Paracetamol half-life

Most studies investigating paracetamol pharmacokinetics in patients with liver disease used single doses only. A 50% reduction in clearance and a corresponding increase in half-life have been seen in severe acute hepatitis, the longest half-life being seen in patients with a raised prothrombin time (PT). It may therefore be prudent to extend the dose interval in these patients. Cirrhotic patients with a low albumin and a raised PT were also noted to have a prolonged paracetamol half-life, although no accumulation or hepatotoxicity was observed when normal therapeutic doses were administered to these patients for up to five days. In contrast, cirrhotic patients with normal albumin and PT demonstrated... 

Other studies have also demonstrated similar increases in half-life when comparing paracetamol pharmacokinetics in patients with decompensated chronic liver disease to normal subjects. Patients with cirrhosis who have a normal plasma albumin concentration and PT have been shown to have a similar paracetamol half-life and clearance to those of healthy subjects. However, cirrhotic patients with a low plasma albumin and an increased PT were found to have a prolonged paracetamol half-life. Despite this, no accumulation and no evidence of hepatotoxicity was demonstrated when therapeutic doses of paracetamol were given to patients with decompensated liver diseases for three to five days [21]. 

Patients Plasma paracetamol half-life (h) 4 h after ingestion 12 h after ingestion... 

Paracetamol, synonym acetaminophen, is world wide probably the most popular analgesic and antipyretic. Its mechanism of action is not well understood. It is not really an NSAID as it is only a very weak inhibitor of cyclo-oxygenase and has hardly any anti-inflammatory activity. For the same reason paracetamol gives only negligible gastrointestinal irritation and gives hardly any blockade of platelet aggregation. Paracetamol concentrations in plasma reach a peak in 30-60 minutes, and the half-life in plasma is about 2 hours. Almost 100% of... 

The half-life will be independent of the dose, provided that the elimination is first order and therefore should remain constant. Changes in the half-life, therefore, may indicate alteration of elimination processes due to toxic effects because the half-life of a compound reflects the ability of the animal to metabolize and excrete that compound. When this ability is impaired, for example, by saturation of enzymic or active transport processes, or if the liver or kidneys are damaged, the half-life may be prolonged. For example, after overdoses of paracetamol, the plasma half-life increases severalfold as the liver damage reduces the metabolic capacity, and in some cases, kidney damage may reduce excretion (see chap. 7). 

By measurement of the blood level of paracetamol in overdose cases, it is possible to estimate the likely outcome of the poisoning, and hence determine the type of treatment. Measurement of the blood level of paracetamol and its various metabolites at various times after the overdose showed that the half-life was increased several folds (Table 7.3), and the patients who sustained liver damage had an impaired ability to metabolize paracetamol to conjugates (Fig. 7.16). 

Table 7.3 Mean Plasma Concentration and Half-Life of Unchanged Paracetamol in Patients with and Without Paracetamol-Induced Liver Damage...

Paracetamol is a widely used analgesic, which causes liver necrosis and sometimes renal failure after overdoses in many species. The half-life is increased after overdoses because of impaired conjugation of the drug. Toxicity is due to metabolic activation and is increased in patients or animals exposed to microsomal enzyme inducers. The reactive metabolite (NAPQI) reacts with GSH, but depletes it after an excessive dose and then binds to liver protein. Cellular target proteins for the reactive metabolite of paracetamol have been detected, some of which are enzymes that are inhibited. Therefore, a number of events occur during which ATP is depleted, Ca levels are deranged, and massive chemical stress switches on the stress response. 

Paracetamol reaches peak plasma concentrations within the first hour after oral administration and shows only a low tendency for plasma protein binding at therapeutic concentrations. The elimination half-life is between 1 and 3 h. Paracetamol is metabolized mainly in the liver and excreted in the urine as glucuronide and sulphate conjugates. The metabolic pathway of paracetamol is shown in Schemes 66 and 67 ... 

The half-life of paracetamol has been shown to be prolonged during acute viral hepatitis and in patients with severe chronic liver disease. Most studies were single-dose studies. One study looked at the pharmacokinetics of paracetamol (1 g) in ten patients with acute viral hepatitis (ALT increased at least tenfold and acute onset of symptoms) and 20 controls. In the hepatitis patients the paracetamol dose was given in both the acute phase and in the convalescence phase (approximately one month after complete biochemical recovery). At the time of the acute attack, peak concentrations of paracetamol did not differ significantly compared to the recovery phase, nor to the 20 controls. However, during acute hepatitis the half-life of paracetamol was significantly increased compared to the convalescent phase (3.2 h vs... 

