Paracetamol is poorly soluble in cold water, but more so in hot water. One part of paracetamol is soluble in 70 parts of water at room temperature, and 1 in 20 parts in boiling water. The aqueous solubility is elsewhere reported as 14.7 mg.ml-1 at 20°C, 14.3 mg.ml-1 at 25°C and 23.7 mg.ml-1 at 37°C. [iii] It is soluble in methanol, ethanol, dimethylformamide, ethylene dichloride, acetone and ethyl acetate. It is slightly soluble in ether and practically insoluble in petroleum ether, pentane and benzene. [iv]
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History
The analgesic and antipyretic properties of paracetamol were first discovered in the late nineteenth century. Two agents were already in use for the treatment of mild to moderate pain, acetanilide and phenacetin. In 1889 paracetamol was shown to be excreted in the urine of patients who had taken these drugs. In 1948 Brodie and Axelrod established that paracetamol was the major metabolite of both phenacetin and acetanilide. This led to the belief that the clinical effects of these two drugs were entirely due to the rapid conversion to paracetamol. It was later shown that phenacetin had some activity in its own right, but only at very high doses, as a great proportion is converted to paracetamol. However, by this stage phenacetin was believed to have greater toxicity than paracetamol due to somewhat circumstantial evidence of its role in causing analgesic nephropathy. Phenacetin disappeared from the market as paracetamol’s popularity grew. In 1956 500mg tablets became commercially available in the United Kingdom as a prescription drug, and in 1963 as an over-the-counter drug. It was subsequently combined with a variety of compound analgesics to provide multi-modal analgesia. [v] , [vi]
Function and mechanism of action
Paracetamol has analgesic and antipyretic properties and weak anti-inflammatory activity. It is indicated for management of mild to moderate pain and fever. [vii] It has been used in the perioperative period because of its opioid-sparing effect.
The mechanism of action is not clearly elucidated. Most agree that paracetamol is active centrally, an impression supported by the fact that paracetamol is found in significant concentrations in cerebrospinal fluid of both adults and children after infusion. [viii] Theories of action include:
Activation of descending serotonergic pathways which modulate pain perception. Allouia et al supported this theory by showing that administering a 5-HT3 antagonist blocks the pain-modulating activity of intrathecal paracetamol. [ix]
Inhibition of central prostaglandin synthesis by inactivating (reducing) the active (oxidized) form of cyclo-oxygenase.
Stimulation of endogenous cannabinoid receptors. Paracetamol is metabolized to AM404 (also known as N-arachidonoylphenolamine) which prevents the reuptake of endogenous cannabinoids from the synaptic cleft. This theory has gained popularity since Ottani et al showed that the blockade of the cannabinoid type 1 (CB1) receptors attenuated the action of paracetamol. [x] , [xi]
Paracetamol does not significantly affect peripheral cyclo-oxygenase, perhaps accounting for its limited or absent anti-inflammatory effects.
Dosing
The recommended dosage is
Adults: 0.5-1g 4-6hrly (max 4 g.day-1)
Children older than one month: 20 mg.kg-1 6hrly (max 90 mg.kg-1.d-1)
Term neonates: 20 mg.kg-1 8hrly up to a maximum of 60 mg.kg-1.d-1).
At these doses it has an excellent safety profile, notably lacking the gastrointestinal side effects of aspirin and most non-steroidal anti-inflammatory agents.
Pharmacokinetic properties
Absorption:
Absolute bioavailability in the fasted fasting state ranges between 62%-89%. Peak concentrations are reached within 0.17 and 1.2 hours. The presence of food in the stomach decreases the absorption of paracetamol by increasing tmax and decreasing Cmax values as it delays gastric emptying.
Distribution:
The apparent volume of distribution of paracetamol is 0.69-1.36 L.kg-1. Plasma protein binding is 20%-25% at therapeutic doses. After overdosage, 20% – 50% of the drug may be protein bound. Paracetamol crosses the placenta and into breast milk, where 85% is bound to milk proteins. [xii]
Degradation
In vitro:
Paracetamol degradation in vitro occurs through 2 pathways. It is either degraded by oxidation to quinone-imines or by hydrolysis of the amino group generating p-aminophenol. P-aminophenol is quickly degraded producing p-benzoquinoneimine. Deacetylation takes places both under acid and (much faster) basic conditions [xiii] .
