Chapter 80 Salicylates
Salicylates represent perhaps the earliest class of antiinflammatory agents and possess analgesic and antipyretic properties.1 Aspirin is both the most commonly used and most commonly recognized salicylate. The active ingredient of aspirin is the phenol-derived chemical compound, acetylsalicylic acid.1 Although replaced in some cases by newer antiinflammatory agents, aspirin remains a common over-the-counter analgesic for humans, with application to small animal veterinary patients as well. Although salicylates represent the third most common cause of nonsteroidal antiinflammatory drug toxicity in dogs and cats, intoxication is seen relatively infrequently by the small animal practitioner.2 However, salicylate toxicity still represents an important toxicity because of the serious and complex impact on the patient’s physiology.
Salicylates are used commonly to treat mild to moderate pain and fever.3 The mechanism of analgesia provided by salicylates involves nonselective inhibition of cyclooxygenase (peripherally and centrally mediated).3,4 Additional antipyretic effects of the drug are centrally mediated at the level of the hypothalamus.3 Salicylic acid is a potent inhibitor of thromboxane production and, as such, has long been used therapeutically as an antithrombotic agent because of its negative effect on platelet function.3
Salicylates are common ingredients in a variety of prescription and over-the-counter compounds.5 Aspirin is probably the most familiar source of salicylate for the small animal veterinarian. Other common sources include oil of wintergreen, Pepto-Bismol, Percodan, and BENGAY. As with other antiinflammatory agents, salicylates may be formulated in combination with other drugs (i.e., opioids, acetaminophen, decongestants) and, whether in combination or alone, they are available as oral tablets, liquid suspensions, and topical preparations.5
The availability of alternative cyclooxygenase-selective analgesics limits the contemporary use of high-dose aspirin therapy for analgesia in both dogs and cats; however, therapeutic administration of aspirin at appropriate dosage is considered acceptable for both species. The recommended dosage for antiinflammatory or analgesic effect is 10 to 25 mg/kg PO q8-12h for dogs and 10 to 20 mg/kg PO q48-72h for cats.4,6 Adverse effects with therapeutic use of aspirin include gastrointestinal (GI) upset, mucosal ulceration, acute GI bleeding, and altered hemostasis (primarily irreversible platelet dysfunction that persists for several days).
Salicylates are absorbed rapidly after oral administration.3–6 Initial serum levels are detected within 30 minutes of ingestion and peak levels occur within 2 to 4 hours. Sustained release and enteric-coated preparations have less predictable pharmacokinetics. More importantly, massive ingestions cause delayed gastric emptying and, hence, result in serum levels that may continue to rise for several hours.7,8
After absorption, aspirin is hydrolyzed in intestinal, hepatic, and red blood cells to form salicylic acid. This active substance reversibly binds to serum proteins (principally albumin). Upon saturation of all available binding sites, any additional ingestion results in a significant increase in free salicylate and a parallel increase in tissue concentrations. Salicylate undergoes renal clearance and may be excreted unchanged or following glucuronidation. A small amount may also undergo conjugation with glycine or hydroxylation before renal excretion. Under circumstances of acute toxicity (rather than therapeutic dosage), metabolic pathways become saturated and clearance is determined by urinary excretion, which in turn is influenced by urine pH.7–9 It is the urinary excretion rate that determines the drug half-life in these circumstances, and urinary excretion may increase to several times greater than normal. The serum half-life of aspirin in humans following acute intoxication exceeds 30 hours.7,9 In cats the serum half-life is normally quite long (35 to 40 hours), thus creating less of a prolongation of half-life following toxic exposure. The normal half-life in the dog (with therapeutic administration) is between 6 and 9 hours.4 However, the relative effect of toxic ingestion on serum half-life in the dog would be expected to parallel the effect seen in humans.
