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
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 45-75 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.
TABLE I. Details of patients
Number
(yr)
Average weight (kg)
15
30
59
10
41
62
12
32
59
10
32
57
10
26
57
10
29
56
Average age
Diazepam with Metoclopramide 10 mg i.v. Morphine 10 mg i.m. Pethidine 100 mg i.m. Atropine 0.6 mg i.m. Atropine 0.6 mg i.v.
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 10 mg for all patients, given with a small sip of water. Patients receiving morphine 10 mg or pethidine 100 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 10-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 15, 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,
Downloaded from http://bja.oxfordjournals.org/ at University of Winnipeg on August 12, 2015
Plasma diazepam concentrations were measured by gas-liquid chromatography in samples of blood from adult female patients following diazepam 10 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.
BRITISH JOURNAL OF ANAESTHESIA
1182 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
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 10 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 10 mg orally alone or in combination with intravenous or intramuscular atropine.
TABLE I I . Mean ( + SEM) plasma diazepam concentrations {ngjml) over the first 90 min following diazepam 10 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 Metoclopramide Morphine Pethidine Atropine i.m. Atropine i.v.
Number
15
30
15 10 12 10 10 10
65 + 22.3 218 + 53.6* 12 ±5.8* 32 + 12.0 24 + 7.8 17 + 6.3*
122+18.2 240 + 27.7** 38 + 7.7** 74 + 24.5 92 + 27.7 52 ±15.5*
* P
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
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 45-75 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.
TABLE I. Details of patients
Number
(yr)
Average weight (kg)
15
30
59
10
41
62
12
32
59
10
32
57
10
26
57
10
29
56
Average age
Diazepam with Metoclopramide 10 mg i.v. Morphine 10 mg i.m. Pethidine 100 mg i.m. Atropine 0.6 mg i.m. Atropine 0.6 mg i.v.
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 10 mg for all patients, given with a small sip of water. Patients receiving morphine 10 mg or pethidine 100 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 10-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 15, 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,
Downloaded from http://bja.oxfordjournals.org/ at University of Winnipeg on August 12, 2015
Plasma diazepam concentrations were measured by gas-liquid chromatography in samples of blood from adult female patients following diazepam 10 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.
BRITISH JOURNAL OF ANAESTHESIA
1182 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
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 10 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 10 mg orally alone or in combination with intravenous or intramuscular atropine.
TABLE I I . Mean ( + SEM) plasma diazepam concentrations {ngjml) over the first 90 min following diazepam 10 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 Metoclopramide Morphine Pethidine Atropine i.m. Atropine i.v.
Number
15
30
15 10 12 10 10 10
65 + 22.3 218 + 53.6* 12 ±5.8* 32 + 12.0 24 + 7.8 17 + 6.3*
122+18.2 240 + 27.7** 38 + 7.7** 74 + 24.5 92 + 27.7 52 ±15.5*
* P
