Analgesic Antipyretics Toxicity (PDF)

Acute intoxication with analgesic antipyretics (Salicylates and acetaminophen) Paracetamol Aspirin Dr. Asmaa Sharif Associate professor of Forensic Medicine and Clinical toxicology College of Medicine, DAU...

Acute intoxication with analgesic antipyretics (Salicylates and acetaminophen) Paracetamol Aspirin Dr. Asmaa Sharif Associate professor of Forensic Medicine and Clinical toxicology College of Medicine, DAU 10/29/2024 1  Learning objectives 1. Understand Pathophysiology of ASPIRIN overdose. 2. Master the clinical presentation of ASPIRIN toxicity. 3. Aware of the antidote and its time of administrations. 4. Aware of ASPIRIN toxicity management. 5. Understand Pathophysiology of Acetaminophen overdose. 6. Master the clinical presentation of Acetaminophen toxicity. 7. Aware of the antidote and its time of administrations. 8. Acetaminophen drug level and timing. 9. Aware of Acetaminophen toxicity management.  1) Salicylates o  dose Patieyenson Antiplifftelammatory 5or20 Circumstances of Salicylate toxicity Salicylic acid derivatives are OTC drugs, including the aspirin, amino salicylic acid, methyl salicylate, salicylic acid etc. Aspirin: Is a Non-steroidal anti-inflammatory drugs (NSAIDs) exposure Accidental used gymation Toxicokinetics of aspirin YET.ir 00 Rapidly absorbed intact from the GI tract, with appreciable serum concentrations within 30 0 minutes. 2/3 of a therapeutic dose is absorbed in 1 hour Peak levels occur in 2 to 4 hours. f Serum concentrations may rise for more than 12 hrs. after large ingestions in ingestions of enteric capsules. In the intestinal wall, liver, and red blood cells, aspirin is hydrolyzed to free salicylic acid, which o reversibly binds to albumin. A toxic dose of aspirin is 200 to 300 mg/kg. 500 mg/kg is potentially lethal. 5 Toxicokinetics of aspirin Metabolism Primary Metabolism: Salicylates are metabolized in the liver. The major pathways include conjugation with glycine to form salicyluric acid and with glucuronic acid to form salicyl acyl and G phenolic glucuronides. ristsknolicsiucurE Metabolic Saturation: In cases of overdose, the metabolic pathways can become saturated, sqedfefsair.ie.EE leading to a nonlinear increase in plasma salicylate levels with increasing dose. e Excretion a Renal Elimination: Salicylates are primarily excreted by the kidneys. The excretion involves both glomerular filtration and tubular secretion. Urine pH: The renal elimination of salicylates is highly pH-dependent. Alkalinization of the urine increases the ionization of salicylic acid, reducing its reabsorption and enhancing excretion. Conversely, acidic urine promotes reabsorption and prolongs toxicity. in t.in io zation  Mechanism of action of aspirin Aspirin: Is a Non-steroidal anti-inflammatory drugs (NSAIDs) that irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) by covalent acetylation that decrease the synthesis of TXA2 and prostaglandins.  r Pathophysiology of aspirin toxicity o 1. Acid-Base Disturbances and Metabolic Effects Early: u Salicylate (aspirin) stimulates the medullary respiratory center, and hyperventilation develops early, due to increases the sensitivity of the respiratory center to pH and carbon dioxide partial pressure (PCO2) inducing respiratory alkalosis Subsequently, the kidenyes compensates through excreting bicarbonate, sodium and potassium (compensatory G mechanism) lead to the metabolic acidosis. first respiratoryAlkalosis he Depress Lately: metabolic Prolonged high aspirin serum concentrations eventuallysynd depress the respiratoryAcidosis center. t.rs IIe e  Pathophysiology of aspirin toxicity 2. Disturbance of oxidative phosphorylation: BATP O - It reduces production of ATP causing hyperthermia. - Hypoglycemia by increasing the tissue glycolysis. 