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Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 71 No. 1 pp.

11ñ23, 2014 ISSN 0001-6837 Polish


Pharmaceutical Society

PARACETAMOL: MECHANISM OF ACTION, APPLICATIONS


AND SAFETY CONCERN
MARTA JӏWIAK-B BENISTA* and JERZY 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 and
antipyretic 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 synthases

Paracetamol (an international name used in


Europe) and acetaminophen (an international name
used in the USA) are two official names of the same
chemical compound derived from its chemical name:
N-acetyl-para-aminophenol (the segment ëícetíí
inserted 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 Figure 1. Chemical structure of analgesics - aniline derivatives.
noticed that the drug had a small impact on intestinal Phenacetin until the 80s of the 20th century was included in the
composition of numerous mixtures. Saridon (Roche firm) and the
parasites, however, it signifi-cantly decreased high
so-called in Polish ìtablets with crossî produced by Polpharma
temperature. Young doctors - Arnold Chan and Paul SA in Starogard GdaÒski (previously Starogardzkie Zak≥ady
Heppa - quickly published their discovery and Farmaceutyczne Polfa) and Marcmed from Lublin are the most
acetanilide was introduced into medical practice in well-known preparations. Due to its carcinogenic action
damaging the kidneys and the liver as well as the patientsí
1886 under the name of antifebrin (1). Soon it tendency towards an overuse, the drug was withdrawn from the
appeared that although the pro-duction of this drug American market in 1983 (in Saridon, phenacetin was replaced
was very cheap, acetanilide by paracetamol). In Poland, it happened as late as in 2004

* Corresponding author: e-mail: marta.jozwiak-bebenista@umed.lodz.pl; phone/fax: +48 42 639-32-90

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12 MARTA JӏWIAK-B BENISTA and JERZY Z. NOWAK

Figure 2. Paracetamol on the WHO analgesic ladder (the rules for using analgesics, which consider individual intensity of pain).

could not be used as an antipyretic medicament due to The use of paracetamol


its high toxicity, the most alarming of which was Paracetamol was introduced into the pharma-
methemoglobinemia. This resulted in a great deal of cological market in 1955 by McNeil Laboratories as a
research on less toxic derivatives of acetanilide. prescribed analgesic and antipyretic drug for chil-dren
Phenacetin and N-acetyl-p-aminophenol appeared to under its trade name Tylenol Childrenís Elixir (the
be the most satisfying compounds, which had been name tylenol derives from its chemical name ñ N-
earlier synthesized by Harmon Northrop Morse in acetyl-p-aminophenol). One year later, 500-mg tablets
1878 (Fig. 1) (2). The first clinical trials with those of paracetamol were available over the counter in
two acetanilide derivatives were performed by a Great Britain under the trade name of Panadol, which
German pharmacologist Joseph von Mering. On the were produced by Frederick Stearns
basis of the obtained results, a faulty conclusion was & Co, the branch of Sterling Drug Inc. In Poland,
drawn that paracetamol was characterized by high paracetamol became available in 1961 and since
toxicity similar to acetanilide, therefore phenacetin then it has belonged to the one of the most
was the first derivative to be introduced into medical frequent-ly sold analgesic medications. There are
practice in 1887. Phenacetin was widely used in about a 100 preparations in the trade offer, which
analgesic mixtures until the time when it was associ- contain para-cetamol alone or in combination with
ated with the development of analgesic nephropathy other active substances.
after a prolonged usage (3). In Poland, phenacetin was The paracetamol place on the WHO
used as a component of very popular and avail-able analgesic ladder, which precisely defines the
everywhere analgesic ëítablets with the crossíí. In fact,
rules for applica-tion of analgesic drugs, is
acetaminophen/paracetamol became popular half a
year later in 1948 when Bernard Brodie and Julius impressive. This drug has been placed on all
Axelrod demonstrated that paracetamol was the main three steps of pain treatment intensity. In
active metabolite of acetanilide and phenacetin different pains of moderate intensity,
responsible for their analgesic and antipyretic action paracetamol as a weak analgesic together with
and that methemoglobinemia was induced by another
non-steroidal analgesic drugs or coanalgesics
metabolite, phenylhydroxyl-amine (4). That discovery
revolutionized the phar-maceutical market of analgesic
(e.g., caf-feine) is a basic non-opioid analgesic
drugs and since then paracetamol has started its (the first step of the analgesic ladder). When
staggering career. 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,
Paracetamol: mechanism of action, applications and safety concern 13

