Plasma paracetamol concentration

After a single oral dose of 0.9 g to 9 subjects, peak plasma-phenacetin concentrations of 0.2 to 7.4 Lig/ml (mean 2.3) were attained in 1 to 2 hours, and peak plasma-paracetamol concentrations of 3.1 to 11.9 ig/ml (mean 7.9) were attained in 2 to 3.5 hours plasma-phenacetin concentrations were reported to be lower in 9 smokers (E. J. Pantuck et al., Clin. Pharmac. Ther., 1974,15, 9-17). 

Fulminant hepatic failure occurs in 1-5% of cases of paracetamol overdosage 3-6 days after ingestion (71), with frequent deaths in people who take 20-25 g. There is only a narrow margin between the normal maximum 24-hour dosage and that which can cause liver damage and acute hepatic failure. Undoubtedly, some people are more susceptible than most to paracetamol toxicity, since although 6 g has been reported as toxic in some cases, most toxicity is seen with 12 g upwards (72,73). Nomograms have been developed to show the relation between plasma paracetamol concentrations over time and the risk of a serious outcome (SEDA-18, 94). 

We used our specific RIA methods for B, and Bj subunits to investigate the time course of hepatocellular damage in 19 patients admitted with paracetamol overdose (B12, B14). Seven patients had plasma paracetamol concentrations that were below the treatment line and four of these patients had marginal elevations (approximately one and a half times the upper reference limit) of B, upon admission within 4 hr of the overdose. Only one of the seven patients subsequently showed a significant rise in plasma GST B, to nine times the upper reference limit but in this patient and in each of the other seven patients no abnormalities in ALT were found at any time during their hospitalization. 

It is still prudent to consider patients who are alcoholics as being at high risk of hepatotoxicity after a paracetamol overdose, and to treat them with acetylcysteine. Some workers have questioned the use of a lower plasma-paracetamol concentration threshold for the treatment of paracetamol poisoning in alcoholics, but most advocate treatment at the lower threshold. Possible malnutrition and fasting in these patients would further support the need for such treatment. ... 

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... 

Paracetamol might have a similar effect to ascorbic acid, that is competition with ethinylestradiol for sulfation capacity in the gut. Paracetamol significantly reduced the AUC of ethinylestradiol sulfate but had no effect on plasma levonorgestrel concentrations... 

A 64-year-old man with type II diabetes, hypertension, and bilateral renal artery stenosis presented with confusion and dysarthria related to profound hypoglycemia (2.2 mmol/1). He was taking naproxen 500 mg bd, ramipril 2.5 mg/day, glibenclamide 2.5 mg bd, metformin 850 mg bd, a thiazide diuretic, terazosin, ranitidine, paracetamol, and codeine. His plasma creatinine concentration, previously 185 pmol/1, was 362 pmol/1 and it fell to 210 imol/l after the withdrawal of ramipril and naproxen. 

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]. 

Paracetamol—Cresol-ammonia test. To 0.5 ml of urine add 0.5 ml of hydrochloric acid and heat for 10 minutes at 100° to 2 drops of the mixture add 10 ml of water, 1 ml of 1 % o-cresol in water, and 4 ml of 2M ammonium hydroxide. A blue colour appears if paracetamol is present. The test is very sensitive and can detect therapeutic concentrations. The presence of the parent drug and its conjugated metabolites can be detected for several days after overdose. If a positive result is obtained, a plasma-paracetamol determination should be carried out immediately (p. 23). 

For salicylate and paracetamol, plasma drug concentrations are used in prognosis and should always be requested. 

After oral administration, paracetamol is completely absorbed from the gastrointestinal tract with peak plasma concentrations being reached in less than an hour. The drug is eliminated by conjugation with glucoronic acid in the liver. The chemical structure is liable to oxidation. 

Paracetamol is given orally and is well absorbed, peak plasma concentration is reached in 30 to 60 minutes. About l/3rd is bound to plasma proteins and the drug is inactivated in the liver, being conjugated to give the glucu-ronide or sulphate which are excreted in urine. 

