PARACETAMOL: MECHANISM OF ACTION, APPLICATIONS

Paracetamol (an international name used in. Europe) and acetaminophen (an international name used in the USA) are two official names of the same.

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Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 71 No. 1 pp. 11ñ23, 2014ISSN 0001-6837 Polish Pharmaceutical SocietyParacetamol(an international name used inEurope) and acetaminophen(an international nameused in the USA) are two official names of the same chemical compound derived from its chemical name: N-acetyl-para-aminophenol(the segment ëícetííinserted between ëíparaíí and ëíaminoíí) and N- acetyl-para-aminophenol. This drug has a long his-tory and, as it often happens with important discov- eries, it was found by chance. In the 80s of the 19th century, two young doctors at the University of Strasburg, in order to eradicate worms by mistake dispensed acetanilide to a patient instead of naphtha- lene (Fig. 1). They noticed that the drug had a small impact on intestinal parasites, however, it signifi- cantly decreased high temperature. Young doctors – Arnold Chan and Paul Heppa – quickly published their discovery and acetanilide was introduced into medical practice in 1886 under the name of antifebrin (1). Soon it appeared that although the pro- duction of this drug was very cheap, acetanilidePARACETAMOL: MECHANISM OF ACTION, APPLICATIONS AND SAFETY CONCERNJERZY Z. NOWAK Department of Pharmacology, Chair of Pharmacology and Clinical Pharmacology at the Medical University of £Ûdü, Øeligowskiego 7/9, 90-752 £Ûdü, Poland Abstract: Paracetamol / acetaminophen is one of the most popular and most commonly used analgesic andantipyretic drugs around the world, available without a prescription, both in mono- and multi-component prepa- rations. It is the drug of choice in patients that cannot be treated with non-steroidal anti-inflammatory drugs (NSAID), such as people with bronchial asthma, peptic ulcer disease, hemophilia, salicylate-sensitized people, children under 12 years of age, pregnant or breastfeeding women. It is recommended as a first-line treatment of pain associated with osteoarthritis. The mechanism of action is complex and includes the effects of both the peripheral (COX inhibition), and central (COX, serotonergic descending neuronal pathway, L-arginine/NO pathway, cannabinoid system) antinociception processes and ìredoxî mechanism. Paracetamol is well tolerat- ed drug and produces few side effects from the gastrointestinal tract, however, despite that, every year, has seen a steadily increasing number of registered cases of paracetamol-induced liver intoxication all over the world. Given the growing problem of the safety of acetaminophen is questioned the validity of the sale of the drug without a prescription. This work, in conjunction with the latest reports on the mechanism of action of parac- etamol, trying to point out that it is not a panacea devoid of side effects, and indeed, especially when is taken regularly and in large doses (> 4 g/day), there is a risk of serious side effects.Keywords:paracetamol, acetaminophen, toxic effects, mechanism of action, cyclooxygenase, cannabinoid,serotonergic, prostaglandin-endoperoxide synthases11*Corresponding author: e-mail: marta.jozwiak-bebenista@umed.lodz.pl; phone/fax: +48 42 639-32-90 Figure 1. Chemical structure of analgesics – aniline derivatives.Phenacetin until the 80s of the 20th century was included in the composition of numerous mixtures. Saridon (Roche firm) and the so-called in Polish ìtablets with crossî produced by Polpharma Farmaceutyczne Polfa) and Marcmed from Lublin are the most well-known preparations. Due to its carcinogenic action damaging the kidneys and the liver as well as the patientsí tendency towards an overuse, the drug was withdrawn from the American market in 1983 (in Saridon, phenacetin was replaced by paracetamol). In Poland, it happened as late as in 2004

