Br. J. clin. Pharmac. (1975), 2, 509-513
INHIBITION OF GASTRIC EMPTYING AND DRUG ABSORPTION BY NARCOTIC ANALGESICS W.S. NIMMO', R.C. HEADING', J. WILSON2, P. TOTHILL3 & L.F. PRESCOTT' Departments of Therapeutics' , Anaesthetics2 and Medical Physics3, University of Edinburgh, The Royal Infirmary, Edinburgh EH3 9YW
1 The effect of intramuscular pethidine or diamorphine on gastric emptying and the absorption of orally administered paracetamol was assessed in eight normal subjects. 2 Both drugs produced a significant and striking delay in gastric emptying and absorption of paracetamol. 3 It seems inevitable that pethidine and diamorphine will retard the absorption of other orally administered drugs.
Introduction
Methods
In a previous study of obstetric patients, we observed that the administration of narcotic analgesics to women in labour was associated with a striking reduction in the rate of absorption of orally administered paracetamol (Nimmo. Wilson & Prescott, 1975). Since paracetamol absorption is dependent on gastric emptying (Heading, Nimmo, Prescott & Tothill, 1973) it seemed likely that this delay in paracetamol absorption was due to delayed gastric emptying. However, it was not possible to distinguish between the effects of the narcotics themselves and any delay associated with the increasing distress of labour and approaching delivery which constituted the clinical indication for narcotic administration. Although narcotic analgesics undoubtedly have marked effects on the smooth muscle of the gastrointestinal tract and interfere with normal peristalsis (Daniel, Suther land & Bogoch, 1959, Burks & Long, 1967 Cairnie, Kosterlitz & Taylor, 1961) their effects on gastric emptying in man are not clear. A radiological study has suggested that morphine has a diphasic effect, initially stimulating and then inhibiting gastric emptying of a barium sulphate suspension (Crone & Ardran, 1957). Interference with the absorption of orally administered drugs is not a recognised consequence of the clinical use of narcotic analgesics. The magnitude of the effect we observed in the obstetric patients seemed sufficient to justify further study and we have now examined the effects of pethidine and diamorphine on gastric emptying and paracetamol absorption in healthy volunteers to define more precisely the effect of narcotic administration on the absorption of an orally administered drug.
Gastric emptying and paracetamol absorption were measured simultaneously in eight adult male volunteers aged 26 to 39 years. After fasting overnight, each subject drank orange juice (400 ml) containing paracetamol (20 mg/kg) in solution together with 113m In DTPA (300 mCi) as a non-absorbable isotopic marker for the emptying measurement. The drink was consumed within 2 minutes. The gastric emptying rate was determined directly by serial scintiscans of the subject's abdomen and counting the dots in the stomach area (Heading, Tothill, Laidlaw & Shearman, 1971). A quantitation of emptying between the times of ingestion of the drink and performance of the first scan was included (Colmer, Owen & Shields, 1973). After correcting for isotopic decay, the results were expressed as the time taken to empty 50% of the ingested dose from the stomach. Serial blood samples were taken at intervals for 8 h after ingestion for assessment of paracetamol absorption. The plasma was stored frozen and the concentration of unchanged paracetamol was measured by gas-liquid chromatography (Prescott, 1971). Urine was collected for 24 h and where possible, 2 hourly collections were made for the first 12 hours. The total unchanged and conjugated paracetamol in each sample was estimated by gas-liquid chromatography (Prescott,
33
1971). No food, drink or tobacco was permitted for 4 h after ingestion of the solution and the subjects remained supine throughout this period. Each subject was studied on two occasions at least 7 days apart. On one occasion an intramuscular injection of pethidine (150 mg) or diamorphine (10 mg) was given 30 min before the paracetamol
510
W.S. NIMMO, R.C. HEADING, J. WILSON, P. TOTHILL & L.F. PRESCOTT
and on the other occasion subjects received a placebo injection of 0.9% w/v NaCl (saline). Four subjects were given pethidine and four received diamorphine. The order of narcotic and placebo administration was determined on a random basis and the subjects were not told beforehand which injection they would receive. However, following the administration of the active drug. all subjects developed typical narcotic effects such as lightheadedness and drowsiness and were thus aware of the treatment they had received.
Coo
E 7550
-
g25
E ~~50
3< o
Results
Gastric emptying was rapid in all the control studies following placebo injection. The time for 50%o emptying of the ingested solution from the stomach ranged from 4 to 22 min (mean 11.9 min) (Table 1). Paracetamol absorption was correspondingly rapid with a mean peak plasma concentration of 20.0 ,ug/ml occurring 22 min after ingestion (Table 2). After pethidine, however, the mean time for 50o emptying of the ingested solution was prolonged to 89.5 min (Table 1). Similarly, the mean peak paracetamol concentration was only 13.8 ,g/ml and was delayed until 114 min after ingestion (Table 2). The effects of pethidine on gastric emptying and paracetamol absorption in one subject are shown in Figure 1.
100
l50
Time after ingestion(mi)
10)20
Time after ingestion (min) Figure 1 The effect of pethidine (150 mg i.m., e) on gastric emptying and paracetamol absorption compared with saline injection (o) in one volunteer.
