SOME PHARMACOLOGICAL FACTORS INFLUENCING THE ABSORPTION OF DIAZEPAM FOLLOWING ORAL ADMINISTRATION

Transcription

1 Br.J. Anaesth. (1976), 48, 1181 SOME PHARMACOLOGICAL FACTORS INFLUENCING THE ABSORPTION OF DIAZEPAM FOLLOWING ORAL ADMINISTRATION J. A. S. GAMBLE, J. H. GASTON, S. G. NAIR AND J. W. DUNDEE SUMMARY Plasma diazepam concentrations were measured by gas-liquid chromatography in samples of blood from adult female patients following diazepam mg orally, alone or in combination with metoclopramide, morphine, pethidine or atropine. Patients receiving metoclopramide had higher plasma diazepam concentrations than those in the control group, while the addition of morphine, pethidine or atropine resulted in lower plasma diazepam concentrations throughout the 90-min period of the study. In the control group peak plasma concentrations were reached by 60 min. The addition of metoclopramide increased the rate of diazepam absorption and peak concentrations were reached by 30 min, while morphine, pethidine and atropine reduced the rate of absorption with no apparent peak being reached by 90 min. Following the oral administration of a drug, several factors influence its absorption. These include the rate of disintegration and dissolution, and the gastrointestinal activity. The first two factors are related to the formulation and physical properties of the drug, while the latter is influenced by a variety of physiological and pharmacological factors. A large number of drugs, either by a direct action on the intestinal tract or indirectly via the autonomic nervous system, alter gastrointestinal motility. Thus they may influence the gastrointestinal absorption of concurrently administered drugs. We have investigated the influence of various commonly used drugs metoclopramide, morphine, pethidine and atropine on the absorption of diazepam given by the oral route. Metoclopramide was included because of claims that it enhances gastric emptying (James and Hume, 1968; Nimmo et al., 1973) while the other drugs are used commonly for preanaesthetic medication. METHODS Sixty-seven adult female patients scheduled for minor gynaecological operations were investigated. Their weights were within the range kg and all were less than 60 years of age. All patients were in the American Society of Anesthesiologists classification of physical fitness grades 1 or 2. Patients with a history of gastrointestinal disease were excluded as J. A. S. GAMBLE, M.D., F.F.A.R.C.S.; J. H. GASTON, M.B., F.F.A.R.C.S.; S. G. NAIR, M.B., M.S., F.F.A.R.C.S., D.A.; J. W. DUNDEE, M.D., PH.D., F.F.A.R.C.S., M.R.C.P.; Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland. Diazepam with Metoclopramide mg i.v. Morphine mg i.m. Pethidine 0 mg i.m. Atropine 0.6 mg i.m. Atropine 0.6 mg i.v. TABLE I. Details of patients Number 12 Average age (yr) Average weight (kg) were any who had taken diazepam within the previous 4 weeks. Details of the patients, dose regime and route of administration are shown in table I. The patients were fasted for at least 6 h before the investigation. The dose of diazepam was mg for all patients, given with a small sip of water. Patients receiving morphine mg or pethidine 0 mg were given the narcotic i.m. 60 min before oral diazepam. Those receiving metoclopramide or atropine did so with the diazepam. Metoclopramide was given as a -mg dose i.v. and the effect of atropine 0.6 mg was studied using the i.v. and i.m. routes. Following insertion of an 18-s.w.g. i.v. cannula (Medicut) 5 ml of blood was sampled before (control) and at, 30, 45, 60 and 90 min following diazepam. (The 45-min samples were omitted in the control group and the 90-min samples in the metoclopramide group.) The blood was placed in a heparinized tube,

2 1182 BRITISH JOURNAL OF ANAESTHESIA stored in a refrigerator at 4 C, and centrifuged within 1 h. Following centrifugation, the plasma was stored at 20 C until analysed. All samples were analysed in duplicate using tie method described by Gamble and colleagues (1975). RESULTS Table II and figures 1 and 2 show the mean plasma diazepam concentrations, while figure 3 shows the average "peak" diazepam concentrations reached by 90 min in the various series. Metoclopramide. Plasma diazepam concentrations increased rapidly in the patients who received metoclopramide, reaching a peak by 30 min; they were significantly higher than the control group at and 30 min. The peak plasma concentrations (average 335 ± 32 ng/ml) occurred earlier in the patients who received metoclopramide than in the control group (average ng/ml); the difference between these is highly significant (P<0.02). Morphine and pethidine. Both narcotics delayed the absorption of diazepam, the administration of morphine resulting in significantly lower plasma concentrations throughout the 90-min period. The average concentrations were lower also, but not significantly so when pethidine was given, although the mean peak plasma concentrations were significantly less after the narcotics (P< for morphine ng/ml O ALONE» + ATROPINE I.M. A + ATROPINE I.V. MINUTES FIG. 1. Mean ± SEM plasma diazepam concentrations over the first 90 min following diazepam mg orally, alone or in combination with metoclopramide, pethidine or morphine. FIG. 2. Mean + SEM plasma diazepam concentrations over the first 90 min following diazepam mg orally alone or in combination with intravenous or intramuscular atropine. TABLE II. Mean ( + SEM) plasma diazepam concentrations {ngjml) over the first 90 min following diazepam mg orally alone or accompanied by various drugs. The probability of the differences in the concentrations between the control and the other groups having occurred by chance is indicated by the P value Minutes Diazepam with Number Metoclopramide Morphine Pethidine Atropine i.m. Atropine i.v * 12 ±5.8* * ** ** ±.5* ± ±12.6** ** 194 ±22.6 5±11.8** 135 ± * P<0.05; ** P< 0.005; no sample analysed.

