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Aspirin

The Elephant Formulary
© 2003-06 Susan K. Mikota DVM and Donald C. Plumb, Pharm.D.
Published by Elephant Care International -
www.elephantcare.org


Elephant specific information, if available, is in blue.

Chemistry - Aspirin, sometimes known as acetylsalicylic acid  or ASA , is the salicylate ester of acetic acid. The compound occurs as a white, crystalline powder or tabular or needle-like crystals. It is a weak acid with a pKa of 3.5. Aspirin is slightly soluble in water and is freely soluble in alcohol. Each gram of aspirin contains approximately 760 mg of salicylate.

 

Storage/Stability/Compatibility - Aspirin tablets should be stored in tight, moisture resistant containers. Do not use products past the expiration date or if a strong vinegar-like odor is noted emitting from the bottle.

 

Aspirin is stable in dry air, but readily hydrolyzes to acetate and salicylate when exposed to water or moist air. It will then exude a strong vinegar-like odor. The addition of heat will speed the rate of hydrolysis. In aqueous solutions, aspirin is most stable at pH’s of 2-3 and least stable at pH’s below 2 or greater than 8. Should an aqueous solution be desirable as a dosage form, the commercial product Alka-Seltzer®  will remain stable for 10 hours at room temperature in solu­tion.

 

Pharmacology - Aspirin inhibits cyclooxygenase (prostaglandin synthetase) thereby reducing the synthesis of prostaglandins and thromboxanes. These effects are thought to be how aspirin produces analgesia, antipyrexia, and reduces platelet aggregation and inflammation. Most cells can synthesize new cyclooxygenase, but platelets cannot. Therefore, aspirin causes an irreversible effect on platelet aggregation. Aspirin has been shown to decrease the clinical symptoms of experimentally induced anaphylaxis in calves and ponies.

 

 

Pharmacokinetics - Aspirin is rapidly absorbed from the stomach and proximal small intestine in monogastric animals. The rate of absorption is dependent upon factors as stomach content, gastric emptying times, tablet disintegration rates and gastric pH. Absorption is slow from the GI tract in cattle, but approximately 70% of an oral dose will be absorbed.

 

During absorption, aspirin is partially hydrolyzed to salicylic acid where it is distributed widely throughout the body. Highest levels may be found in the liver, heart, lungs, renal cortex, and plasma. The amount of plasma protein binding is variable, depending on species, serum salicylate and albumin concentrations. At lower salicylate concentrations, it is 90% protein bound, but only 70% protein bound at higher concentrations. Salicylate is excreted into milk, but levels ap­pear to be very low. Salicylate will cross the placenta, and fetal levels may actually exceed those found in the mother.

 

Salicylate is metabolized in the liver primarily by conjugation with glycine and glucuronic acid via glucuronyl transferase. Because cats are deficient in this enzymatic pathway, they have prolonged half-lives and are susceptible to accumulating the drug. Minor metabolites formed include gentisic acid and 2,3-dihydroxybenzoic acid, and 2,3,5-trihydroxybenzoic acid. Gentisic acid appears to be the only active metabolite, but because of its small concentrations, it appears to play an insignificant role therapeutically. The rate of metabolism is determined by both first order ki­netics and dose-dependent kinetics depending on which metabolic pathway is looked at. Generally, steady-state serum levels will increase to levels higher (proportionally) than expected with dosage increases. These effects have not been well studied in domestic animals, however.

 

Salicylate and its metabolites are rapidly excreted by the kidneys by both filtration and renal tubular secretion. Significant tubular reabsorption occurs which is highly pH dependent. Salicylate excretion can be significantly increased by raising urine pH to 5-8. Salicylate and metabolites may be removed using peritoneal dialysis or more rapidly using hemodialysis.

 

Uses/Indications - Aspirin is used in all species for its analgesic and antipyretic effects. It is the one nonsteroidal anti-inflammatory agent that is relatively safe to use in both dogs and cats. Besides its analgesic, anti-inflammatory and antipyretic effects, aspirin is used therapeutically for its effects on platelet aggregation in the treatment of DIC and pulmonary artery disease secondary to heartworm infestation in dogs. It is also used in cats with cardiomyopathy.

