Transcript Salicylate Toxicity

Salicylate Toxicity
Trina Banerjee, Renal Fellow
Acid-Base Conference
Pharmacokinitics
and Mechanism of
Action
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
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
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
Clinical
Manifestations
Respiratory alkalosis
 Increases tidal volume and respiratory rate
 Majority of the effect comes from the CNS
respiratory centers
 Peripheral chemoreceptors may contribute
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.
Hypoglycemia
 Salicylate causes secretion of insulin
 Salicylate can also decreased glucose levels
in the CNS despite normal serum glucose
Water and Electrolyte
Losses
 Hyperthermia causing skin insensible losses
 Increased pulmonary insensible losses
 Vomiting
 Increased renal excretion of bicarbonate,
sodium and K+ follow.
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
Predictors of
Toxicity
Based on Amount
Ingested
 Requires the patient’s report of how much
was taken. It may be difficult to obtain this
information, or it may be unreliable.
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.
Management
Step 1: Decrease level
 Gastric lavage/activated charcoal
 Alkalinization of the plasma
 Alkalinization of the urine
 Dialysis
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 pH=7.5 to 8
Dialysis
 Reasons to Perform It
 How to Do it
Reasons
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Serum concentration >100mg/100ml
CNS dysfunction
Renal failure
Pulmonary Edema
Severe acid/base electrolyte disturbances
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
Step 2: Manage
Complications
 Correct hypokalemia
 Correct hypoglycemia
 Avoid intubation if possible