Download references. Pharbita BV, C. You can also search for this author in PubMed Google Scholar. Reprints and Permissions. Tukker, J. Bioavailibility of paracetamol after oral administration to healthy volunteers. Pharmaceutisch Weekblad Scientific Edition 8, — Download citation.
Received : 15 November Accepted : 15 May Issue Date : August Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Serotonergic pathways are part of the descending pain system, originating in the brainstem nuclei, hypothalamus, and cortex, and interact with pain afferents in the dorsal horn.
Serotonin receptors are present throughout the central nervous system, involved in a number of functions, including consciousness, mood, memory, and nausea and vomiting, the latter of which are mediated via the 5-HT 3 -receptor subtype. It has become widely accepted that the activation of descending serotonergic pathways plays a key role in the action of paracetamol, and it has been demonstrated that the anti-nociceptive effects of paracetamol can be partially inhibited by co-administration of 5-HT 3 -receptor antagonists, interestingly using anti-emetic drugs which are indeed frequently given together with paracetamol in the perioperative period.
In the presence of fatty acid amide hydrolase FAAH , an enzyme found predominantly in the central nervous system, paracetamol via an intermediary, p -aminophenol, formed in the liver is conjugated with arachidonic acid to form the active metabolite, N -arachidonoylphenolamine AM Analogous to the action of serotonin or norepinephrine reuptake inhibitors, AM inhibits the reuptake of the endocannabinoid, anandamide, from synaptic clefts, increasing cannabinoid receptor activation on the post-synaptic membrane.
This would explain the experiences of relaxation, tranquility, and euphoria reported by many paracetamol users, apparently independent of analgesia. AM appears to be a key player in a number of pain pathways. The central production of AM would also account for the antipyretic effect of paracetamol, known to be related to inhibition of prostaglandin production in the brain, whilst still without peripheral actions Fig.
Paracetamol demonstrates efficacy comparable with that of standard equivalent doses of many NSAIDs including ibuprofen, diclofenac, ketorolac, and parecoxib , tramadol, and 10 mg i. As a component of a multimodal analgesic regime, it is generally considered to have useful opioid-sparing effects; a reduction in opioid consumption is mostly if not universally borne out with the statistical significance in clinical studies, but the addition of regular paracetamol invariably reduced pain scores and the incidence of nausea and vomiting, and improved patient satisfaction.
It is a useful first-line drug, and works in synergy when combined with a number of other agents including ibuprofen, codeine, tramadol, and caffeine, improving analgesic efficacy whilst minimizing side-effects of the adjunct agent. Although the onset of action of i.
This was, however in healthy, fasted individuals with presumed normal gastric emptying, undergoing daycase surgery, and results may not be readily extrapolated to other patient groups. The Medicines and Healthcare products Regulatory Agency MHRA licensed dose of paracetamol is the same for all routes of administration in adults over 50 kg i.
Despite its high lipid solubility and low protein binding, a weight-adjusted dosing regime has never been endorsed. However, in view of the pharmacokinetic data of paracetamol, a case has been made for a single loading dose of 2 g, followed by 4—6 hourly 1 g doses, and this has found its way into clinical practice over recent years.
Studies comparing 2 g with 1 g loading doses for postoperative analgesia in otherwise healthy adult patients have demonstrated lower pain scores and greater duration of effective pain relief with no increase in side-effects or markers of toxicity.
In the UK, there have been seven reports of overdose in infants and neonates. In most of these cases, a fold overdose was reported, most probably due to confusion between doses calculated in milligrams vs millilitres. Oral paracetamol is absorbed, mainly from the small bowel, by passive transport, and has high, though variable, bioavailability. It is metabolized in the liver, predominantly by glucuronidation and sulphation to non-toxic conjugates, but a small amount is also oxidised via the cytochrome P enzyme system to form the highly toxic metabolite, N -acetyl- p -benzo-quinone imine NAPQI.
Under normal conditions, NAPQI is detoxified by conjugation with glutathione to form cysteine and mercapturatic acid conjugates, which are then renally excreted. However, when there is insufficient glutathione e. Thus a CYP-2D6 ultra-rapid and extensive metabolizer is at higher risk of developing toxicity than a slow metabolizer.
Although the product information does not recommend any dose adjustment in the elderly, as pharmacokinetics of paracetamol are not specifically modified, glutathione stores may be low in certain patient groups and conditions, including the elderly, infants, and in starvation or malabsorption, etc.
Whilst this does not preclude the use of paracetamol, the interval between doses should be a minimum of 6 h. Paracetamol is safe for use in pregnancy and lactation, with only a negligible amount of the drug reaching breast milk. Interestingly, the total clearance of paracetamol has been demonstrated to be higher in women at delivery including by Caesarean section compared with 10—15 weeks postpartum, which itself was significantly lower than in the normal healthy volunteer population data.
