Salicylate Toxicity

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Salicylate Toxicity
Trina Banerjee, Renal Fellow Acid-Base Conference
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Pharmacokinitics and Mechanism of Action
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Pharmacokinetics I

• ASA and salicylic acid are absorbed within 15-30
  minutes
• Salicylate is 90 bound to albumin
• An acidic pH promotes the movement of salicylate
  into the tissues

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Pharmacokinetics II

• After absorption ASA is de-acetylated
• 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

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Mechanism of Action

• Inhibition of COX-1 and COX-2
• Interference with oxidative phosphorylation and
  the Krebs cycle
• Activation of the CTZ on the Medulla
• Activation of the Respiratory Center in the
  Medulla

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Clinical Manifestations
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Respiratory alkalosis

• Increases tidal volume and respiratory rate
• Majority of the effect comes from the CNS
  respiratory centers
• Peripheral chemoreceptors may contribute

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Metabolic Acidosis

• Prevents the formation of ATP and promotes the
  formation of lactate and pyruvate
• Inhibits the Krebs cycle enzymes, encouraging
  lipid metabolism and ketogenisis
• Inhibition of amino acid metabolism leads to
  amino aciduria.

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Hypoglycemia

• Salicylate causes secretion of insulin
• Salicylate can also decreased glucose levels in
  the CNS despite normal serum glucose

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Water and Electrolyte Losses

• Hyperthermia causing skin insensible losses
• Increased pulmonary insensible losses
• Vomiting
• Increased renal excretion of bicarbonate, sodium
  and K follow.

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Coagulation Abnormalities

• Decrease in thromboxane A2 causes inablility to
  activate platelets
• If ASA toxicity is severe the liver may not be
  able to produce factors 2, 7, 9, and 10

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Predictors of Toxicity
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Based on Amount Ingested

• Requires the patients report of how much was
  taken. It may be difficult to obtain this
  information, or it may be unreliable.

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Based on the Serum level

• Blood level of salicylate should be measured for
  at least 6 hours after acute intoxication, or any
  time after chronic intoxication.
• Plasma levels should be checked every 2 hours
  until levels peak. Enteric coated tablets may
  take more than 24 hours to be absorbed.

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Management
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Step 1 Decrease level

• Gastric lavage/activated charcoal
• Alkalinization of the plasma
• Alkalinization of the urine
• Dialysis

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Alkalinization

• Alkalinizing the serum ionizes the salicylate,
  which keeps it from entering the tissues. Serum
  pH should be in the 7.5-7.6 range (no higher than
  7.6)
• Alkalinizing the urine to pH7.5 to 8

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Dialysis

• Reasons to Perform It
• How to Do it

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Reasons

• Serum concentration gt100mg/100ml
• CNS dysfunction
• Renal failure
• Pulmonary Edema
• Severe acid/base electrolyte disturbances

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How To

• Molecular weight of ASA is 138 kDa
• Volume of distribution is 0.2L/kg
• Toxic levels are less protein bound
• Blood flow should be 350-400cc/hr for 3.5 to 4
  hours

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Step 2 Manage Complications

• Correct hypokalemia
• Correct hypoglycemia
• Avoid intubation if possible