Download Paracetamol toxicity is caused by excessive use or

Drug Toxicity
 Paracetamol toxicity:
Paracetamol toxicity is caused by excessive use or overdose of the medication acetaminophen.
Most people with paracetamol toxicity have no symptoms in the first 24 hours following overdose.
Others may initially have nonspecific complaints such as abdominal pain and nausea. With time,
signs of liver injury may develop; these include low blood sugar, easy bleeding, and hepatic
encephalopathy.
Paracetamol-Normal Metabolism
Paracetamol converted→→ inactive glucuronide + sulfate conjugates
↓ Metabolism in the liver (P450)
↓
N-Acetyl-p-benzoquinonamine (TOXIC) conjugated with Glutathione→ NON TOXIC
metabolite
Paracetamol Metabolism in Overdose
Paracetamol converted →→ N-Acetyl-p-benzoquinonamine (excess) &depletion of hepatic
glutathione →→ binds covalently (to cysteine residues on protein) →→toxicity
The metabolism of acetaminophen (paracetamol) by the hepatocyte. Acetaminophen is
predominantly conjugated into glucuronate and sulfate moieties. A small percentage is
metabolized by the cytochrome P450 pathway to a toxic metabolite, NAPQI. NAPQI is conjugated
by glutathione to non-toxic metabolites. In cases of acetaminophen toxicity, the conjugation
enzymes are saturated, and a higher fraction is converted to NAPQI. The conjugation of NAPQI
to these metabolites occurs until glutathione is depleted from hepatic reserves, after which the
toxic NAPQI accumulates and causes damage to the hepatocytes. N-acetylcysteine or NAC is a
glutathione precursor and functions by repleting glutathione stores.
Antidote for acetaminophen overdose
Reactive NAPQI N-acetylcysteine (NAcCys) Provides the Sulphydryl groups→→→
N-acetylcysteine adduct (inactive & is excreted in urine)
Paracetamol Overdose-management
 Initial ABC (usually well systemically)
 Get a good history (Time taken, Amount, Any other medication, History of Liver disease)
 Measure levels of Paracetamol in blood to know whether amount taken is enough to be
Hepatotoxic
(IF IN DOUBT start treatment before the Paracetamol levels get back to save time)
 N-Acetylcysteine. Shown to be advantageous if given in the first 10 hours Provides the
Sulphydryl groups needed to ↑availability of Glutathione.
So Body can turn TOXIC metabolite →→ non toxic form & prevent Liver Cell Damage and
NECROSIS
 Opiate Poisoning:
Heroin, Methadone, Analgaesics in Elderly
Action on mu receptors giving the effects in overdose.
1. PINPOINT PUPILS
2. RESPIRATORY DEPRESSION
3. COMA
Opiate Overdose-Management
INITIAL MANAGEMENT
1. A B C D
2. NALOXONE

High Affinity for the opiate receptors (Little side effects)

Rapid onset

Effects last 2-4 hrs, may need repeated doses (Give I-M or I-V)
 Salicylate (Aspirin) Poisoning
Toxicity occurs due to disturbance in Acid-Base Balance
1. Respiratory Alkalosis
2. Metabolic Acidosis
Mechanism
1. Direct stimulation of respiratory centre → overbreathe, Hyperventilation →Resp. Alkalosis.
2. Kidney attempts to compensate for alkalosis by excreting alkali ---------→metabolic Acidosis
3. Inhibits normal metabolic pathways of CHO, Fat, Protein. ---→ Build up of Organic Acids
(KETONES, LACTATE, PYRUVATE)
↓
&MORE METABOLIC ACIDOSIS
Clinical Features
COMMON: Vomiting, Dehydration, Tinnitus, Vertigo, Sweating, Hyperventilation
UNCOMMON: Confusion, clotting abnormalities, Coma, Convulsions, Haematemesis,
Hypepyrexia, renal failure, Disorientation,
Aspirin overdose - Management
 Take Salicylate levels to help guide treatment options (management according to amount
taken) If small amounts and asymptomatic need no treatment.
 General: ABCD.
 Specific: When high levels ingested and patients are symptomatic
1. ↓ ABSORPTION
 Activated Charcoal in those who taken more than 250mg/Kg & less than 1
hour ago.
 Gastric Lavage in those who taken more than 500mg/kg & less than 1 hour
ago.
2. ↑ DRUG ELIMINATION
 Urinary Alkalinisation ↑urinary pH from 5 to 8 (10-20 fold) ↑renal salicylate
clearance. Infusion of Sodium Bicarbonate. (Care must be taken because of it’s
dangerous & can cause severe Acid - Base Disturbances)
 Haemodialysis in severe life threatening overdose to correct Acid Base
disturbances while removing Salicylate