The increased total paracetamol clearance at delivery is attributed to a disproportionate increase in glucuronidation clearance and a proportional increase in both its oxidation clearance and of unchanged paracetamol. Interaction with a variety of other drugs may occur, and warrant caution in co-administration. For example, concomitant intake of enzyme-inducing substances, such as carbamazepine, phenytoin, or barbiturates, as well as chronic alcohol excess, may increase NAPQI production and the risk of paracetamol toxicity.
Concurrent use with isoniazid also increases the risk of toxicity, though as an enzyme inhibitor, the mechanism is not entirely clear. Concomitant use of paracetamol 4 g per day for at least 4 days with oral anticoagulants may lead to slight variations in INR values. Increased monitoring of INR should be conducted during the period of concomitant use as well as for 1 week after paracetamol treatment has been discontinued Table 2.
However, usage within the therapeutic range, particularly frequent regular use, can also impact on other organ systems, with effects that are less widely acknowledged. Paracetamol overdose is the most common and predictable cause, but, in certain individuals, hepatotoxicity may occur with doses within the therapeutic range. The plasma half-life is usually normal in patients with mild chronic liver disease, but its prolonged in those with decompensated liver disease. Abstract In therapeutic doses paracetamol is a safe analgesic, but in overdosage it can cause severe hepatic necrosis.
Publication types Review. An indirect paracetamol concentration-effect model i. Linear regression analyses were performed using Prism version 6. Non-normally distributed data were compared by the Mann-U Whitney test. Parasite clearance half-life was calculated for the pharmacodynamic analysis using the Worldwide Antimalarial Resistance Network WWARN parasite clearance estimator [ 25 ].
Secondary pharmacokinetic parameters in both groups i. Twenty-one adults with acute falciparum malaria were included in this analysis Fig.
Admission temperature ranged from Baseline characteristics are shown in Table 1. Of the 21 patients, seven received extra doses of paracetamol during the 2-day study period. One patient in Group 1 withdrew from the study 12 h after the initial oral dose and did not receive the intramuscular dose on the second day.
No patient reported excessive alcohol intake. Patient flow diagram. After enrolment to the studies, patients admitted to Mae Sot Hospital had blood collected prior to paracetamol administration followed by timed blood collections.
Group 1 received oral syrup paracetamol PO on day 0 then intramuscular paracetamol IM on day 1; Group 2 received intramuscular paracetamol on day 0 then oral syrup paracetamol on day 1. One patient in Group 1 did not receive the intramuscular dose of paracetamol on day 1 due to self-discharge from the hospital; one patient from Group 2 did not receive oral paracetamol on day 1 as the patient received multiple doses of paracetamol during the study period.
All patients were included in the pharmacokinetic analysis. Of the 21 patients, plasma paracetamol concentrations were included in the pharmacokinetic analysis. Paracetamol concentration—time data were well described by a two-compartment disposition model.
Furthermore, the terminal half-life estimated from the three-compartment disposition model was unrealistically long median terminal half-life of h compared to extensive previous investigations 1. Thus, the two-compartment disposition model was carried forward. Allometric scaling of pharmacokinetic parameters did not improve model fit significantly. Thus, body weight was not incorporated into the final model.
The stepwise covariate search showed no significant relationships in this population. Parameter estimates from the final paracetamol pharmacokinetic model are shown in Tables 2 and 3. The final paracetamol pharmacokinetic model showed satisfactory goodness-of-fit diagnostics Fig. The numerical predictive check after intramuscular administration resulted in 1. The numerical predictive check after oral administration resulted in 1.
Goodness-of-fit diagnostics of the final population pharmacokinetic model for paracetamol in patients with falciparum malaria. Observations are represented by black circles , solid black lines represents the line of identity or zero line, and the local polynomial regression fitting for all observations is represented by the dashed black line. The observed paracetamol concentrations, population predictions and individual predictions were transformed into their logarithms base Visual predictive check of the final population pharmacokinetic model for paracetamol in patients with falciparum malaria stratified by route of drug administration.
Two simulated dosing regimens of mg intramuscular and oral syrup every 6 h Fig. However, lower peak concentrations were seen after the first dose, which suggested the need for a mg loading dose in order to achieve a rapid onset of maximum therapeutic efficacy Fig.
A fixed maintenance dose of mg intramuscular or oral syrup every four hours also showed adequate steady state concentrations but this regimen failed to reach the therapeutic levels during the first 6 h after administration Fig. Simulations from the final population pharmacokinetic model for paracetamol. Upper panel population mean plasma concentration—time profiles after intramuscular IM administration of a study dosing regimen; mg every 4 h, b normal dosing regimen; mg every 6 h and c modified dosing regimen; mg loading dose followed by mg every 6 h.
Lower panel population mean plasma concentration—time profiles after oral syrup PO administration of d study dosing regimen; mg every 4 h, e normal dosing regimen; mg every 6 h and f modified dosing regimen; loading followed by mg every 6 h.
Although paracetamol has been used clinically as an antipyretic for over years, there is a paucity of literature describing its pharmacokinetic properties after intramuscular administration.
