Salicylate poisoning

very informative

1. SALICYLATE POISONING Dr. Yuva Sri Sai Anumula Assistant Professor Department of Pharmacy practice Nirmala College of Pharmacy

2. OBJECTIVES Introduction Therapeutic uses of salicylates & product strength Toxic dose and Assessing poisoning dose Pharmacokinetics Pathophysiology Clinical presentation Acute vs Chronic Diagnosis Treatment

3. INTRODUCTION Aspirin is one of the oldest medications that remains a part of current practice Intentional salicylate overdose usually occurs predominantly in adolescents & young adults. Overdoses in children are usually accidental & in the elderly they occur as therapeutic misadventures. This is an important problem because delay in treatment of severe intoxication is associated increased mortality in severe cases. With good management mortality rates are low but even at best about 5% of severely toxic patients die, u sually from cardiovascular & central nervous system complications.

4. THERAPEUTIC USES & PRODUCT STRENGTH OF SALICYLATES Aspirin is widely used in clinical medicine as analgesics, antipyretics, anti-inflammatory, antiplatelet and antirheumatics. Adult Aspirin ( 150mg, 300mg, 325 mg) Baby Aspirin (81 mg) Bismuth subsalicylate 1 ml is equivalent to 8.77 mg of salicylic acid. 60 ml is equivalent to a therapeutic dose (650 mg) of aspirin . Methylsalicylate 1 teaspoonful (100% MS) = 7000 mg salicylate ( 21 * 325mg adult strength aspirin )

5. TOXIC DOSE Toxic dose = 150 mg/kg Minimal lethal dose = 450 mg/kg Assessing Salicylate Poisoning Dose Less than 150 mg/kg of aspirin - no symptoms to mild toxicity Ingestions of 150-300 mg/kg - mild to moderate toxicity Ingestions of 300-500mg/kg – Serious toxicity Greater than 500mg/kg – potentially lethal

6. pharmacokinetics Absorption: Rapidly absorbed by passive diffusion in the stomach After absorption ASA is de-acetylated Distribution: 90% bound to albumin in the blood at a dose of 10 mg/dL An acidic pH promotes the movement of salicylate into the tissues Has a very short half-life (30 min ). Reach peak levels in 15-60 minutes Elimination: 90 % metabolized in the liver, 10% unchanged Salicylate is either metabolized to gentisic acid or bound to glycine or glucuronide , or excreted as salicylate In tubular fluid, nonionized salicylate is reabsorbed. Ionized salicylate cannot be reabsorbed Excreted in the urine (PH dependent ).

7. PATHOPHYSIOLOGY CENTRAL NERVOUS SYSTEM 1 ) Increased central respiratory drive : Mechanism of action is unclear. The most likely explanation may be the direct stimulation of medullary regulatory activity by salicylic acid. Hyperventilation predominates early in the course of salicylate toxicity resulting in respiratory alkalosis, decreased ionized calcium, and compensatory renal excretion of potassium, sodium, and bicarbonate. 2) Seizures and coma E tiology : As glucose utilization increases, a decrease in brain glucose concentrations may occur producing a relative CNS hypoglycemia despite normal blood glucose concentrations. Cerebral edema by an, as yet unexplained mechanism Metabolic acidosis

8. B. METABOLIC: Uncoupling of oxidative phosphorylation leads to a disruption in cellular metabolism due to the interference of the Kreb’s cycle and impaired carbohydrate and lipid metabolism. Substrates are metabolized but the energy produced is dissipated as heat instead of being used to produce adenosine triphosphate (ATP). The basal metabolic rate increases, placing increased demands on the cardiorespiratory system. Excess lactic acid results from nonmitochondrial ATP production.

