Salicylate Toxicity

1. Salicylate Toxicity Trina Banerjee, Renal Fellow Acid-Base Conference

2. Pharmacokinitics and Mechanism of Action

4. 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

5. 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

6. 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

10. Clinical Manifestations

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

12. 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.

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

14. Water and Electrolyte Losses • Hyperthermia causing skin insensible losses • Increased pulmonary insensible losses • Vomiting • Increased renal excretion of bicarbonate, sodium and K+ follow.

15. 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

17. Predictors of Toxicity

18. 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.

20. 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.

22. Management

23. Step 1: Decrease level • Gastric lavage/activated charcoal • Alkalinization of the plasma • Alkalinization of the urine • Dialysis

24. 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

25. Dialysis • Reasons to Perform It • How to Do it

27. Reasons • Serum concentration >100mg/100ml • CNS dysfunction • Renal failure • Pulmonary Edema • Severe acid/base electrolyte disturbances

28. 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

29. Step 2: Manage Complications • Correct hypokalemia • Correct hypoglycemia • Avoid intubation if possible