3 PHARMACOLOGICAL INFLUENCES ON DIAZEPAM ABSORPTION PLASMA DIAZEPAM ng/ml I CONTROL I METOCLOPRAMIDE PETHIDINE MORPHINE ATROPINE I.M. ATROPINE I.V. FIG. 3. Mean±SEM peak plasma diazepam concentration reached by 90 min following diazepam mg orally alone or in combination with one of several drugs. and < 0.02 for pethidine) than in the control series. Following oral diazepam, the average peak plasma concentrations were reached by 60 min following administration, decreasing by 90 min. When preceded by either morphine or pethidine, the plasma diazepam concentrations increased slowly throughout the 90-min period. Atropine. The addition of atropine, given by either route, resulted in lower plasma diazepam concentrations throughout the 90-min study, these being decreased significantly for the first 60 min following i.v. atropine. The peak concentrations were also decreased significantly after i.v. (P< 0.005) and i.m. (P< 0.02) atropine. DISCUSSION The finding of an increased rate of absorption of diazepam when given with metoclopramide is in keeping with the results found with other drugs. Manninen and others (1973) have shown that metoclopramide hastens the absorption of digoxin and Nimmo and others (1973) reported similar results with paracetamol. In radiographic studies James and Hume (1968) demonstrated that metoclopramide promotes gastric emptying and accelerates the transit of barium through the small intestine. Thus it would appear that the increased plasma diazepam concentrations were a result of more rapid entry of the drug into the small intestine. The decrease in plasma diazepam concentrations was more marked following morphine than with the other drugs studied. Undoubtedly, the decreased rate of absorption of diazepam following the administration of morphine was a result of delayed gastric emptying. It is well known that morphine slows gastric emptying, and it may delay the passage of gastric contents through the duodenum for as long as 12 h (Jaffe, 1970). Whether this effect is mediated via the vagi or is a direct action on the stomach wall is unclear. This investigation shows also that pethidine, less than morphine, decreased the absorption of diazepam. Nimmo, Wilson and Prescott (1975) have shown that pethidine reduces the absorption of paracetamol in women in labour but its effect, relative to morphine, is not known. Narcotic analgesics frequently cause nausea and vomiting as a result of their effect on the chemoreceptor trigger zone in the central nervous system. Vomiting involves the mechanisms of reverse peristalsis and, although in the present study there was no evidence of nausea or vomiting, the delayed absorption of diazepam may have been a result of inhibition of gastrointestinal motility or even minor degrees of reversed peristalsis.