9. Normal Energy Generation Glucose Pyruvate Kreb’s Cycle CO 2 NADH 2 H 2 O ATP Glycolysis Pyruvate decarboxylase Oxidative Phosphorelation

10. Salicylate Uncoupling Glucose Pyruvate Kreb’s Cycle CO 2 NADH 2 H 2 O ATP SALICYLATES ATP Lactate Glycolysis Pyruvate decarboxylase Oxidative Phosphorelation

11. Disrupted cellular metabolism produces: 1 . Increased oxygen consumption; compensatory increase in heart rate. (tachycardia) 2 . Increased CO2 production due to abnormal cellular respiration. ( hypercapnea ) 3 . Increased heat production (hyperthermia) 4 . Patient’s commonly present with hyperglycemia but increased glucose utilization, impaired glucose production, and eventually reduced tissue glucose concentrations may lead to ( hypoglycemia ) 5 . Increased production of organic acids (metabolic acidosis)

12. C. PULMONARY: Noncardiogenic pulmonary edema : Mechanism of action is unclear, but the most favored postulated mechanism proposes a direct toxic effect of salicylates on pulmonary endothelium producing an extravasation of fluids . D. HEMATOLOGIC: Therapeutic Use: inhibits prothrombin synthesis and platelet aggregation. Overdose: Decreased prothrombin formation Decreased factor VII production Increased capillary fragility Decreased platelet adhesiveness

13. C L I N I C A L P R E S E N T A T I O N CVS: Tachycardia, Hypotension Dysrhythmias Asystole - With severe intoxication

14. Chronic Salicylism Most common in the elderly-unintentional May include any sign consistent with acute toxicity May also present as: Delerium Dementia Encephalopathy of unknown origin Congestive heart failure

15. DIAGNOSIS History: Amount Approximate Time Of Ingestion Possibility Of Long-term Ingestion Potential Co-ingestants Approximate Time Of Ingestion Presence Of Other Medical Conditions (Eg, Cardiac, Renal Diseases) Physical E xamination : Vital signs. CVS , Chest , Abdomen, CNS

16. Assessing Salicylate Poisoning from Clinical Evaluation Mild (150mg/kg) Moderate (150-300 mg/kg) Severe (300-500 mg/kg) Nausea Nausea Vomiting Delerium Hallucinations Convulsions Coma Vomiting Dizziness Tinnitus Headache Confusion Hyperventilation Tachycardia Fever Respiratory arrest

17. Rapid ASA Confirmation + FeCl 2 Salicylic Acid (Purple colored complex)

18. Diagnosis continued • 3 criteria in the ‘point of care’ setting that can rapidly indicate salicylate poisoning are: – Positive urine ketones • Increase in fatty acid metabolism – Whole blood glucose and electrolyte determination • Shows decreased bicarbonate and other electrolyte and glucose abnormalities – Whole blood ABG • Shows characteristic acid-base disturbance of salicylate toxicity

19. MANAGEMENT EMERGENCY AND SUPPORTIVE MEASURES: Maintain airway and assist ventilation if necessary. Administer supplemental oxygen and establish intravenous access. Fluid resuscitation : Correction of dehydration with 0.9% sodium chloride or lactated Ringer solution, 10 to 20 mL/kg/h over 1 to 2 hours until a good urine flow is established of at least 2 to 3 mL/kg/h

20. GI decontamination : Gastric lavage in the first hr (warmed NS 38C,protect airway) Activated charcoal in the first 4 hr, 1-2g/kg (maximum 100g) Whole-bowel irrigation (WBI) with polyethylene glycol(enteric coated or slow release formulas, 2 L/h (20 mL/kg/h until the rectal effluent is clear)

21. Enhanced elimination: Urinary alkalinization with sodium bicarbonate : 1 to 2 mEq/kg of sodium bicarbonate IV bolus, then infusion of DW5% with 100 to 150 mEq of sodium bicarbonate and 20 to 40 mEq of potassium chloride in each liter at a rate of 1.5 to 2.5 mL/kg/h Hemodialysis : Management of patients with salicylate poisoning and a serum salicylate level >100 mg/dL after acute ingestion or >40 mg/dL after chronic ingestion, altered mental status , renal failure, pulmonary edema, progressive clinical deterioration, refractory acidosis , or failure to respond to more conservative therapy .