Paracetamol
Paracetamol (acetaminophen) is a pain reliever and a fever reducer. The exact mechanism of action of is not known. Paracetamol is
used to treat many conditions such as headache, muscle aches, arthritis,
backache, toothaches, colds, and fevers.
Types of paracetamol
You can buy most types of
paracetamol from supermarkets or pharmacies. Some types are only available on
prescription.
Paracetamol is available as:
tablets or caplets
capsules
liquid – usually for children
soluble tablets (tablets that dissolve
in water to make a drink)
suppositories (capsules inserted
into the back passage)
an injection given into
a vein – normally only used in hospital
Important information
Do not use more of this medication than is recommended. An
overdose of paracetamol can cause serious harm.
Mechanism of Action
It is surprising that after more than 100 years, the exact
mechanism of action of paracetamol remains to be determined. There is evidence
for a number of central mechanisms, including effects on prostaglandin
production, and on serotonergic, opioid, nitric oxide (NO), and cannabinoid
pathways, and it is likely that a combination of interrelated pathways are in
fact involved. A few of these are outlined below.1, 4
Prostaglandin inhibition
Paracetamol is termed a simple analgesic and an antipyretic.
Despite enduring assertions that it acts by inhibition of cyclooxygenase
(COX)-mediated production of prostaglandins, unlike non-steroidal
anti-inflammatory drugs (NSAIDs), paracetamol has been demonstrated not to
reduce tissue inflammation. Two explanations have been put forward for this.
The enzyme responsible for the metabolism of arachidonic acid to
the prostanoids (including prostaglandins and thromboxanes), commonly referred
to as cyclooxygenase, is also more appropriately called prostaglandin H2 synthetase
(PGHS), and possesses two active sites: the COX and the peroxidase (POX) sites.
The conversion from arachidonic acid to the prostanoids is in fact a two-stage
process, requiring activity at the COX site to first produce the unstable
intermediate hydroperoxide, prostaglandin G2 (PGG2), which is then converted to prostaglandin H2 (PGH2) via POX. The
enzymatic activity of COX relies on its being in the oxidized form and it is
suggested that paracetamol interferes indirectly with this by acting as a reducing
co-substrate at the POX site. In intact cells, when levels of arachidonic acid
are low, paracetamol is a potent inhibitor of PG synthesis, by blocking the
physiological regeneration of POX. However, in broken cells, where the
concentration of hydroperoxides is high, prostaglandin synthesis is only weakly
inhibited. This peroxide-dependent COX inhibition explains the differential
activity of paracetamol in the brain where peroxide concentrations are low, vs peripheral
sites of inflammation with high peroxide levels.
Role of paracetamol in inhibition
of prostaglandin production.
An alternative suggestion was that, unlike NSAIDS, which act on
COX-1 and -2, paracetamol may act on a discrete COX-1 splice variant (initially
thought to be a distinct isoenzyme, COX-3). This COX-1 variant was thought to
be active in the central nervous system, rather than at the site of injured or
inflamed tissue, such that inhibition by paracetamol here would explain its
lack of anti-inflammatory and anti-platelet activity, whilst still affording it
highly effective analgesic and antipyretic properties. However, the original
work for this was performed on canine tissue, in which the COX-1 splice variant
retains a COX-like action; in humans, however, the expressed protein has no
role in the physiology of prostaglandins.1, 4, 5
Serotoninergic pathway activation
Serotonergic pathways are part of the descending pain system,
originating in the brainstem nuclei, hypothalamus, and cortex, and interact
with pain afferents in the dorsal horn. Serotonin receptors are present
throughout the central nervous system, involved in a number of functions,
including consciousness, mood, memory, and nausea and vomiting, the latter of
which are mediated via the 5-HT3-receptor subtype. It has become widely accepted
that the activation of descending serotonergic pathways plays a key role in the
action of paracetamol, and it has been demonstrated that the anti-nociceptive
effects of paracetamol can be partially inhibited by co-administration of 5-HT3-receptor
antagonists, interestingly using anti-emetic drugs which are indeed frequently
given together with paracetamol in the perioperative period.5
Endocannabinoid enhancement
In the presence of fatty acid amide hydrolase (FAAH), an enzyme
found predominantly in the central nervous system, paracetamol (via an
intermediary, p-aminophenol,
formed in the liver) is conjugated with arachidonic acid to form the active
metabolite, N-arachidonoylphenolamine
(AM404). Analogous to the action of serotonin or norepinephrine reuptake
inhibitors, AM404 inhibits the reuptake of the endocannabinoid, anandamide,
from synaptic clefts, increasing cannabinoid receptor activation on the
post-synaptic membrane. This would explain the experiences of relaxation,
tranquility, and euphoria reported by many paracetamol users, apparently
independent of analgesia.
