Source: Health Products Regulatory Authority (IE) Revision Year: 2022 Publisher: Clonmel Healthcare Ltd, Waterford Road, Clonmel, Co. Tipperary, E91 D768, Ireland
Pharmacotherapeutic group: analgesics and antipyretics, anilides
ATC‐Code: N02AJ06
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.
Paracetamol is rapidly and completely absorbed with oral administration. (0,5–1,5 hours until the maximum serum levels are reached). Concentration in plasma reaches a peak in 30‐60 minutes upon administration.
It is widely metabolized in the liver by direct conjugation with glucoronic acid or sulfuric acid. A small part is metabolized through the Cytochrome P450 system (mainly CYP2E1) resulting in the production of the toxic metabolite N‐acetyl‐p‐benzochinonimine that is normally bound and excreted, the concentration is increased, however, in the event of massive intoxication.
The drug is eliminated via the kidney. Ninety percent of the absorbed amount is eliminated via the kidneys mainly as glucuronides (60 to 80%) and sulfate conjugates (20 to 30%) within 24 hours. Less than 5% remain unchanged and is thus eliminated. The elimination half life amounts to approx. two hours. In cases of renal disorder or after overdose or in newborns the half life is prolonged.
The maximum action and the average period of action (4 to 6 hours) correlate approx. with the plasma concentration.
In cases of severe renal insufficiency (creatinine clearance <10 ml/min) the elimination of paracetamol and its metabolites is retarded.
Codeine is rapidly absorbed after oral administration. Concentration in plasma reaches a peak within approx. one hour.
It is metabolized in the liver (huge interindivudual differences).
The main metabolites are morphine, norcodeine as well as morphine and codeine conjugates. The conjugate levels are substantially higher than that of the parent substances.
The elimination half life of 3 to 5 hours is prolonged to 9 to 18 hours in cases of renal insufficiency and is also prolonged in elderly patients. The substance is eliminated mainly via the kidneys and approx. 10% of codeine remains unchanged and is thus eliminated.
Codeine passes through the placenta barrier and enters the fetal circulation. Pharmacologically relevant concentrations are reached in the breast milk after high doses of codeine are administered.
Paracetamol and codeine show similar absorption speed and time of plasma concentration peaks as well as approx. same period of action. Furthermore, their biotransformation steps do not obstruct each other and no obstruction is given in the elimination via the kidneys.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