In vivo metabolism and elimination:
In vivo, Paracetamol is metabolised primarily in the liver into non-toxic, inactive products via three metabolic pathways:
Glucuronidation is believed to account for 40% to two-thirds of the metabolism of paracetamol.
Sulfation (sulfate conjugation) may account for 20-40%.
N-hydroxylation and conjugation to glutathione accounts for less than 15%. The hepatic cytochrome P450 enzyme system (specifically CYPA2 and CYP2E1, and to a lesser extent CYP2D6) metabolizes paracetamol. A minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzo-quinoneimine) is formed. NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione to form mercapturic acid conjugates and cysteine.
All three pathways yield final products that are inactive, non-toxic, and eventually excreted by the kidneys. [xiv]
Elimination
Elimination is renally mediated but since only 5% of the drug is eliminated unchanged in the urine, patients with renal failure rarely have a prolonged drug effect. Plasma clearance is between 11.8-22.3 L.h-1. The elimination half-life is reported to be between 1.9 and 4.3 h.
Adverse effects
At therapeutic doses, side effects of paracetamol are few. Allergic skin rashes and chronic nephritis occasionally occur with prolonged usage. [xv] It is however advisable that a patient is well hydrated before paracetamol administration.
However, acute overdose can be extremely serious. This causes hepato- and occasionally renotoxicity. Ingestion of 10-15g of paracetamol by an adult may cause severe hepatocellular necrosis. Doses of 20-25g are potentially fatal.
These effects occur when the liver enzymes that normally conjugate metabolites become saturated. According to the third pathway mentioned above, NAPQI accumulates when glutathione is depleted, leading to cellular necrosis. [xvi]
Patients who may be particularly at risk for toxicity are:
Those with genetic polymorphisms of the CYP-450 gene. They are rapid metabolisers and therefore more prone to NAPQI production.
Those taking drugs which cause CYP P450 induction, such as ethanol, phenytoin or rifampicin.
Fasted patients as they have a decreased ability to conjugate paracetamol with glucuronic acid due to decreased hepatic carbohydrate reserves. This may lead to increased microsomal oxidation and therefore increased risk of hepatotoxicity. [xvii]
Neonates and young children display different metabolism to adults. Here the main pathway is sulphate conjugation rather than glucuronidation. The normal ratio of glucuronidation:sulphation (2:1) is achieved by 12 years. The cytochrome P450 isoenzyme responsible for creating NAPBQI is less active than in adults, which offers some protection against hepatotoxicity in children. However, glutathione can become depleted in malnutrition and chronic paracetamol therapy putting the child at risk of toxicity.
Analysing paracetamol
Multiple methods have been used to analyse paracetamol. Most research is now directed at finding a single method to analyse combination drugs, as paracetamol is often a component of compound analgesic tablets. Liquid chromatographic methods have been most widely accepted for use in detecting paracetamol. [xviii] , [xix]
According to Shah et al, a reversed phase high performance liquid chromatographic (RP-HPLC) method is best for the simultaneous analysis of paracetamol and lornoxicam in tablet dosage form. In this study, a Brownlee C-18, 5 μm column having 250Ã-4.6 mm internal diameter in isocratic mode, with mobile phase containing 0.05 M potassium dihydrogen phosphate:methanol (40:60, v/v) was used. The flow rate was 1.0 ml.min-1 and effluents were monitored at 266 nm. The retention time of paracetamol was 2.7 min. The linearity for paracetamol was in the range of 5-200 μg.ml-1. Shah’s method will be replicated in this study.