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12JERZY Z. NOWAK could not be used as an antipyretic medicament dueto its high toxicity, the most alarming of which was methemoglobinemia. This resulted in a great deal of research on less toxic derivatives of acetanilide. Phenacetin and N-acetyl-p-aminophenol appeared to be the most satisfying compounds, which had been earlier synthesized by Harmon Northrop Morse in 1878 (Fig. 1) (2). The first clinical trials with those two acetanilide derivatives were performed by a German pharmacologist Joseph von Mering. On the basis of the obtained results, a faulty conclusion was drawn that paracetamol was characterized by high toxicity similar to acetanilide, therefore phenacetin was the first derivative to be introduced into medical practice in 1887. Phenacetin was widely used in analgesic mixtures until the time when it was associ- ated with the development of analgesic nephropathy after a prolonged usage (3). In Poland, phenacetin was used as a component of very popular and avail- able everywhere analgesic ëítablets with the crossíí. In fact, acetaminophen/paracetamol became popular half a year later in 1948 when Bernard Brodie and Julius Axelrod demonstrated that paracetamol was the main active metabolite of acetanilide and phenacetin responsible for their analgesic and antipyretic action and that methemoglobinemia was induced by another metabolite, phenylhydroxyl- amine (4). That discovery revolutionized the phar- maceutical market of analgesic drugs and since then paracetamol has started its staggering career. The use of paracetamolParacetamol was introduced into the pharma-cological market in 1955 by McNeil Laboratories as a prescribed analgesic and antipyretic drug for chil- dren under its trade name Tylenol Childrenís Elixir (the name tylenol derives from its chemical name ñN-acetyl-p-aminophenol). One year later,500-mgtablets of paracetamol were available over the counter in Great Britain under the trade name of Panadol, which were produced by Frederick Stearns& Co, the branch of Sterling Drug Inc. In Poland, paracetamol became available in 1961 and since then it has belonged to the one of the most frequent- ly sold analgesic medications. There are about a 100 preparations in the trade offer, which contain para- cetamol alone or in combination with other active substances.The paracetamol place on the WHO analgesicladder, which precisely defines the rules for applica- tion of analgesic drugs, is impressive. This drug has been placed on all three steps of pain treatment intensity. In different pains of moderate intensity, paracetamol as a weak analgesic together with non- steroidal analgesic drugs or coanalgesics (e.g., caf- feine) is a basic non-opioid analgesic (the first step of the analgesic ladder). When pain maintains or increases, paracetamol is used as an additional anal- gesic with weak (e.g., caffeine, tramadol) or strong (e.g., morphine, phentanyl) opioids from the second and third step of the analgesic ladder, respectively,Figure 2. Paracetamol on the WHO analgesic ladder (the rules for using analgesics, which consider individual intensity of pain).

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Paracetamol: mechanism of action, applications and safety concern13Fig. 2). Paracetamol, if efficient, is a recommendedoral analgesic of a first choice to be used for a long time, e.g., in symptomatic treatment of slight and moderate pain occurring in osteoarthritis as well as in muscle or tendon pains. Moreover, it is a drug of choice in patients in whom application of non- steroidal anti-inflammatory drugs (NSAIDs) are contraindicated, e.g., in the case of gastric ulcers, hypersensitivity to aspirin, impairments in blood coagulation, in pregnant women, nursing mothers and children with fever accompanying a disease (5). The use of paracetamol in children requires special care and maintain in an adequate dosage (based on age), which significantly differs from standard adult. The recommended dosage for children consider the metabolism of paracetamol, which determines the toxicity of the drug, especially hepatotoxicity (see below). In children, paracetamol metabolism changes with age: in younger children the sulfation pathway is dominated route of paracetamol elimina- tion (which is mature at birth); the glucuronidation pathway takes about two years to mature. The oxi- dation of paracetamol, which takes place mainly with the participation of the enzyme CYP2E1 in neonates is negligible, because the activity of CYP2E1 increases with age, reaching the adult value at age 1-10 years. For comparison, in adults, paracetamol is metabolized mainly in the liver viaglucuronidation (50-60%), sulfation (25-30%) and oxidation (< 10%) (see below in the section on adverse effects). Therefore, according to Ji et al. (6), the proposed dosage of paracetamol in children up to 12 years is as follows:under 2 years ñ no recommended dose; treatment under the supervision