Pharmacology of PARACETAMOL & Acute Paracetamol poisoning.

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Today we will discuss about Paracetamol. 

    This topic includes :-

1. General properties & Mechanism of action
2. Dosage
3. Use
4. Adverse reactions
5. Toxicity, Clinical features & How to Manage Paracetamol toxicity 

1) GENERAL PROPERTIES AND MECHANISM OF ACTION :-

General properties:-

• Paracetamol / N-acetyl P-aminophenol / Acetaaminophene is classified under group of drugs called Para-aminophenol derivatives under Major group called NSAIDs Non Steroidal Anti Inflammatory Drugs.
• Acetanilide is the parent member of this group of drug.
• it was first used in medicine by Von Mering in 1893.
  

• Peak plasma concentration Cp = In ½ to 1 hour. 
• t ½ is 2hours
• Protein binding is 20 to 50%
• Metabolized by Glucuronides (60%) and Sulfates (35%)

Mechanism of Action :- 

• It has both Anti Pyretic and Anti Inflammatory activity.
• but Anti pyretic effect is more pronounced.
• M.O.A.:- weak Nonspecific COX (Cyclooxygenase) enzyme
  inhibition by binding to peroxide site.
• But less Anti-inflammatory action is due to presence of
  peroxidase at inflammation site. so site is not available for Paracetamol binding.
• Good analgesic/antipyretic effects are equivalent to aspirin,

 

2) DOSAGE :- 

• Conventional oral dose = 325 to 650 mg every 4 to 6 hourly. ( Oral acetaminophen has an excellent bio availability. ) 
• Total daily dose should Not exceed 4000 mg / 24 hour but according to newer guidelines it should be < 2600mg / 24 hour. 
• In chronic alcoholics Total daily dose should Not exceed 2000 mg / 24 hour. 
• Max single dose is 650 mg 
• Dosing in adults is 10-15 mg/ kg.

3) USE :-

• Paracetamol is available as an OTC ( over the counter) drug. 

• commonly used for as an analgesic in 

1. Headache
2. Mild migrain
3. Musculoskeletan pain 
4. Dysmenorrhoea

• It is the Best Anti-Pyretic agent. so useful in Febrile illness.
  
• Acetaminophen is a suitable substitute for aspirin for analgesic or anti pyretic uses, 
• it is also used for patients in whom aspirin is contraindicated (e.g., those with peptic ulcer, children with a febrile illness).
• Also useful in Osteoarthritis   
• Can be used in all age group infants to elderly, pregnant and lactating woman. ( except it is not used in premature infants because of hepato-toxicity.

4) ADVERSE EFFECTS :- 

• In Anti pyretic doses Paracetamol is safe and well tolerated drug.
• Analgesic Nephropathy :- Due to years of heavy ingestion of paracetamol it causes Papillary necrosis, Tubular atrophy , followed by Renal fibrosis.

5) ACUTE PARACETAMOL POISONING :- ( Toxicity )

• Acute toxicity >7.5 grams leads to toxicity
• Most dangerous is fatal hepatic necrosis.
• Others are renal tubular necrosis and hypoglycaemic coma.
• Hepatotoxicity occurs at :- 10 to 15 grams (10,000 to 15,000 mg) (>150 mg/kg)
• Dose >20 to 25 grams is Fatal (250 mg / kg )
• Severe liver damage occurs in 90% of patients with plasma concentrations of acetaminophen > 300 mg/ml at 4 hours or 45 mg/ml at 15 hours after the ingestion of the drug.
  

Mechanism of hepatic injury:-

• After metabolism of Paracetamol minor amount of NAPQI (N- Acetyl P Benzoquinoneimine) is formed.
• When Large doses of Paracetamol is taken; Glutathione conjugation capacity is saturated so excess of Paracetamol undergoes CYP mediated N-hydroxylation to form NAPQI Toxic metabolite which will bind to Liver proteins and causes Hepatic necrosis.
• In chronic alcoholics due to induced CYP2E1 enzyme; which metabolises Paracetamol to toxic NAPQI so, Toxicity threshold is lowered.
  

Clinical features of Acute paracetamol toxicity :-

• Gastro Intestinal symptoms appears during the first two days of acute poisoning
• Gastric distress (e.g.,nausea,abdominal pain,anorexia) is seen
• Hepatic damage manifests within 2-3 days of ingestion of toxic  PCM doses.

• Plasma transaminases SGPT & SGOT become elevated in 12 to 36 h after ingestion.
• It presents as Right subcostal pain, Tender hepatomegaly, Jaundice, and Coagulopathy.
• Liver enzyme abnormalities typically peak 72 to 96 h after ingestion

• Biopsy of the liver reveals centri lobular necrosis with sparing of the periportal area. which maybe associated with Renal tubular necrosis and Hypoglycaemic coma.
• In nonfatal cases, the hepatic lesions are reversible over a period of weeks or months.  

Management of Paracetamol toxicity :-  

General Measures :- 

• Gastric lavage with activated charcoal within  4 hours
• Induce Vomiting.
• other symptomatic management

Specific Management :-

Oral route :-

• NAC (N Acetyl Cystine) - 140 mg/kg loading dose(oral) 
• followed by 70 mg/kg every 4 hours till 17 doses.(oral)

Intravenous Route :-

• Total dose - 300 mg / kg
  
• 150 mg/kg in 200 ml 5% dextrose over 15 min to 1 hour.
  
• f/b 50 mg/kg in 500 ml 5% dextrose over 4 hours.
  
• f/b 100 mg /kg in 1000 ml 5% dextrose over 16 hours.