Salicylates - Salicylate toxicity and Antidote PDF

Preview

Summary

Salicylate toxicity and Antidote...

Description

Salicylates (ASA) 1. Pharmacology a. Salicylates inhibits cyclooxygenase (COX) enzymes that are responsible for the synthesis of prostaglandins which are key in mediating inflammation and fever (IL-1, IL-6, α and β interferons, and TNF-α). b. Covalently modifies (acetylates) COX-1 (low doses) and both COX-1 and COX-2 (high doses) c. Once the salicylate inactivates the COX-1, the platelets cannot regenerate it and it remains inactivate for the 8-12 days’ lifespan of the platelets. d. Prototype for salicylate is aspirin but the group also includes topical salicylates, Oil of Wintergreen (methyl salicylate), and bismuth subsalicylate. 2. Clinical Uses a. Effective anti-inflammatory b. Antipyretic c. Analgesic for mild-to-moderate pain d. Prophylactic against clot formation (low dose) 3. Side Effects/ Toxicity a. Gastric ulcers b. Increased bleeding c. Interference with platelet adherence d. Metabolic and organ-specific 4. Pharmacokinetics a. ASA is rapidly converted to salicylic acid and absorbed from the stomach. b. The pKa of ASA is 3.5 and the pH of stomach is around 1-2. When the aspirin gets to the stomach, the majority is unionized (acetylsalicylic acid form). c. ASA reaches it therapeutic serum concentrations in 30 minutes and attains peak concentration within 1 hour. d. ASA undergoes liver biotransformation and then renally eliminated. It demonstrates dose dependent elimination. 5. Toxicokinetics a. Management of salicylate toxicity is complicated because there are several factors that alter the pharmacokinetic parameters. b. The severity and duration of the toxicity is mainly determined by the dose but other factors such as formulation, gastric empting rate, gastric/serum/urine pH, hepatic/renal function and bezoar formation also plays an important role. c. The enteric coated ASA achieves its peak concentration in 4-6 hours at therapeutic dose but when there is poisoning, it is delayed by ~24 hours. d. The half life is also significantly altered when salicylates are used at therapeutic concentration (2-4 hours) compared to toxic concentration (20 hours). e. The toxic concentration of the salicylates also changes the elimination kinetics from first order kinetics to zero order kinetics. f. Topical Salicylates and methyl salicylate are rarely responsible for salicylate poisoning but excessive application can result in poisoning. g. The risk of salicylate toxicity of Oil of Wintergreen (methyl salicylate) increases significantly if it is ingested. 1 mL of 98% Oil of Wintergreen contains an

equivalent quantity of salicylate as 1.4 g of ASA. The minimum toxic salicylate dose is ~150mg/kg. h. The symptoms present within 2 hours of ingestion and majority of the patients with methyl salicylate toxicity have died in less than 6 hours so prompt management is required. 6. Pathophysiology of Salicylate Toxicity a. The therapeutic range of [salicylate] for anti-inflammatory effects is 15-30 mg/dL. b. Typically, concentrations > 30 mg/dL are associated with signs and symptoms of toxicity. c. Acid–Base and Metabolic Effects i. Salicylate acts to uncouple oxidative phosphorylation which leading to accumulation of lactic acid and pyruvic acid and also induces metabolism of fatty acids which generates ketones bodies. The toxic concentration of salicylate impairs the renal hemodynamics causing all the inorganic compounds to accumulate. Leading to a primary elevated anion gap metabolic acidosis. ii. In mice, there is significant increases in serum lactate concentration because of enhanced glycogenolysis to compensate for the loss of energy by uncoupling of oxidative phosphorylation. iii. There is increased oxygen consumption even at low salicylate concentration because of salicylate-induced uncoupling of oxidative phosphorylation which eventually increases the body temperature. d. Neurologic Effects i. Due to uncoupling of oxidative phosphorylation, salicylate toxicity causes decreased brain glucose even at normal plasma glucose levels. ii. This can cause CNS adverse effects of hypoglycemia even at normal blood glucose levels (confusion, altered mental status, seizures, coma). b. Hepatic Effects i. Hepatic dysfunction is very rare from the salicylate toxicity. Differential diagnosis should be evaluated if the patient presents with elevated aminotransferases or bilirubin. ii. Historically, there is a link between ASA and Reye syndrome where there is a build up of fatty acids causing steatosis of hepatocytes. The fatty acids are not being transported to cytoplasm for beta-oxidation because of depletion of intrahepatocyte coenzyme A. c. Otolaryngologic Effects i. Ototoxicity: not completely understood mechanism but it is multifactorial. It is hypothesized to be because of the inhibition of COX in the ear and also due to vasoconstriction brought on by prevention of prostaglandin synthesis. d. Pulmonary Effects i. Salicylic acid also directly stimulates the respiratory drive in the medullary respiratory neurons which leads to a primary respiratory alkalosis. This also causes clinical manifestations like tachypnea and hyperpnea. e. Gastroinstestinal Effects