Paracetamol is by far the most widely used antipyretic in malaria, one of the most common causes of fever in tropical countries. Patients with malaria often vomit, particularly with high fever, and in cerebral malaria are unconscious, so the intramuscular route provides an alternative administration option in the absence of a bleeding tendency. In this study the disposition of paracetamol was best described by a two-compartment disposition model, which is consistent with previous pharmacokinetic reports [ 27 ].
Since one-compartment structural models of oral syrup paracetamol pharmacokinetics have been reported, separate analyses of structural models for intramuscular and oral administration were performed [ 28 ].
The results showed that the two-compartment disposition of the final pharmacokinetic model was driven by the intramuscular data. A one-compartment disposition model was adequate for oral syrup administration demonstrating that the rapid distribution phase after parenteral administration was obscured by the oral absorption phase.
As expected, the absorption of paracetamol administered intramuscularly and orally was best described by zero-order and first-order absorption, respectively.
A more flexible transit absorption model did not result in a statistical improvement when fitting the absorption data after oral administration. This may be a consequence of few data in the absorption phase.
The C MAX was observed at approximately 40 min after both intramuscular and oral administration, which is also similar to previous reports [ 26 , 29 ]. However, few data points in the absorption phase might bias these estimates and they should be interpreted with caution. The relative oral bioavailability compared to intramuscular administration was This bioavailability of oral tablets of paracetamol is usually reported as slightly lower i. The C MAX of paracetamol after intramuscular and oral administration mg were The lower C MAX of oral paracetamol is explained by incomplete absorption and the first-pass metabolism that occurs during absorption before paracetamol enters the systemic circulation, and the slower absorption obscuring distribution from an apparent central compartment [ 9 ].
While the pharmacokinetics of paracetamol in severe falciparum malaria have not been studied, the bioavailability of oral paracetamol may be even lower given the decrease in gastric emptying [ 33 ] and splanchnic blood flow [ 34 ] observed in severe malaria. Slower absorption of intramuscular paracetamol would also be expected in severe malaria. Although the bioavailability of intramuscular paracetamol is higher than the oral route, the relatively high cost of a 3 day course 1 g every 6 h of parenteral paracetamol intramuscular: 4.
The population pharmacokinetic model of paracetamol showed large inter-individual variability in most pharmacokinetic parameters, probably due to small sample size and limited data for each route of administration. However, the visual predictive check of the final pharmacokinetic model suggested adequate predictive performance.
Dosing simulations of a mg loading dose followed by a maintenance dose of mg every 6 h resulted in more favourable paracetamol plasma concentration—time profiles, reaching maximum therapeutic concentrations rapidly after the first dose.
This suggests that a loading dose might be needed for a rapid onset of maximum antipyretic effects. Dosing simulations of intramuscular and oral syrup paracetamol administered at a dose of mg every 4 h showed that this regimen reached therapeutic steady state concentrations but with a delayed onset of action.
However, the total daily dose of paracetamol that would be administered with the loading dose regimens would be 4. Administration of tablets and suppositories may not reach therapeutic concentrations because of lower bioavailability compared to orally administered paracetamol syrup [ 15 , 26 , 36 — 38 ].
Thus, currently recommended dose regimens for tablets and suppositories may not be sufficient to reach similar steady-state concentrations compared to paracetamol syrup. Therefore, the limited effect of paracetamol on fever clearance reported in uncomplicated malaria studies that administer suppositories or tablets, or do not directly observe therapy, may reflect sub-therapeutic paracetamol levels [ 6 , 39 ].
A single 2 g dose of intravenous paracetamol for post-operative pain has been shown to be efficacious and safe in patients undergoing dental surgery compared to a 1 g dose [ 40 ]. A multiple dose regimen of 2 g intravenous paracetamol followed by 1 g every 6 h total, 5 g in 24 h in healthy subjects showed no drug accumulation during the regimen and no hepatotoxicity at 72 h after the first dose [ 41 ].
The mean C MAX measured 15 min after the 2-g intravenous infusion was Multiple-dose regimens of 6 g per day for 3 days 1 g orally every 4 h studied in stroke patients showed a significant temperature lowering effect and no significant hepatotoxicity compared to placebo [ 42 , 43 ].
In the current study, a simulated mg loading dose followed by mg every 6 h achieved therapeutic concentration—time profiles of paracetamol rapidly when administered by either route.
Although the total daily dose of this regimen 4. Evidently, larger clinical safety and efficacy assessments of this regimen would be required to confirm the general applicability of loading doses of paracetamol in this population. Febrile temperatures have been shown to accelerate and increase cytoadherence of parasitized erythrocytes in vitro [ 3 ]. In a study of African children receiving regularly dosed rectal paracetamol, it was suggested that those receiving paracetamol had a prolonged parasite clearance time compared to patients treated with mechanical antipyresis [ 6 ].
One hypothesis is that paracetamol reduces fever, which may then result in less cytoadherence, sequestration and thus increase circulating peripheral blood parasitaemia.
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