This patient has a massively raised ALT, indicating considerable hepato-cyte damage. All functions of the liver are likely to be affected, including reduced secretory and excretory function, demonstrated in this case by a raised bilirubin reduced synthetic function, shown by the raised INR (albumin is imaffected at this time due to its long half life) reduced metabolic function, indicated by accumulation of ammonia and other toxins leading to encephalopathy. Blood flow through the liver is likely to be unaffected, as there is no cirrhosis/portal hypertension. As with all other functions of the liver, this patient s ability to metabolise drugs is likely to be severely affected. Renal function is also impaired secondary to paracetamol toxicity. 

GRAPEFRUIT JUICE PARACETAMOL t half-life of paracetamol. White grapefruit juice t plasma concentrations in 1 hour, while pink grapefruit juice caused the t in 2 hours Attributed to t elimination half-life of paracetamol caused by grapefruit juice Be aware... 

Half-life. Plasma half-life, phenacetin 0.7 to 1.5 hours, paracetamol 1,5 to 3 hours. 

In six adults the half-life of chloramphenicol, 1 g intravenously was increased from 3.3 to 15 hours by paracetamol 100 mg intravenously (72). 

In contrast, in five children aged 2.5-5 years paracetamol 50 mg/kg/day for several days significantly lowered the Cmax of chloramphenicol, increased its apparent volume of distribution and clearance, and slightly shortened its half-life (73). 

The A-hydroxylation of acetylaminofluorene and paracetamol are two toxicologically important examples illustrating species differences (see Chapter 7). Another example is the metabolism of amphetamine, which reveals marked species differences in the preferred route, as shown in figure 5,8. Species differences in the rate of metabolism of hexobarbital in vitro correlate with the plasma half-life and duration of action in vivo as shown in table 5,10. This data shows that the marked differences in enzyme activity between species is the major determinant of the biological activity in this case. 

TABLE 12 Mean plasma concentration and half -life of unchanged paracetamol in patients with and withoutparacetamolinduced liver damage... 

The drug paracetamol decays by first-order kinetics in the body with a half-life of 4.0 h. A person s blood is found to contain 50 mg dm 3 of paracetamol 8.0 h after ingestion of the drug. 

A study in 8 healthy subjects found that paracetamol 2.7 g daily reduced the AUC of a 300-mg dose of lamotrigine by 20% and reduced its half-life by 15%. ... 

In a study in 6 healthy subjects, lansoprazole 30 mg once daily for 3 days increased the peak level of paracetamol (given as a single 1-g dose in solution) by 43%, and decreased the time to peak paracetamol levels by half (from about 35 to 17.5 minutes). However, lansoprazole had no effect on the AUC and elimination half-life of paracetamol. ... 

Three studies report alterations in the pharmacokinetics of chloramphenicol hy paracetamol. The first was conducted in 6 adults in intensive care after an ohservafion thaf fhe half-life of chloramphenicol was prolonged hy paracefamol in children wifh kwashiorkor. The addition of 100 mg of intravenous paracetamol inereased the half-life of chloramphenicol in the adults from 3.25 to 15 hours. Ttowever, this study has been criticised because of potential errors in the method used to calculate the half-life, the unusual doses and routes of administration used, and because the pharmacokinetics of the chloramphenicol with and without paracetamol were calculated at different times after the administration of chloramphenicol. ft has also been pointed out that malnutrition (e.g. kwashiorkor) can increase the elimination rate and AUC of chloramphenicol independently of paraeetamol. ... 

The seeond study demonstrated a different interaetion, in that the elear-ance of chloramphenicol was increased and the half-life reduced This study has also been criticised as it does not account for the fact that chloramphenicol clearance increases over the duration of a treatment course, which suggests that the changes seen in the pharmacokinetics of chloramphenicol may be independent of the paracetamol. The authors later admit this as a possibility. The third study found no differences in the pharmacokinetics of chloramphenicol after the first dose, but at steady state, the AUC and peak serum levels of chloramphenicol were lower in children who also received paracetamol. ... 

The amount of the substance and mode of eiqiosure is much more important than any assumed tolerance that might develop toward poisons. A careful look at Table 1.3 will reveal a number of natural and artificial substances listed such as paracetamol, aspirin, caffeine, sodium nitrite and nicotine, which are more or less toxic, but still used in everyday life. This might seem contradictory at first sight, but there is a marked dose-response relationship. A lot of toxic substances may also have positive effects and can be used if there is a large difference between beneficial and toxic doses. There is an old Latin saying sola dosis facit venenum—it is the dose that makes the poison. Even very toxic botulinum toxin has an everyday use in cosmetics, it removes wrinkles when applied cautiously on the forehead between the eyebrows. This Botox cure has an effect for more than half a year a lot of celebrities use it instead of plastic surgeries. 

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