Fig. 2). Paracetamol, if efficient, is a recommended dosage schedules in pediatric patients should be as
oral analgesic of a first choice to be used for a long follows: 10-15 mg/kg oral dose and 15-20 mg/kg
time, e.g., in symptomatic treatment of slight and rectal dose every 4-6 h, maximum of 5 doses/day;
moderate pain occurring in osteoarthritis as well as in in newborns orally or rectally 10 mg/kg of body
muscle or tendon pains. Moreover, it is a drug of weight every 4 h or 15 mg/kg every 6 h (maximum
choice in patients in whom application of non- daily dose in newborns is 60 mg/kg).
steroidal anti-inflammatory drugs (NSAIDs) are
contraindicated, e.g., in the case of gastric ulcers, Mechanism of action
hypersensitivity to aspirin, impairments in blood Although paracetamol was discovered over
coagulation, in pregnant women, nursing mothers and 100 years ago and has been widely used in medical
children with fever accompanying a disease (5). The practice for more than half the century, its mecha-
use of paracetamol in children requires special care nism of action has not been elucidated until now
and maintain in an adequate dosage (based on age), (7). It has analgesic and antipyretic properties
which significantly differs from standard adult. The similarly to NSAIDs, but contrary to them, it does
recommended dosage for children consider the not possess any anti-inflammatory activity. When
metabolism of paracetamol, which determines the applied in recommended doses, it does not induce
toxicity of the drug, especially hepatotoxicity (see typical for NSAIDs gastrointestinal side effects.
below). In children, paracetamol metabolism changes However, it suppresses prostaglandin production
with age: in younger children the sulfation pathway is likewise NSAIDs.
dominated route of paracetamol elimina-tion (which is Due to lack of an anti-inflammatory compo-
mature at birth); the glucuronidation pathway takes nent, paracetamol has not been regarded as a mem-
about two years to mature. The oxi-dation of ber of the NSAIDs family in pharmacological text-
paracetamol, which takes place mainly with the books, although what is interesting, it has been
participation of the enzyme CYP2E1 in neonates is always discussed together with these drugs.
negligible, because the activity of CYP2E1 increases Therefore, the discussion on the mechanism of
with age, reaching the adult value at age 1-10 years. action of paracetamol should begin from the analy-
For comparison, in adults, paracetamol is metabolized sis of NSAIDs action.
mainly in the liver via glucuronidation (50-60%), All conventional NSAIDs inhibit the conver-tion
sulfation (25-30%) and oxidation (< 10%) (see below of arachidonic acid (AA) into prostaglandin H - PGH2.
in the section on adverse effects). Therefore, according The stage is catalyzed by prostaglandin H synthase
to Ji et al. (6), the proposed dosage of paracetamol in (PGHS), at present referred to as cyclooxy-genase
children up to 12 years is as follows: (COX) within which isoenzymes COX-1 (PGHS-1)
and COX-2 (PGHS-2) occur (8). The prevalence and
● under 2 years ñ no recommended dose; treatment the role of the third isoenzyme COX-3 is the subject of
under the supervision of a physician; ongoing to date discussions (read further). PGHS is a
● 2-3 years ñ 160 mg (daily dose divided into two bifunctional enzyme and possesses two different
dose units, i.e., 2 ◊ 80 mg); total dose corresponds enzymatic activities: cyclooxygenase and peroxidase
to 1/2 of a single dose for an adult, i.e., 325 mg; (POX). The conver-sion of AA→PGH2 involves two
● 4-6 years ñ 240 mg (daily dose divided into three reactions: cycliza-tion of AA to unstable 15-
dose units, i.e., 3 ◊ 80 mg); total dose hydroxyperoxide (PGG2) with the involvement of a
corresponds to 3/4 of a single dose for an adult; cyclooxygenase compo-nent and double oxidation in
● 6-9 years ñ 320 mg (daily dose divided into four position 9 and 11; whereas the reduction of PGG 2
dose units, i.e., 4 ◊ 80 mg); total dose is the same molecule to its 15-hydroxy analogue, unstable
as a single dose for an adult; structure of PGH2, takes place due to peroxidase
● 9-11 years ñ 320-400 mg (daily dose divided into activity of PGHS (POX).
four-five dose units, i.e., 4-5 ◊ 80 mg; total dose Prostaglandin H2 (PGH2) is a substrate for spe-
corresponds to 1-1 1/4 of a single dose for an cific synthases, tissue-dependent isomerases
adult; catalysing its further conversions into different
● 11-12 years ñ 320-480 mg (daily dose divided in endogenous regulators, namely: prostaglandins of the
the four-six dose units, i.e 4-6 ◊ 80 mg; total dose D (PGD2), E (PGE2), F (PGF2) series and prostacyclin
corresponds to 1 ñ 1 1/2 of a single dose for an (PGI2; prostacyclin is not a prostaglandin and a com-
adult. monly used abbreviation is historically conditioned)
According to the 20th edition of Drugs of and thromboxanes (TXA2 and TXB2). They all are
Contemporary Therapy (Polish), the acetaminophen characterized by different biological activity and
14 MARTA JӏWIAK-B BENISTA and JERZY Z. NOWAK

