Paracetamol (INN) (IPA:
/ˌpærəˈsiːtəmɒl, -ˈsɛtə-/) or acetaminophen (USAN), is the active metabolite of phenacetin, a
so-called coal tar analgesic. It is an effective substitute for aspirin, due to its
analgesic and antipyretic properties. However, unlike
aspirin, it is not a very effective anti-inflammatory agent. It is well tolerated,
lacks many of the side effects of aspirin, and is available over-the-counter, so
it is commonly used for the relief of fever, headaches, and
other minor aches and pains. Paracetamol is also useful in the management of more severe pain, where it allows lower dosages of
additional non-steroidal anti-inflammatory drugs (NSAIDs) or
opioid analgesics to be used, thereby minimizing overall side effects. It is a major ingredient
in numerous cold and flu medications, including
Tylenol and Panadol, among others. It is considered safe for human use at recommended doses, however, acute
overdose can cause fatal hepatic damage, and the number of accidental self-poisonings and
suicides has grown in recent years.
The words acetaminophen and paracetamol both come from the chemical names for the compound:
N-acetyl-para-aminophenol and para-acetyl-amino-phenol. In some contexts, it is
shortened to APAP, for N-acetyl-para-aminophenol.
History
In ancient and medieval times, known antipyretic agents were compounds contained in white
willow bark (a family of chemicals known as salicins, which led
to the development of aspirin), and compounds contained in cinchona bark.[1]
Cinchona bark was also used to create the anti-malaria drug quinine. Quinine itself also has antipyretic effects. Efforts to refine and isolate salicin and salicylic acid took place throughout the middle- and
late-19th century, and was accomplished by Bayer chemist Felix
Hoffmann (this was also done by French chemist Charles Frédéric
Gerhardt 40 years earlier, but he abandoned the work after deciding it was too impractical).[2]
When the cinchona tree became scarce in the 1880s, people began to look for alternatives. Two alternative antipyretic agents
were developed in the 1880s: acetanilide in 1886 and phenacetin in 1887. Harmon Northrop Morse first synthesized paracetamol via
the reduction of p-nitrophenol with tin in glacial
acetic acid in 1878, however, paracetamol was not used medically for another 15 years. In
1893, paracetamol was discovered in the urine of individuals who had taken phenacetin, and
was concentrated into a white, crystalline compound with a bitter taste. In 1899, paracetamol was found to be a metabolite of
acetanilide. This discovery was largely ignored at the time.
In 1946, the Institute for the Study of Analgesic and Sedative Drugs awarded a grant to the New York City Department of Health
to study the problems associated with analgesic agents. Bernard Brodie and Julius Axelrod
were assigned to investigate why non-aspirin agents were associated with the development of methemoglobinemia, a condition that decreases the oxygen-carrying capacity of blood and is potentially
lethal. In 1948, Brodie and Axelrod linked the use of acetanilide with methemoglobinemia and determined that the analgesic effect
of acetanilide was due to its active metabolite paracetamol. They advocated the use of paracetamol, since it did not have the
toxic effects of acetanilide.[3]
The product was first sold in 1955 by McNeil Laboratories as a pain and fever reliever for children, under the brand name
Tylenol Children's Elixir.[4]
In 1956, 500 mg tablets of paracetamol went on sale in the United Kingdom under the
trade name Panadol, produced by Frederick Stearns & Co, a subsidiary of Sterling
Drug Inc. Panadol was originally available only by prescription, for the relief of pain and fever, and was advertised as
being "gentle to the stomach," since other analgesic agents of the time contained aspirin, a known stomach irritant. In June 1958
a children's formulation, Panadol Elixir, was released.
In 1963, paracetamol was added to the British Pharmacopoeia, and has
gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical
agents.
The U.S. patent on paracetamol has long expired and generic versions of the drug are widely
available under the Drug Price Competition and Patent
Term Restoration Act of 1984, although certain Tylenol preparations are protected until 2007. U.S. patent 6,126,967 filed
September 3, 1998 was granted for "Extended release
acetaminophen particles."
