Paracetamol

[SH4:p285-286]

aka acetaminophen

Usage

• Analgesic
• Antipyretic
• Weak antiinflammatory effect

Structure

• Not considered a true NSAID due to the lack of significant antiinflammatory effects

Pharmacodynamics

Mechanism of action

• Modest peripheral inhibition of prostaglandin synthesis
• Strong central inhibition of prostaglandin synthesis
  * Inhibition of cyclo-oxygenase 3 in hypothalamus [BJA Vol95(1):p64]
• Precise mechanism has YET to be established
  * [PI per MIMS (Perfalgan)]

Effects

Advantage

• Does NOT produce gastric irritation
• No effect on platelet aggregation
• Does not antagonise uricosuric drugs

Side effects

Renal toxicity

• Renal toxicity
  * Renal papillary necrosis
  * Renal medullary ischaemia

Hepatic toxicity

• See "Overdose"

 

Overdose

• Overdose results in hepatic toxicity
  --> Hepatic necrosis and death
• Due to formation of N-acetyl-p-benzoquinone (at high doses of paracetamol)
• Jaundice and coagulation defects occur about 2-6 days after overdose
• Symptoms and signs of overdose
  * N&V
  * Anorexia
  * Pallor
  * Abdominal pain
  * Increased AST, ALT, LDH, bilirubin
  * Decreased prothrombin in 12-48 hours after administration
  * Metabolic acidosis, encephalopathy, hepatocellular insuffiency, coma, death
• On liver biopsy
  --> Centrilobular necrosis
• Acetylcysteine (or N-acetyl cysteine (NAC))
  * Antioxidant
  * Substitutes for glutathione as a scavenger
  * When administered within the first 8 hours after paracetamol overdose --> Prevents liver damage

 

Pharmacokinetics

Absorption

• Nearly complete after oral
• Can be given PO, IV, PR
• Food intake delays absorption
• PR absorption is variable
• IV
  * Onset of action = 5 - 10 minutes
  * Peak analgesic effect = 1 hour
  * Duration = 4 - 6 hours
  *[PI]

Distribution

• No significant protein-binding
• Vd = 1-1.2 L/kg

Metabolism

• Conjugation and hydroxylation in liver
  --> Inactive metabolites
• One of the metabolites, p-aminophenol is nephrotoxic
• In adults, paracetamol is mainly conjugated with
  * Glucuronide 45-55%
  * Sulfate 20-30%
  * Conjugation with sulfate is predominant in infants and children

P-aminophenol

• Concentrated in the hypertonic renal papillae
• P-aminophenol's oxidised metabolites bind covalently to sulfhydryl-containing tissue macromolecules and deplete stores of reduced glutathione
  --> Cell necrosis

N-acetyl-p-benzoquinone

• N-acetyl-p-benzoquinone is normally an intermediate metabolite
• <4% of paracetamol is metabolised into N-acetyl-p-benzoquinone (by CYP3A4 in liver)
• Intracellular antioxidant, glutathione, normally scavenges the metabolite
  --> Normally no toxic effect
• At high doses, glutathione store is depleted
  --> Accumulation of N-acetyl-p-benzoquinone
  --> Hepatic damage
• Alcoholics at risk for toxicity at lower doses
  * Increased P450 activity
  * Decreased glutathione store

Elimination

• <5% of the drug is excreted unchanged in urine
• Elimination half-life = 1-3 hours

Action profile

• IV equilibration half-time (with CSF) = 45 min
  * [BJA Vol95(1): p64]
  * I think the authors meant equilibration time
• Therapeutic level = 10-20mg/L
  * [BJA Vol95(1): p64]
  * Authors said mg/mL, but elsewhere in the article and in another article, it is mcg/mL or mg/L

Pharmaceutics

Presentation

• PO, PR
• IV
  * Paracetamol 1% 100mL (1000mg)

Formulation

IV formulation (Perfalgan)

100mLs

• Active
  * Paracetamol (1%)
• Inactive
  * Mannitol (3850mg as solubilising agent)
  * Cysteine hydrochloride (25mg)
  * Sodium phosphate-dibasic dihydrate (13mg)
  * Sodium hydroxide and hydrochloric acid for pH adjustment
  * Water for injection

Clinical

Administration

Adults

• Paracetamol 1g up to 4 times a day
  * No more than 4g/day

Neonates and children weighing up to 33kg

• Paracetamol 15mg/kg up to 4 times a day
• Daily maximum not exceeding 60mg/kg

Neonates < 10 days

• Reduce dose by half
  --> Paracetamol 7.5mg/kg up to 4 times a day

Precaution

IV paracetamol should be used with caution in

• Hepatocellular insufficiency
• Severe renal insufficiency (creatinine clearance <30mL/min)
• Chronic alcoholism
• Chronic malnutrition (low reserves of hepatic glutathione)
• Dehydration

Special consideration

Pregnancy

• Category A

 

Trivia

Phenacetin

• Paracetamol is one of the metabolites of phenacetin
• Phenacetin was withdrawn from the market due to analgesic-induced nephropathy
• Phenacetin may also cause methaemoglobinaemia and haemolytic anaemia in patients with glucose-6-phosphate deficiency in erythrocytes
  --> Due to metabolites oxidising glutathione and components of erythrocyte membrane