of a physician;2-3 years ñ 160 mg (daily dose divided into two to 1/2 of a single dose for an adult, i.e., 325 mg;4-6 years ñ 240 mg (daily dose divided into three to 3/4 of a single dose for an adult; 6-9 years ñ 320 mg (daily dose divided into four as a single dose for an adult; 9-11 years ñ 320-400 mg (daily dose divided into corresponds to 1-1 1/4 of a single dose for an adult; 11-12 years ñ 320-480 mg (daily dose divided in corresponds to 1 ñ 1 1/2 of a single dose for an adult. According to the 20th edition of Drugs ofContemporary Therapy (Polish),the acetaminophen dosage schedules in pediatric patients should be asfollows: 10-15 mg/kg oral dose and 15-20 mg/kg rectal dose every 4-6 h, maximum of 5 doses/day; in newborns orally or rectally 10 mg/kg of body weight every 4 h or 15 mg/kg every 6 h (maximum daily dose in newborns is 60 mg/kg).Mechanism of action Although paracetamol was discovered over100 years ago and has been widely used in medical practice for more than half the century, its mecha- nism of action has not been elucidated until now (7). It has analgesic and antipyretic properties similarly to NSAIDs, but contrary to them, it does not possess any anti-inflammatory activity. When applied in recommended doses, it does not induce typical for NSAIDs gastrointestinal side effects. However, it suppresses prostaglandin production likewise NSAIDs. Due to lack of an anti-inflammatory compo-nent, paracetamol has not been regarded as a mem- ber of the NSAIDs family in pharmacological text- books, although what is interesting, it has been always discussed together with these drugs. Therefore, the discussion on the mechanism of action of paracetamol should begin from the analy- sis of NSAIDs action. All conventional NSAIDs inhibit the conver-tion of arachidonic acid (AA) into prostaglandin H - PGH2. The stage is catalyzed by prostaglandin Hsynthase (PGHS), at present referred to as cyclooxy- genase (COX) within which isoenzymes COX-1 (PGHS-1) and COX-2 (PGHS-2) occur (8). The prevalence and the role of the third isoenzyme COX-3 is the subject of ongoing to date discussions (read further). PGHS is a bifunctional enzyme and possesses two different enzymatic activities: cyclooxygenase and peroxidase (POX). The conver- sion of AAPGH2involves two reactions: cycliza-tion of AA to unstable 15-hydroxyperoxide (PGG2)with the involvement of a cyclooxygenase compo- nent and double oxidation in position 9 and 11; whereas the reduction of PGG2 molecule to its 15-hydroxy analogue, unstable structure of PGH2, takesplace due to peroxidase activity of PGHS (POX).Prostaglandin H2 (PGH2) is a substrate for spe-cific synthases, tissue-dependent isomerases catalysing its further conversions into different endogenous regulators, namely: prostaglandins of the D (PGD2), E (PGE2), F (PGF2) series and prostacyclin(PGI2; prostacyclin is not a prostaglandin and a com-monly used abbreviation is historically conditioned) and thromboxanes (TXA2and TXB2). They all arecharacterized by different biological activity and PAGE - 4 ============ 14JERZY Z. NOWAK many of them have anti-inflammatory properties.Thus, the action of NSAIDs, which inhibits the stage of conversion AAPGH2, and also the formation ofthe aforementioned regulators, have some favorable (anti-inflammatory, analgesic and antipyretic) and side effects (associated with the inhibition of synthe- sis of particular regulators in different tissues). A pre- cise mechanism of NSAID action together with ther- apeutic and side effects has been presented in the recently published large study by Nowak and Dzielska-Olczak (9) and Nowak (10, 11).While traditional NSAIDs and selective COX2inhibitors inhibit cyclooxygenase (PGHS) through competing with arachidonic acid for the active site of the enzyme (12), paracetamol is likely to act as a fac- tor reducing a ferryl protoporphyrin IX radical cation (Fe4+=OPP*+) within the peroxidase site of the PGHSenzyme. In turn, the Fe4+=OPP*+generates tyrosineradicals in the place of PGHS cyclooxygenase, which are essential for catalyzation of AA oxidation reaction (12-16) (Fig. 3). Due to a fact that hydroper- oxides of fatty acids, like PGG2(reduced by POX),oxidize porphyrin within the peroxidase site of the enzyme, cyclooxygenase inhibition by paracetamol is difficult in the presence of high peroxide levels. Graham and Scott suggested that paracetamol should be classified to the group of the so-called atypical NSAIDs, determined as