Chemistry
Structure and reactivity
Paracetamol consists of a benzene ring core, substituted
by one hydroxyl group and the nitrogen atom of an
amide group in the para (1,4) pattern.
The amide group is acetamide (ethanamide). It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the
benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon and the lone pair on the carbonyl oxygen are all conjugated. The presence of two activating
groups also make the benzene ring highly reactive towards electrophilic aromatic
substitution. As the substituents are ortho,para directing and para with respect to each other, all positions on the ring are
more or less equally activated. The conjugation also greatly reduces the basicity of
the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the phenoxide anion.
Synthesis
From the starting material phenol, paracetamol can be made in the following manner:
- Phenol is nitrated using sulfuric acid and sodium nitrate (as phenol is highly
activated, its nitration requires very mild conditions compared to the oleum-fuming nitric acid mixture required to nitrate
benzene).
- The para isomer is separated from the ortho isomer by fractional distillation (there will be little of meta as OH is o-p
directing).
- The 4-nitrophenol is reduced to 4-aminophenol using a reducing agent such as sodium
borohydride in basic medium.
- 4-aminophenol is reacted with acetic anhydride to give paracetamol.
Notice that the synthesis of paracetamol lacks one very significant difficulty inherent in almost all drug syntheses: lack of
stereocenters means there is no need to design a stereo-selective synthesis. More efficient, industrial syntheses are also
available.
Available forms
Tablets are the most common form of paracetamol.
500 mg Panadol suppositories
Panadol, which is marketed in Europe, Africa, Asia, Central America, and Australasia, is the most widely available brand, sold in over 80 countries. In North America, paracetamol is
sold in generic form (usually labelled as acetaminophen) or under a number of trade names: for instance Tylenol
(McNeil-PPC, Inc), Anacin-3, Tempra, and Datril.
In some formulations paracetamol is combined with the opioid codeine, sometimes referred to as co-codamol (BAN). In the United States and Canada, this is marketed under the name of Tylenol #1/2/3/4 which
contain approximately 1/8 grain, approximately 1/4 grain, approximately 1/2 grain, and approximately
1 grain of codeine respectively. A US
grain is 64.78971 milligrams - this is usually rounded in manufacture down to a
multiple of 5 mg (so that a #3 contains 30 mg, and a #4 contains 60 mg, while a #1 may be 8 or 10 mg depending on
manufacturer. In the U.S. this combination is only available by prescription, while the lowest strength is over-the-counter in
Canada, and in other countries, other strengths may be over the counter. There are generics as well. In the UK and in many other
countries, this combination is marketed under the names of Tylex CD and Panadeine. Other names include Captin, Disprol, Dymadon,
Fensum, Hedex, Mexalen, Nofedol, Paralen, Pediapirin, Perfalgan, and Solpadeine. Paracetamol is also combined with other opioids
such as dihydrocodeine, referred to as co-dydramol
(BAN), oxycodone or hydrocodone, marketed in the U.S. as Percocet and Vicodin, respectively. Another very commonly used analgesic combination includes paracetamol in combination
with propoxyphene napsylate, sold under the brand name Darvocet. A combination of paracetamol, codeine, and the calmative doxylamine succinate is marketed as Syndol or Mersyndol.
Paracetamol is commonly used in multi-ingredient preparations for migraine headache,
typically including butalbital and paracetamol with or without caffeine, and sometimes containing codeine.
It is commonly administered in tablet, liquid suspension, suppository, intravenous or intramuscular form. The common adult dose is 500 mg to
1000 mg. The recommended maximum daily dose, for adults, is 4 grams. In recommended doses paracetamol is safe for
children and infants as well as for adults.