many of them have anti-inflammatory properties. etamol decreased prostaglandin synthesis ten times
Thus, the action of NSAIDs, which inhibits the stage stronger in the brain than in the spleen (18).1
of conversion AA→PGH2, and also the formation of At that time COX isoforms were not known
the aforementioned regulators, have some favorable because isoenzyme, COX-2, was identified only at the
(anti-inflammatory, analgesic and antipyretic) and side beginning of the 90s of the previous century (25, 26).
effects (associated with the inhibition of synthe-sis of Ten years later, the experiments performed on the
particular regulators in different tissues). A pre-cise dogís brain tissue revealed the presence of the third
mechanism of NSAID action together with ther- COX isoform, COX-3, which demonstrated special
apeutic and side effects has been presented in the sensitivity to paracetamol (27). However, it soon
recently published large study by Nowak and appeared that so sensitive to paracetamol COX-3 does
Dzielska-Olczak (9) and Nowak (10, 11). not function in the human organism. The human
While traditional NSAIDs and selective COX2 analogue of dogís COX-3, which occurs in some
inhibitors inhibit cyclooxygenase (PGHS) through tissues especially of the central nervous sys-tem, is an
competing with arachidonic acid for the active site of alternative splice variant of COX-1 with-out a
the enzyme (12), paracetamol is likely to act as a fac- preferential sensitivity to paracetamol, encod-ing
tor reducing a ferryl protoporphyrin IX radical cation proteins of amino acid sequence different from COX
(Fe4+=OPP*+) within the peroxidase site of the PGHS and not exhibiting COX activity (28-30). Thus, COX-
enzyme. In turn, the Fe4+=OPP*+ generates tyrosine 3 involvement in the mechanism of action of
radicals in the place of PGHS cyclooxygenase, which paracetamol in humans has not been justi-fied, which
are essential for catalyzation of AA oxidation reaction has been confirmed by Kis et al. as well as by Hinz
(12-16) (Fig. 3). Due to a fact that hydroper-oxides of and Brune (15, 29). However, the dis-cussions
fatty acids, like PGG2 (reduced by POX), oxidize regarding a potential role of identified three COX
porphyrin within the peroxidase site of the enzyme, isoenzymes in the mechanism of paracetamol action
cyclooxygenase inhibition by paracetamol is difficult are still being continued (31-34).
in the presence of high peroxide levels. Graham and The concept regarding COX-dependent central
Scott suggested that paracetamol should be classified mechanism of paracetamol action has not stood the
to the group of the so-called atypical NSAIDs, test of time (29). Firstly, the studies by Graham and
determined as peroxide sensitive analgesic and Scott have shown that paracetamol really inhibited
antipyretic drugs (PSAAD) (17). prostaglandin synthesis in well-functioning cells,
For the last decades, it was thought that para- however, it did not exert the same effect in the tis-
cetamol reveals analgesic and antipyretic properties by sue/cell homogenate, where the concentration of
acting centrally and its inhibitory effect on COX-1 and arachidonic acid is low (35). Secondly, paracetamol
COX-2 activity, i.e., prostaglandin synthesis was low. has been found to have an inhibitory impact on COX-
This concept was based on the original research 1 and COX-2 activity in peripheral tissues, although
carried out by Vane and colleagues, which was not to the same extent, since a stronger effect was
published at the beginning of the 70s of the pre-vious always observed in relation to COX-2, especially in
century. Those authors observed that parac- the cells of the vascular endothelium.

1
In numerous academic textbooks including those published during the last decade, the central mechanism of paracetamol action has been
discussed 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 even
in 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 the
spleen (18). At that time, John R. Vane, the future Noble Prize winner in physiology and medicine (John R. Vane, Sune K. Bergstrom and
Bengt I. Samuelsson ñ îNobel Prizeî in 1982 for discoveries on prostaglandin and related biologically active substances) was the author of
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, concluded
that analgesic, antipyretic and anti-inflammatory action of aspirin, indomethacin and salicylate is associated with a lower prostaglandin
production resulting from cyclooxygenase inhibition (COX). Other articles published in the same magazine Nature by Vane et al.:
îIndomethacin and aspirin abolish prostaglandin release from spleenî and by Smith and Willis: ìAspirin selectively inhibits prostaglandin
production in human plateletsî contained the results confirming those observations (23, 24). It is worth remembering that COX
isoenzymes were not discovered at that time.
Paracetamol: mechanism of action, applications and safety concern 15

Figure 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 PGH 2. The reaction occurs via two stages: 1. AA
oxidation to PGG2 depends on tyrosine radical (Tyr385 *) in the COX site. 2. PGG2 undergoes reduction to PGH 2 in the POX site, which results in
the oxidation of the peroxidase heme radical. 3. A formed ferryl protoporphyrin IX radical cation (Fe 4+=OPP*+) generates Tyr385* radicals. Thus,
the POX part is ìself-sufficientî, whereas COX depends on POX. Paracetamol reduces an iron cation in protoporphyrin IX radical (Fe 4+=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; Fe 3+ - enzyme at rest; Fe4+=O
ñ protoporphyrin IX (heme); Fe4+=OPP*+ - protoporphyrin radical IX; HPETE ñ hydroperoxides of fatty acids; PGG 2* - prostaglandin G2
containing peroxide radical; PGH2 ñ prostaglandin H; ROH ñ alcohol; Tyr385* ñ tyrosine radical (12, 16, 38).