peroxide sensitive analgesic and antipyretic drugs (PSAAD) (17). For the last decades, it was thought that para-cetamol reveals analgesic and antipyretic properties by acting centrally and its inhibitory effect on COX- 1 and COX-2 activity, i.e., prostaglandin synthesis was low. This concept was based on the original research carried out by Vane and colleagues, which was published at the beginning of the 70s of the pre- vious century. Those authors observed that parac-etamol decreased prostaglandin synthesis ten timesstronger in the brain than in the spleen (18).1 At that time COX isoforms were not knownbecause isoenzyme, COX-2, was identified only at the beginning of the 90s of the previous century (25, 26). Ten years later, the experiments performed on the dogís brain tissue revealed the presence of the third COX isoform, COX-3, which demonstrated special sensitivity to paracetamol (27). However, it soon appeared that so sensitive to paracetamol COX-3 does not function in the human organism. The human analogue of dogís COX-3, which occurs in some tissues especially of the central nervous sys- tem, is an alternative splice variant of COX-1 with- out a preferential sensitivity to paracetamol, encod- ing proteins of amino acid sequence different from COX and not exhibiting COX activity (28-30). Thus, COX-3 involvement in the mechanism of action of paracetamol in humans has not been justi- fied, which has been confirmed by Kis et al. as well as by Hinz and Brune (15, 29). However, the dis- cussions regarding a potential role of identified three COX isoenzymes in the mechanism of paracetamol action are still being continued (31-34).The concept regarding COX-dependent centralmechanism of paracetamol action has not stood the test of time (29). Firstly, the studies by Graham and Scott have shown that paracetamol really inhibited prostaglandin synthesis in well-functioning cells, however, it did not exert the same effect in the tis- sue/cell homogenate, where the concentration of arachidonic acid is low (35). Secondly, paracetamol has been found to have an inhibitory impact on COX-1 and COX-2 activity in peripheral tissues, although not to the same extent, since a stronger effect was always observed in relation to COX-2, especially in the cells of the vascular endothelium.1In numerous academic textbooks including those published during the last decade, the central mechanism of paracetamol action has beendiscussed emphasizing its weaker inhibitory effect on the cyclooxygenase activity and prostaglandin production as compared to NSAIDs.The early study by Flower and Vane from 1972 in the prestige magazine Nature announced the mechanism of paracetamol activity evenin its title: îInhibition of prostaglandin synthetase in brain explains the antipyretic activity of paracetamol (4-acetamidophenol) î (18).Scientific prestige of the future Nobel prize winner, John R. Vane, was so high that despite later published articles, which did not com-pletely confirm the original results of the British researchers (19-21) that study was still citied and its results were considered the substan-tial basis of the mechanism of paracetamol action for many pharmacologists and doctors. Flower and Vane indicated that prostaglandin production in the brain was 10-fold more sensitive to paracetamol action than in thespleen (18). At that time, John R. Vane, the future Noble Prize winner in physiology and medicine (John R. Vane, Sune K. Bergstrom andBengt I. Samuelsson ñ îNobel Prizeî in 1982 for discoveries on prostaglandin and related biologically active substances) was the authorof many other essential for medicine innovative observations that were published in prestige magazines, e.g. ìInhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugsî (22). John Vane, using a guinea pig lung homogenate in his study, concludedthat analgesic, antipyretic and anti-inflammatory action of aspirin, indomethacin and salicylate is associated with a lower prostaglandinproduction resulting from cyclooxygenase inhibition (COX). Other articles published in the same magazine Nature by Vane et al.:îIndomethacin and aspirin abolish prostaglandin release from spleen î and by Smith and Willis: ìAspirin selectively inhibits prostaglandin production in human platelets î contained the results confirming those observations (23, 24). It is worth remembering that COX isoenzymeswere not discovered at that time. PAGE - 5 ============ Paracetamol: mechanism of