Salicylates

Elora Apantaku, MD
 History and Epidemiology
salicin ● Use since ancient times ● Analgesics,
across the world. including ASA, are
● 1829 - salicin extracted from
willow bark. the most common
salicylic
acid ● 1833 - salicylic acid was exposures given
isolated. their widespread
● 1899 - acetylsalicylic acid availability.
(ASA) was commercially ● Tens of deaths
introduced by Bayer.
attributable to ASA
acetylsalicylic
acid annually
 Pharmacology
● Irreversibly Inhibits the cyclooxygenase (COX) enzyme.
○ COX synthesizes prostaglandins, local hormones that transmit pain information,
Salicylates

modulate the hypothalamic thermostat, and cause inflammation.

● Blocks the formation of thromboxane A2 in platelets → inhibits clotting.
● Stimulates hyperventilation → respiratory alkalosis.
● Uncouples oxidative phosphorylation, interrupts glucose and fatty acid
metabolism → metabolic acidosis.
● Therapeutic serum salicylate concentration is 10-30 mg/dL.
○ > 30 mg/dL associated with signs of toxicity.
○ >90 mg/dL associated with severe toxicity.
 Pharmacokinetics
● Absorption: ASA is quickly absorbed from the stomach & small intestine
Salicylates

(enteric coating and large tablet masses may slow this down).
● ASA is rapidly hydrolyzed to salicylate.
● Tmax .5 - 2 hrs; Tmax (enteric coated) 4-6 hours post ingestion.
● Plasma half-life is dose dependent (2-3 hrs for 81 mg; 12 hrs for 325
mg)
● Vd is affected by large doses/acidemia (0.2 L/kg → 0.5 L/kg)
 Toxicokinetics

● ASA has 5 pathways for elimination, but at toxic doses,

some pathways become saturated and overall salicylate
elimination changes from first-order to zero-order
kinetics. Normal Toxic
concentrati concentrati
● Saturation kinetics can occur at as little as 1 to 2 g of on on
acute aspirin ingestion (12 baby aspirin). Protein
90% 75%
● Acute ingestions: Binding
○ 150-200 mg/kg Half-life 2-4 hours 20 hours
○ 300-500 mg/kg severe
Peak Serum
● Chronic Ingestions: > 200 mg/kg/day for > 2 days concentratio 4-6 hours 24 hours
n
 Other Salicylates
Methyl salicylate (oil of wintergreen) Bismuth subsalicylate (Pepto-Bismol)
● Topical absorption is possible, ● 1 mL contains 8.7 mg of salicylic
but rarely to dangerous levels. acid
● 5 mL of oil of wintergreen
= 5 g methyl salicylate
= 7.5 g of aspirin
● Toxic Doses for Children:
○ Children < 6: greater than a taste
○ Children > 6: More than 4 mL
Physiologic & Clinical Effects
Metabolic Neuro Hepatic ENT Pulm GI Renal Heme

Direct
Uncouples
oxidative Inhibits stimulation Disrupts the
Anion gap cochlear COX, of the
metabolic phosphory enables medulla gastric mucosal
acidosis (limit lation in lining, ulcers,
Ca2+flux, and and
ATP, uncouples neurons, NMDA on decreased nausea, &
oxidative apoptosis, None vomiting.
(hepatic neurons while pH Platelet
phosphoryl- cerebral encephalopathy Central None
ation), edema. in Reye decreasing increase stimulation of dysfunction
hyperglycemia Confusion
syndrome) cochlear blood respiratory the chemo-
then flow. Tinnitus, drive,
agitation, receptor trigger
hypoglycemia, alteration of pulmonary
lethargy, perceived edema, zone causes
hyperthermia. seizures, emesis.
sound. ARDS (7%
coma.
of cases)
Clinical Presentation

Early: Respiratory alkalosis, alkalemia, and alkaluria

Intermediate: Respiratory alkalosis, metabolic acidosis,
alkalemia, and aciduria
Late: Metabolic acidosis with either a respiratory
alkalosis/acidosis, acidemia, and aciduria
Chronic Salicylate Poisoning: Much of the same symptoms
with an insidious onset, may mimic other conditions (e.g.
sepsis)
Evaluation and Diagnostic Testing
Laboratory Studies:
Serum salicylate concentration↾, ABG/VBG, ketones, lactate,
BMP (for an anion gap, K, and glucose)
↾Certain drugs can falsely elevate salicylate levels: thioridazine, promethazine, prochlorperazine,
chlorpromazine, N-acetylcysteine, and cysteamine.
Additionally, given the different preparations of ASA, serial levels are encouraged q3-4hrs.
Management

There are no antidotes.

Activated Charcoal - 10:1 ratio of AC to ingested salicylate,
multiple-doses can be considered
Fluid Replacement -to balance losses from symptoms:
hyperventilation, vomiting, fever, and polyuria
 Management
Serum & Urine Alkalinization - shifts salicylate out of brain and
tissues into serum and kidneys for elimination
( traps salicylic acid in its ionized form in alkaline urine)

- IV sodium bicarbonate is recommended (doesn’t cross BBB)

- 1 to 2 mEq/kg of NaHCO3 followed by infusion of 3 ampules of
sodium bicarb in 1 L of D5 at 1.5 - 2x maintenance fluid range
- Urine pH should be maintained at 7.5 to 8.0
- Increasing pH from 5 to 8 increases renal salicylate clearance from
1.3 mL/min to 100 mL/min
- Hypokalemia is a common issue
 Management
Glucose Supplementation -
- CSF glucose < serum glucose
- Liberal dextrose administration
is recommended for any patient
with AMS and salicylate toxicity
Hemodialysis (HD) recs:
- Salicylate concentration >100
mg/dL (or > 90 w/ impaired renal
function)
- AMS
- New hypoxemia requiring O2
- systemic pH < 7.2
- Stop HD when:
- clinical improvement
- salicylate concentration < 19
mg/dL