Chapter 147 – Aspirin and Non-steroidal Agents
Aspirin
Pharmacokinetics

Absorption: ASA is rapidly absorbed from the GI tract b/c ASA is in its unionized form in the acidic
stomach. Peak serum levels occur at 2 – 4 hrs. Levels may continue to rise for > 12 hrs in large
ingestions b/c ASA forms concretions which ↓ dissociation.

Distribution: In therapeutic doses, largely protein-bound (overwhelmed with acute OD and chronic
toxicity). Low Vd.

Metabolism/Elimination:
o Small amt is hepatically conjugated with glycine & glucoronic acid
o Most is eliminated unchanged in the urine
o At therapeutic levels, elimination follows 1st order kinetics, but in overdose elimination is zero
order b/c of enzyme saturation
Drug is metabolized at a constant rate,
regardless of concentration
Drug is metabolized at a fixed %
per unit time, thus quantity of drug
metabolized is concentration
dependant
Pathophysiology
Salicylic acid dissociates at normal pH to salicylic acid (salicylic acid ↔ H+ + salicylate)
Therefore ↓ pH → ↑ [salicylic acid]. In its non-ionized form, salicylic acid readily crosses the blood-brain
barrier. This means that acidosis promotes entry of salicylates into the CSF, and therefore as respiratory
acidosis develops, salicylate toxicity worsens, often with a paradoxical ↓ in serum levels.
Chronic Ingestion
This occurs more commonly older people due to a number of physiologic changes that promote decreased
clearance of ASA and higher levels of unbound ASA.

Decreased hepatic blood flow   hepatic conjugation

Decreased renal function   elimination

Chronic exposure to ASA leads to  albumin binding   levels of free (active) drug which cause
toxicity with relatively low serum levels.
Effects of ASA
Respiratory:

ASA acts on the central respiratory centres to ↑ the respiratory drive, producing a respiratory
alkalosis

Prolonged high serum concentrations of ASA eventually depress the respiratory centre, leading to
respiratory acidosis

Non-cardiogenic pulmonary edema can occur with ASA overdose. Risk factors are:
o In adults: age > 30 yrs, smoker, chronic toxicity, neurologic symptoms, ASA > 3 mmol/L
o In kids: high serum levels, low PCO2, ↓ serum K+
Metabolic:

Mobilization of glycogen stores → hyperglycemia initially. This followed by hypoglycaemia d/t
inhibition of gluconeogenesis

Uncoupling of oxidative phosphorylation → ↑ anaerobic metabolism with lactic acidosis and ↑
levels of Kreb’s cycle intermediates (pyruvate, ketoacids, organic acids). This process also → heat
production

Hypokalemia: Occurs through multiple mechanisms
o Intracellular shift d/t respiratory alkalosis
o Exchange of H+ with K+ in the kidneys as the kidneys excrete HCO3- as compensation for
the respiratory alkalosis
o Vomiting d/t stimulation of medullary chemoreceptor trigger zone → K+ losses
Neurologic:

Cerebral edema

Tinnitus
Diagnosis
Any pt with an acute ingestion > 150 mg/kg or symptoms of toxicity and a history of chronic use should be
assessed in the Ed.

Levels: Serum ASA levels should be obtained 6+ hrs after ingestion. A 2nd level should be obtained 2
hrs after the 1st to ensure that the serum level is not still climbing. Toxic levels:
o Acute toxicity: > 3 mmol/L
o Chronic toxicity: levels are difficult to interpret

Acid-base status

Electrolytes & renal function (especially potassium
Treatment

ABCs: Airway mgmt – avoid intubation if possible… may lead to worsening of metabolic acidosis. If
intubation necessary, give Na HCO3- boluses first and ventilator rate post-intubation matches preintubation rate ensure adequate CO2 clearance

Decontamination: MDAC is recommended d/t the formation of concretions

Supportive Care: Most pts are hypovolemic and almost all require K+ replacement

Elimination: Urine alkalization
o Increase urinary pH that ASA will be in its ionized form in the urine and thus will not be
reabsorbed
o Need to correct hypokalemia first or you will not be able to alkalize the urine d/t exchange of
H+ with K+ in the tubule
o Start with 1-2 mEq/kg IV then infusion at 2x’s maintenance
o Add 3 amps NaHCO3 + 40 mEq KCl to 1L D5W to create an isotonic solution
o Goals: urine pH 7.5 – 9 & serum pH 7.45 – 7.55
o Follow ASA levels q1-2 hr until consistent ↓ is seen
Indications for dialysis

Hemoperfusion + hemodialysis preferred for pts with significant toxicity for maximal clearance.
Hemoperfusion achieves more effective clearance, but hemodialysis permits modification of electrolytes.
In most centres, only hemodialysis is used.