Mechanism of action
The mechanism by which paracetamol reduces fever and pain is still a source of considerable debate. The reason for this
confusion has largely been due to the fact that paracetamol reduces the production of prostaglandins, pro-inflammatory chemicals the production of which is also inhibited by aspirin, but unlike aspirin, paracetamol does not have much anti-inflammatory action. Likewise, while aspirin
inhibits the production of the pro-clotting chemicals thromboxanes, paracetamol does not.
Aspirin is known to inhibit the cyclooxygenase (COX) family of enzymes, and because of
paracetamol's partial similarity of aspirin's action, much research has focused on whether paracetamol also inhibits COX. It is
now clear, however, that paracetamol acts via (at least) two pathways.[5][6][7][8]
The COX family of enzymes are responsible for the metabolism of arachidonic acid to
prostaglandin H2, an unstable molecule, which is in turn converted to
numerous other pro-inflammatory compounds. Classical anti-inflammatories, such as the NSAIDs, block this step. The activity of the COX enzyme relies on it being in the
oxidized form, specifically tyrosine 385 must be oxidized to a radical.[9][10] It has been shown that paracetamol reduces the oxidized form of the COX enzyme, preventing
it from forming pro-inflammatory chemicals.[6][11]
Further research has shown that paracetamol also modulates the endogenous cannabinoid
system.[12] Paracetamol is
metabolized to AM404, a compound with several actions; most importantly, it inhibits the reuptake
of endogenous cannabinoids and activates the nociceptor TRPV1. Either of these two actions by
themselves has been shown to reduce pain, and both are a possible mechanism for paracetamol, though it has been demonstrated that
after blocking cannabinoid receptors and hence making any action of cannabinoid reuptake irrelevant, paracetamol no longer has
any analgesic effect, suggesting its pain-relieving action is indeed mediated by the endogenous cannabinoid system.[13]
A theory that held some sway, but has now largely been discarded, is that paracetamol inhibits the COX-3 isoform of the
cyclooxygenase family of enzymes.[5][14] This enzyme, when expressed in dogs, shares a strong similarity to the other COX enzymes,
produces pro-inflammatory chemicals and is selectively inhibited by paracetamol. However, in humans or mice, the COX-3 enzyme is
without inflammatory action, and is not modulated by paracetamol.[5]
Metabolism
Paracetamol is metabolised primarily in the liver,
where its major metabolites include inactive sulfate and glucuronide conjugates, which are
excreted by the kidneys. Only a small, yet significant amount is metabolised via the hepatic cytochrome P450 enzyme system (specifically, its CYP2E1 and
CYP1A2 isoenzymes), which is responsible for the toxic effects of paracetamol due to a minor
alkylating metabolite (N-acetyl-p-benzo-quinone imine, abbreviated as NAPQI).[15] There is
a great deal of polymorphism in the P450 gene, and genetic polymorphisms in
CYP2D6 have been studied extensively. The population can be divided
into "extensive", "ultrarapid" and "poor metabolizers" depending on their levels
of CYP2D6 expression. CYP2D6 may also contribute to the formation of NAPQI, albeit to a lesser extent than other P450 isozymes,
and its activity may contribute to paracetamol toxicity, particularly in extensive and ultrarapid metabolizers and when
paracetamol is taken at very large doses.[16]
The metabolism of paracetamol is an excellent example of toxication, because the
metabolite NAPQI is primarily responsible for toxicity rather than paracetamol itself.
Paracetamol overdose results in more calls to poison control centers in the US than any other pharmacological substance,
accounting for more than 100,000 calls, as well as 56,000 emergency room visits, 2,600 hospitalizations, and 458 deaths due to
acute liver failure per year.[17] A recent study of cases of acute liver failure between November 2000 and October 2004
by the Centers for Disease Control and Prevention (US) found
that paracetamol was the cause of 41% of all cases in adults, and 25% of cases in children.[18]
At usual doses, the toxic metabolite NAPQI is quickly detoxified by combining irreversibly with the sulfhydryl groups of glutathione or administration of a sulfhydryl compound
such as N-acetylcysteine, to produce a non-toxic conjugate that is eventually excreted by the kidneys.[15]
Additionally, methionine has been recommended in some cases,[19] although recent studies show that N-acetylcysteine is a more
effective antidote to paracetamol overdose.[20]
Comparison with NSAIDs
Paracetamol, unlike other common analgesics such as aspirin and ibuprofen, has relatively little anti-inflammatory properties, and
so it is not a member of the class of drugs known as non-steroidal
anti-inflammatory drugs (NSAIDs).
