APAP and Salicylate Poisoning

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Salicylates
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-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
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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

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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

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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.

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Acute vs. chronic
MORE DANGEROUS!
Features Acute Chronic Age Young
adult Older adult/infants Etiology OD Therapeut
ic 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
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methylsalicylate
Free tissue SA
90 of free SA binds albumin at conc lt 10mg/dL
2.5 excreted unchanged in urine (pH independent)
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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.

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Mechanism of toxicity
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
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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.

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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.

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Treatment

• Treatment Goals prevent gt 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

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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.

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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