AM404 appears to be a key player in a number of pain pathways.
Apart from endocannabinoid reuptake inhibition, it has also been shown to
activate transient receptor potential vanilloid type 1 (TRPV1) and inhibit
cyclooxygenase, NO and tumor necrosis factor-alpha (TNF-α), all involved in
acute and chronic pain states. The central production of AM404 would also
account for the antipyretic effect of paracetamol, known to be related to
inhibition of prostaglandin production in the brain, whilst still without peripheral
actions.
Conversion of paracetamol to
AM404, an endocannabinoid reuptake inhibitor.
Efficacy
Paracetamol demonstrates efficacy comparable with that of
standard equivalent doses of many NSAIDs (including ibuprofen, diclofenac,
ketorolac, and parecoxib), tramadol, and 10 mg i.v. morphine, with fewer
side-effects.6 This
applies across a variety of surgical procedures, as well as for other sources
of acute and chronic pain such as musculoskeletal pain and headaches, including
tension-type headache and migraine. As a component of a multimodal analgesic
regime, it is generally considered to have useful opioid-sparing effects; a
reduction in opioid consumption is mostly if not universally borne out with the
statistical significance in clinical studies, but the addition of regular
paracetamol invariably reduced pain scores and the incidence of nausea and
vomiting, and improved patient satisfaction.7
It is a useful first-line drug, and works in synergy when
combined with a number of other agents including ibuprofen, codeine, tramadol,
and caffeine, improving analgesic efficacy whilst minimizing side-effects of
the adjunct agent.
Although the onset of action of i.v. paracetamol is much faster
compared with oral, a recent study showed no significant difference in overall
efficacy between the two routes, as measured using pain scores at 1 h after
administration in patients having third molar extractions. This was, however in
healthy, fasted individuals with presumed normal gastric emptying, undergoing day
case surgery, and results may not be readily extrapolated to other patient
groups
Before taking this medicine
Do not use this medication if you are allergic to acetaminophen
or paracetamol.
Ask a doctor or pharmacist if it is safe for you to take
paracetamol if you have:
- liver
disease; or
- a history
of alcoholism;
Who can take
paracetamol
Most people can take paracetamol
safely, including:
pregnant women
breastfeeding women
children over 2 months of
age – lower doses are recommended for young children
If you're not sure whether you can
take paracetamol, check the leaflet that comes with it or ask your pharmacist
or doctor for advice.
Always get advice before
taking paracetamol if you:
have liver or kidney problems
have problems with alcohol, such as
long-term alcohol misuse
are very underweight
are taking other medications
Don't take paracetamol if
you've had an allergic reaction to
it in the past.
How should use paracetamol?
Use paracetamol exactly as prescribed by your doctor.
Do not use more of this medication than is recommended. An
overdose of paracetamol can cause serious harm. The maximum amount for adults
is 1 gram (1000 mg) per dose and 4 grams (4000 mg) per day. Using more
paracetamol could cause damage to your liver
What happens if miss a dose?
Since paracetamol is often used only when needed, you may not be
on a dosing schedule
What happens if overdose?
Seek emergency medical attention if you think you have used too
much of this medicine.
Paracetamol side effects
Get emergency medical help if you have any of these signs of an
allergic reaction to paracetamol: hives; difficulty breathing; swelling of your
face, lips, tongue, or throat. Stop using this medication and call your doctor
at once if you have a serious side effect such as:
- low fever
with nausea, stomach pain, and loss of appetite;
- dark
urine, clay-colored stools; or
- jaundice
(yellowing of the skin or eyes).
Paracetamol dosing information
Usual Adult Paracetamol Dose:
General Dosing Guidelines: 325 to 650 mg every 4 to 6 hours or
1000 mg every 6 to 8 hours orally or rectally.
Paracetamol 500 mg tablets: Two 500 mg tablets orally every 4 to 6 hours
Paracetamol 500 mg tablets: Two 500 mg tablets orally every 4 to 6 hours
Usual Pediatric Dose:
Oral or Rectal:
<=1 month: 10 to 15 mg/kg/dose every 6 to 8 hours as needed.
>1 month to 12 years: 10 to 15 mg/kg/dose every 4 to 6 hours as needed (Maximum: 5 doses in 24 hours)
>=12 years: 325 to 650 mg every 4 to 6 hours or 1000 mg every 6 to 8 hours.
<=1 month: 10 to 15 mg/kg/dose every 6 to 8 hours as needed.