Efficacy
Regarding comparative efficacy, studies show conflicting results when comparing to
NSAIDs. A randomized
controlled trial of chronic pain from osteoarthritis in adults found similar benefit from acetaminophen and
ibuprofen. [21] However, a randomized controlled
trial of acute musculoskeletal pain in children found that the standard OTC dose of ibuprofen (400 mg) gives greater relief of pain than the standard dose of paracetamol (1000
mg).[22]
Adverse effects
In recommended doses, paracetamol does not irritate the lining of the stomach, affect blood coagulation as much as NSAIDs, or affect function of the kidneys. However,
some studies have shown that high dose-usage (greater than 2000 mg per day) does increase
the risk of upper gastrointestinal complications.[23]
Paracetamol is safe in pregnancy, and does not affect the closure of the fetal ductus
arteriosus as NSAIDs can. Unlike aspirin, it is safe in children as paracetamol is not associated with a risk of
Reye's syndrome in children with viral illnesses.
Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or
alter mood in any way. Paracetamol and NSAIDs have the benefit of bearing a low risk of addiction, dependence, tolerance and withdrawal, but, unlike opioid medications,
may damage the liver; however, this is generally taken into account when compared to the danger of addiction.
Paracetamol, particularly in combination with weak opioids, is more likely than NSAIDs to
cause rebound headache (medication overuse headache), although less of a risk than
ergotamine or triptans used for migraines.[24]
Toxicity
Paracetamol is contained in many preparations (both over-the-counter and
prescription-only medications). In some animals, for example cats, small doses are
toxic. Because of the wide availability of paracetamol there is a large potential for overdose and toxicity.[25] Without timely treatment, overdose can lead to liver failure and death within days; paracetamol toxicity is, by far, the most common cause of acute liver
failure in both the United States and the United Kingdom.[26][27] It is sometimes used
in suicide attempts by those unaware of the prolonged timecourse and high morbidity (likelihood
of significant illness) associated with paracetamol-induced toxicity in survivors.
In the UK, sales of over-the-counter paracetamol are restricted to packs of 32 tablets in pharmacies, and 16 tablets in
non-pharmacy outlets. Up to 100 tablets may be sold in a single transaction. In Ireland, the limits are 24 and 12 tablets
respectively. In Australia, paracetamol tablets are available at supermarkets in small pack sizes, while children's formulations,
pack sizes greater than 48 tablets and suppositories are restricted to pharmacies.
Mechanism
Paracetamol is mostly converted to inactive compounds via Phase II metabolism by
conjugation with sulfate and glucuronide, with a small
portion being oxidized via the cytochrome P450 enzyme system. Cytochromes P450 2E1 (CYP2E1) and 3A4 (CYP3A4)
convert paracetamol to a highly reactive intermediary metabolite, N-acetyl-p-benzo-quinone imine (NAPQI).
Under normal conditions, NAPQI is detoxified by conjugation with glutathione. In cases of
paracetamol toxicity, the sulfate and glucuronide pathways become saturated, and more paracetamol is shunted to the cytochrome
P450 system to produce NAPQI. As a result, hepatocellular supplies of glutathione become exhausted and NAPQI is free to react
with cellular membrane molecules, resulting in widespread hepatocyte damage and death,
clinically leading to acute hepatic necrosis. In animal studies, hepatic glutathione must be depleted to less than 70% of normal
levels before hepatotoxicity occurs.[citation needed]
Toxic dose
The toxic dose of paracetamol is highly variable. In adults, single doses above 10 grams or 150 mg/kg have a
reasonable likelihood of causing toxicity.[28] Toxicity can also occur when multiple smaller doses within 24 hours exceeds these
levels, or even with chronic ingestion of doses as low as 4 g/day, and death with as little as 6 g/day.