This is known as Michaelis-Menten or saturation kinetics. The processes that involve specific interactions between chemicals and proteins such as plasma protein binding, active excretion from the kidney or liver via transporters, and metabolism catalyzed by enzymes can be saturated. This is because there are a specific number of binding sites that can be fully occupied at higher doses. In some cases, cofactors are required, and their concentration may be limiting (see chap. 7 for salicylate, paracetamol toxicity). These all lead to an increase in the free concentration of the chemical. Some drugs, such as phenytoin, exhibit saturation of metabolism and therefore nonlinear kinetics at therapeutic doses. Alcohol metabolism is also saturated at even normal levels of intake. Under these circumstances, the rate of... 

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

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 ... 

In six healthy women, a single dose of paracetamol 1 g significantly increased the AUC of ethinylestradiol by 22% and reduced the AUC of ethinylestradiol sulfate (353). Plasma concentrations of levonorgestrel were unaltered. This interaction could be of clinical significance in women taking oral contraceptives who take paracetamol regularly or suddenly stop taking it, but it is doubtful whether it has any practical repercussions. 

Rogers SM, Back DJ, Stevenson PJ, Grimmer SF, Orme ML. Paracetamol interaction with oral contraceptive steroids increased plasma concentrations of ethiny-loestradiol. Br J Clin Pharmacol 1987 23(6) 721-5. 

Paracetamol is readily absorbed from the gastrointestinal tract, peak plasma concentrations occurring 15 minutes to two hours after ingestion. 

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... 

Carefully remove 2 ml of die supernatant liquid from each of the centrifuge tubes, add to the appropriate 30-ml tube, and allow to stand for 2 to 3 minutes. To each of the tubes add, dropwise, 2 ml of a 15% solution of ammonium sulphamate to remove excess nihous acid (vigorous frodiing occurs), followed by 2 ml of 6M sodium hydroxide mix for a few seconds to remove any gas bubbles, and measure the intensity of the yellow solutions at 450 nm against the plasma blank. Calculate the concentration of paracetamol in the sample by reference to a calibration curve prepared from die values for die standard solutions. Duplicate analyses of samples and standards should be carried out. 

Disposition in the Body. Rapidly and completely absorbed after oral administration, with maximum plasma concentrations achieved after one to two hours. It is distributed throughout the body. The main metabolic reaction is oxidation to paracetamol through which the analgesic and antipyretic effects of the drug are chiefly exerted paracetamol is then conjugated with glucuronic acid or sulphate. A minor reaction is deacetylation of... 

Toxicity. The minimum lethal dose is about 10 g. Symptoms of hepatic damage do not occur for at least 12 hours after overdosage but may not appear until 4 to 6 days later. Plasma concentrations have been used to indicate possible hepatic necrosis at 4 hours, hepatic necrosis is possible at concentrations of paracetamol of 120 to 300 pg/ml, probable at concentrations above 300pg/ml, and unlikely at concentrations below 120pg/ ml. Similarly, at 12 hours, concentrations above 120pg/ml indicate the probability of necrosis, concentrations of 50 to 120 pg/ml indicate that it is possible, and concentrations below 50 pg/ml indicate that it is unlikely. 

Drug toxicity may be more likely. A patient who becomes enzyme-induced by taking rifampicin is more likely to develop liver toxicity after paracetamol overdose by increased production of a hepatotoxic metabolite. (Such a patient will also present with a deceptively low plasma concentration of paracetamol due to accelerated metabolism, see p. 287)... 

The time to maximum plasma-concentration (Tmax) of coadministered soluble paracetamol and nifedipine is significantly decreased when subjects are standing or lying on their right side compared with when they lie on their leftside. These postures also resulted in a significantly higher peak plasma-concentration and area imder the plasma-concentration-time curve of nifedipine. 

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