Paracetamol

Paracetamol also known by its IUPAC name Acetaminophen is an Analgesics and antipyretic agent.

Paracetamol is used in the treatment of Fever and pain.

Paracetamol is de-esterfied, converted into active EPA, and then absorbed in the small intestine. It reaches peak plasma concentration in 5 hours post-oral administration. Very little (<1%) is left circulating in the plasma as EPA incorporates into phospholipids, TG's, and cholesteryl esters.

Paracetamol is available in Capsules, tablets, syrup, elixir, oral liquid, suspension, injection.

Paracetamol is available in India, Germany, Canada, France, USA.

Although not fully elucidated, the analgesic effects are believed to be due to activation of descending serotonergic inhibitory pathways in the CNS. Interactions with other nociceptive systems may be involved as well . Antipyretic effect is produced from inhibition of the hypothalamic heat-regulating center.

Paracetamol also known by its IUPAC name Acetaminophen is used in the treatment of Fever and pain.

 Paracetamol increases the pain threshold by inhibiting two isoforms of cyclooxygenase, COX-1 and COX-2, which are involved in prostaglandin (PG) synthesis. Prostaglandins are responsible for eliciting pain sensations. paracetamol does not inhibit cyclooxygenase in peripheral tissues and, therefore, has no peripheral anti-inflammatory effects. Though acetylsalicylic acid (aspirin) is an irreversible inhibitor of COX and directly blocks the active site of this enzyme, studies have shown that paracetamol (Acetaminophen) blocks COX indirectly.

Paracetamol is approved for use in the following clinical indications

• Fever: Temporary reduction of fever.

• Pain:

Injection: Management of mild to moderate pain in patients ≥2 years of age; management of moderate to severe pain when combined with opioid analgesia in patients ≥2 years.

Oral, Rectal: Temporary relief of minor aches, pains, and headache.

Pain and/or fever

Pain (mild to moderate) and/or fever (monotherapy or as an adjunct):

Oral: 325 to 650 mg every 4 to 6 hours as needed or 1 g every 6 hours as needed; maximum dose: 4 g/day .

Note: Dosage recommendations, including maximum doses.

• Immediate release:

Regular strength (325 mg/tablet): 2 tablets (650 mg) every 4 to 6 hours as needed; maximum daily dose: 10 tablets/day (3.25 g/day).

Extra strength (500 mg/tablet): 2 tablets (1 g) every 6 hours as needed; maximum daily dose: 6 tablets/day (3 g/day).

Extended release (650 mg/tablet): 2 tablets (1.3 g) every 8 hours as needed; maximum daily dose: 6 tablets/day (3.9 g/day).

IV:

≥50 kg: 650 mg every 4 hours or 1 g every 6 hours; maximum single dose: 1 g/dose; maximum daily dose: 4 g/day.

<50 kg: 12.5 mg/kg every 4 hours or 15 mg/kg every 6 hours; maximum single dose: 15 mg/kg/dose (≤750 mg/dose); maximum daily dose: 75 mg/kg/day (≤3.75 g/day). Note: Some experts recommend this reduced dosing if used in patients with chronic alcoholism, malnutrition, or dehydration regardless of weight.

Rectal: 325 to 650 mg every 4 to 6 hours as needed; maximum daily dose: 3.9 g/day. Note: Absorption is irregular; bioavailability may be reduced by ~10% to 20% relative to oral administration.

Paracetamol is available in the dosage strength of 500mg, 160mg/5 ml, 500 mg/15 mL, 160 mg/5 mL, 160 mg/5 mL, 500 mg/15 mL, 50 mL, 100 mL, 5 mL, 10.15 mL, 20.3 mL, 118 mL, 473 mL); 325 mg/10.15 mL (10.15 mL); 650 mg/20.3 mL, 0.5 mg/ ml, 1 mg/ml, 10 mg/ml.

• Dosage Adjustment in Kidney Patient

Mild to severe impairment: No dosage adjustment is likely to be necessary. The manufacturer's labelling for IV paracetamol states that longer dosing intervals and a reduced total daily dose may be warranted in patients with severe kidney impairment (CrCl ≤30 mL/minute); however, paracetamol concentrations and half-life are increased but similar to those in patients with normal renal function. Glucuronide and sulfate conjugate metabolites accumulate in renal impairment, but the clinical effects are unknown.

Hemodialysis, intermittent (thrice weekly): paracetamol and its conjugates are readily dialyzable: No dosage adjustment necessary.

Peritoneal dialysis: Not dialyzed: No dosage adjustment necessary.

