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 -If Poisoning underestimated; leads to metabolic acidosis, seizure, hyperthermia, pulmonary edema, cerebral edema, renal failure & Death

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

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

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.

Acute vs. chronic FeaturesAcuteChronic AgeYoung adultOlder adult/infants EtiologyODTherapeutic misuse Co-ingest.FrequentRare Past historyOD or psychpain/RF PresentationEarlyLate DehydrationModerateSevere Mental status Normal(initially)Altered Serum [conc]40 - ≥120 mg/dL30 to ≥80 mg/dL MortalityLow w/ treatmentHigh MORE DANGEROUS!

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

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.

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

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.

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.

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

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.

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