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According to Franeta et al, RP-HPLC with UV detection without prior derivatization can be used for direct simultaneous determination of acetylsalicylic acid, caffeine, paracetamol and phenobarbital in tablet form. A mixture of acetonitrile:water (25:75 v/v) adjusted to pH 2.5 by adding phosphoric acid was used as a mobile phase at a flow rate of 2.0 ml.min−1. As a compromise, a wavelength of 207 nm was used to detect these products. The graph below indicates the chromatograms for each substance.
The chromatograms of acetylsalicylic acid (tR −7.88), paracetamol (tR−2.97), caffeine (tR −4.86), phenobarbital (tR −9.89) and salicylic acid (tR −11.66) obtained by HPLC (column: Bio SiL HL C18, 5 μm, 250Ã-4.6 mm; mobile phase-acetonitrile: water (25:75 v/v) adjusted to pH 2.5 with phosphoric acid).
Gopinath et al used a simple, selective, rapid, precise and economical reverse phase HPLC method for the simultaneous estimation of paracetamol and aceclofenac. This study was carried out on a Hichrom C18 (25 cmÃ-4.6 mm i.d., 5 µ) column with a mobile phase consisting of acetonitrile:20 mM phosphate buffer (pH 5.0) (60:40 v/v) at a flow rate of 0.8 ml.min−1. Detection was carried out at 265 nm. Etoricoxib was used as an internal standard. The retention time of paracetamol was 4.75 minutes. [xx]
The challenge of creating intravenous paracetamol:
A soluble form of paracetamol has long been desired. While oral paracetamol is the cheapest and easiest mode of administration, this is not an option for intraoperative use or in patients with bowel obstruction. Rectal administration is unreliable with erratic absorption and peak plasma concentration is variable and reached 2-3 hours later than by the oral route. For most drugs, intravenous dosing is the most reliable form of administration and peak plasma concentrations are reached more quickly and consistently than by any other route.
However, due to paracetamol’s poor water solubility, until recently the only intravenous preparation was proparacetamol. This is a pro-drug of paracetamol which requires hydrolysis by plasma esterases to yield the active drug, paracetamol and byproduct, diethylglycine. A dose of 2g of proparacetamol is equivalent to 1g of paracetamol. [xxi] However, the risk of hypersensitivity and pain on injection limits use of proparacetamol. Also, proparacetamol was very expensive, as it needs to be reconstituted in sodium citrate.
Perfalgan®
In recent years, through the use of improved stabilization techniques, paracetamol was developed as an intravenous form, Perfalgan® . Hydrophilic ingredients like mannitol and disodium phosphate were added to make it water soluble. Unlike proparacetamol, this no longer needs the hydrolysis step for activation. In South Africa intravenous paracetamol is marketed by Bristol-MyersSquibb as Perfalgan®.
Contents
Perfalgan® contains mg.ml-1 of paracetamol (a 50mL vial contains 500 mg of paracetamol, a 100mL vial contains 1 g of paracetamol). Other contents include:
mannitol: aids solubility
cysteine hydrochloride and nitrogen: preservatives and antioxidants
sodium phosphate – dibasic dehydrate: buffer (maintains pH of 5.5, minimizing hydrolysis)
sodium hydroxide: buffer
hydrochloric acid
water for injection. , , [xxii]
These additives are called excipients. They can be analysed by nuclear magnetic resonance (NMR), as explained below.
With an osmolarity of 290 mOsm.L-1, Perfalgan® offers little or no pain at the site of injection [xxiii] . It is packaged in a glass container as a clear or slightly yellowish solution.
Storage and shelf-life:
It is recommended that Perfalgan® should be stored below 30°C for no more than 2 years. Before administration, the vial should be inspected for discolouration or particulate matter.
Administration:
Perfalgan® should be infused over 15 minutes. Each vial is advised for single use only. This is presumably due to concerns about degradation of the product and because the vial contains no antimicrobial agent. [xxiv] Perfalgan® 10 mg.ml-1 solution can also be diluted in a 0.9% sodium chloride or 5% glucose solution up to one tenth. In this situation the manufacturers advise that the diluted solution should be used within one hour, including the infusion time. No clear reason for this is given. Common practice is not to dilute the drug, even for paediatric use
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