Hinz et al. indicated that orally administered para- Data concerning central action of paracetamol
cetamol at a dose of 1 g inhibited 80% of the COX- through its effect on descending serotoninergic
2 activity in human blood monocytes (36). The path-ways do not exclude a hypothesis assuming
results of extensive studies by Hinz and Brune pub- the pres-ence (or coexistence) of the inhibition of
lished in the years 2006-2012 reveal that paraceta- prostaglandin synthesis (35). Prostaglandin PGE 2
mol is a preferential inhibitor of COX-2 isoenzyme, modulates numerous physiological processes and
however, its effect depends to a great extent on the can also modulate nociceptive and autonomic
state of environmental oxidation/reduction (redox) processes via its influence on descending serotonin-
(15, 37). ergic antinociceptive system (41).
Among other possibilities of the central action of Novel studies on the mechanism of action of
paracetamol, its stimulating effect on descending paracetamol regard it as a pro-drug, which due to its
serotoninergic pathways, which are involved in inhi- active metabolites demonstrates an association with
bition of pain sensations has been discussed. This the endocannabinoid system. It has been observed that
theory has been confirmed by in vivo studies on ani- in mouse brain and spinal cord, paracetamol is subject
mals as well as on humans. Alloui et al. carried out the to deacetylation to p-aminophenol that in turn reacts
study on analgesic and anti-inflammatory action of with arachidonic acid affected by fatty acid amide
paracetamol in rats which were given caragenin. No hydrolase (FAAH), resulting in the for-mation of an
anti-inflammatory effect of paracetamol was observed, active metabolite of the drug, the fatty acid amide N-
however, central antinociceptive effect of this drug arachidonoylphenolamine (AM404) (42, 43). AM404
with the involvement of the 5-HT 3 subtype of does not act directly on cannabi-noid receptors,
serotonin receptors was detected (38). The study on however, it increases activity of endocannabinoid
healthy volunteers in whom the pain was induced system in an indirect way (44). On one hand, this
through electrical stimulation of the median nerve compound is a strong activator of the vanilloid
showed that analgesic action of paracetamol was receptor subtype 1 (TRPV1), being a lig-and of
completely blocked in the group of subjects treated receptors for cannabinoids CB1, and on the other hand,
with paracetamol combined with tropisetron or it leads to an increase in the endogenous pool of these
granisetron (5-HT3 receptor antagonists) (39, 40). compounds as an inhibitor of the
16 MARTA JӏWIAK-B BENISTA and JERZY Z. NOWAK

endogenous cannabinoid (anandamide) reuptake (45). centration of FAAH enzyme can be observed, e.g., in
Endogenous cannabinoids, e.g., anandamide, act the mesencephalic trigeminal nucleus, primary sensory
antinociceptively both at the level of the spinal cord as neurons. In these areas of the brain an increased
well as the brain. The study on rats per-formed by production of the active metabolite AM404 can be
Bertolini et al. presented that an earlier administration found, and this in turn may to a cer-tain degree explain
of the CB1 receptor inhibited AM404 activity and the inhibitory action of paraceta-mol towards
completely blocked analgesic action of paracetamol in cyclooxygenases in the CNS (46).
the animals (46). Moreover, cannabi-noids Inhibition of nitrogen oxide (NO) formation
considerably lower body temperature through the might be also an alternative mechanism of
activation of CB1 receptors in the pre-optic area (47). analgesic action of paracetamol. The L-
It has been known that analgesic derivatives of aniline arginine/NO pathway activated by substance P and
have a similar action as cannabinoids, such as mood NMDA receptors leads to NO synthesis, which is
improvement, psychic relaxation and seda-tion. Such an important neurotrans-mitter in the nociceptive
properties have not been observed so far in the case of processes of the spinal cord (49, 50).
paracetamol, although some authors ascribe poor Summing up, paracetamol acts at all levels of
sedative properties to it (29, 48). Furthermore, pain stimulus conduction from the tissue receptors
different concentrations of AM404 have been found to through the spinal cord to the thalamus and the cere-
inhibit COX-1 and COX-2 enzymes. This mechanism bral cortex in which pain sensations are evoked. The
may be important espe-cially in such areas of the brain mechanism of analgesic action of paracetamol is
in which a high con- complex. The following possibilities are still taken

Table 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 (t 1/2 2h)
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 efficiency
● analgesic action at a dose of 1 g administered 2, 3, and 4 times a day
● low anti-inflammatory action
hepatotoxicity
● increased aminotransferase activity at therapeutic doses
● hepatic failure in the case of overuse (two-fold overuse of a therapeutic dose)
● enhanced previous liver damage caused by alcohol consumption
● combinations with traditional NSAIDs can result in a higher prevalence of digestive tract ulceration
Paracetamol: mechanism of action, applications and safety concern 17

