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Salicylates

Salicylates. -Salicylic Acid salts absorbed rapidly GI tract; serum concentrations 2/3 of dose in 1hr & peak 2-4hrs -ASA hydrolyzed to free Salicylic acid via RBC, Liver, Intestinal wall & reversibly binds albumin -Free Salicylate & conjugates excretion is Renal

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Salicylates

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  1. Salicylates

  2. -Salicylic Acid salts absorbed rapidly GI tract; serum concentrations 2/3 of dose in 1hr & peak 2-4hrs -ASA hydrolyzed to free Salicylic acid via RBC, Liver, Intestinal wall & reversibly binds albumin -Free Salicylate & conjugates excretion is Renal -If Poisoning underestimated; leads to metabolic acidosis, seizure, hyperthermia, pulmonary edema, cerebral edema, renal failure & Death

  3. ASA dosing • Adult acc. to the FDA: • 650mg po /4h for • Initial dose can be 1000mg.  max: 3900mg/day for adults • Child: no more than 15mg/kg q4

  4. Factors which may delay salicylate absorption in an OD situation • Enteric coating • Salicylate-induced pylorospasm • Gastric outlet obstruction • Concomitant ingestion of sustance which decreases gastric motility

  5. Factors which enhance the toxicity of topical salicylates (i.e. oil of wintergreen)? • heat • occlusive dressings • young age (high BSA to weight ratio) • inflammation • psoriasis/break of the skin • long application ** real danger is through oral ingestion of topical ingestion.

  6. Acute vs. chronic MORE DANGEROUS! FeaturesAcute Chronic Age Young adult Older adult/infants Etiology OD Therapeutic misuse Co-ingest. Frequent Rare Past history OD or psych pain/RF Presentation Early Late Dehydration Moderate Severe Mental status Normal(initially) Altered Serum [conc] 40 - ≥120 mg/dL 30 to ≥80 mg/dL Mortality Low w/ treatment High

  7. methylsalicylate Free tissue SA 90% of free SA binds albumin at conc < 10mg/dL 2.5% excreted unchanged in urine (pH independent)

  8. Metabolism in OD • Metabolizing enzymes get saturated: switch from first  zero order kinetics. • Decrease in albumin binding at toxic levels. • Urinary excretion is fixed. • SA = weak acid: • at physiologic pH most SA is ionized  does not penetrate tissues well. • acidosis  more unionized SA  greater tissue penetration.

  9. Mechanism of toxicity -Salicylate stimulates medullary respiratory center : hyperpnea, tachypnea ,respiratory alkalosis -Inhibition of Krebs cycle  amounts lactic & pyruvic acid. -Uncoupling oxidative phosphorylation;  metabolism &Temp, with  CO2 production & O2 use,  glycolysis -K+; Vomiting,  Renal Na+,K+,HCO3 loss -Uncoupling OP also  K+ by inhibiting active transport Mechanism of toxicity

  10. Met acidosis in ASA • Salicylate ion = weak acid which contributes to the acidosis. • Dehydration from hyperpnea, vomiting, diaphoresis and hyper-thermia contributes to lactic acidosis. • Uncoupling of mitochondrial oxidative phosphorylation  anaerobic metabolism  lactate and pyruvate production. • Increased fatty acid metabolism (as a consequence of uncoupling of oxydative phosphorylation)  lipolysis  ketone formation. • In compensation for the initial respiratory alkalosis the kidneys excrete bicarbonate which later contributes to the metabolic acidosis. • Increased sodium and potassium accompany the initial renal bicarbonate diuresis  hypokalemia  hydrogen ion shift out of cell to maintain electrical neutrality. • Renal dysfunction  accumulation of SA metabolites which are acids: sulfuric and phosphoric acids.

  11. Clinical manifestations • CNS:tinnitus, decreased hearing, vertigo, hallucinations, agitation, hyperactivity, delirium, stupor, coma, lethargy, seizures, cerebral edema • Hem:hypoprothrombinemia, platelet dysfunction and bleeding • GI:n/v, hemorrhagic gastritis, decreased GI motility, pylorospasm • Met:fever, hyperglycemia, hypoglycemia, ketosis, ketonuria • Pulm:tachypnea • Volume:diaphoresis and dehydration.

  12. Treatment Treatment Goals prevent > absorption, correct fluid acid-base deficit & excretion • Gastric lavage ,Activated charcoal ,Cathartics. • Intubations ,ventilation and shock treatment in severely intoxicated victem. • Urine alkalization with sodium bicarbonate to correct acidosis. • Potassium replacement in case of hypokalemia. • Vit K for treatment hypoprothrombinemia. • Correct dehydration with saline and fluids. • Treat pulmonary oedema with oxygen and intubations. • Glucose to correct hypoglycaemia and to prevent CNS depression. • Treat seizures with diazepam. • Cooling blankets or ice tocorrect hyperpyrexia. • DIALYSIS IF; Coma/Seizure, Hepatic failure, Pulm edema,or Severe acid-base imbalance

  13. Ion trapping •  the more acidic the compartment the more SA will be NONionized because SA is a weak acid (the stronger acids will dissociate and give off their H+ first.) • the more basic a compartment the more IONIZED SA will be because there is a relative lack of H+  so because SA is an acid it will give off its H+ and be ionized, i.e. “trapped” in that milieu.

  14. Indications for hemodialysis in SA poisoned patients. • Renal failure ,CHF • Pulmonary edema or acute lung injury • Refractory acidosis or electrolyte imbalance despite maximal therapy • Persistent CNS symptoms

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