 

Contraindications/Precautions - Aspirin is contraindicated in patients demonstrating previous hypersensitivity reactions to it. It is also contraindicated in patients with bleeding ulcers. It is relatively contraindicated in patients with hemorrhagic disorders, asthma, or renal insufficiency.

 

Because aspirin is highly protein bound to plasma albumin, patients with hypoalbuminemia may require lower dosages to prevent symptoms of toxicity. Aspirin should be used cautiously, with enhanced monitoring, in patients with severe hepatic failure or diminished renal function. Because of its effects on platelets, aspirin therapy should be halted, if possible, one week prior to surgical procedures. Aspirin has been shown to delay parturition and therefore should be avoided during the last stages of pregnancy.

 

Aspirin must be used cautiously in cats because of their inability to rapidly metabolize and excrete salicylates. Symptoms of toxicity may occur if dosed recklessly or without stringent monitoring. Aspirin should be used cautiously in neonatal animals; adult doses may lead to toxicity.

 

Adverse Effects/Warnings - The most common adverse effect of aspirin at therapeutic doses is gastric or intestinal irritation with varying degrees of occult GI blood loss occurring. The resultant irritation may result in vomiting and/or anorexia. Severe blood loss may result in a secondary anemia or hypoproteinemia. In dogs, plain uncoated aspirin may be more irritating to the gastric mucosa than either buffered aspirin or enteric coated tablets. Hypersensitivity reactions have been reported in dogs, although they are thought to occur rarely.

 

Salicylates are possible teratogens and their use should be avoided during pregnancy, particularly during the later stages.

 

Overdosage - Symptoms of acute overdosage in dogs and cats include: depression, vomiting (may be blood tinged), anorexia, hyperthermia, and increased respiratory rate. Initially, a respiratory alkalosis occurs with a compensatory hyperventilation response. A profound metabolic aci­dosis follows. If treatment is not provided, muscular weakness, pulmonary and cerebral edema, hypernatremia, hypokalemia, ataxia and seizures, may all develop with eventual coma and death.

 

Treatment of acute overdosage initially consists of emptying the gut if ingestion has occurred within 12 hours, giving activated charcoal and an oral cathartic, placing an intravenous line, beginning fluids and drawing appropriate lab work (e.g., blood gases). Some clinicians suggest performing gastric lavage with a 3-5% solution of sodium bicarbonate to delay the absorption of aspirin. A reasonable choice for an intravenous solution to correct dehydration would be dextrose 5% in water. Acidosis treatment and forced alkaline diuresis with sodium bicarbonate should be performed for serious ingestions. Diuresis may be enhanced by the administration of mannitol (1-2 gm/kg/hr). Seizures may be controlled with IV diazepam. Treatment of hypoprothrombinemia may be attempted by using phytonadione (2.5 mg/kg divided q8-12h) and ascorbic acid (25 mg parenterally), but ascorbic acid may negate some of the urinary alkalinization effects of bicarbonate. Peritoneal dialysis or exchange transfusions may be attempted in very severe ingestions when heroic measures are desired.

 

