Aspirin (ASA, Saliciylates)
Acetylsalicylic Acid and Methyl Salicylate (Oil of Wintergreen) from willow bark. 1.4 g per cc in pure form, less in Bengay (also can be absorbed topically)
· Hyperventilation from direct effects on the respiratory center.
· Uncouples oxidative phosphorylation giving lactic acidosis and hyperthermia (the uncoupling, rather than blocking leads to heat production. Other agents that uncouple ox phos are dinitrophenol and pentrophenol. Used as an aborted experiment for heat production, in cold soldiers in Russia, as well as fat burning tool.)
· Burns off all glucose, so gluconeogenesis with ketonemia. Hyperglycemia becomes hypoglycemia when can not keep up with demand.
· Also blocks Kreb’s Cycle.
· Vomiting (central and peripheral causes) and Gastritis
· Pulmonary and Cerebral Edema. The NCPE of this toxin can be confused with pneumonia.
· Renal Failure,
· Initially respiratory alkalosis from direct effects on respiratory center, then metabolic acidosis from ketones, salicylate, and lactate.
· Pts stay alkalemic until end, acidemia is indicative of high morbidity.
· Seizures are preterminal event
· Tinnitus or hearing loss may be only initial symptom.
very large doses (
≥500 mg/kg) required for fatal ingestions, but
aspirin inexpensive and available in large quantities;
oil of wintergreen7000 mg salicylate per teaspoon (ie, potentially
fatal dose may occur with relatively small quantity)
increases spread to other organs); therapeutic doses metabolized into nontoxic metabolites in liver;
above therapeutic doses, hepatic enzymes become saturated, and importance of kidneys increases;
uncoupling; dehydration; buildup of acidic metabolites; aspirin prevents oxidative phosphorylation of adenosine
diphosphate (ADP) to adenosine triphosphate (ATP) on membrane of mitochondria; respiration increases but no ATP
ie, respiration uncoupled from production of ATP); patients feel warm
acute toxicityeffects include electrolyte imbalance and effects on CNS, heart, and GI system; longterm
subtle presentation; patients often do not provide history of taking aspirin; salicylate levels may not indicate
overdose, but patient may have large stores of salicylates in body;
presentationmay include pulmonary edema and
altered mental status; sometimes called pseudosepsis syndrome (fever, tachycardia, elevated white blood cell [WBC]
count, and altered mental status); may progress to renal problems, fluid retention, and pulmonary edema
rehydrate patient; check acid-base status; replace potassium; alkalinize serum (to prevent dissociation from
binding sites and minimize spread to tissues) by adding bicarbonate to IV fluids to get pH up to 7.4;
note pH of urine
may remain low because of hydrogen-potassium exchange in distal tubules; body retains potassium and automatically
dumps hydrogen ions into urine;
dialysisrefer patients with altered mental status to nephrologist for assessment; delayed
dialysis may result in refractory acute respiratory distress syndrome (ARDS), hypoxia, cerebral edema, herniation, and
Salicylates act directly on the respiratory center, causing hyperpnea and tachypnea, which leads to a respiratory alkalosis. Metabolic acidosis results from several mechanisms, including the ability of salicylate to block alpha ketoglutaric dehydrogenase and succinic acid dehydrogenase. This blockage interrupts the tricarboxylic acid (Krebs) cycle and mitochondrial oxidation. In addition, there are two other mechanisms that contribute to the acidosis: 1) increased lipid metabolism producing ketone bodies, and 2) inhibition of the aminotransferases resulting in increased levels of circulating amino acids. The uncoupling of oxidative phosphorylation results in an increase in pyruvic and lactic acid. Lastly, as a result of the respiratory alkalosis, bicarbonate is lost in the urine, so the body has a diminished ability to compensate for the acidosis (4, 5 and 6). The common result is a mixed metabolic acidosis and respiratory alkalosis. When you find this mixture, think of salicylate intoxication. Not every patient will have the useful clue of tinnitus, or be able to recount their medications.
