PubMed · 8029721
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C Gerson. 1994. [Paracetamol].. https://pubmed.ncbi.nlm.nih.gov/8029721/
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The in vitro interference of some of most important nonsteroidal anti-inflammatory drugs (NSAIDs) with the respiration of rat kidney (renal cortex) mitochondria and ATP synthesis was evaluated. Acetylsalicylic acid, diclofenac sodium, mefenamic acid, and piroxicam both uncoupled and inhibited oxidative phosphorylation in mitochondria energized with glutamate plus malate or with succinate, while dipyrone only uncoupled and paracetamol only inhibited it. The drug concentrations affecting mitochondrial respiration were in the low to middle micromolar range for diclofenac, mefenamic acid, and piroxicam, and in the low millimolar range for acetylsalicylic acid, dipyrone, and paracetamol. The pattern of inhibition, except for the paracetamol, was similar to that expressed by the respiratory chain inhibitors. NSAIDs also inhibited the rate of ATP synthesis in mitochondria energized with glutamate plus malate, as well as the phosphorylation potential of mitochondria. The IC50 values for rate of ATP synthesis, using 2 mM ADP, were about 0.1 mM for diclofenac sodium and mefenamic acid, 0.7 mM for piroxicam, and in the range of 5-8 mM for acetylsalicylic acid, dipyrone, and paracetamol. The potential for renal energetic cytotoxicity of NSAIDs is discussed considering their ability to interact with the oxidative phosphorylation in rat renal cortex mitochondria. A comparison is made with the interference of salicylate, the main metabolite of acetylsalicylic acid, and a classical uncoupler of oxidative phosphorylation.
AIM: Paracetamol is an analgesic/antipyretic widely used in children. The drug can cause hepatic and renal damage due to cumulative toxicity when used in excess of 90 mg/kg@day. There are no dosing guidelines for paracetamol use in children under 1 month of age. We wished to discern current paracetamol prescribing habits in order to establish safety of current practices and offer recommendations towards rational use. METHODS: An anonymous questionnaire was sent to all medical staff working in a university childrenís hospital. We sought information about paracetamol prescribing regimes for children 4 months and over, 3 months and under and neonates in the first 2 weeks of life. Pharmacists audited daily prescription charts of inpatients without hepatic or renal disease over a 2 month period. The maximum possible daily dose was calculated for each child and note was made if a dose in excess of 95 mg/kg was given. RESULTS: There were 53 respondents to the 80 questionnaires posted. There was a trend to use lower daily doses in the younger age group. Similarly, more practitioners either did not use or did not know safe dosing schedules in children 3 months and younger. During the 2 month period there were 823 prescriptions for children 4 months and over, 85 for infants 3 months and under and seven for under 2 week old neonates. In the children 4 months and over 25 of 140 prescriptions exceeding 95 mg/kg/day were given and two of six were given in infants 3 months and younger. CONCLUSION: Many medical staff were unsure of current safe dosing regimens, particularly in the younger age groups. Seventeen percent of prescriptions were above 95 mg/kg/day although only 3% of children were given these doses due to on demand charting and due to audit by pharmacy and nursing staff. There are few guidelines for children 3 months and under. The literature suggests 60-65 mg/kg/day in infants 1-3 months, although this dose was only charted in 16% of prescriptions and phamacokinetic data favours a higher dose. In neonates 30 mg/kg/day achieves effective therapeutic concentrations but further studies are needed.