>1 month to 12 years: 10 to 15 mg/kg/dose every 4 to 6 hours as needed (Maximum: 5 doses in 24 hours)
>=12 years: 325 to 650 mg every 4 to 6 hours or 1000 mg every 6 to 8 hours.
MHRA
guidelines for i.v. paracetamol dosing in children
Dosage
by Weight:
Dose per
administration
|
Max. daily
dose
|
|
Term newborn
infants, up to children <10 kg
|
7.5 mg kg−1
|
30 mg kg−1
|
Weight 10–33
kg
|
15 mg kg−1
|
60 mg kg−1 up to max. 2 g
|
Weight 33–50
kg
|
15 mg kg−1
|
60 mg kg−1 (max. 3 g)
|
Weight >50
kg
|
1 g
|
4 g
|
Taking paracetamol
with other medicines, food and alcohol
Paracetamol can react unpredictably with certain other
medications. This can affect how well either medicine works and might increase
the risk of side effects.
It may not be safe to take paracetamol at the same time as:
other products containing
paracetamol – including combination products where paracetamol is one of
the ingredients
carbamazepine – used to
treat epilepsy and some types of pain
colestyramine – used to reduce
itchiness caused by primary biliary cirrhosis (a type of liver
disease)
imatinib and busulfan – used to
treat certain types of cancer
ketoconazole – a type of antifungal
medicine
lixisenatide – used to treat type
2 diabetes
metoclopramide – used to
relieve nausea and vomiting
phenobarbital, phenytoin and
primidone – used to control seizures
warfarin – used to prevent blood
clots
Side effects of paracetamol
Side effects from paracetamol are rare, but can include:
an allergic reaction, which can
cause a rash and swelling, flushing,
low blood pressure and a
fast heartbeat – this can sometimes happen when paracetamol is given
in hospital into a vein in your arm
blood disorders, such as
thrombocytopenia (low number of platelet cells) and leukopenia (low number of
white blood cells)
liver and kidney damage if you take
too much (overdose) – this can be fatal in severe cases
Speak to a pharmacist or doctor if you develop any
troublesome side effects that you think could be caused by paracetamol.
Paracetamol
poisoning
Key points
- Suspect
paracetamol poisoning in all adolescent deliberate self-poisonings.
- N-acetylcystine
(NAC) is a safe and effective antidote. Time to NAC is crucial to protect
the liver from significant toxicity.
- Stated
timing and dose are often unreliable and this needs to be taken into
consideration.
- Complicated overdose, including of a longer-acting form of paracetamol (e.g., Panadol osteo) and staggered ingestions should be discussed with a toxicologist.
Patients requiring assessment
- Acute
ingestion of >200mg/kg
- Ingestion
of unknown quantity
- Repeated
supratherapeutic ingestion of >100mg/kg/day
Risk Assessment
History:
Dose:
Dose:
Stated or likely dose taken
Presented as syrup, immediate or modified- release tablets
If possible determine the exact name and tablet size.
Calculate the maximum possible dose per kg
Presented as syrup, immediate or modified- release tablets
If possible determine the exact name and tablet size.
Calculate the maximum possible dose per kg
Consider the possibility of co ingestions, either accidental or
deliberate
Clinical Signs & Symptoms
Most patients who present within 24 hours of ingestion are asymptomatic.
Most patients who present within 24 hours of ingestion are asymptomatic.
- Occasionally
they complain of nausea, vomiting, pallor and diaphoresis.
Right upper quadrant tenderness may begin to develop after this
time.
In untreated or undertreated cases, signs of hepatotoxicity
and hepatic failure usually take 48 to 72 hours to develop, and may include
hypotension and encephalopathy.
- Signs of
fulminant hepatic failure and coagulopathy may occur even later than this.
Acute Management
- Serum
paracetamol concentration at (or as soon as possible after) 4 hours post
ingestion determines the need for N-acetyl cysteine (NAC)
administration. (see nomogram)
- There is
no benefit in measuring paracetamol concentration earlier than 4 hours
post ingestion.
- It is safe
to wait for the paracetamol concentration to decide on the need for NAC in
all cases that present within 8 hours of ingestion AND where a paracetamol
concentration result will be available for interpretation within 8 hours
of ingestion.
- Children
who present >8 hours after a toxic ingestion (>200 mg/kg) or after
an ingestion in association with symptoms of toxicity (RUQ pain or
tenderness, nausea, vomiting) should be commenced on NAC
immediately. The decision to continue or cease NAC is then based on
the paracetamol concentration.
- Delaying
NAC administration beyond 8 hours post ingestion is associated with a progressive
increased risk of liver injury.