Ingestion of more than 150 mg/kg necessitates treatment
>30 will show signs
>100 critical level, will require dialysis
Ferric Chloride turns purple in presence of ASA in the urine, use 2 drops of 10%
ketones in urine
Charcoal 50-100 g then 20-60 Q2 x 5 total doses (Only 1st c sorbitol), change to aqueous when charcoal stools
Hydrate-enough to generate 3cc/kg/hr urine
Correct K (must be normal in order to allow alkalinization of urine) and Ca
Alkalinize Urine >7.5, 50 cc NaHCO3 increases serum pH ~ 0.1
Bolus 1-2 meq/kg then In 1 liter D5W, add 3 amps Bicarb and 40 meq KCl and run at 2x maintenance. Urine pH of 7.5-8 and serum 7.45-7.55
If these folks get acidemic, Renal ASA is resorbed and more ASA crosses the blood brain barrier. ASA is a weak Acid with a pKA of 3.5
If you tube these folks, they will get acidotic. Hyperventilate like mad before and after tube.
Dialysis if coma, renal/hepatic/pulmonary failure, severe acid/base
HD/HP do dialysis first. Acute>100 or chronic >60.
Dont intubate, it lowers pH allowing ASA to rush to the brain. Need 20 L per minute volume.
EARLY RENAL CONSULT
ASA Levels Q2 HR
can cause falsely elevated chloride levels (Ann Emerg Med 2011;58(3):280)
From Twin Cities Tox Blog:
Aspirin still kills…
There’s nothing like starting your day off with a
little uncoupling of your oxidative phosphorylation, right? Too many
people feel this way. Looking at national poison center data, aspirin
continues to be one of our more common overdoses, and it continues to be one of the overdoses responsible for the most deaths as well.
Please don’t underestimate aspirin overdoses, and remember the following tidbits in your management of these patients:
1) ASA screening – A salicylate level should not be obtained as a part of “overdose labs” in general.
It is a waste of money because aspirin will let you know it’s present
(nausea and vomiting early, tachypnea, acid/base imbalance, altered
mental status from cerebral edema, pulmonary edema, etc). If these signs are present, then it makes sense to get a level, otherwise don’t do it.
2) Interpreting salicylate levels – At therapeutic
doses asa is absorbed quickly, partly in the stomach and partly in the
duodenum. In overdose this is not necessarily the case. Because of
general delayed absorption and also bezoar formation, levels may not
peak until very late. Dulaney and Kerns described a case in which the peak level wasn’t reached until 98hrs post-ingestion (Dulaney A, Kerns W. Delayed peak salicylate level following intentional overdose. Clin Toxicol 2010;48:610). Expect to start seeing symptoms once levels are greater than 50 mg/dL in acute ingestions, but remember that the Done nomogram is basically worthless
and the specific level means much less than in acetaminophen, for
example (the only sign/symptom that follows the level fairly well is
tinnitus). In chronic overdoses, severe symptoms may be present at levels less than 40 mg/dL. Note units on the levels too, as different labs occasionally use different units.
3) GI decon – At least in vitro, aspirin binds very well to activated charcoal. Consider using it, even though I know you recognize that we’re recommending charcoal less and less these days.
4) Urinary alkalinization – In theory (I say in
theory because looking at the log math of pH, urinary alkalinization
shouldn’t make as much difference as it does, and there are dissenting
opinions about why alkalinizing works) by raising the urinary pH you can trap this weak acid in the urine, thus helping the body rid itself of the toxin. The higher the pH is away from the pKa of asa (roughly 3), the more charged form will be in the urine. You
can start by giving 50-100 mEq sodium bicarbonate initially followed by
a bicarb drip. For the drip I would use 1L D5W with 3 amps (150 mEq)
bicarb and 40 mEq potassium given at 1.5-2 times maintenance rate (for
5) Don’t forget the K – Again, in theory, if the potassium level in the serum is not in the low to mid 4s, the kidney will try to retain K and will dump protons into the urine in exchange for it, thus making urinary alkalinization virtually impossible.