In children acute doses above 200 mg/kg could potentially cause toxicity. This higher threshold is largely due to
children having larger kidneys and livers relative to body size than adults and hence being more tolerant of paracetamol overdose
than adults.[29]
Acute paracetamol overdose in children rarely causes illness or death with chronic supratherapeutic doses being the major cause
of toxicity in children.
In a normal dose of 1 gram of acetaminophen four times a day, one third of patients may have an increase in their
liver function tests to three times the normal value.[30] However, it is doubtful that this
leads to liver failure.[31]
Since paracetamol is often included in combination with other drugs, it is important to include all sources of paracetamol
when checking a person's dose for toxicity. In addition to being sold by itself, paracetamol may be included in the formulations
of various analgesics and cold/flu remedies as a way to increase the pain-relieving properties of the medication and sometimes in
combination with opioids such as hydrocodone to deter people
from using it recreationally or becoming addicted to the opioid substance, as at higher doses than intended the paracetamol will
cause irreversible damage to the liver. In fact, the human toll of acetaminophen, in terms of both fatal overdoses and chronic
liver toxicity to habitual abusers of pain medication, likely far exceeds the damage caused by the opioids themselves.[32][page # needed] To prevent overdoses, one should read medication labels carefully
for the presence of paracetamol and check with a pharmacist before using over-the-counter medications.
Risk factors
Chronic excessive alcohol consumption can induce CYP2E1, thus increasing the potential toxicity of
paracetamol.[33] For this reason, other analgesics such as
aspirin or ibuprofen are sometimes recommended for
hangovers.
Fasting is a risk factor, possibly because of depletion of hepatic glutathione reserves.
It is well documented that concomitant use of the CYP2E1 inducer isoniazid increases the
risk of hepatotoxicity, though whether 2E1 induction is related to the hepatotoxicity in this case is unclear.[34][35] Concomitant use of other drugs which induce CYP enzymes such as antiepileptics
(including carbamazepine, phenytoin and
barbiturates) have also been reported as risk factors.
Natural history
Individuals who have overdosed on paracetamol generally have no specific symptoms for the first 24 hours. Although
nausea, vomiting, and diaphoresis may occur initially, these symptoms generally resolve after several hours. After resolution of
these symptoms, individuals tend to feel better, and may believe that the worst is over. If a toxic dose was absorbed, after this brief feeling of relative wellness, the individual develops overt hepatic
failure. In massive overdoses, coma and metabolic
acidosis may occur prior to hepatic failure.
Damage generally occurs in hepatocytes as they metabolize the paracetamol. Rarely, acute
renal failure also may occur. This is usually caused by either hepatorenal
syndrome or Multiple organ dysfunction syndrome. Acute renal
failure may also be the primary clinical manifestation of toxicity. In these cases, it has been suggested that the toxic
metabolite is produced more in the kidneys than in the liver.[36]
The prognosis of paracetamol toxicity varies depending on the dose and the appropriate treatment. In some cases, massive
hepatic necrosis leads to fulminant hepatic failure with complications of bleeding,
hypoglycemia, renal failure, hepatic encephalopathy, cerebral edema, sepsis, multiple organ failure, and death within days. In many cases, the hepatic necrosis may run its course,
hepatic function may return, and the patient may survive with liver function returning to normal in a few weeks.
