52: Salicylate Overdose

INTRODUCTION

Salicylates have been used since the 19th century.¹ Today, salicylates are used therapeutically throughout the world. The most commonly encountered salicylate is acetylsalicylic acid (aspirin). Other medications include the liniment methyl salicylate (oil of wintergreen) and bismuth subsalicylate, the active ingredient in Pepto-Bismol. Because salicylates are ubiquitous, there is great potential for toxicity, intentional or accidental. In 2012, there were about 19,000 aspirin-alone exposures reported and about 1,500 aspirin coingestions reported to the National Poison Data System.²

PHARMACOKINETICS

At therapeutic concentrations, salicylate ingested is rapidly absorbed into the bloodstream with a peak serum concentration in 1 hour. When gastric contents are present, absorption may be delayed. Eighty to 90% of plasma salicylate is bound to protein, especially albumin. Most salicylate is biotransformed by the hepatic endoplasmic reticulum but about 10% is eliminated unchanged in the urine. Salicylate and its metabolized products are renally eliminated in a pH-dependent manner. The difference between alkaline and acidic urine can cause free excretion to vary from >30% to as little as 2%.³

In overdoses, plasma peak concentrations are often delayed up to 35 hours, especially when ingesting extended-release and/or enteric-coated tablets.^4,5 Bezoar may also form, extending the time of absorption and making the time of peak concentration impossible to predict in any given overdose. As salicylate concentration rises above normal, protein binding and hepatic metabolization are saturated. As a result of the saturation, salicylate metabolism changes from first- to zero-order kinetics,⁶ and a larger portion of the unmetabolized salicylate is excreted in the urine (see Figure 52-1).³

PATHOPHYSIOLOGY OF SALICYLATE POISONING

In plasma, salicylates are in equilibrium between the protonated (uncharged) and unprotonated (charged) forms. Salicylic acid is a weak acid (pK_a 3.5), which means that a majority of the drug exists in the protonated (uncharged) form. In its uncharged form, it can move easily across membranes and deposit into various tissues, most importantly the CNS. At acidic pH, the equilibrium is shifted farther toward the protonated (uncharged) form, increasing the amount of salicylate able to diffuse across the membranes. Conversely, at high serum pH, equilibrium is shifted toward the unprotonated (charged) form. In this charged form, it cannot cross membranes and becomes “trapped” (see Figure 52-2).⁷