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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