CRRT: Dialyzed : No dosage adjustment necessary .

PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary

• Dosage Adjustment in Hepatic impairment Patient

Child-Turcotte-Pugh class A:

Patients actively consuming alcohol while taking paracetamol (regardless of amount or frequency): IV, oral, rectal: Use of the lowest effective dose is preferred (eg, 325 to 500 mg every 4 to 6 hours); use with caution. Maximum total daily dose: 2 g per day from all paracetamol sources (any duration of treatment).

Patients who are not actively consuming alcohol: IV, oral, rectal:

Short-term use (≤14 days): No dosage adjustment is necessary. Maximum total daily dose: 4 g per day from all acetaminophen sources.

Long-term use (>14 days): Use of the lowest effective dose is preferred (eg, 325 to 500 mg every 4 to 6 hours); use with caution. Maximum total daily dose: 3 g per day from all acetaminophen sources.

Child-Turcotte-Pugh class B:

Patients actively consuming alcohol while taking paracetamol (regardless of amount or frequency): IV, oral, rectal: Use of the lowest effective dose is preferred (eg, 325 mg every 4 to 6 hours); use with caution.

Maximum total daily dose: 2 g per day from all paracetamol sources (any duration of treatment).

Patients who are not actively consuming alcohol: IV, oral, rectal:

Short-term use (≤14 days): Use of the lowest effective dose is preferred (eg, 325 to 500 mg every 4 to 6 hours); use with caution.

Maximum total daily dose: 3 g per day from all paracetamol sources.

Long-term use (>14 days): Use of the lowest effective dose is preferred (eg, 325 mg every 4 to 6 hours); use with caution.

Maximum total daily dose: 2 g per day from all paracetamol sources.

Child-Turcotte-Pugh class C:

All patients (regardless of alcohol consumption):

IV: Use generally not recommended. If use of IV paracetamol is deemed necessary, intermittent (eg, as needed) dosing instead of scheduled (eg, around-the-clock) dosing is preferred due to lack of data regarding accumulation; use with extreme caution.

Maximum total daily dose: 2 g per day from all paracetamol sources. Note: The manufacturer’s labeling for the IV formulation states use is contraindicated in severe hepatic impairment or severe active liver disease.

Oral, rectal: Use of the lowest effective dose is preferred (eg, 325 mg every 4 to 6 hours); use with caution.

Maximum total daily dose: 2 g per day from all paracetamol sources (any duration of treatment)

Dosage Adjustment for Pediatric Patients

• Pain (mild to moderate) or fever: Note: All sources of paracetamol (eg, prescription, OTC, combination products) should be considered when evaluating a patient's maximum daily dose. To lower the risk for hepatotoxicity, limit daily dose to ≤75 mg/kg/day (maximum of 5 daily doses), not to exceed 4,000 mg/day; while recommended doses are generally considered safe, hepatotoxicity has been reported (rarely) even with doses below recommendations.

Oral:

• Weight-directed dosing: Infants, Children, and Adolescents: 10 to 15 mg/kg/dose every 4 to 6 hours as needed ; do not exceed 5 doses in 24 hours; maximum daily dose: 75 mg/kg/day not to exceed 4,000 mg/day.

Fixed dosing:

• Oral suspension, chewable tablets: Infants and Children <12 years: Consult specific product formulations for appropriate age groups. See table; use of weight to select dose is preferred; if weight is not available, then use age; doses may be repeated every 4 hours; maximum: 5 doses/day.

Children 6 to 11 years: 325 mg every 4 to 6 hours; maximum daily dose: 1,625 mg/day; Note: Do not use more than 5 days unless directed by a physician.

Children ≥12 years and Adolescents:

Regular strength: 650 mg every 4 to 6 hours; maximum daily dose: 3,250 mg/day unless directed by a physician; under physician supervision daily doses ≤4,000 mg may be used.

Extra strength: 1,000 mg every 6 hours; maximum daily dose: 3,000 mg/day unless directed by a physician; under physician supervision daily doses ≤4,000 mg may be used.

Extended release: Children ≥12 years and Adolescents: 1,300 mg every 8 hours; maximum daily dose: 3,900 mg/day.

IV:

Infants and Children <2 years:

Fever: 15 mg/kg/dose every 6 hours; maximum daily dose: 60 mg/kg/day.

Alternate dosing: Limited data available: Pain and fever: 7.5 to 15 mg/kg/dose every 6 hours; maximum daily dose: 60 mg/kg/day

Children ≥2 years :

<50 kg: 15 mg/kg/dose every 6 hours or 12.5 mg/kg/dose every 4 hours; maximum single dose: 15 mg/kg up to 750 mg; maximum daily dose: 75 mg/kg/day not to exceed 3,750 mg/day.

