodologies used and different times of exposure to the anticonvulsants ^16,17,25,42.

In the present study, the period of seven days was not enough to produce enzymatic induction but, according to prior studies, the fact that the effects of atracurium are not influenced by anticonvulsants is not related with changes in hepatic metabolism since their metabolism is organ-independent ^17,25,43.

As for rocuronium, contrary to the in vivo experiments, in vitro promoted a greater degree of muscular blockade in preparations of rats treated with carbamazepine when compared to that obtained in non-treated rats, which is similar to the behavior reported after the acute exposure to anticonvulsants ^39,40. Those results, which are different than the results reported in the literature, can be explained by the fact that seven days were not enough to cause changes in the neuromuscular junction and enzymatic induction capable of reducing the degree and duration of the neuromuscular blockade produced by neuromuscular blockers, especially the aminosteroids.

There is evidence that the sensitivity to aminosteroid neuromuscular blockers in patients in chronic treatment with anticonvulsants is decreased. This reduced sensitivity to neuromuscular blockers is not clearly established. The etiology of this interaction seems to be multifactorial and the mechanisms most likely to be involved are: enzymatic induction, with an increase in hepatic metabolism and clearance, increased inactivation and elimination of those drugs; increased concentration of acid a₁-glycoprotein, resulting in greater protein binding, reduced fraction of free cationic drugs and change in distribution; reduced sensitivity of the receptor to acetylcholine; proliferation of receptors in the muscular membrane ^{6,13,17,19,25,32,34,41,44-50}.

The attempt to correlate the in vitro results with clinical practice is a difficult task and for this reason in vivo assays, more appropriate in the pharmacological study of drugs, were undertaken.

The results allow the conclusion that the time of exposure to carbamazepine was not sufficient to cause enzymatic induction and/or changes that hindered the effects of neuromuscular blockers. Therefore, one can infer that there was an acute interaction between carbamazepine and rocuronium, justifying the greater degree of neuromuscular blockade, demonstrating the importance of monitoring neuromuscular transmission when neuromuscular blockers and carbamazepine are used concomitantly.

REFERENCES

Submitted em 26 de fevereiro de 2007

Accepted para publicação em 5 de dezembro de 2007

* Received from Departamento de Farmacologia da Faculdade de Ciências Médicas da Unicamp (FCM-UNICAMP), Campinas, SP

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Publication Dates

• Publication in this collection
  11 Mar 2008
• Date of issue
  Apr 2008

History

• Accepted
  05 Dec 2007
• Received
  26 Feb 2007