action, applications and safety concern15Hinz et al. indicated that orally administered para-cetamol at a dose of 1 g inhibited 80% of the COX- 2 activity in human blood monocytes (36). The results of extensive studies by Hinz and Brune pub- lished in the years 2006-2012 reveal that paraceta- mol is a preferential inhibitor of COX-2 isoenzyme, however, its effect depends to a great extent on the state of environmental oxidation/reduction (redox) (15, 37). Among other possibilities of the central actionof paracetamol, its stimulating effect on descending serotoninergic pathways, which are involved in inhi- bition of pain sensations has been discussed. This theory has been confirmed by in vivostudies on ani-mals as well as on humans. Alloui et al. carried out the study on analgesic and anti-inflammatory action of paracetamol in rats which were given caragenin. No anti-inflammatory effect of paracetamol was observed, however, central antinociceptive effect of this drug with the involvement of the 5-HT3 subtypeof serotonin receptors was detected (38). The study on healthy volunteers in whom the pain was induced through electrical stimulation of the median nerve showed that analgesic action of paracetamol was completely blocked in the group of subjects treated with paracetamol combined with tropisetron or granisetron (5-HT3receptor antagonists) (39, 40).Data concerning central action of paracetamolthrough its effect on descending serotoninergic path- ways do not exclude a hypothesis assuming the pres- ence (or coexistence) of the inhibition of prostaglandin synthesis (35). Prostaglandin PGE2modulates numerous physiological processes and can also modulate nociceptive and autonomic processes viaits influence on descending serotonin-ergic antinociceptive system (41). Novel studies on the mechanism of action ofparacetamol regard it as a pro-drug, which due to its active metabolites demonstrates an association with the endocannabinoid system. It has been observed that in mouse brain and spinal cord, paracetamol is subject to deacetylation to p-aminophenol that in turn reacts with arachidonic acid affected by fatty acid amide hydrolase (FAAH), resulting in the for- mation of an active metabolite of the drug, the fatty acid amide N-arachidonoylphenolamine (AM404) (42, 43). AM404 does not act directly on cannabi- noid receptors, however, it increases activity of endocannabinoid system in an indirect way (44). On one hand, this compound is a strong activator of the vanilloid receptor subtype 1 (TRPV1), being a lig- and of receptors for cannabinoids CB1, and on theother hand, it leads to an increase in the endogenous pool of these compounds as an inhibitor of theFigure 3. The complex of prostaglandin H synthase (PGHS) including two components: cyclooxygenase (COX) and hydroperoxidase(POX) is a bifunctional enzyme, responsible for the metabolism of arachidonic acid (AA) to prostaglandin PGH2. The reaction occurs viatwo stages: 1. AA oxidation to PGG2depends on tyrosine radical (Tyr385*) in the COX site. 2.PGG2undergoes reduction to PGH2in thePOX site, which results in the oxidation of the peroxidase heme radical. 3.A formed ferryl protoporphyrin IX radical cation (Fe4+=OPP*+)generates Tyr385* radicals. Thus, the POX part is ìself-sufficientî, whereas COX depends on POX. Paracetamol reduces an iron cation inprotoporphyrin IX radical (Fe4+=OPP*+) in the POX part, which contributes to a lower amount of Tyr385*radical formation. Abbreviations:AA ñ arachidonic acid; AA*ñ arachidonic acid radical; A*- oxidized cosubstrate; AH ñ reduced cosubstrate; Fe3+- enzyme at rest; Fe4+=Oñ protoporphyrin IX (heme); Fe4+=OPP*+ - protoporphyrin radical IX; HPETE ñ hydroperoxides of fatty acids; PGG2*- prostaglandin G2containing peroxide radical; PGH2ñ prostaglandin H; ROH ñ alcohol; Tyr385* ñ tyrosine radical (12, 16, 38). PAGE - 6 ============ 16JERZY Z. NOWAK endogenous cannabinoid (anandamide) reuptake(45). Endogenous cannabinoids, e.g., anandamide, act antinociceptively both at the level of the spinal cord as well as the brain. The study on rats per- formed by Bertolini et al. presented that an earlier administration of the CB1receptor inhibited AM404activity and completely blocked analgesic action of paracetamol in the animals (46). Moreover, cannabi- noids considerably lower body temperature through the activation of CB1receptors in the pre-optic area(47). It has been known that analgesic derivatives of aniline have a similar action