4 1184 BRITISH JOURNAL OF ANAESTHESIA Atropine is used primarily in clinical medicine for its ability to block parasympathetic activity and, in particular, its ability to increase heart rate and reduce salivary and bronchial secretions. Because of the widespread influence of the parasympathetic nervous system throughout the body, blocking it has widespread effects, including a decrease in gastric secretions and slowing of gastric emptying. It is probably an effect on gastric motility which caused the decrease in diazepam absorption in the present study. This applies to other drugs, since Adjepon-Yamoah, Scott and Prescott (1973) found that the concurrent administration of atropine delayed the absorption of lignocaine administered orally. The smaller decrease in plasma diazepam concentrations following i.m. atropine compared with i.v. atropine reflects the time-course of absorption of atropine from muscle. Burchell and Swasdio (1966) have shown, in man, that the maximum effect of i.m. atropine occurs 40 min after drug administration. In conclusion, the maximum effect from oral diazepam cannot be expected when it is combined with either a narcotic or an anticholinergic drug. Metoclopramide may be used to speed the absorption of diazepam, but it seems invidious to give an i.v. injection to speed the uptake of an oral preparation, especially if the latter can be given i.v. ACKNOWLEDGEMENTS We thank the staff of the gynaecological departments of Musgrave Park and Belfast City Hospitals for their cooperation in this study, and Mrs Margaret Kennedy and Mr P. J. Howard for their technical assistance. During this work J. A. S. G. was in receipt of a Research Fellowship from the Royal Victoria Hospital, while part of the technical assistance was provided by a grant from Roche Products Ltd and the Northern Ireland Eastern Health and Social Services Board. REFERENCES Adjepon-Yamoah, K. K., Scott, D. B., and Prescott, L. F. (1973). Impaired absorption and metabolism of oral lignocaine in patients undergoing laparoscopy. Br. J. Anaesth., 45, 143. Burchell, R. C, and Swasdio, K. (1966). Broad ligament absorption of atropine. Obstet. Gynecol., 27, 714. Gamble, J. A. S., Assaf, R. A. E., Mackay, J. S., Kennedy, M. S., and Howard, P. J. (1975). Estimation of plasma diazepam. Critique of a method using gas-liquid chromatography and benzene extraction. Anaesthesia, 30, 9. Jaffe, J. H. (1970). Narcotic analgesics; in The Pharmacological Basis of Therapeutics, (eds L. S. Goodman and A. Gilman), 4th edn, p London: Macmillan. James, W. B., and Hume, R. (1968). Action of metoclopramide on gastric emptying and small bowel transit time. Gut, 9, 203. Manninen, V., Apajalahti, A., Melin, J., and Karesoja, M. (1973). Altered absorption of digoxin in patients given propantheline and metoclopramide. Lancet, 1, 398. Nimmo, J., Heading, R. C, Tothill, P., and Prescott, L. F. (1973). Pharmacological modification of gastric emptying: effects of propantheline and metoclopramide on paracetamol absorption. Br. Med. J., 1, 587. Nimmo, W. S., Wilson, J., and Prescott, L. F. (1975). Narcotic analgesics and delayed gastric emptying during labour. Lancet, 1, 890. QUELQUES FACTEURS PHARMACOLOGIQUES INFLUENCANT L'ABSORPTION DE DIAZEPAM APRES ADMINISTRATION ORALE RESUME Des concentrations de diazepam dans le plasma ont ete mesurees par chromatographie en phase gazeuse/liquide dans des 6chantillons de sang preleves sur des femmes adultes malades apres l'administration orale de mg de diazepam, seul ou en combinaison avec de la metoclopramide, de la morphine, de la pethidine ou de l'atropine. Les patientes ayant recu de la metoclopramide ont accuse de plus fortes concentrations de diazepam dans le plasma que celles du groupe temoin, alors que l'addition de morphine, de pethidine ou d'atropine a eu pour resultat de plus faibles concentrations de diazepam dans le plasma, pendant la periode de 90 min necessaires a l'etude. Dans le groupe temoin, les concentrations dans le plama ont atteint leur crete apres 60 min. L'addition de metoclopramide a fait augmenter le taux d'absorption du diazepam et les concentrations ont atteint leur crete apres 30 min, alors que la morphine, la pethidine et l'atropine ont fait diminuer le taux d'absorption, aucune crete apparante n'ayant et atteinte apres 90 min. EINIGE PHARMAKOLOGISCHE FAKTOREN, DIE DIE ABSORPTION VON DIAZEPAM NACH ORALER VERABREICHUNG BEEINFLUSSEN ZUSAMMENFASSUNG Plasma-Diazepamkonzentrationen wurden mittels Gas- Flussigkeitschromatografie in den Blutproben weiblicher Patientinnen gemessen, nachdem diese oral mg Diazepam entweder allein oder in Verbindung mit Metoclopramid, Morphium, Pethidin oder Atropin erhalten hatten. Patientinnen mit Metoclopramid hatten hohere Plasma-Diazepamkonzentrationen als diese in der Kontrollgruppe, wahrend die Zufugung von Morphium, Pethidin oder Atropin wahrend der gesamten eineinhalbstundigen Versuchsdauer zu geringeren Diazepamkonzentrationen fuhrten. In der Kontrollgruppe wurden die hochsten Konzentrationen nach 60 min erreicht. Die Zufugung von Metoclopramid erhshte das Tempo der Diazepamabsorption, und Spitzenkonzentrationen wurden nach 30 min erreicht, wahrend Morphium, Pethidin und Atropin die Absorptionsrate verringerten, so dass nach 90 min kein erkennbarer Spitzenwert erreicht wurde.

5 PHARMACOLOGICAL INFLUENCES ON DIAZEPAM ABSORPTION 1185 ALGUNOS FACTORES FARMACOLOGICOS QUE INFLUYEN LA ABSORCION DE DIAZEPAM TRAS LA ADMINISTRACION ORAL SUMARIO Se midieron las concentraciones plasmaticas de diazepam mediante cromatografia gas-liquido en muestras de sangre tomadas de pacientes femeninos tras tomar oralmente mg de diazepam, solo o en combination con metoclopramida 5 morfina, petidina o atropina. Las pacientes que recibieron metoclopramida tenian concentraciones mas altas de diazepam en el plasma que las del grupo testigo, mientras que la adicion de morfina, petidina o atropina resulto en concentraciones plasmaticas de diazepam mas bajas durante todo el periodo de estudio de 90 min. En el grupo testigo se alcanzaron concentraciones plasmaticas maximas a los 60 min. La adicion de metoclopramida aumento el indice de diazepam absorbido y se alcanzaron maximas concentraciones a los 30 min. 3 mientras que morfina, petidina y atropina disminuyeron el indice de absorcion sin alcanzarse ninguna maxima aparente en 90 min.