Salicylate toxicosis in the dog most commonly results from accidental ingestion.2 However, deliberate but inappropriate administration by an owner or veterinary professional can also result in toxicosis. The level of exposure capable of causing toxicosis is not clear, perhaps due in part to variable susceptibility among individuals.11 GI signs alone may occur with dosages of 50 mg/kg.4,11 Severe signs of toxicity are reported to occur over a wide dosage range of 100 to 500 mg/kg.11
Cats are more susceptible to salicylate toxicity, because this species is deficient in glucuronidation pathways. Cases of toxicosis in this species are most often the result of inappropriate administration. Cats may experience toxicosis at dosages exceeding 50 mg/kg, but severe toxicosis was not seen in an experimental setting until repeated exposures greater than 80 mg/kg were administered.11 Similarly, the threshold for lethal exposure is not clear, but any exposure exceeding 100 mg/kg should be considered serious, with the potential for lethality.
Toxicity from salicylates results from uncoupling of oxidative phosphorylation and disruption of the Krebs cycle.7–9 This mechanism of toxic injury affects multiple organ systems in high-level exposures. Minor exposure may result predominantly in GI signs (i.e., vomiting, nausea, or diarrhea), and toxicity in such cases is predominantly mediated by the direct antagonism of prostaglandins in the GI tract, which normally serve to increase epithelial cell turnover and mucus and bicarbonate secretion.2,4 Severe toxicities result in respiratory alkalosis (via direct central stimulation) or a mixed acid-base abnormality (typically characterized by a metabolic acidosis and respiratory alkalosis).
Initial effects of a toxic ingestion include direct stimulation of the respiratory center resulting in tachypnea and a primary respiratory alkalosis. The respiratory alkalosis results in a compensatory loss of bicarbonate via urinary excretion. Ultimately, the compensatory excretion of bicarbonate will exacerbate the impending metabolic acidosis. Uncoupling of oxidative phosphorylation leads to an accumulation of organic acids, predominantly lactic acid and ketoacids. It is these organic acids which contribute the most to the resultant metabolic acidosis and increased anion gap. The specific contribution of the salicylic acid itself exerts a minimal contribution to the anion gap.7–9 A list of organ systems affected by toxic exposure, the associated mechanisms of injury, and their clinical signs are summarized in Table 80-1. Susceptible organ systems include the central nervous system (CNS), the respiratory system with potential development of noncardiogenic pulmonary edema, and kidneys (acute renal failure [ARF]).
|Organ System||Mechanism of Injury||Site of Injury or Clinical Signs|
|Central nervous system||Direct stimulation||Stimulation of respiratory center leads to primary respiratory alkalosis|
|Uncoupling of oxidative phosphorylation||Decreased glucose in CSF and brain (independent of plasma glucose)|
|Respiratory or pulmonary||Increased pulmonary capillary permeability (possibly via inhibition of prostacyclin or altered platelet-vessel interactions)||Noncardiogenic pulmonary edema|
|Renal||Compensatory response to respiratory alkalosis||Increased renal excretion of sodium, potassium, bicarbonate|
|Direct increase in tubular permeability||Additional loss of potassium, imbalance of sodium and water|
|Uncoupling of oxidative phosphorylation||Additional potassium loss due to inhibition of active transport|
|Decreased renal blood flow with or without direct renal injury||Acute renal failure (may be nonoliguric or oliguric)|
|Salicylate-induced inappropriate antidiuretic hormone||Oliguria|
|Hepatic and metabolic||Disruption of Krebs cycle and inhibition of dehydrogenases||Increased production of lactate and pyruvate (important source of metabolic acidosis)|
|Increased lipolysis||Increased production and accumulation of ketone bodies|
|Uncoupling of oxidative phosphorylation||Increased systemic metabolism and tissue glycolysis (typical sequelae include: increased body temperature; increased CO2 production; increased O2 consumption; hypoglycemia)|
|Gastrointestinal||Direct injury with or without prostaglandin-mediated injury||Gastric irritation or ulceration, GI hemorrhage, vomiting|
|Direct central stimulation of the chemoreceptor trigger zone||Vomiting (contributes to dehydration, loss of potassium)|
|Coagulation||Antagonism of vitamin K (direct effect of salicylate analogous to that of warfarin)||Drug-related coagulopathy with prolongation of prothrombin time|
|Irreversible inhibition of platelet function||Decreased platelet aggregation, altered primary hemostasis|
CO2, Carbon dioxide; CSF, cerebrospinal fluid; GI, gastrointestinal; O2, oxygen.