i. Nausea/vomiting is the most common manifestation brought on by the disruption of mucosal barrier, local gastric irritation as well as central stimulation of CTZ. f. Renal Effects i. The kidneys are the major organ responsible for the excretion of salicylate and the metabolites. Individuals with salicylate toxicity end up excreting large amount of bicarbonate, sodium, potassium and other organic acids. Salicylate toxicity can also precipitate prerenal acute kidney injury. g. Hematological Effects i. Hypoprothrombinemia and platelet dysfunction are the two main hematologic complications of salicylate toxicity. Salicylate toxicity decrease the plasma concentration of coagulation factors and causes accumulation of vitamin K dependent carboxylase substrates in the liver. 7. Clinical Manifestations of Salicylate Poisoning a. Tinnitus: mechanism not completely understood b. Tachypnea and hyperpnea: due to central stimulation of respiratory drive c. Nausea/vomiting: disruption of mucosal barrier and local gastric irritation d. CNS: uncoupling of neuronal oxidative phosphorylation (confusion, altered mental status, seizures, coma) e. Hyperthermia: due to uncoupling of oxidative phosphorylation f. Acute Toxicity and Chronic Toxicity Acute Chronic Age Younger patients without Older patients (chronic medical problem) medical problems Diagnosis Easy Goes unrecognized Etiology (SI) Known / intentional Often unintentional (Atypical SI) ingestion(Typical SI) Mortality Uncommon, if promptly treated Increased mortality (delay in diagnosis and underlying comorbidities) g. Diagnostics ii. Systemic toxicity 1. Ingestions of 150 mg/kg or 6.5 g of aspirin 2. Ingestion of greater than a lick or taste of oil of wintergreen (98% methyl salicylate) by children 6 years of age. iii. Salicylate Analysis 1. Salicylate concentration can indicate the severity of the toxicity. Serum salicylate concentrations are commonly reported in mg/dL in the United States but you might see it reported as mg/L or mcg/mL. Example: 170 mg/dL (symptomatic) compared to 170 mg/L (likely asymptomatic). iv. Blood Gas (VBG or ABG) 1. Classical sign of possible salicylate toxicity: primary metabolic acidosis with primary respiratory alkalosis 2. Patients will often present with normal pH to slightly alkaline pH.

v. BMP 1. Elevated anion gap metabolic acidosis 2. Salicylate can falsely elevated chloride and making it appear as though anion gap is normal 3. Acute kidney injury 4. Hypokalemia 8. Management a. Initial Management i. GI decontamination 1. Orogastric lavage and activated charcoal. Repetitive or multipledose AC (MDAC) recommended to achieve desired AC: Salicylate ratio. Whole-bowel irrigation (WBI) with polyethylene glycol electrolyte lavage solution (PEG-ELS) + AC reduces absorption but no increase in the clearance of absorbed salicylate. ii. Fluid Replacement: Majority if the patients with salicylate poisoning are hypovolemic because of hyperventilation, vomiting, hypermetabolic state, polyuria and diaphoresis. Adequately assess the fluid requirements as well as any electrolyte abnormalities. iii. Treat hypokalemia 1. During hypokalemia, renal tubules reabsorbs potassium ions in exchange for hydrogen ions and thus preventing the alkalinization of the urine. iv. Alkalinization with Sodium Bicarbonate 1. Primary objective is to increase the pH of serum and urine to shift the equilibrium towards charged state to prevent additional neurotoxicity and increase elimination through the urine. 2. Indicted for: all symptomatic patients with serum salicylate concentrations above therapeutic range and for suspected salicylate toxicity until lab results obtained. 3. Bolus of 1-2 mEq/kg followed by a drip followed by bicarb drip with 3 ampules of sodium bicarbonate in 1L of D5W. 4. These patients are hypovolemic so run the drip1.5-2X maintenance fluid rate to replenish the fluid lost. 5. Goal urine pH 7.5-8.0 9. Hemodialysis (HD) a. HD may be indicated if no positive result even after trying to alkalinize and eliminate salicylate with bicarbonate, b. Indications for HD: salicylate concentration >100 mg/dL, salicylate concentration >90 mg/dL with impaired kidney function, persistent altered mental status, renal/hepatic/cardiac failure and systemic pH...