into consideration: affecting both peripheral (inhibi- positories) differs from other analgesic medica-
tion of COX activity) and central (COX, descending ments: e.g., sodium diclophenac in the form of sup-
serotoninergic pathways, L-arginine/NO pathway, positories in the preparations Dicloberl (50 mg of
cannabinoid system) antinociceptive processes as well the active substance) or Dicloratio (25, 50 and 100
as the redox mechanism (51). The studies on the mg) achieves the maximal blood concentration after
mechanism of paracetamol action require further 30 min since the application, in the preparations:
verification - they should concern not only the ther- Diclac and Diclofenac GSK (50 or 100 mg) or
apeutic action of this drug but also more frequently Voltaren (25, 50, 100 mg) ñ after 60 min, and in Olfen
reported poisoning, especially strong hepatotoxicity (50 and 100 mg) ñ after 2 h (data according to
resulting from the drug overdose since numerous Pharmindex 2012). These data show that the speed of
preparations containing paracetamol are available absorption of an active substance from the drug
without a prescription. administered per rectum (affecting the occurrence of
the therapeutic effect) is influenced by the form and
Paracetamol on the pharmaceutical market composition of the adjuvant substances contained in
Paracetamol is available on the market under suppositories; the same factors affect the supposito-
different trade names in simple (sold over the count- ries containing paracetamol. Slower absorption of the
er) or more complex preparations combined with an drug is usually associated with its longer pres-ence in
additional active substance obtainable only by pre- the organism, i.e., with a longer time of action, which
scription (with tramadol) or without it (in combina- in the case pain complaints is of con-siderable
tion with codeine phosphate, ascorbic acid or importance.
diphenhydramine hydrochloride as well as NSAIDs Paracetamol can be also used intravenously (i.v.)
such as ibuprofen or propyphenazone. Paracetamol and therefore is widely used in the hospital health
occurs in the form of tablets, effervescent tablets, service, e.g., in the postoperative pain thera-py (it has
suspension, powder to prepare oral liquid medicine been evidenced that administration of paracetamol
(sachets) and rectal suppositories. When adminis-tered especially during the first hour of treat-ment is more
orally, clinical effect of paracetamol appears after 30 efficient in reducing pain intensity than given orally),
min. Paracetamol content in oral medica-ments differs; in order to quickly decrease high fever or in the case
most frequently it equals 500 mg, however, there are when another route of adminis-tration is not possible
preparations (most often com-plex) which contain 325 (52, 53). At the beginning, propacetamol ñ precursor
mg of paracetamol or 750 mg (e.g., Febrisan, Coldrex) of paracetamol (Pro-DafalganÆ, Bristol-Myers Squibb;
or even 1000 mg (e.g., Efferalgan Forte, Codrex Pro-Efferalgan, UPSA) was used which after the i.v.
MaxGrip, Flucontrol Hot). The fastest action of administration underwent hydrolysis to paracetamol
paracetamol, already after 15 min, occurs in the case and diethyl-glycine under the influence of plasma
of using fast-release tablets, enriched with sodium esterases. In 2005, an intravenous form of new
bicarbonate which enhances stomach emptying. Due generation para-cetamol was registered as a solution
to this process, paracetamol quicker passes to the ready to be infused at the concentration of 500 mg/50
small intestine where it under-goes absorption (e.g., mL or 1 g/100 mL (PerfalganÆ, Bristol-Myers Squibb)
Panadol RapidÆ). When administered rectally which completely removed proparacetamol from
(suppositories), bioavailability of paracetamol is medical practice (53, 54).
lower, about two thirds of avail-ability as compared to
oral administration. The time necessary to achieve the
therapeutic concentration for suppositories is 120-180 Side effects
min, which means that analgesic action occurs after 2- When appropriate dosage of medicaments con-
3 h since the drug intake. Bioavailability and speed of taining paracetamol is used, i.e., maximum dose of 4
absorption of paracetamol in the form of suppositories g/24 h, (as one can read in the leaflet) no serious side
depend on numerous factors: the drug dose (in adults effects have been observed, besides possible allergic
usually 650 mg; in children 80-325 mg), the size of skin reactions, although after higher doses or
the sup-pository (the smaller and the lower dose the prolonged duration of taking the drug, some side
better bioavailability is), the type of vehicle (the effects may occur, especially in the liver (Table 1)
higher vehicle lipophilicity, the greater bioavailability (55). Interesting is that at the beginning of 2013, the
and the faster effect but the shorter time of drug United States Food and Drug Administration (US
action) and the degree of rectal vascularization. FDA) introduced paracetamol on the list of the
Slower absorption of paracetamol applied via rectum preparations, which will undergo specific monitor-ing
(sup- on the basis of information from the system on
18 MARTA JӏWIAK-B BENISTA and JERZY Z. NOWAK

adverse reactions (FEARS, the FDA Adverse Event (HIV)), alcohol overuse or application of paraceta-
Reporting System) collected during the period from mol combined with drugs inducing cytochrome
October to December 2012. The preparations con- P450 (rifampicin, barbiturates, carbamazepine) can
taining paracetamol will be evaluated in terms of lead to hepatic impairment much easier, even when
inducing adverse skin reactions. the compound is used in therapeutic doses.
After ingestion of paracetamol, about 90% of the Development of acute hepatic failure as a result of
compound undergoes metabolism in the liver in paracetamol overuse (i.e., 7.5-15 g /24 h) as well as
conjugation with glucuronic acid (50-60%), sulfuric the methods of its treatment have been precisely
acid (25-35%) and cystine (approximately 3%) to dis-cussed in many studies for the last ten years
form pharmacologically inactive metabolites, which (46, 58-60). The authors of the present study
are eliminated with urine. A small amount of the drug concentrate on other (likely to be potential) adverse
(about 5%) is eliminated in an unchanged form by reactions of paracetamol, which result from its
kidneys. Subsequent 5% of paracetamol is sub-jected mechanism of action.
to N-hydroxylation in the liver with the involvement Results of recent reports on paracetamol as a
of cytochrome P450 enzymes (particu-larly CYP2E1) peripheral selective COX-2 inhibitor encourage
to form a toxic metabolite N-acetyl-p-benzoquinone researchers to analyze this drug more critically. The
imine (NAPQI), which is very quickly inactivated by question arises as to whether paracetamol revealing a
glutathione sulfhydryl groups and excreted with urine similar pharmacological profile to coxibs may induce
as mercapturic acid (46). the same side effects, especially when the drug is used
Severe liver impairment after paracetamol for a long time.2 A permanent blockade of
overdose was documented for the first time in Great prostaglandin synthesis through selective COX-2
Britain in 1966 (56). Since then, a steady increase in inhibitors is currently regarded as a cause of adverse
the number of accidental or intended poisonings has cardiovascular reactions in patients after a pro-longed
been noted all over the world including Poland. The use of these drugs (15, 36, 37, 61). Long-lasting COX-
main cause of this situation is a huge amount of 2 inhibition decreases the production of vasoprotective
preparations containing paracetamol, which are prostacyclin (PGI2) by vascular endothelial cells,
available on the pharmaceutical market without any which inhibits platelet aggregation and has
prescription (according to the 20th edition of Dugs of vasodilational capacity. This impairs the balance
Contemporary Therapy, the number of such between tromboxane and prostacyclin and causes
preparations reaches 92 items, including 39 single and thrombus formation. Contrary to the inflam-matory
53 complex products). Depletion of hepatic glu- tissue, the endothelial cells possess a low level of
tathione stores occurs as a result of the intensive peroxides, so they are not likely to inhibit paracetamol
metabolism following intentional and unintentional activity against COX-2 (14).
overdose of paracetamol (ingestion of more than 4 It has been shown that oral administration of
g/24 h, i.e., over 8 tablets, 500 mg each!). In such a paracetamol at the dose of 500 mg decreases the
situation, paracetamol becomes a dangerous and life- amount of excreted with urine 2,3-dinor-6-keto PGF 1α,
threatening drug because a highly reactive NAPQI the main stable inactive metabolite of prosta-cyclin,
metabolite covalently binds to hepatocyte whose synthesis is mediated by endothelial COX-2
macromolecules leading to impoverishment of (62). Likewise, 50% reduction in this metabolite
enzymatic systems and structural and metabolic excretion in the urine of pregnant women was noted
damage to the liver (potential lethal hepatic necro-sis). after ingestion of 1 g of paracetamol (63). Taking into
In the later stage of poisoning, renal tubular necrosis consideration aforementioned results obtained by Hinz
and hypoglycemic coma may appear (57). It is worth et al. (36), regarding over 80% inhibition of COX-2 in
mentioning that the weakened hepatic function the vascular endothelium caused by paracetamol, it
(caused by slimming, malnutrition, hepati-tis C virus can be speculated that such a mechanism of action
(HCV), human immunodeficiency virus would be responsible