0 is ñ - Disturbed mental status due to decreased brain glucose, even in the absence of hypoglycemia Tst 3. Gastrointestinal effect: TT signoffspivinton Nausea and vomiting because of stimulation of medullary chemoreceptor trigger hemorrhagic zone, also direct irritation causing gastritis and hemorrhage. of 4. Hematological: inhibition of platelet aggregation and affected factor VII leads to hypoprothrombinemia. Others: soneteen - Tinnitus and hearing defects. - Severe dehydration leads to oliguria and tubular damage.  o Pathophysiology of aspirin toxicity 5. Fluid and Electrolyte Abnormalities Salicylate may cause acute non-oliguric renal failure because it decreases renal blood flow and its direct nephrotoxicity. Salicylate-induced secretion of inappropriate antidiuretic hormone may also affect renal function. Hyperpnea, vomiting, sweating and fever. Increase NA, K, and water excretion (dehydration). 6. Pulmonary and Cerebral Edema (SOB) Any alteration in sensorium is evidence of cerebral edema and is a grave prognostic sign. Factors causing cerebral edema are unknown. Patients with cerebral or pulmonary edema require immediate dialysis.  Grading of Salicylate poisoning __ 1. Mild: Mainly GIT manifestations neusea , vomiting, epigastric pain and tinnitus OF 2. Moderate: mrevn.tiyg.ie Hypotension, hypoglycemia, hyperthermia, Qureshi tachycardia, metabolic acidosis with kaussmal breathing pattern and subconjunctival hemorrhage. 3. Severe: - CNS psychosis, convulsions o - Respiratory pulmonary edema - CVS cardiovascular failure - Renal oliguria and renal failure  or Laboratory investigations of salicylate toxicity 1. Serum level of drug nor t.ee o3sIF A serum salicylate I5Eshould concentration ntYebe measured 2. ABG (pH state) 6 hours or more after ingestion. 6h 2h 3. Electrolytes A second sample should be obtained 2 hours later. 4. Heaven Blood Glucose level If 2nd concentration is greater than the 1st serial or 5. Renal functions concentrations should be obtained to monitor continued absorption. 6. Liver functions 0 Monitoring of arterial pH is necessary to guide 7. Coagulation profile treatment. 8. Chest x ray and ECG Low pH and bicarbonate levels indicate severe disease tox.ie zo 50 100 lethal  Managment of salicylate toxicity Initial evaluation: Physical examination, including vital signs. Chest auscultation may provide evidence of pulmonary edema. ABG are obtained early to rapidly assess acid-base and compensatory status. 1. Supportive treatments: Infuse intravenous fluids: D5 with 100–150 mEq bicarbonate/L. Monitor serum pH; do not cause systemic alkalosis. Monitor for dialysis indications: Coma, seizure Renal, hepatic, or pulmonary failure Pulmonary edema Severe acid-base imbalance Dialysis  Managment of salicylate toxicity 2. Decontamination: E - Gastric lavage up to 24 hrs. - Multiple doses of activated charcoal with cathartics 3. Enhancement of elimination: O 0 A. Alkalinization of urine using IV sodium bicarbonate : ion trapping in both blood so can’t diffuse into cells (BBB) and renal tubules so inhibiting its reabsorption B. Hemodialysis : for more severe cases as severe acidosis or hypotension despite fluid I resuscitation 0 Hemodialysis removes also salicylates and lactate, which should improve the patient’s metabolic acidosis 4. Symptomatic treatment: - Potassium for hypokalemia - Vitamin K for coagulopathy - Sodium bicarbonate for metabolic acidosis  Points not to be missed t - Salicylate stimulate respiratory centre early producing respiratory alkalosis - Brain glucose is decreased even when blood glucose is normal - Vomiting is central and local at GIT - Electrolytes ↓( Na- K- HCO3- pH- Glucose) - Sodium bicarbonate has 2 functions 1. Alkalinization of urine 2. Treating the metabolic acidosis 2) Acetaminophen Paracetamol Circumstances of acetaminophen toxicity Acetaminophen may be found as an isolated product or in combination medications. Poisoning is usually accidental Suicidal poisoning is also common.  Toxicokinetics of acetaminophen Acetaminophen is absorbed rapidly Peak plasma concentrations generally occurring within 1 hour Complete absorption occurs within 4 hours. Metabolized in the liver by conjugation into nontoxic glucuronide and sulphate conjugates that will be excreted in urine. CPUSO 21 A small percentage (