as cannabinoids, such as mood improvement, psychic relaxation and seda- tion. Such properties have not been observed so far in the case of paracetamol, although some authors ascribe poor sedative properties to it (29, 48). Furthermore, different concentrations of AM404 have been found to inhibit COX-1 and COX-2 enzymes. This mechanism may be important espe- cially in such areas of the brain in which a high con-centration of FAAH enzyme can be observed, e.g.,in the mesencephalic trigeminal nucleus, primary sensory neurons. In these areas of the brain an increased production of the active metabolite AM404 can be found, and this in turn may to a cer- tain degree explain the inhibitory action of paraceta- mol towards cyclooxygenases in the CNS (46). Inhibition of nitrogen oxide (NO) formationmight be also an alternative mechanism of analgesic action of paracetamol. The L-arginine/NO pathway activated by substance P and NMDA receptors leads to NO synthesis, which is an important neurotrans- mitter in the nociceptive processes of the spinal cord (49, 50). Summing up, paracetamol acts at all levels ofpain stimulus conduction from the tissue receptors through the spinal cord to the thalamus and the cere- bral cortex in which pain sensations are evoked. The mechanism of analgesic action of paracetamol is complex. The following possibilities are still takenTable 1. Advantages and disadvantages of paracetamol therapy.Advantages (when the drug is administered in the recommended therapeutic doses max. 4 g/24 h)wide therapeutic application checked and examined well tolerated good bioavailability after oral administration (t1/22h) fast elimination cheep a small number of interactions with other drugs low toxicity at low doses (2 g / d) to the digestive tract and kidneys low toxicity in children rare side effects (main allergic skin reactions) available in different pharmaceutical forms Disadvantages metabolized to a toxic metabolite (N-acetyl-p-benzoquinone imine) therapeutic index (often not efficient at a low dose) long-term application may cause:renal functioning disorder higher blood pressure increased prevalence of heart infarction low therapeutic efficiencyanalgesic action at a dose of 1 g administered 2, 3, and 4 times a day low anti-inflammatory action hepatotoxicityincreased aminotransferase activity at therapeutic doseshepatic failure in the case of overuse (two-fold overuse of a therapeutic dose) enhanced previous liver damage caused by alcohol consumptioncombinations with traditional NSAIDs can result in a higher prevalence of digestive tract ulceration PAGE - 8 ============ 18JERZY Z. NOWAK adverse reactions (FEARS, the FDA Adverse EventReporting System) collected during the period from October to December 2012. The preparations con- taining paracetamol will be evaluated in terms of inducing adverse skin reactions.After ingestion of paracetamol, about 90% ofthe compound undergoes metabolism in the liver in conjugation with glucuronic acid (50-60%), sulfuric acid (25-35%) and cystine (approximately 3%) to form pharmacologically inactive metabolites, which are eliminated with urine. A small amount of the drug (about 5%) is eliminated in an unchanged form by kidneys. Subsequent 5% of paracetamol is sub- jected to N-hydroxylation in the liver with the involvement of cytochrome P450 enzymes (particu- larly CYP2E1) to form a toxic metabolite N-acetyl- p-benzoquinone imine (NAPQI), which is very quickly inactivated by glutathione sulfhydryl groups and excreted with urine as mercapturic acid (46). Severe liver impairment after paracetamoloverdose was documented for the first time in Great Britain in 1966 (56). Since then, a steady increase in the number of accidental or intended poisonings has been noted all over the world including Poland. The main cause of this situation is a huge amount of preparations containing paracetamol, which are available on the pharmaceutical market without any prescription (according to the 20th edition of Dugs of Contemporary Therapy, the number of such preparations reaches 92 items, including 39 single and 53 complex products). Depletion of hepatic glu- tathione stores occurs as a result of the intensive metabolism following intentional and unintentional overdose of paracetamol (ingestion of more than 4 g/24 h, i.e., over 8 tablets, 500 mg each!). In such a situation, paracetamol becomes a dangerous and life-threatening drug because a highly reactive NAPQI metabolite covalently