Table 1 Effect (mean ± s.e. mean) of pethidine and diamorphine on gastric emptying rate Time to 50% gastric emptying of ingested solution (min) Control (n = 8) Pethidine (n = 4) Diamorphine (n = 4) *
11.9 ± 2.5 89.5 ± 24 >130
INHIBITION OF GASTRIC EMPTYING AND DRUG ABSORPTION BY NARCOTIC ANALGESICS W.S. NIMMO', R.C. HEADING', J. WILSON2, P. TOTHILL3 & L.F. PRESCOTT' Departments of Therapeutics' , Anaesthetics2 and Medical Physics3, University of Edinburgh, The Royal Infirmary, Edinburgh EH3 9YW
1 The effect of intramuscular pethidine or diamorphine on gastric emptying and the absorption of orally administered paracetamol was assessed in eight normal subjects. 2 Both drugs produced a significant and striking delay in gastric emptying and absorption of paracetamol. 3 It seems inevitable that pethidine and diamorphine will retard the absorption of other orally administered drugs.
Introduction
Methods
In a previous study of obstetric patients, we observed that the administration of narcotic analgesics to women in labour was associated with a striking reduction in the rate of absorption of orally administered paracetamol (Nimmo. Wilson & Prescott, 1975). Since paracetamol absorption is dependent on gastric emptying (Heading, Nimmo, Prescott & Tothill, 1973) it seemed likely that this delay in paracetamol absorption was due to delayed gastric emptying. However, it was not possible to distinguish between the effects of the narcotics themselves and any delay associated with the increasing distress of labour and approaching delivery which constituted the clinical indication for narcotic administration. Although narcotic analgesics undoubtedly have marked effects on the smooth muscle of the gastrointestinal tract and interfere with normal peristalsis (Daniel, Suther land & Bogoch, 1959, Burks & Long, 1967 Cairnie, Kosterlitz & Taylor, 1961) their effects on gastric emptying in man are not clear. A radiological study has suggested that morphine has a diphasic effect, initially stimulating and then inhibiting gastric emptying of a barium sulphate suspension (Crone & Ardran, 1957). Interference with the absorption of orally administered drugs is not a recognised consequence of the clinical use of narcotic analgesics. The magnitude of the effect we observed in the obstetric patients seemed sufficient to justify further study and we have now examined the effects of pethidine and diamorphine on gastric emptying and paracetamol absorption in healthy volunteers to define more precisely the effect of narcotic administration on the absorption of an orally administered drug.
Gastric emptying and paracetamol absorption were measured simultaneously in eight adult male volunteers aged 26 to 39 years. After fasting overnight, each subject drank orange juice (400 ml) containing paracetamol (20 mg/kg) in solution together with 113m In DTPA (300 mCi) as a non-absorbable isotopic marker for the emptying measurement. The drink was consumed within 2 minutes. The gastric emptying rate was determined directly by serial scintiscans of the subject's abdomen and counting the dots in the stomach area (Heading, Tothill, Laidlaw & Shearman, 1971). A quantitation of emptying between the times of ingestion of the drink and performance of the first scan was included (Colmer, Owen & Shields, 1973). After correcting for isotopic decay, the results were expressed as the time taken to empty 50% of the ingested dose from the stomach. Serial blood samples were taken at intervals for 8 h after ingestion for assessment of paracetamol absorption. The plasma was stored frozen and the concentration of unchanged paracetamol was measured by gas-liquid chromatography (Prescott, 1971). Urine was collected for 24 h and where possible, 2 hourly collections were made for the first 12 hours. The total unchanged and conjugated paracetamol in each sample was estimated by gas-liquid chromatography (Prescott,
33
1971). No food, drink or tobacco was permitted for 4 h after ingestion of the solution and the subjects remained supine throughout this period. Each subject was studied on two occasions at least 7 days apart. On one occasion an intramuscular injection of pethidine (150 mg) or diamorphine (10 mg) was given 30 min before the paracetamol
510
W.S. NIMMO, R.C. HEADING, J. WILSON, P. TOTHILL & L.F. PRESCOTT
and on the other occasion subjects received a placebo injection of 0.9% w/v NaCl (saline). Four subjects were given pethidine and four received diamorphine. The order of narcotic and placebo administration was determined on a random basis and the subjects were not told beforehand which injection they would receive. However, following the administration of the active drug. all subjects developed typical narcotic effects such as lightheadedness and drowsiness and were thus aware of the treatment they had received.
Coo
E 7550
-
g25
E ~~50
3< o
Results
Gastric emptying was rapid in all the control studies following placebo injection. The time for 50%o emptying of the ingested solution from the stomach ranged from 4 to 22 min (mean 11.9 min) (Table 1). Paracetamol absorption was correspondingly rapid with a mean peak plasma concentration of 20.0 ,ug/ml occurring 22 min after ingestion (Table 2). After pethidine, however, the mean time for 50o emptying of the ingested solution was prolonged to 89.5 min (Table 1). Similarly, the mean peak paracetamol concentration was only 13.8 ,g/ml and was delayed until 114 min after ingestion (Table 2). The effects of pethidine on gastric emptying and paracetamol absorption in one subject are shown in Figure 1.
100
l50
Time after ingestion(mi)
10)20
Time after ingestion (min) Figure 1 The effect of pethidine (150 mg i.m., e) on gastric emptying and paracetamol absorption compared with saline injection (o) in one volunteer.
Table 1 Effect (mean ± s.e. mean) of pethidine and diamorphine on gastric emptying rate Time to 50% gastric emptying of ingested solution (min) Control (n = 8) Pethidine (n = 4) Diamorphine (n = 4) *
11.9 ± 2.5 89.5 ± 24 >130
