Analgesic Toxicity PDF

Analgesic Toxicity Nourhan Khattab  most common pharmaceutical Analgesic agent involved in overdose. Toxicity Include: 1. Aspirin 2. Paracetamol  1- Aspirin poisoning (salicylism) Aspirin is another name for acetylsalicylic acid....

Analgesic Toxicity Nourhan Khattab  most common pharmaceutical Analgesic agent involved in overdose. Toxicity Include: 1. Aspirin 2. Paracetamol  1- Aspirin poisoning (salicylism) Aspirin is another name for acetylsalicylic acid. Uses: 1. Antiplatelet 2. Analgesic for mild and moderate pain 3. Anti-inflammatory 4. Antipyretic  Aspirin poisoning or salicylism acute or chronic poisoning A single overdose may Continuous usage of an cause acute poisoning. elevated dosage over 2% mortality rate long periods of time can cause initial may cause chronic respiratory alkalosis poisoning. followed by metabolic 25% mortality rate acidosis. severe in children. Mechanism of aspirin toxicity Mechanism of aspirin toxicity Mechanisms of aspirin toxicity Activation of the medulla within the brainstem results in hyperventilation (tachypnea) resulting in respiratory alkalosis Salicylates cause inhibition of oxidative phosphorylation, increased renal bicarbonate excretion, lipolysis, leading to metabolic acidosis It is these two mechanisms that lead to the mixed respiratory alkalosis/metabolic acidosis  Respiratory alkalosis is a medical condition in which increased respiratory rate that result in: Increase blood pH above the Decrease in normal range arterial levels (7.35-7.45) of carbon dioxide  Metabolic acidosis is a condition that occurs when the body produces excessive quantities of acid or when the kidneys are not removing enough acid from the body. Low level of bicarbonate ( blood pH is low normal range (less than 7.35) 22-26 mEq/L)  Neurological: lethargy, coma, seizures. Extreme Cardiac: acidemia arrhythmias. Vascular: Hypotension.  Early: ringing in the ears (tinnitus) Hyperventilation vomiting. Clinical manifestation: Late: Drowsiness, fever, convulsions, collapse, confusion, coma hypotension Tachycardia Nausea and vomiting Bleeding Diagnosis  Management 1. Gastric lavage 2. Activated charcoal (within 2 hr of ingestion) 3. IV fluids & NaHCO3 infusion (correction of acidoses & enhances elimination of aspirin in the urine). 4. Hemodialysis (sever case). 5. Correction of hypokalemia 6. No specific antidote Toxicity of paracetamol 2- Toxicity of paracetamol Acetaminophen is a safe analgesic, but an overdose of more than 4 gram (8 tablets) cause acute hepatic necrosis (fatal). 4 gm daily for two weeks can lead to toxicity. Acetaminophen poisoning → half cases of acute liver failure in the US.  ❖93% undergo Hepatic glucuronide conjugation & Hepatic sulfate conjugation to inactive metabolites excreted in the urine. Metabolic ❖2% Excreted unchanged in the pathways of urine. acetaminophen ❖5% Oxidation by cytochrome P450 to NAPQI and then: Inactivated by combine with glutathione(GSH) → produce nontoxic cysteine conjugates → excreted in urine.  Acetaminophen toxicity is an example of saturation of deactivation pathways. ❖↑ dose → ↑ NAPQI → deplete Paracetamol hepatic GSH → extensive covalent Mechanism of binding of reactive metabolite to liver macromolecules → hepatic toxicity necrosis. ❖The early administration of sulfhydryl (SH) compounds such as N- Acetylcysteine (NAC) → prevents liver damage.  Phase 1: (few hrs-24 hrs after ingestion): Nausea , vomiting and diaphoresis. Phase 2: (within 1-3 day): Increase Clinical in liver enzymes (transaminases are peaking), increase serum bilirubin manifestation: and pain. Phase 3: (within 3-5 day): Hepatic necrosis and encephalopathy. Hepatic failure can develop in 4th or in the 5th day if hepatic damage is sever and death can occur.  Factors which affect paracetamol toxicity ✓Enzyme inhibitors (omeprazole) ↓ hepatotoxicity of acetaminophen ✓ Enzyme inducers (carbamazepine) ↑ hepatotoxicity of acetaminophen ✓Patients with low glutathione reserve: AS history of chronic ethanol abuse, fasting, malnutrition, or HIV infection is at high risk for toxicity ✓ Competing for glucuronidation pathways: as Sulfa drug and azathioprine.  1- General measures: Gastric lavage Activated charcoal 2- specific management saline sulfate are preferred to Management enhance sulfate metabolic pathway. Antidote: N-acetylcysteine (NAC) IV or oral. - most effective if given in the first 8 hours of paracetamol ingestion.  NAC acts as antidote through several mechanisms including: 1. It acts as a precursor to cysteine to produce glutathione. 2. It provides sulfhydryl donors to which NAPQI can bind and be detoxified. NAC 3. It may also enhance sulfation of any remaining acetaminophen resulting in the reduction in the amount of NAPQI that is produced. 4. Act as free radical scavenger and enhancing oxygen uptake and utilization. NAC administration