Diagnosis
Evidence of liver toxicity may develop in one to four days, although in severe cases it may be evident in 12 hours. Right
upper quadrant tenderness may be present. Laboratory studies may show evidence of massive hepatic necrosis with elevated
AST, ALT, bilirubin, and prolonged coagulation times (particularly, elevated prothrombin time). After paracetamol overdose, when AST and ALT exceed 1000 IU/L,
paracetamol-induced hepatotoxicity can be diagnosed. However, the AST and ALT levels can exceed 10,000 IU/L. Generally the
AST is somewhat higher than the ALT in paracetamol-induced hepatotoxicity.
A drug nomogram was developed in 1975 which estimated the risk of toxicity based on the
serum concentration of paracetamol at a given number of hours after ingestion.[37] To determine the risk of potential hepatotoxicity, the
paracetamol level is traced along the standard nomogram. A paracetamol level drawn in the first four hours after ingestion may
underestimate the amount in the system because paracetamol may still be in the process of being absorbed from the
gastrointestinal tract. Delay of the initial draw for the paracetamol level to account for this is not recommended since the
history in these cases is often poor and a toxic level at any time is a reason to give the antidote.
Treatment
Initial measures
The initial treatment for uncomplicated paracetamol overdose, similar to most other
overdoses, is gastrointestinal decontamination. In addition, the antidote, acetylcysteine plays an important role. Paracetamol absorption from the gastrointestinal tract is
complete within two hours under normal circumstances, so decontamination is most helpful if performed within this timeframe.
Absorption may be somewhat slowed when it is ingested with food. There is considerable room for physician judgement regarding
gastrointestinal decontamination; activated carbon administration is the most commonly
used procedure, however, gastric lavage may also be considered if the amount ingested is
potentially life threatening and the procedure can be performed within 60 minutes of ingestion.[38] Syrup of ipecac has no role in paracetamol overdose because the vomiting it induces delays the effective
administration of activated carbon and oral acetylcysteine.
Activated carbon adsorbs paracetamol, reducing its gastrointestinal absorption.
Administering activated carbon also poses less risk of aspiration than gastric
lavage. Previously there was reluctance to give activated carbon in paracetamol overdose, because of concern that it may also
absorb acetylcysteine. Studies have shown that no more than 39% of an oral acetylcysteine is absorbed when they are administered
together.[39]
Other studies have shown that activated carbon seems to be beneficial to the clinical outcome. It appears the most benefit from
activated carbon is gained if it is given with two hours of ingestion.[40] However, administering activated carbon later than this
can be considered in patients who may have delayed gastric emptying due to co-ingested drugs or following ingestion of sustained
or delayed release paracetamol preparations. Activated carbon should also be administered if co-ingested drugs warrant
decontamination. There are conflicting recommendations[39][41] regarding whether to change the dosing of oral acetylcysteine after the
administration of activated carbon, and even whether the dosing of acetylcysteine needs to be altered at all.
Acetylcysteine
Acetylcysteine (also called N-Acetylcysteine or NAC) works to reduce paracetamol
toxicity by supplying sulfhydryl groups (mainly in the form of glutathione, of which it is a
precursor) to react with the toxic NAPQI metabolite so that it does not damage cells
and can be safely excreted. (NAC can be bought as a dietary supplement in the United States.)
If the patient presents less than eight hours after paracetamol overdose, then acetylcysteine significantly reduces the risk
of serious hepatotoxicity. If NAC is started more than 8 hours after ingestion, there is a sharp decline in its effectiveness
because the cascade of toxic events in the liver has already begun and the risk of acute hepatic necrosis and death increases
dramatically. Although acetylcysteine is most effective if given early, it still has beneficial effects if given as late as 48
hours after ingestion.[42] In
clinical practice, if the patient presents more than eight hours after the paracetamol overdose, then activated carbon is
probably not useful, and acetylcysteine is started immediately. In earlier presentations the doctor can give carbon as soon as
the patient arrives, start giving acetylcysteine, and wait for the paracetamol level from the laboratory.
In United States practice, intravenous (IV) and oral administration are
considered to be equally effective. However, IV is the only recommended route in Australasian and British practice.
