Complete Knowledge About Paracetamol

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

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.

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

1. Suspect paracetamol poisoning in all adolescent deliberate self-poisonings.
2. N-acetylcystine (NAC) is a safe and effective antidote. Time to NAC is crucial to protect the liver from significant toxicity.
3. Stated timing and dose are often unreliable and this needs to be taken into consideration.
4. 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:

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 

Consider the possibility of co ingestions, either accidental or deliberate

Clinical Signs & Symptoms 
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:

1. 200 mg/kg over 4 hours
2. 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.