2 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, later clinical observations indicated that patients using coxibs for a long time developed adverse cardiovascular reactions. Thus, because of a higher risk of such perturbations in those patients, coxibs

(etoricoxib, lumiracoxib, rofecoxib and valdecoxib) have been withdrawn from sale. Rofecoxib known under the trade name of Vioxx (Merck & Co.) was withdrawn as the first one in 2004 after the 5-year existence on the 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.
Paracetamol: mechanism of action, applications and safety concern 19

for adverse cardiovascular reactions in patients who (unlike acidic NSAIDs gathering in the gastric
take this drug regularly. It should be emphasized epithelial cells) and on the other hand, due to a
that paracetamol due to its short half-life (approxi- weak impact on COX-1. However, the results of
mately 2 h) induces a short-lasting inhibition of epidemiological studies suggest that paracetamol at
COX-2 activity. Thus, in order to eliminate pain it daily doses higher than 2-2.6 g increases the risk of
is necessary to administer repeated 1 g doses of serious side effects in the upper segment of the
parac-etamol for maintaining constant (80%) digestive tract such as bleeding or perforations (69).
inhibition of COX-2. This fact has to be considered Therefore, it is postulated that a long-term effect of
by a doctor prior to making the decision about paracetamol on the digestive tract should be exam-
long-term treat-ment with paracetamol in order to ined in randomized studies, especially in patients
avoid the drug overdose. with osteoarthrisis who require high doses of this
Epidemiological data reveal that long-lasting drug for a long time. Paracetamol like coxibs does
administration of paracetamol affects blood pres-sure. not induce bronchial spasm in patients with aspirin
Nursesí Health Studies present two cohort asthma. In the strategy for treatment of pain in asth-
investigations performed among younger and older matics, it is recommended to ingest this drug at
women. One of them demonstrated that in patients doses lower than 1000 mg in order to avoid poten-
who regularly took paracetamol (over 500 mg/24 h), a tial bronchial spasm (15).
relative risk (RR) for development of hypertension Bearing in mind a preferential action of parac-
was considerably higher as compared to women who etamol on COX-2, the differences between the drug
did not use this drug (RR 1.93 for older women; discussed and coxibs, selective inhibitors of this
RR 1.99 for younger) (64). Moreover, it worth isoenzyme, should be emphasized. Paracetamol in
emphasizing that the risk associated with paraceta- opposition to selective inhibitors of COX-2, despite
mol was similar to traditional NSAIDs (RR 1.78 for a similar mechanism of action, reveals weak anti-
older women; RR 1.60 for younger). The second inflammatory activity. It is likely to result from the
cohort investigation carried out in the same study extracellular accumulation of arachidonic acid and
group indicated that in women who frequently used peroxides in the inflammatory tissues, which
paracetamol (= 22 days a month), the risk of serious reduce an inhibitory effect of paracetamol on the
cardiovascular events (such as heart infarction or prostaglandin production (Fig. 3) (14, 35). Indeed,
cerebral stroke) was nearly the same as after tradi- paracetamol did not decrease prostanoid concentra-
tional NSAIDs (RR 1.35 for paracetamol; RR 1.44 tions in the joint fluid of patients suffering from
for traditional NSAIDs). Similarly, application of osteoarthrisis (70). On the other hand, paracetamol
paracetamol in the amount of 15 tablets or more per reduced tissue swelling with similar to ibuprofen
week is associated with the risk of cardiovascular efficiency after the oral cavity surgery in humans
events comparable to traditional NSAIDs (RR 1.68 (71). There have been also some studies which
for paracetamol; 1.86 for traditional NSAIDs) (65). demonstrated anti-inflammatory action of paraceta-
According to the guidelines of the American Heart mol, e.g., nociceptive inhibition and carrageenan-
Association acetaminophen (paracetamol) is nowa- induced rat paw edema (72). Therefore, the notion
days a drug of choice in patients with concomitant that paracetamol exhibits weak anti-inflammatory
cardiovascular disorders (66). The prospective dou- properties seems to be more legitimate than the
ble-blind trial was performed in patients with stable assumption that this drug is devoid of such an
coronary disease who used paracetamol at the dose action.
of 1 g three times a day for two weeks and the drug As regards safety of paracetamol application in
increased their blood pressure. Its effect was similar pregnancy, prospective cohort studies in humans have
to that exerted by diclofenac and ibuprofen. not shown an increase in the prevalence of
Paracetamol due to its selective action towards developmental fetal anomalies in pregnant women
COX-2 and similarly to coxibs but contrary to typ- who took paracetamol in therapeutic doses, although
ical NSAIDs does not possess antiaggregatory in some experimental studies on animals paraceta-mol
properties. The drug does not inhibit blood platelet administered at doses twice as high as the max-imum
action when taken at a single oral dose of 1000 mg. single dose demonstrated embriotoxic action (73).
However, clinical studies indicate antiaggregatory Considering the fact that paracetamol is the drug of
action of paracetamol in the case of parenteral choice in pregnant women, it should be emphasized
administration in high doses (67, 68). Paracetamol that epidemiological studies report the possibility of
can be safely used in the digestive tract; on one the association between application of this drug in
hand due to its non-acidic chemical structure pregnancy and development of asthma
20 MARTA JӏWIAK-B BENISTA and JERZY Z. NOWAK