6) Pour some sugar on me – I know, I know, that song is about cocaine, not actual sugar. With aspirin overdoses, often time patients will get a CNS relative hypoglycemia. The CNS glucose level can be significantly lower than the serum level measured in the bmp or finger stick. Maintain the serum glucose in the 150 range to be safe.
7) They can die a respiratory death – When the
patient comes in breathing at 30-40 times per minute and then poops out,
you intubate them, right? Then the vent gets set at 12 breaths per
minute with a tidal volume of 500 mL, and the patient dies an acidotic
death in 10 minutes. If they’re breathing that fast it’s for a
reason! Make sure you set the minute ventilation high and then check a
VBG to see where you’re at (the VBG vs ABG discussion is for another
8) Dialysis – Consider dialysis for end organ findings (cerebral edema, pulmonary edema, severe acidosis, etc) and for likely large ingestions with quickly escalating levels. Please don’t rule out dialysis just because the level hasn’t reached some arbitrary level you read in a textbook. That’s how patients die.
Literally, a couple of deaths in our poison center’s catch area last
year were likely related to the primary provider not starting the
recommended dialysis because the level “wasn’t high enough”.
9) Continued lab testing – Get a salicylate level,
bmp, and vbg every 2-6 hours during the early portion of management.
When the patient is doing well and you have 2 consecutive levels
declining, then you can stop getting this stuff and dispo the patient.
Again, don’t underestimate this just because you have seen it
before. You can prevent these patients from dying, but you need to know
the above in order to ensure it.
Happy New Year!
Most serious overdose. Only available for veterinary use. Seizures and multiorgan failure
Fenamates (Mefenamic Acid)
GI distress, muscle twitching, seizures
Acetic Acids (Toradol, Indocin)
GI distress, tinnitus, drowsiness
Propionic Acid (Nalfon, Ibuprofen, Naprosyn, Daypro)
GI distress, tinnitus, drowsiness and headache
>400 mg/kg of ibuprofen can give met. Acidosis, seizures, coma
daypro can test false positive for benzos
Cox-2 Inhibitors (Celebrex, Vioxx, Bextra)
Pyrazolones and Fenamates are most serious overdoses
Mostly benign, monitor renal function for at least 4 hours 1 dose AC
Ibuprofen overdose can cause aseptic meningitis. It is an idiosyncratic reaction, usually following first or early doses. (Ann Pharmocother 1997,31:1009)
acute toxicityingestions ≥250 mg/kg of ibuprofen and ≥200 mg/kg of naproxen; for smaller ingestions, no
treatment necessary unless patient symptomatic; no antidote for overdose (supportive treatment only); serum
concentrations not predictive of clinical effects; most common symptoms include nausea and vomiting; massive ingestion
may result in renal effects or self-limited convulsions (rare);
long-term toxicityalmost every organ system affected by
long-term use; renal failure may occur (especially in diabetics); neuropsychiatric problems include vertigo, altered mental
status (especially in elderly patients), drowsiness, aseptic meningitis, and seizures (especially with meclofenamate
[Meclomen]); some drugs pulled from market because of problems with idiopathic hepatitis;
charcoal acceptable (but not necessary) in cases of acute overdose; observation and supportive care generally sufficient;
patient often cleared in
≈6 hr; warningsrecent label mandated by Food and Drug Administration (FDA) advises patients
who drink >3 alcoholic beverages daily to check with physician before taking ibuprofen (Motrin)
Mexican Drug-“Neo-melubrina” (Metamizole) It is a potentially harmful home remedy often given for fever management. It is a pyrazolone nonsteroidal antiinflammatory agent associated with fatal agranulocytosis. Potential for both peripheral and bone marrow cell lysis. When used in pregnancy (pt was 33 weeks gestation) it has been associated with increased risk of Wilm’s tumor and infant leukemia.