≥50 kg: 15 mg/kg/dose every 6 hours or 12.5 mg/kg/dose every 4 hours; maximum single dose: 15 mg/kg up to 1,000 mg; maximum daily dose: 75 mg/kg/day not to exceed 4,000 mg/day.

Adolescents:

<50 kg: 15 mg/kg/dose every 6 hours or 12.5 mg/kg/dose every 4 hours; maximum single dose: 15 mg/kg up to 750 mg; maximum daily dose: 75 mg/kg/day not to exceed 3,750 mg/day.

≥50 kg: 1,000 mg every 6 hours or 650 mg every 4 hours; maximum single dose: 1,000 mg; maximum daily dose: 4,000 mg/day.

• Rectal:

Weight-directed dosing: Limited data available: Infants and Children <12 years: 10 to 20 mg/kg/dose every 4 to 6 hours as needed; do not exceed 5 doses in 24 hours ; maximum daily dose: 75 mg/kg/day not to exceed 1,625 mg/day.

• Fixed dosing:

Infants 6 to 11 months: 80 mg every 6 hours; maximum daily dose: 320 mg/day.

Infants and Children 12 to 36 months: 80 mg every 4 to 6 hours; maximum daily dose: 400 mg/day.

Children >3 to 6 years: 120 mg every 4 to 6 hours; maximum daily dose: 600 mg/day.

Children >6 up to 12 years: 325 mg every 4 to 6 hours; maximum daily dose: 1,625 mg/day.

Children ≥12 years and Adolescents: 650 mg every 4 to 6 hours; maximum daily dose: 3,900 mg/day.

• Pain; peri-/postoperative management; adjunct to opioid therapy:

IV:

Infants and Children <2 years: Limited data available: 7.5 to 15 mg/kg/dose every 6 hours; maximum daily dose: 60 mg/kg/day.

Children ≥2 years :

<50 kg: 15 mg/kg/dose every 6 hours or 12.5 mg/kg/dose every 4 hours; maximum single dose: 15 mg/kg up to 750 mg; maximum daily dose: 75 mg/kg/day not to exceed 3,750 mg/day.

≥50 kg: 15 mg/kg/dose every 6 hours or 12.5 mg/kg/dose every 4 hours; maximum single dose: 15 mg/kg up to 1,000 mg; maximum daily dose: 75 mg/kg/day not to exceed 4,000 mg/day.

Adolescents:

<50 kg: 15 mg/kg/dose every 6 hours or 12.5 mg/kg/dose every 4 hours; maximum single dose: 15 mg/kg up to 750 mg; maximum daily dose: 75 mg/kg/day not to exceed 3,750 mg/day.

≥50 kg: 1,000 mg every 6 hours or 650 mg every 4 hours; maximum single dose: 1,000 mg; maximum daily dose: 4,000 mg/day.

Rectal: Limited data available: Children:

Loading dose: 40 mg/kg for 1 dose, in most trials, the dose was administered postoperatively ; a maximum dose of 1,000 mg was most frequently reported. However, in one trial evaluating 24 older pediatric patients (all patients ≥25 kg; mean age: ~13 years), the data suggested that a dose of 1,000 mg does not produce therapeutic serum concentrations (target for study: >10 mcg/mL) compared to a 40 mg/kg dose (up to ~2,000 mg); the resultant C_max was: 7.8 mcg/mL (1,000 mg dose group) vs 15.9 mcg/mL (40 mg/kg dose group). Note: Therapeutic serum concentrations for analgesia have not been well-established.

Maintenance dose: 20 to 25 mg/kg/dose every 6 hours as needed for 2 to 3 days has been suggested if further pain control is needed postoperatively; maximum daily dose: 100 mg/kg/day not to exceed 4,000 mg/day; therapy longer than 5 days has not been evaluated.

Paracetamol is contraindicated in patients with:

Hypersensitivity (e.g., anaphylactic reaction) to paracetamol or any component of the formulation.

Concerns related to adverse effects:

• Bleeding: Bleeding, including serious events, has been reported; risk may be increased with concomitant anticoagulant/antiplatelet use. Prolongation of bleeding

• time not exceeding normal limits has also been observed; use with caution in patients with coagulopathy. Monitor for signs and symptoms of bleeding.

• Fish allergy: Use with caution in patients with known allergy or sensitivity to fish and/or shellfish.

