Chapter 37: Salicylates

INTRODUCTION

HISTORY AND EPIDEMIOLOGY

The Ancient Egyptians recognized the pain-relieving effects of concoctions made from myrtle and willow leaves. Hippocrates was among the first reported to use willow bark and leaves from the Salix species to relieve fever, but it was not until 1829 that the glycoside salicin was extracted from the willow bark and used as an antipyretic. Seven years later, salicylic acid was isolated, and by the late 1800s, it was being used to treat gout, rheumatic fever, and elevated body temperature. The less irritating acetylated salicylate compound was first synthesized in 1833, and in 1899, acetylsalicylic acid was commercially introduced as aspirin by Bayer. With that, the modern era of aspirin therapy and salicylate toxicity began.

The American Association of Poison Control Centers (AAPCC) National Poison Data System (NPDS) collects and reports annual exposure data in the United States. Analgesics, which include both aspirin and acetaminophen (APAP), continue to rank first among pharmaceuticals most frequently reported in human exposures (Chap. 130). Salicylate toxicity and fatalities have long been a major toxicological concern. From the 1950s to 1970s, salicylates were the leading cause of fatal childhood poisoning. The association with Reye syndrome, safer packaging, and the increased use of nonsteroidal antiinflammatory drugs (NSAIDs), APAP, and other alternatives to aspirin decreased the incidence of unintentional salicylate poisoning. In the annual 2015 NPDS review of fatalities, 18 cases of death were documented from single substance acetylsalicylic acid exposures and another 31 fatalities included acetylsalicylic acid as part of the exposure (Chap. 130).⁹³ A query of the same NPDS database for single-agent aspirin poisoning deaths occurring from 2008 to 2012 yielded 83 cases in which death was coded as a direct consequence of aspirin poisoning.⁴⁵ Despite decline in general use, it is still imperative that clinicians are adept at early recognition and swift management of patients with salicylate overdose.

Aspirin and other salicylate-containing products continue to be some of the most common prescription and nonprescription xenobiotics used by the general public. Since landmark trials demonstrated the inhibition of platelet function by aspirin in the 1970s, its use became the standard of care for cardiovascular disease prevention and treatment. Subsequent investigations demonstrated potential benefits of aspirin in primary and secondary prevention of myocardial infarction, colon cancer, and transient ischemic attack. Its antiinflammatory properties continue to make it an active investigational xenobiotic for cancer.¹ Thus salicylates continue to be readily available and will continue to lead to significant morbidity and mortality in overdose.

PHARMACOLOGY

Aspirin and other salicylates have analgesic, antiinflammatory, and antipyretic properties, a combination of traits shared by all of the NSAIDs (Chap. 35). Most of the beneficial effects of NSAIDs result from their inhibition of cyclooxygenase (COX). This enzyme enables the synthesis of prostaglandins, which in turn mediate inflammation and fever.^110...