Level > 3 mmol/L + end-organ symptoms:
o CNS toxicity
o Pulmonary edema
o Coagulopathy

Absolute levels:
o Acute toxicity: 7 mmol/L
o Chronic toxicity: 4 mmol/L

Clinical deterioration despite adequate supportive care

Unable to alkalinize urine b/c pt cannot tolerate fluid load (CHF, renal failure)

Renal failure

Dialysis duration: The necessary length of the run is not well defined. Recommendations are typically
3.5 – 4 hrs with blood pump speeds of 250 – 350 cc/hr. Repeat levels are required after dialysis to
ensure adequate clearance.
Non-Steroidal Agents
Pharmacokinetics

Absorption: Rapidly absorbed from the GI tract with peak levels < 2 hrs after ingestion, except
sustained release preparations. Weak acid, so unionized in stomach → passage into gastric
mucosal cells.

Distribution: Highly protein bound with low Vd

Metabolism/Elimination:
o Primarily hepatic metabolism
o < 10% excreted unchanged in urine
Classes

Salicylate

Pyrazolones – phenylbutazone

Anthranilic acids (fenamates) – mefanamic acid

Acetic Acids (end in ac) – diclofenac, ketorolac

Proprionic acids (end in profen) – ibuprofen, ketoprofen, naproxen

Oxicam – peroxicam

COX-2 Inhibitors (end in ib) – celecoxib, rofecoxib
Mechanism of Action
Inhibition of cyclooxygengase → ↓ prostaglandin production. COX-1 is responsible for the production of
physiologic prostaglandins (hemostasis, GI protection, renal function). COX-2 is an inducible enzyme with ↑
activity in the setting of inflammation.
Therapeutic Adverse Effects
GI
Nausea, vomiting, AP, gastritis, PUD, bleeding
Bleeding is d/t direct mucosal irritation + inhibition of cytoprotective prostaglandin production
GU
↓ prostaglandins → vasoconstriction with ↓ renal blood flow. This results in ↓ GFR and retention of
Na+, K+ and H2O
NSAIDs are also a major cause of AIN (immune-mediated)
Immun Anaphylactoid reaction (25% of pts with asthma + nasal polyps)
Heme ↓ plt aggregation
Neuro Confusion, delirium, HA
Tinnitus or hearing loss
Visual disturbances
Aseptic meningitis
MSK
Fasciulations
Metab Anion gap metabolic acidosis
CVS
Mild hypotension
Toxic Ingestions
In general, NSAIDs are safe, and cause minimal symptoms even with lg overdoses. The exceptions are:

Pyrazolones: Early GI symptoms followed by acid-base & electrolyte disturbances, pulmonary
edema, seizures and ↓ LOC, hypotension, cardiopulmonary arrest. MDAC and gastric lavage
recommended, as there is no specific antidote

Fenamates: Muscle twitching and seizures + GI symptoms
Renal failure occurs rarely with significant overdoses in the setting of hypotension.
Assessment

All pts who have ingested pyrazolones or fenamate should be assessed.

For other NSAIDs, doses < 100 mg/kg do not require medical assessment. Pts who have ingested
100 – 300 mg/kg and have symptoms or have ingested > 300 mg/kg (approximately 5x’s the daily
dose) should be assessed.
Management

Decontamination: gastric lavage and MDAC should be considered in pts with pyrazolone or
fenamate ingestion. Consider AC for pts with other NSAID ingestions.

Supportive Care: Treat hypotension aggressively to avoid renal impairment

Enhanced Elimination: No role for HD or HP.
Disposition

Discharge if asymptomatic x 4 hrs (8 hrs if pyazolone or fenamate)