in early childhood. The metabolism of paracetamol the withdrawal of packages containing high amounts
has been suggested to be responsible for this effect of paracetamol from the market, e.g., containers
because a large amount of glutathione is used to comprising even 100 single doses (e.g., Apap - 100
deactivate the toxic metabolite. Lungs of the devel- tablets, Codipar - 50 tablets), and the introduction of
oping fetus might deplete glutathione, the main blisters that should enable the patient to control the
antioxidant of this organ, which can lead to oxida-tive amount of ingested drug. Furthermore, the packag-ing
stress and inflammation of the respiratory air-ways. In should be labelled with the information about the risk
some investigations, the occurrence of wheezing of liver damage caused by the overuse of the drug. It
breath in very small children was observed, which also seems justifiable to use only one inter-national
however, is a very weak indicator of asthma (74). name, either paracetamol or acetamino-phen, and not
Epidemiological studies from differ-ent research two different names of the same drug because it can be
centres provide controversial results on the association misleading for the patient (if not properly informed the
between paracetamol ingestion by pregnant women unaware patient can ingest the same active substance
and the development of bronchial asthma later in under different names). The most drastic proposal
childhood (74, 75). This happens because a number of suggested by FDA is the with-drawal of all complex
other factors such as fever, cold, inflammation of fetal drugs, both available over the counter (OTC) and by
membranes or other infections of pregnant women can prescription, because, as the various study results
induce develop-ment of asthma in small children, indicate, they are responsible, to a great degree, for
leading thus to fal-sification of study results. Thus, a acute paracetamol poisoning. The data obtained by the
randomized study with placebo as a control could Toxic Exposure Surveillance System (TESS) in 2005
solve this problem. However, such a study would be showed that among all acute paracetamol poisonings,
unethical from the point of view of good clinical 6.3% (i.e., 3,845 of the 61,289 reported) was caused
practice (GCP) which requires application of a by OTC preparations and 1.5% (41 of the 2,698
standard drug as a com-parator, and as NSAIDs are reported) involved severe hepatic damage, while 54%
contraindicated in preg-nancy, one group of women of over-doses (i.e., 1,470 of the 2,698 reported) were
with pain and fever would not be treated at all. At record-ed in the case of using complex drugs available
present, there is no convincing evidence allowing to by prescription. As regards the latter drugs, it has not
unequivocally determine that application of been completely elucidated to which extent a nar-cotic
paracetamol in preg-nant women may lead to asthma ingredient present in the preparation con-tributed to
development in small children. Therefore, paracetamol the poisoning (76). At present, in all com-plex
still remains an analgesic and antipyretic drug of preparations available by prescription in the USA, a
choice in preg-nant patients. However, it should be single dose of contained paracetamol cannot exceed
stressed that the aforementioned data do not concern 325 mg, whereas the way of the drug dosage, despite a
complex preparations containing paracetamol or those decrease in a single dose, remains the same. Although
for i.v. infusion (safety for this route of administration paracetamol is not so toxic for chil-dren as for adults
has not been determined due to lack of sufficient clini- (children do not have a well-developed cytochrome
cal data). P450 system so the toxic metabolite is not formed),
FDA also recommends that liquid paracetamol should
be available only in a single established dose, e.g., 160
Precautions and attempts to counteract toxicity mg/5 mL (accord-ing to FDA information;
of paracetamol www.fda.gov).
Due to an easy overdose of paracetamol, the
US FDA has proposed to implement new solutions, Another solution aimed at prevention of
which to a certain degree would limit this growing parac-etamol hepatotoxicity in Great Britain was
problem. A decrease in the maximum permissible
the intro-duction of tablets containing
single dose of paracetamol from 1000 mg to 650
mg seems to be one of the crucial problems. Thus, a
paracetamol and methionine, which after the
question arises what will happen to numerous OTC conversion into cysteine and then glutathione in
preparations containing paracetamol in the dose hepatocytes would inactivate the active
exceeding 650 mg. It has been suggested that high- metabolite, NAPQI. Moreover, due to such a
er doses of this drug, i.e., above 325 mg should be combination, there is no time wasted from the
available only by prescription (according to the
moment of intentional or unintentional
information of the US FDA; www.fda.gov).
Another suggested solution postulated by FDA is ingestion of a toxic dose of paracetamotol to the
application of antidote, e.g., N-acetylcysteine
(hepatic damage occurs 24 h after the
overdose). Nowadays, the only such preparation
registered in Great Britain is
Paracetamol: mechanism of action, applications and safety concern 21