RTA from Ibuprofen
Renal tubular acidosis is an underreported complication of ibuprofen misuse, and can result in life-threatening hypokalaemia. We describe four patients who presented with profound hypokalaemia and muscle weakness associated with excessive ibuprofen ingestion. Ibuprofen cessation and supportive management resulted in complete biochemical resolution within a few days. These cases remind practitioners about potential complications of unmonitored use of over-the-counter analgesics, including those with potential for misuse due to their codeine content. (MJA 2011; 194: 313-316)Back to top
ASA and NSAIDS in “Therapeutic” Doses (from Emedhome.com Article accessed 10/4/03)
~16000 deaths per year from NSAIDS prescribed for arthritis
cellular insult produces phospholipids which form arachadonic acid then with cox enzyme to prostacyclins and thromboxane
Cox 1: forms thromboxane in platelets and produces gastroprotective prostacyclins in the gastric mucosa
Cox 2: an inducible enzyme producing the inflammatory response
Cox 3: present in the brain and spinal cord regulating pain and fever; believed to be the site of action of APAP
Analgesic effect has a ceiling, large doses are needed only for the anti-inflammatory effect which should only be used to treat gout, RA, lupus, etc.
SSRIs in combination with NSAIDs may increase bleeding risk
Modified from: Rodriguez G et al, Risk of Hospitalization for Upper Gastrointestinal Tract Bleeding Associated With Ketorolac, Other Non-Steroidal Anti-inflammatory Drugs, Calcium Antagonists, and other Antihypertensive drugs. Arch Intern Med, 1998; 158: 33-39.
Probably no hepatotoxicity even in alcoholics and cirrhotics if taking less than 4 grams/day.
Unknown analgesic ceiling dose, very little anti-inflammatory effects. ? Cox 3 is active site.
Only one article addressing the analgesic ceiling, which sets it at 600 mg for ASA
At analgesic doses, its relative risk for GI side effects (bleeding) is about 8-11 but even at antiplatelet doses, the relative risk is still roughly doubled
The relative risk of taking ibuprofen over no NSAID is elevated at prescription doses, as noted earlier. Depending on the study, the RR is anywhere from 2-4 times the baseline risk of GI bleeding, at the 600-800mg doses
Analgesic Ceiling 200-400 mg; at these doses, probably as safe as tylenol
It is a crappy anti-inflammatory drug (Kantor TG, Ibuprofen. Ann Int Med, 1979; 91: 877-882)
Ketorolac is a very good analgesic. It is not considered an anti-inflammatory medication and recently its properties as an antipyretic have been evaluated. There are some studies indicating it is effective for treating fever Also, with a relative risk for GI bleed of 25 (see table above), it is the single most likely NSAID to cause GI bleeding. Analgesic ceiling is 10 mg, there is no anti-inflammatory dose.
The amount of pain relief and the time to onset is identical between 60 mg ketorolac IM and 800 mg ibuprofen PO, but the ketorolac is most likely to cause GI upset. (Neighbor ML et al, Intramuscular ketorolac vs. oral ibuprofen in Emergency Department patients with acute pain. Acad Emerg Med, 1998; 5(2) 118-122 / Turturra MA et al, Intramuscular ketorolac versus oral ibuprofen in acute musculoskeletal pain. Ann Emerg Med, 1995; 26(2) 117-120 / Wright JM et al, NSAID use and efficacy in the Emergency Department: Single doses of oral ibuprofen versus intramuscular ketorolac. Ann Pharm, 1994; 28: 309-312) Ketorolac IM has more GI side effects than ibuprofen PO
One study disproved the notion that a shot is needed for the placebo effect.
Has antipyretic properties when given IV (Journal of Emergency Medicine Volume 26, Issue 4 , May 2004, Pages 407-410)
Cox 2 Inhibitors
all studys compared anti-inflammatory doses of nsaids with standard doses of Cox 2s
may cause thrombosis by not blocking Cox 1 allowing thromboxane to be produced
If the patient is already on anti-platelet doses of ASA then Cox 1 is already blocked and there is no reason to use Cox 2 instead of ibuprofen; all Cox 2 studies excluded ASA use.
If people are old prescribe NSAIDS and PPIs (Laine L. The role of proton pump inhibitors in NSAID associated gastropathy and gastrointestinal symptoms. Gastroenterol Disord 2003;(suppl 4):5430-9.)
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