- There is
little evidence to guide management in repeated supratherapeutic
doses. Potential toxicity should be assessed and a toxicologist
consulted when:
- >200
mg/kg (or 10g) ingested over a 24 hour period
- >150
mg/kg/day (or 6 g) ingested over a 48 hour period
- >100
mg/kg/day ingested over a 72 hour period
- Consult
Toxicologist in very large or massive dose ingestion (>30g) or if
initial paracetamol concentration very high (ie ≥ double the nomogram
value).
- For IV
paracetamol medication errors consult a toxicologist.
- See
management algorithm and NAC infusion guide.
Paracetamol ingestion flowchart
Sustained Release Paracetamol
NAC should be commenced in any child who reports ingestion of
>200 mg/kg or 10g of sustained release paracetamol.
An initial paracetamol concentration should be measured 4 hours
post ingestion or immediately if presentation is >4 hours after ingestion.
If this concentration is above the treatment line in the nomogram then the full
20 hour infusion of NAC is required.
If the initial paracetamol concentration is below the line in
the nomogram then NAC should be continued and another paracetamol concentration
obtained 4 hours after the initial concentration. NAC can be discontinued if
both paracetamol concentrations are below the treatment line and are declining.
N-Acetyl
cysteine (NAC) infusion instructions
The standard administration of NAC is a 2 stage infusion (recently changed from 3 stage infusion) giving a total dose of 300 mg/kg:
The standard administration of NAC is a 2 stage infusion (recently changed from 3 stage infusion) giving a total dose of 300 mg/kg:
- 200 mg/kg
over 4 hours
- 100 mg/kg over
the next 16 hours
DOSE
Calculated based on actual body weight. For children >110 kg, calculate the
dose based on 110 kg body weight.
NAC
may be diluted in 5% glucose or 0.9% sodium chloride (normal saline). It
can also be diluted in combination glucose-sodium chloride solutions not
exceeding these concentrations including 0.45% sodium chloride in 5% glucose,
and 0.9% sodium chloride in 5% glucose.
The
volume and choice of fluid for each stage of the infusion needs to be
appropriate for the age and weight of the child and clinical
circumstances. In the adolescent child, it is generally appropriate to
follow the standard published recommendations for NAC administration.
The
volume of NAC needs to be included in the TOTAL volume of the infusion to avoid
under-dosing (volumes specified in tables below are TOTAL volumes – ie. NAC
volume plus fluid volume combined).
For
children >20 kg body weight:
NAC Dose |
Dilute
to
(using sodium chloride or glucose) |
Rate
and Duration
|
200
mg/kg
|
TOTAL
volume 250 mL
|
62.5
mL/hr for 4 hours
Infuse entire bag |
100
mg/kg
|
TOTAL
volume 500 mL
|
31.25
mL /hr for 16 hours
Infuse the entire bag |
NOTE: this results in a total of 750
mL of fluid which is inappropriate for smaller children.
For
children ≤20 kg body weight:
NAC Dose |
Dilute
to
(using sodium chloride or glucose) |
Rate
and Duration
|
200
mg/kg
|
TOTAL
volume 250 mL**
|
62.5
mL/hr** for 4 hours
Infuse entire bag |
100
mg/kg
|
TOTAL
volume 250 mL**
|
15
ml/hr** for 16 hours
Infuse entire bag |
**For
infants,
even smaller volumes may be required. Doses can be diluted in 100 ml bags
if available (note: the entire dose must be administered over the specified
time.). For infants who are fluid restricted with concerns about fluid
overload and a smaller total volume is required, contact hospital pharmacist
for advice.
Infant example
NAC Dose |
Dilute
to
(using sodium chloride or glucose) |
Rate
and Duration
|
200
mg/kg
|
TOTAL
volume 100 mL
|
25
mL/hr for 4 hours
Infuse entire bag |
100
mg/kg
|
TOTAL
volume 250 mL
|
15.7
mL/hr for 16 hours
Infuse entire bag |
Additional
Fluids
In
all cases, additional maintenance fluids can be given if required, or NAC may
be administered in larger volume bags if more convenient.
Monitoring
At
18 hours into the NAC infusion (2 hours before completion), send bloods for
- Paracetamol
level
- ALT
- Urea,
electrolytes, creatinine (5% of patients with paracetamol toxicity will
develop acute renal injury)
If
the ALT or renal function is elevated or the paracetamol concentration is >
120 micromol/L continue the NAC infusion at the current rate and seek
specialist advice.
Dosing
Errors
NAC
dosing or administration errors should be discussed with a toxicologist.
Additional Notes
Anaphylactoid reactions to NAC may occur (wheeze, rash).
In these cases, cease the infusion for 30 minutes, give promethazine then
recommence the infusion at half the previous rate. Slowly increase to the
full rate over 30 minutes.
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