Paradote (Penn Pharmaceuticals) containing 500 mg used sporadically. It should be remembered that a
of paracetamol and 100 mg of methionine. Other single dose of paracetamol should not exceed 1 g
preparations of this type, e.g., Pameton (SmithKline and daily dose 4 g; the US FDA suggests these val-
Beecham), have been withdrawn. In other European ues should be decreased to 0.65 g and 3.25 g,
countries and the USA such combinations of parac- respec-tively. In the case of combined application
etamol do not exist on the pharmaceutical market of para-cetamol with NSAIDs, paracetamol dosage
because so far no efficient and safe dosage of should be considerably lower than the
methionine has been established for patients; also aforementioned values.
safety of the long-term application of these prepara-
tions has not been investigated yet (some carcino- CONCLUSIONS
genic effect of methionine has been suggested).
Besides, the price of such a drug is higher than for a Summing up, paracetamol monotherapy is effi-
preparation containing paracetamol alone (77). cient, well tolerated by the majority of patients and
In the light of novel studies, the application of safe, on condition that the drug is administered at
traditional NSAIDs in combination with paraceta-mol therapeutic doses. Table 1 sums up the advantages and
has not been recommended, particularly when active disadvantages of paracetamol. We should, how-ever,
substances occur in higher doses (8, 69). Rahme et al. bear in mind that the paracetamol overuse or
(69) published the retrospective cohort study application even at therapeutic doses in some situa-
performed in 644,183 patients aged over 65 years who tions like improper slimming, smoking, alcohol abuse
had been receiving paracetamol (at daily doses: < 3 g or ingestion of other medicines may cause severe
and > 3 g) and/or traditional NSAIDs (with or without hepatic damage or death. Therefore, the ques-tion
a proton pump inhibitor) for 6 years. The risk of arises as to whether the patient knows that a safe dose
hospitalization due to gastroin-testinal events of paracetamol (assuming that the above-mentioned
(ulceration, perforation, bleeding from the upper or situations are not present) comprises only eight tablets
lower segment of the digestive tract) appeared to be of 500 mg or four sachets, each one containing 1000
two-fold higher in the case of taking paracetamol in mg, per day and that paracetamol is ëíhiddeníí in other
combination with traditional NSAIDs as compared to preparations under different names (here are about 100
NSAIDs used in monother-apy. The authors of that simple and complex preparations in Poland). Thus, it
study (69), as well as other researchers analyzing the is very important to the patient to be warned by
problem of interaction between paracetamol and doctors or pharmacists about the risk connected with
NSAIDs (8), explain the results in relation to the the ingestion and par-ticularly with the overuse of this
additional COX-1 inhibition caused by paracetamol. drug. It appears in the light of new data that despite
This hypothesis seems to be reliable in the light of frequent applica-tion of paracetamol as an efficient
new data showing that para-cetamol synergistically analgesic and antipyretic drug, the action of this
enhances inhibitory effect of diclofenac on platelet medicament has not been completely understood and
activity (68, 78). Thus, safety and usefulness of this little unknown part may cause irreversible damage
complex preparations containing paracetamol to the organism when the drug is overused. A long-
combined with NSAIDs appearing on the term application of high doses of paracetamol carries
pharmaceutic market are still the matter of dis-cussion. the risk of adverse reactions typical for COX-2
It is worth paying attention to preparations containing inhibitors (coxibs) such as hypertension, heart
paracetamol and NSAIDs (ibuprofen and infarction or renal failure. It results from a peripher-al
propyphenazone) available on the Polish market selective inhibition of COX-2 by paracetamol.
without a prescription (Cefalgin and Saridon - Moreover, it appears that the use of paracetamol
paracetamol + propyphenazone and Metafen and combined with NSAIDs is not beneficial because an
Nurofen ultima - paracetamol + ibuprofen). The increase in the occurrence of gastrointestinal events
aforementioned drugs contain paracetamol at doses of can be observed. On the other hand, i.v. adminis-tered
250-500 mg and NSAIDs: ibuprofen - 200 mg or paracetamol at high doses inhibits platelet
propyphenazone - 150 mg. According to the manu- aggregation, which is very important in the treat-ment
facturers information, a single dose of these drugs is 1- of patients with disorders of hemostasis.
2 tablets with the possibility of three-fold applica-tion
per day. Considering the maximum dosage (2 tablets 3 It should be remembered that despite the fact
times a day), a total dose of paracetamol would range that paracetamol has a wide clinical application it is
from 1.5 g to 3 g, which is in compli-ance with the not a drug devoid of side effects. Therefore, before
contemporary knowledge (8, 69) if taking a decision about the treatment of the patient
22 MARTA JӏWIAK-B BENISTA and JERZY Z. NOWAK

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Received: 11. 04. 2013