binds to hepatocyte macromolecules leading to impoverishment of enzymatic systems and structural and metabolic damage to the liver (potential lethal hepatic necro- sis). In the later stage of poisoning, renal tubular necrosis and hypoglycemic coma may appear (57). It is worth mentioning that the weakened hepatic function (caused by slimming, malnutrition, hepati- tis C virus (HCV), human immunodeficiency virus(HIV)), alcohol overuse or application of paraceta-mol combined with drugs inducing cytochrome P450 (rifampicin, barbiturates, carbamazepine) can lead to hepatic impairment much easier, even when the compound is used in therapeutic doses. Development of acute hepatic failure as a result of paracetamol overuse (i.e., 7.5-15 g /24 h) as well as the methods of its treatment have been precisely dis- cussed in many studies for the last ten years (46, 58- 60). The authors of the present study concentrate on other (likely to be potential) adverse reactions of paracetamol, which result from its mechanism of action.Results of recent reports on paracetamol as aperipheral selective COX-2 inhibitor encourage researchers to analyze this drug more critically. The question arises as to whether paracetamol revealing a similar pharmacological profile to coxibs may induce the same side effects, especially when the drug is used for a long time.2 A permanent blockadeof prostaglandin synthesis through selective COX-2 inhibitors is currently regarded as a cause of adverse cardiovascular reactions in patients after a pro- longed use of these drugs (15, 36, 37, 61). Long- lasting COX-2 inhibition decreases the production of vasoprotective prostacyclin (PGI2) by vascularendothelial cells, which inhibits platelet aggregation and has vasodilational capacity. This impairs the balance between tromboxane and prostacyclin and causes thrombus formation. Contrary to the inflam- matory tissue, the endothelial cells possess a low level of peroxides, so they are not likely to inhibit paracetamol activity against COX-2 (14). It has been shown that oral administration ofparacetamol at the dose of 500 mg decreases the amount of excreted with urine 2,3-dinor-6-keto PGF1, the main stable inactive metabolite of prosta-cyclin, whose synthesis is mediated by endothelial COX-2 (62). Likewise, 50% reduction in this metabolite excretion in the urine of pregnant women was noted after ingestion of 1 g of paracetamol (63). Taking into consideration aforementioned results obtained by Hinz et al. (36), regarding over 80% inhibition of COX-2 in the vascular endothelium caused by paracetamol, it can be speculated that such a mechanism of action would be responsible2 Coxibs, NSAIDs selectively inhibiting COX-2 activity, do not affect (in therapeutic doses) COX-1 at the same time. Due to such a mech-anism of coxibs, their side effect on the digestive system, which happens in the case of traditional NSAIDs, was eliminated. However, laterclinical observations indicated that patients using coxibs for a long time developed adverse cardiovascular reactions. Thus, because of ahigher risk of such perturbations in those patients, coxibs (etoricoxib, lumiracoxib, rofecoxib and valdecoxib) have been withdrawn fromsale. Rofecoxib known under the trade name of Vioxx (Merck & Co.) was withdrawn as the first one in 2004 after the 5-year existence onthe pharmaceutical market; valdecoxib (Bextra, Pfizer) was the next drug withdrawn in 2005. At present, only one drug of this type, cele-coxib (Celebrex; Pfizer Europe), is used in Poland. PAGE - 9 ============ Paracetamol: mechanism of action, applications and safety concern19for adverse cardiovascular reactions in patients whotake this drug regularly. It should be emphasized that paracetamol due to its short half-life (approxi- mately 2 h) induces a short-lasting inhibition of COX-2 activity. Thus, in order to eliminate pain it is necessary to administer repeated 1 g doses of parac- etamol for maintaining constant (80%) inhibition of COX-2. This fact has to be considered by a doctor prior to making the decision about long-term treat- ment with paracetamol in order to avoid the drug overdose. Epidemiological data reveal that long-lastingadministration of paracetamol affects blood pres- sure. Nursesí Health Studiespresent two cohortinvestigations performed among younger and older women. One of them demonstrated that in patients who regularly took paracetamol (over 500 mg/24 h), a relative risk (RR) for development of