Oral acetylcysteine is given as a 140 mg/kg loading dose followed by 70 mg/kg every four hours for 17 more doses.
Oral acetylcysteine may be poorly tolerated due to its unpleasant taste, odor, and its tendency to cause nausea and vomiting. It
can be diluted to a 5% solution, from its marketed 10% or 20% solutions, to improve palatability. Where oral acetylcysteine is
required, the inhalation formulation of acetylcysteine (Mucomyst) is often given orally. The respiratory formulation can also be
diluted and filter sterilized by a hospital pharmacist for IV use, however this is an uncommon practice. If repeat doses of
carbon are indicated because of another ingested drug, then subsequent doses of carbon and acetylcysteine should be staggered
every two hours.
Intravenous acetylcysteine (Parvolex/Acetadote) is used as a continuous intravenous infusion over 20 hours (total dose
300 mg/kg). Recommended administration involves infusion of a 150 mg/kg loading dose over 15 minutes, followed by
50 mg/kg infusion over four hours; the last 100 mg/kg are infused over the remaining 16 hours of the protocol.
Intravenous acetylcysteine has the advantage of shortening hospital stay, increasing both doctor and patient convenience, and it
allows administration of activated carbon to reduce absorption of both the paracetamol and any co-ingested drugs without concerns
about interference with oral acetylcysteine.[43]
Baseline laboratory studies include bilirubin, AST, ALT, and prothrombin time (with INR). Studies are repeated at least daily. Once it has been determined that a
potentially toxic overdose has occurred, acetylcysteine is continued for the entire regimen, even after the paracetamol level
becomes undetectable in the blood. If hepatic failure develops, acetylcysteine should be continued beyond the standard doses
until hepatic function improves or until the patient has a liver transplant.
Prognosis
The mortality rate from paracetamol overdose increases two days after the ingestion, reaches a maximum on day four, and then
gradually decreases. Patients with a poor prognosis are usually identified for likely liver transplantation. Acidemia is the most important single indicator of probable mortality and the need for transplantation. A
mortality rate of 95% without transplant was reported in patients who had a documented pH less than
7.30. Other indicators of poor prognosis include renal insufficiency, grade 3 or worse
hepatic encephalopathy, a markedly elevated prothrombin time, or a rise in
prothrombin time from day three to day four. One study has shown that a factor V level less
than 10% of normal indicated a poor prognosis (91% mortality) while a ratio of factor VIII
to factor V of less than 30 indicated a good prognosis (100% survival).[44]
Prevention
Besides simply preventing an overdose, one way to prevent liver damage may be the use of Paradote. Paradote is a combination
tablet containing 100 mg methionine and 500 mg paracetamol (i.e. 20% methionine). Methionine
is included in order to ensure sufficient levels of glutathione in the liver are maintained to minimize the liver damage caused if a paracetamol overdose is taken.
Effects on animals
Paracetamol is extremely toxic to cats, and should not be given to them under any circumstances.
Cats lack the necessary glucuronyl transferase enzymes to safely break paracetamol down and tiny fractions of a normal tablet for
humans may prove fatal.[45] Initial symptoms include vomiting, salivation and discolouration of the tongue and
gums. After around two days liver damage is evident, typically giving rise to jaundice. Unlike
an overdose in humans it is rarely liver damage which is the cause of death, instead methaemoglobin formation and the production of Heinz bodies in red
blood cells inhibit oxygen transport by the blood, causing asphyxiation. Effective treatment is
occasionally possible for small doses, but must be extremely rapid.
In dogs, paracetamol is a useful anti-inflammatory with a good safety record, causing a lower incidence of gastric ulceration
than NSAIDs. It should only be administered on veterinary advice. A paracetamol-codeine product (trade name Pardale-V)[46] licensed for use in dogs is available on veterinary
prescription in the UK.[47]
Any cases of suspected ingestion in cats or overdose in dogs should be taken to a veterinarian immediately for detoxification.[48] The effects of toxicity can include liver damage,
