Paracetamol and aspirin absorption from Safapryn and Safapryn-Co.
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Biomedical subjects
Publications and source records attributed to L F Prescott.
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Eight healthy male volunteers ingested an aqueous solution containing acetaminophen (20 mg/kg) and a nonabsorbable isotopic marker. The concentrations of unconjugated acetaminophen in samples of blood plasma taken at frequent intervals were measured by gas-liquid chromatography. The data points followed a smooth curve in most cases and were fitted to the classical two-compartment pharmacokinetic model to obtain KA, the apparent first-order rate constant for absorption from the gastrointestinal tract. Gastric emptying was measured simultaneously from serial scintiscans of the subject's abdomen. The subjects were also studied after intramuscular injection of meperidine (150 mg) and pentazocine (60 mg) with and without naloxone (1.2 mg). The acetaminophen absorption curves and gastric emptying patterns were consistent with negligible absorption from the stomach. A new model is proposed in which the conventional single compartment used to represent the gastrointestinal tract is replaced by two compartments: one represents the stomach and the other the small intestine, from which absorption occurs rapidly. Pharmacokinetic analysis using this model showed good agreement in all cases, and provided an estimate of KA, the first-order rate constant for drug transfer from the intestinal lumen into the systemic circulation. The mean half-time for transfer was 6.8 +/- 0.9 min. As expected, KA was greater than KG (the first-order rate constant for gastric emptying), showing that gastric emptying was rate-limiting in the absorption of acetaminophen. The value of KA was greater than KA and the two were not related. The value of KA was not equal to KG in most studies because gastric emptying was not a single exponential process.
Flunitrazepam or diazepam with atropine and a combination of phenoperidine, droperidol and cyclizine (neuroleptanalgesia) were compared as premedication in three groups of 25 patients undergoing routine upper gastrointestinal endoscopy. Drug doses were titrated carefully against response and all three regimes were found to be similar in terms of safety, patient co-operation, relaxation and speed of recovery. Neuroleptanalgesia however produced a statistically significant rise in endtidal pCO2 and systolic blood pressure. The benzodiazepines, and in particular flunitrazepam, produced a significantly greater amnesia for the procedure, patients given these drugs being more willing to undergo repeat endoscopy.
Using the rate of absorption of paracetamol following oral administration of the drug, gastric emptying was measured in 21 patients following hysterectomy. Gastric emptying was inhibited markedly in patients receiving narcotic analgesia after operation, but only a moderate delay was observed in patients undergoing extradural analgesia.
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Fifteen patients with paracetamol (acetaminophen) poisoning were treated with intravenous N-acetylcystein (300 mg/kg given over 20 h). Mean admission and 4 h plasma-paracetamol concentrations were 262 and 369 microgram/ml, respectively. Liver-function tests remained normal or were only slightly disturbed in 11 of 12 patients treated within 10 h of paracetamol ingestion. Severe liver damage developed in the other patient and in the three in whom treatment was started more than 10 h after paracetamol ingestion. In contrast to cysteamine, N-acetylcysteine was very well tolerated and has the advantage of being available as a pharmaceutical preparation in a 20% sterile solution.
The plasma half lives of antipyrine, paracetamol, and lignocaine given by mouth were measured in 23 patients with stable chronic liver diseases of varying severity. Fifteen patients received all three drugs and 19 at least two. The half life of paracetamol was abnormally prolonged in nine out of 17 patients (mean 2-9 hours, normal 2-0 hours), of antipyrine in 10 out of 19 patients (mean 30-4 hours, normal 12-0 hours), and of lignocaine in 19 out of 21 patients (mean 6-6 hours, normal 1-4 hours). Prolongation of the half lives of all three drugs was significantly correlated with an increase of the vitamin-K1-corrected prothrombin time ratio and a reduction in serum albumin concentration. There was no correlation with serum bilirubin concentration or serum alanine aminotransferase activity. This suggests that impaired drug elimination was related to depressed hepatic protein synthesis. Considerable prolongation of the half life of one drug was invariably associated with delayed elimination of the others. The half life of lignocaine, however, was always the most prolonged and was a highly sensitive indicator of hepatic dysfunction. The pharmacokinetic characteristics of a drug as well as the severity of liver disease should be taken into account when considering drug dosage in patients with chronic liver disease.
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