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Paracetamol

Recent drug, use started in 1949. Derivative of phenacitin, use of which has been discontinued because of nephrotoxicity. This drug is relatively free of toxicity.

Chemically it is acetaminophen.

  1. Acetyl,
  2. amino radical and
  3. benzene rings are present.

Antipyretic action is present because of anime benzene ring.

Mechanism of Action

It is a good antipyretic and analgesic. Mechanisms are same, it blocks prostaglandins synthesis.

  1. Anti-inflammatory action is very weak. The reason is that at site of inflammation super oxides, hydrogen peroxide and oxidative radicals are present, in presence of which actions of paracetamol are absent or very weak due to:
  • Inability to inhibit COX
  • Does not suppress phagocytes directly (immunologic process)
  • More effective COX-3 inhibitor
  1. All other additional effects like suppression of neutrophils and interleukin production are not present.
  2. Antipyretic due to amino benzene ring
  3. Inhibition of COX-3, a splice variant of COX-1 found in CNS
  4. Analgesic

Thus cannot be used for treatment of rheumatoid arthritis, ankylosing spondylitis, also cannot be used for gout.

Pharmacological Actions
  1. No effect on respiration
  2. No adverse effect on cardiovascular system
  3. GIT- less chances of GIT damage
  4. Paracetamol can be used preferentially in cases of GI ulceration
  5. No effect on uric acid excretion
  6. All metabolic actions seen with aspirin are not present.
  7. CNS –devoid of salicylism

It is thus a very safe drug, this being the reason for popularity.

Pharmacokinetics

Well absorbed orally (as opposed to aspirin)

Plasma protein binding is low 50%

Main importance is of metabolism, which may take place in liver,

  1. about 60% drug glucuronide conjugation
  2. 30% sulphate conjugation
  3. 3% cysteine conjugation
  4. 1-2% N-hydroxylation (phase I reaction)

As a result of N-hydroxylation, converted into N-acetyl benzoquinoneimine

Normal range of 4-5 g/day dose is handled by hepatic glutathione, which converts it into mercapturic acid, which is non-toxic and easily excreted.

When person ingests toxic amounts of 10-15 g/day (1 tablet 500 mg, more than 20 tablets) this 1-2% N-hydroxylation production of toxic radical is increased. Sulfhydryl groups of glutathione are overwhelmed, leading to reaction with sulfhydryl groups, producing damage and centrilobular hepatic necrosis.

Reports indicate that in some individuals, esp. chronic alcohol intake, can be toxic even at 4-5 g/day.

Signs and symptoms of hepatotoxicity

If the person does not give history, the diagnosis becomes difficult.

  1. Nausea
  2. Vomiting
  3. Anorexio abdominal pain (acute gastroenteritis symptoms)
  4. After 24-48 hrs hepatocellular damage, jaundice, increased ALT, AST, increased prothrombin time

Biochemical markers start rising within 4-15 hours.

Treatment
  1. If person is received within 4 hours, gastric lavage
  2. Specific antidote for paracetamol poisoning is N-acetyl cysteine which has sulfhydryl groups in structure, which alternate the suphydral groups for detoxification. Liver enzymes regenerate glutathione, within 8-12 hours.
  3. Other supportive measures include acid base balance, cardiac and respiratory support, etc.
Therapeutic Uses

Very good drug when used for anti-pyretic actions and as analgesic.

It is the drug of choice in children as no Reye’s syndrome is associated.

Adverse effects

Very safe drug, until toxic doses are taken (hepatotoxic).

Aspirin Paracetamol
Chemistry Salicylate P-amino phenol derivative
Anti-inflammatory Yes No
Anti-platelet Yes No
COX-1 inhibition Peripherally Centrally
COX-3 inhibition No Yes (in CNS)
Kinetics Above 600mg- 0 orderBelow 600mg -1st order 1st order
Metabolism
Half life 15 minutes 2-3 hours
Tablet weight 300 mg 500 mg
Toxic metabolite No N-acetyl benzoquinonimum
Centrilobular hepatocellular damage No Yes
Reye’s syndrome Yes No
Salicylism and cinchonism Yes No
GI bleeding More risk Less risk
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