Disease related concerns:

• Atrial fibrillation: Atrial fibrillation (AF) or flutter requiring hospitalization may occur; risk increased in patients with a history of AF or flutter.

• Conditions associated with abnormal lipids: Manage concurrent conditions (eg, diabetes, hypothyroidism, excessive alcohol intake) that may contribute to lipid abnormalities.

• Hepatic impairment: Studies have not been conducted in patients with hepatic impairment; however, ALT/AST levels should be monitored periodically during therapy in hepatically-impaired patients.

Paracetamol may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Paracetamol tablet comes under Pregnancy Category B.

paracetamol injection comes under Pregnancy Category C.

 Paracetamol is used off-label to enhance leflunomide elimination. Use of the enhanced elimination procedure is recommended in all females of reproductive potential upon discontinuation of leflunomide. Pregnancy should be avoided until undetectable serum concentrations (<0.02 mg/L) of leflunomide are verified

• Common Adverse effects:

Nausea, vomiting; redness of rectal mucus membranes

• Less Common Adverse effects:

Rash, pruritus, erythema, urticaria.

Vascular disorders: Hypotension, hypertension, flushing.

• Rare Adverse effects

Insomnia, anxiety.

Reduced rate of absorption with cholestyramine. Increased absorption with metoclopramide and domperidone. Prolonged use of Paracetamol may enhance the anticoagulant effect of warfarin and other coumarins, thus increasing the risk of bleeding. Concomitant use of other potentially hepatotoxic drugs or drugs that induce liver microsomal enzymes (e.g. barbiturates) may increase the risk of paracetamol toxicity. Reduced clearance with probenecid and isoniazid. Elimination half-life may be prolonged with salicylamide. Reduced bioavailability and efficacy of lamotrigine. May increase the plasma concentration of chloramphenicol and busulfan. Increased risk of high anion gap metabolic acidosis with flucloxacillin.

The common side effects of  Paracetamol  include the following :

Nausea, vomiting; redness of rectal mucus membranes

Liver toxicity

Paracetamol overdose may be manifested by renal tubular necrosis, hypoglycemic coma, and thrombocytopenia. Sometimes, liver necrosis can occur as well as liver failure. Death and the requirement of a liver transplant may also occur. Metabolism by the CYP2E1 pathway releases a toxic acetaminophen metabolite known as N-acetyl-p-benzoquinoneimine(NAPQI). The toxic effects caused by this drug are attributed to NAPQI, not acetaminophen alone.

Carcinogenesis

Long-term studies in mice and rats have been completed by the National Toxicology Program to study the carcinogenic risk of paracetamol . In 2-year feeding studies, F344/N rats and B6C3F1 mice consumed a diet containing acetaminophen up to 6,000 ppm. Female rats showed evidence of carcinogenic activity demonstrated by a higher incidence of mononuclear cell leukemia at doses 0.8 times the maximum human daily dose (MHDD). No evidence of carcinogenesis in male rats (0.7 times) or mice (1.2 to 1.4 times the MHDD) was noted. The clinical relevance of this finding in humans is unknown.

Mutagenesis

paracetamol was not found to be mutagenic in the bacterial reverse mutation assay (Ames test). Despite this finding, paracetamol tested positive in the in vitro mouse lymphoma assay as well as the in vitro chromosomal aberration assay using human lymphocytes. In published studies, acetaminophen(Paracetamol) has been reported to be clastogenic (disrupting chromosomes) when given a high dose of 1,500 mg/kg/day to the rat model (3.6 times the MHDD). No clastogenicity was observed at a dose of 750 mg/kg/day (1.8 times the MHDD), indicating that this drug has a threshold before it may cause mutagenesis. The clinical relevance of this finding in humans is unknown.

Impairment of Fertility

In studies conducted by the National Toxicology Program, fertility assessments have been performed in Swiss mice in a continuous breeding study. No effects on fertility were seen.

• Pharmacodynamic

Paracetamol is a para-aminophenol derivative that exhibits analgesic and antipyretic actions and weak anti-inflammatory activity. The mechanism of its analgesic effect has not been fully determined but may be associated with the inhibition of prostaglandin synthesis in the CNS and to a lesser extent, through peripheral blockage of pain-impulse generation. It produces antipyresis by inhibiting the hypothalamic heat-regulating centre.

• Pharmacokinetics

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
• https://reference.medscape.com/drug/colestid-Acetaminophen -342452
• https://go.drugbank.com/drugs/DB00375
• https://www.sciencedirect.com/topics/medicine-and-dentistry/Acetaminophen
• https://europepmc.org/article/med/6988203