Chemical formula: C₂₆H₃₃N₂O₉P Molecular mass: 548.192 g/mol
Paracetamol is an analgesic and antipyretic agent having a very weak anti‐inflammatory action. Its mode of action is still not entirely clear.
However, it is well established that paracetamol inhibits the central prostaglandin synthesis to a far greater extent than the peripheral one. Furthermore, it counteracts the effect of the endogenous pyrogens on the hypothalamic heat‐regulating centre. It may be assumed that there is a correlation between this mechanism and its antipyretic action.
Codeine is a centrally acting weak analgesic. Codeine exerts its effect through μ opioid receptors, although codeine has low affinity for these receptors, and its analgesic effect is due to its conversion to morphine. Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain.
In clinical studies, the association of paracetamol and codeine has been compared with various analgesics and with placebo. In all cases, the fixed dose mixture was shown to be significantly superior to placebo. The results of certain studies suggest that the combination produces a stronger analgesic effect than the single compounds, even after an increase in their doses, providing the risks associated with drug mixtures are found to be acceptable.
The drug is metabolized chiefly in the liver by direct conjugation to glucuronic acid or sulphuric acid. Small amounts are metabolized through the cytochrome P 450 system (mainly CYP2E1) producing a toxic metabolite – N‐acetyl‐p‐benzoquinonimine – which is normally bound and eliminated, although its concentration is substantially increased in case of massive intoxication.
Paracetamol is excreted by the kidney. Ninety per cent of the ingested amount is eliminated within 24 hours, mainly as glucuronides (60 to 80 per cent) and sulphate conjugates (20 to 30 per cent). Less than 5 per cent remains unchanged and is excreted as such. The elimination half life is about two hours. Longer half lives were seen in patients with impaired liver and kidney function, after overdose and in the newborn. The maximum effect of the drug and its average duration of action (four to six hours) correlate more or less with its plasma concentration.
The excretion of paracetamol and its metabolites is delayed in patients with severe renal failure (creatinine clearance below 10 ml/min).
Codeine is rapidly absorbed after administration by mouth. Peak plasma levels are reached after about one hour.
The drug is metabolized in the liver (big differences from one person to the other).
Morphine, norcodeine and conjugates of morphine and codeine are the main metabolites of the drug. The concentrations of the conjugates are far higher than those of the parent substances.
Elimination half‐life ranges between 3 and 5 hours and rises to 9 to 18 hours in subjects affected with renal failure. The excretion of the drug is slower in the elderly. Codeine is excreted mainly by the kidney.
About 10 percent is eliminated from the body unchanged.
Codeine crosses the placental barrier and enters the foetal circulation. Pharmacologically relevant concentrations were found in human milk after the administration of large doses of codeine.
Paracetamol and codeine are comparable as regards absorption rates, occurrence of peak plasma concentrations and duration of action. The successive steps of their biotransformation and the renal elimination processes do not interfere with each other.
Animal studies of the acute, subchronic and chronic toxicity of paracetamol in rats and mice have revealed gastrointestinal lesions, changes to the blood count, degenerative changes to the hepatic and renal parenchyma and necroses. These changes are due to the mode of action and to the metabolism of paracetamol. The metabolites suspected of producing these toxic effects and the resulting organ changes, were encountered in humans as well. Very rare cases of reversible, chronic aggressive hepatitis were observed during the long‐term administration (one year) of maximum therapeutic doses.
Symptoms of poisoning may occur after the ingestion of subtoxic doses over a period of three weeks. Thus, paracetamol should not be given for prolonged periods or in large amounts.
Comprehensive studies failed to provide evidence that paracetamol carries a significant genotoxic risk, as long as the drug is given in therapeutic, i.e. non‐toxic doses.
In long‐term studies performed in rats and mice, no relevant tumorigenic effects were caused by paracetamol administered in doses that do not produce toxic effects on the liver.
Paracetamol crosses the placental barrier.
No evidence of foetal damage was noted in animal studies and in human therapy.
Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.
In vitro and in vivo studies of codeine failed to reveal any mutagenic potential.
No evidence of a tumorigenic potential was provided in long‐term studies conducted in rats and mice.
Animal experiments appear to suggest that the drug has a teratogenic potential.
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