Paramark

Paracetamol produces analgesia by peripheral blockage of pain impulse generation. It produces antipyresis by inhibiting the hypothalamic heat regulating centre. Its weak anti inflammatory activity is related to inhibition of prostaglandin (PG) synthesis in the CNS.

Paracetamol (acetaminophen) is thought to act primarily in the CNS, raising the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1 and COX-2, along with COX-3, enzymes involved in prostaglandin (PG) synthesis. Unlike NSAIDs, paracetamol does not inhibit cyclooxygenase in peripheral tissues, so it has no peripheral anti inflammatory effect. Aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme's active site, but studies have found that paracetamol blocks COX indirectly, and that this blockade is ineffective in the presence of peroxides. This may explain why paracetamol is effective in the central nervous system and in endothelial cells but not in platelets and immune cells, which carry high levels of peroxides. Studies also suggest that paracetamol selectively blocks a variant of the COX enzyme distinct from the known COX-1 and COX-2 variants. This enzyme is now referred to as COX-3. Its exact mechanism of action is still poorly understood, and further research may offer more insight into how it works. The antipyretic properties of paracetamol are likely due to a direct effect on the heat regulating centre of the hypothalamus, resulting in peripheral vasodilation, sweating, and consequent heat loss.

Epidemiological studies during human pregnancy have not shown any harmful effects when Paracetamol is used at the recommended dose, though patients should still follow their doctor's advice about using it. Paracetamol does pass into breast milk, but only in amounts too small to be clinically significant, and the published data available do not point to any reason to avoid breastfeeding.

Pediatric use: Paracetamol IV is supported for treating acute pain and fever in pediatric patients aged 2 years and older. This comes from adequate and well-controlled studies of Paracetamol IV in adults.

Geriatric use: No overall differences in safety or effectiveness were seen between elderly and younger subjects, and other reported clinical experience has not found differences in response between elderly and younger patients.

Patients with hepatic impairment: Paracetamol must not be used in patients with severe hepatic impairment or severe active liver disease. In patients with hepatic impairment or active liver disease, use it with caution. A reduced total daily dose of Paracetamol may be warranted.

Patients with renal impairment: In severe renal impairment (creatinine clearance < 30 ml/min), longer dosing intervals and a reduced total daily dose of Paracetamol may be warranted.

Liver damage is possible in adults who have taken 10 g or more of Paracetamol. Taking 5 g or more may also lead to liver damage if the patient has certain risk factors. These are long term treatment with Carbamazepine, Phenobarbitone, Phenytoin, Primidone, Rifampicin, St John's Wort or other drugs that induce liver enzymes, regularly drinking Ethanol in excess of recommended amounts, or being likely to have low Glutathione (for example in eating disorders, cystic fibrosis, HIV infection, starvation or cachexia).

Symptoms

In the first 24 hours, Paracetamol overdose causes pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death. Acute renal failure with acute tubular necrosis may develop even when the liver damage is not severe, and loin pain, haematuria and proteinuria strongly suggest it. Cardiac arrhythmias and pancreatitis have also been reported.

Treatment

Immediate treatment is essential in the management of Paracetamol overdose. Activated charcoal should be considered if the overdose was taken within 1 hour. Plasma Paracetamol concentration should be measured at 4 hours or later after ingestion, because earlier concentrations are unreliable.

N-acetylcysteine may be used up to 24 hours after ingestion of Paracetamol. The maximum protective effect comes within 8 hours of ingestion, though, and the antidote becomes much less effective after that. If required, the patient should be given intravenous N-acetylcysteine, following the established dosage schedule. If vomiting is not a problem, oral Methionine may be a suitable alternative in remote areas, outside hospital.

Patients who present with serious hepatic dysfunction beyond 24 hours from ingestion should be managed after discussion with the NPIS or a liver unit.

Store Paracetamol in a dry place, away from light and heat. Keep it out of the reach of children.