hypertension was considerably higher as compared to women who did not use this drug (RR 1.93 for older women; RR 1.99 for younger) (64). Moreover, it worth emphasizing that the risk associated with paraceta- mol was similar to traditional NSAIDs (RR 1.78 for older women; RR 1.60 for younger). The second cohort investigation carried out in the same study group indicated that in women who frequently used paracetamol (= 22 days a month), the risk of serious cardiovascular events (such as heart infarction or cerebral stroke) was nearly the same as after tradi- tional NSAIDs (RR 1.35 for paracetamol; RR 1.44 for traditional NSAIDs). Similarly, application of paracetamol in the amount of 15 tablets or more per week is associated with the risk of cardiovascular events comparable to traditional NSAIDs (RR 1.68 for paracetamol; 1.86 for traditional NSAIDs) (65). According to the guidelines of the American Heart Association acetaminophen (paracetamol) is nowa- days a drug of choice in patients with concomitant cardiovascular disorders (66). The prospective dou- ble-blind trial was performed in patients with stable coronary disease who used paracetamol at the dose of 1 g three times a day for two weeks and the drug increased their blood pressure. Its effect was similar to that exerted by diclofenac and ibuprofen. Paracetamol due to its selective action towardsCOX-2 and similarly to coxibs but contrary to typ- ical NSAIDs does not possess antiaggregatory properties. The drug does not inhibit blood platelet action when taken at a single oral dose of 1000 mg. However, clinical studies indicate antiaggregatory action of paracetamol in the case of parenteral administration in high doses (67, 68). Paracetamol can be safely used in the digestive tract; on one hand due to its non-acidic chemical structure(unlike acidic NSAIDs gathering in the gastricepithelial cells) and on the other hand, due to a weak impact on COX-1. However, the results of epidemiological studies suggest that paracetamol at daily doses higher than 2-2.6 g increases the risk of serious side effects in the upper segment of the digestive tract such as bleeding or perforations (69). Therefore, it is postulated that a long-term effect of paracetamol on the digestive tract should be exam- ined in randomized studies, especially in patients with osteoarthrisis who require high doses of this drug for a long time. Paracetamol like coxibs does not induce bronchial spasm in patients with aspirin asthma. In the strategy for treatment of pain in asth- matics, it is recommended to ingest this drug at doses lower than 1000 mg in order to avoid poten- tial bronchial spasm (15). Bearing in mind a preferential action of parac-etamol on COX-2, the differences between the drug discussed and coxibs, selective inhibitors of this isoenzyme, should be emphasized. Paracetamol in opposition to selective inhibitors of COX-2, despite a similar mechanism of action, reveals weak anti- inflammatory activity. It is likely to result from the extracellular accumulation of arachidonic acid and peroxides in the inflammatory tissues, which reduce an inhibitory effect of paracetamol on the prostaglandin production (Fig. 3) (14, 35). Indeed, paracetamol did not decrease prostanoid concentra- tions in the joint fluid of patients suffering from osteoarthrisis (70). On the other hand, paracetamol reduced tissue swelling with similar to ibuprofen efficiency after the oral cavity surgery in humans (71). There have been also some studies which demonstrated anti-inflammatory action of paraceta- mol, e.g., nociceptive inhibition and carrageenan- induced rat paw edema (72). Therefore, the notion that paracetamol exhibits weak anti-inflammatory properties seems to be more legitimate than the assumption that this drug is devoid of such an action. As regards safety of paracetamol application inpregnancy, prospective cohort studies in humans have not shown an increase in the prevalence of developmental fetal anomalies in pregnant women who took paracetamol in therapeutic doses, although in some experimental studies on animals paraceta- mol administered at doses twice as high as the max- imum single dose demonstrated embriotoxic action (73). Considering the fact that paracetamol is the drug of choice in pregnant women, it should be emphasized that epidemiological studies report the possibility of the association between application of this drug in pregnancy and development of asthma 142 KB – 13 Pages