Salicylate Toxicity Dr. Peters (video) Flashcards
What is the MOA of Aspirin?
inactivation of COX1 which is the precursor of prostaglandins
-no platelet activation/aggregation
-less pain, inflammation, fever
What Aspirin doses do we see in practice?
What are doses that are associated with toxicity?
-Baby Aspirin 81 mg (cardioprotective)
-High end: 7g/day divided for inflammatory conditions
-mild toxicity: ingestion of 150-200 mg/kg
-severe toxicity: ingestion of 300-500 mg/kg
-chronic toxicity: ~100 mg/kg/day
What serum concentration of aspirin is associated with toxicity?
> 30 mg/dl
15-30 mg/dl would be therapeutic
How fast does Absorption of Aspirin occur in the stomach?
fast due to it being a weak acid with a pKa of 3.5 -> unionized at low pH (better absorption)
How does Aspirin toxicity affect the absorption of Aspirin?
it is slowed due to the formation of a bezoar
-it can also cause pylorospasm (sphincter to the duodenum is not opening)
How does the time to reach peak concentration change in Aspirin toxicity?
delayed up to 24-36 hours after ingestion
-normally it takes 1 hour
How does the volume of distribution and protein binding of Aspriin change with toxicity?
Vd increases and protein binding decreases
-> larger amounts of free drug in tissues
How does the half-life of Aspirin change with toxicity?
it increases to 12 hours
normal half-life is 2-3 hours
How does metabolism and renal elimination of Aspirin change with toxicity?
Metabolism in the liver becomes saturated
Renal elimination stays constant
What is the primary mechanism of toxicity of Aspirin in cells?
inhibition of cellular respiration by inhibiting the Krebs cycle and uncoupling of oxidative phosphorylation
Clinical effects:
-Acidosis: it increases ventilation (tachypnea) + resp alkalosis bc they try to breathe out the acid (aspirin)
-GI
-Pulmonary
-Neurologic
-Metabolic
-Uncoupling
How does Aspirin affect cell respiration?
disrupts the H+ gradient, which reduces ATP production in the cell
-the energy that is supposed to make ATP leaves in the form of heat -> fever, muscle rigidity
no ATP synthesis -> more pyruvate production (compensation):
-higher levels of Pyruvate are increasingly converted into lactate -> causing lactic acidosis
What are the clinical signs or symptoms of Aspirin toxicity (Uncoupling of oxidative phosphorylation)?
-limited ATP production
-leads to cellular breakdown
-Hyperkalemia (cell breakdown releases cell content) and cardiac arrest
-fever (due to heat produced by the cell)
-no ATP -> muscle rigidity -> rhabdomyolysis
What type of metabolic disorder do we see with aspirin toxicities?
Metabolic acidosis
-Salicylate is an acid
-loss of bicarbonate (N/V)
-Interference with the Krebs-Cycle -> lactate production
-Uncoupling
What are the GI effects of Aspirin toxicity?
-N/V (most common)
-Hemoorhagic gastritis
-Pylorospasm (sphincter to the duodenum closes)
-decreased gastric motility
What are the pulmonary effects of Aspirin toxicity?
-non-cardiac pulmonary edema (due to increased capillary permeability)
-> can cause hypoxia
In which patients do we commonly see pulmonary effects of Aspirin toxicity?
-elderly
-chronic ingestion
-patients who have progressed with neurologic symptoms
What are the neurologic effects of Aspirin toxicity?
-AMS: confusion, agitation, slurred speech
-lethargy, coma
-seizures
-Cerebral edema (unionized salicylate crosses the BBB)
-can cause hypoglycemia in the brain -> neurologic effects
What is the primary treatment strategy for managing serum pH in salicylate toxicity?
Alkalization Therapy
-goal serum pH: 7.45 - 7.55 and urine pH 7.5 - 8
What is the purpose of alkalinizing the serum pH?
pull the drug away from the tissues, and push it towards elimination
When should alkalization therapy be initiated in suspected salicylate toxicity?
-elevated salicylate serum concentration <35 mg/dl
-the patient is symptomatic
-metabolic acidosis present
What treatment is given for salicylate toxicity?
150 meq sodium bicarbonate to 1L D5W
-continuous infusion at 150-200 ml/hr (this is higher than the maintenance infusion rate -> to alkaline serum quickly and increase urine output)
How do potassium levels affect alkalization of the serum?
it prevents alkalization
-so replete K+ if needed
When is hemodialysis recommended for salicylate toxicity treatment?
-acute ingestion with serum concentration > 100 mg/dl
-serum concentration > 90 mg/dl with impaired renal function OR supportive therapy fails
-serum concentration > 80 mg/dl with impaired renal function ANDsupportive therapy fails
-altered mental status secondary to hypoxemia requiring O2
-may be helpful in chronic ingestion and serum concentration of < 60 mg/dl with evidence of severe toxicity
Which laboratory tests should be monitored for salicylate toxicity?
-ICU care: frequent neurologic checks, vital checks
-check serum salicylate levels and BMP every 2h until salicylate peaks (may take 24-36h to peak)
-Blood glucose: hypoglycemia indicates CNS injury
-Hypokalemia (it can prevent alkalization)
-Urine output (oliguria, anuria) - to rule out AKI
-monitor urine pH (not routinely done anymore)
Why should intubation be avoided in patients with salicylate toxicity (often present with fast breathing)?
Because they breathe faster in order to maintain normal serum pH -> it is hard to match the minute ventilation with the ventilator
-when paralyzed, breathing slows down, causing CO₂ to build up in the body, which makes the blood more acidic and lowers pH
-if considering intubation, alkalize as much as possible beforehand with sodium bicarbonate (bolus/infusion)