Drug Interactions - Drugs that alkalinize the urine (e.g., acetazolamide, sodium bicarbonate) significantly increase the renal excretion of salicylates. Because carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide) may cause systemic acidosis and increase CNS levels of salicylates, toxicity may occur. Urinary acidifying drugs (methionine, ammonium chloride, ascorbic acid) will decrease the urinary excretion of salicylates. Furosemide may compete with the renal excretion of aspirin and delay its excretion. This may cause symptoms of toxicity in animals receiving high aspirin doses. Phenobarbital may increase the rate of metabolism of aspirin by inducing hepatic enzymes. Corticosteroids may increase the clearance of salicylates and decrease serum levels. Increased chances of developing GI ulceration exist if administering aspirin with corticos­teroids or phenylbutazone or other non-steroidal agents concurrently. Aspirin may increase the risks of bleeding associated with heparin or oral anticoagulant therapy. At usual doses, aspirin may antagonize the uricosuric effects of probenicid or sulfinpyrazone. Aspirin may inhibit the diuretic activity of spironolactone. Aspirin may displace highly protein bound drugs from plasma proteins thus increasing free drug levels and pharmacologic effect. The following drugs may be affected by this mechanism (clinical significance is unknown, but increased monitoring should be performed if adding as­pirin): methotrexate, valproic acid, phenytoin, oral anticoagulants, penicillins, and sulfon­amides. The antacids in buffered aspirin may chelate tetracycline products if given simultaneously, space doses apart by at least one hour. In dogs, aspirin has been demonstrated to increase the plasma levels of digoxin by decreasing the clearance of the drug. Some clinicians feel that aspirin should not be given concomitantly with aminoglycoside an­tibiotics because of an increased likelihood of nephrotoxicity developing. The actual clinical significance of this interaction is not entirely clear, and the risk versus benefits should be weighed when contemplating therapy.

 

Laboratory Test Interference - At high doses, aspirin may cause false-positive results for urinary glucose if using the cupric sulfate method (Clinitest® , Benedict’s solution) and false-negative results if using the glucose oxidase method (Clinistix® or Tes-Tape® ). Urinary ketones measured by the ferric chloride method (Gerhardt) may be affected if salicy­lates are in the urine (reddish-color produced). 5-HIAA determinations by the fluoremetric method may be interfered by salicylates in the urine. Falsely elevated VMA (vanillylmandelic acid) may be seen with most methods used if salicylates are in the urine. Falsely lowered VMA levels may be seen if using the Pisano method. Urinary excretion of xylose may be decreased if aspirin is given concurrently. Falsely elevated serum uric acid values may be measured if using colorimetric methods.

 

Doses -

Horses:

For analgesia:

a)   Mature Horses: two to four 240 grain boluses PO;

Foals: one to two 240 grain boluses, allow animals to drink water after administration. (Label directions - Vedco Brand)

b)   25 mg/kg PO q12h initially, then 10 mg/kg once daily (Jenkins 1987)

c)   15 - 100 mg/kg PO once daily (Robinson 1987)

 

Monitoring Parameters -

1)   Analgesic effect &/or antipyrexic effect

2)   Bleeding times if indicated

3)   PCV & stool guiaic tests if indicated

 

Client Information - Contact veterinarian if symptoms of GI bleeding or distress occur (black, tarry feces; anorexia or vomiting, etc).

 

Because aspirin is a very old drug, formal approvals from the FDA for its use in animals have not been required (so-called “grandfather” drug). There is no listed meat or milk withdrawal times listed for food-producing animals, but because there are salicylate-sensitive people, in the interest of public health this author suggests a minimum of 1 day withdrawal time for either milk or meat.

 

Dosage Forms/Preparations - Note: Many dosage forms and brand names are commercially available; the following is an abbreviated list of some products that have been used for veterinary indications:

 

Aspirin, Tablets, Children’s; 65 mg (1 grain) and 81 mg (1.25 grains) in bottles of 36, 100, & 1000 tabs (Note: some varieties are chewable; orange flavor)

 

Aspirin, Tablets; plain uncoated;325 mg (5 grain), or 500 mg (7.8 grain) in bottles of 12 - 1000 tablets

 

Aspirin, Tablets; buffered uncoated; 325 mg (5 grain), or 500 mg (7.8 grain) with aluminum &/or magnesium salts in bottles of 12 - 1000 tablets

 

Aspirin Tablets (veterinary) 60 grain (3.89 grams) in 100’s

 

Aspirin Boluses (veterinary) 240 grain (15.55 gram) in boxes/bottles of 50

 

Rectal suppositories, and enteric coated or sustained-release oral dosage forms are also available commercially for human use. A combination veterinary product, Cortaba®   (Upjohn), containing 300 mg of aspirin and 0.5 mg methylprednisolone per tablet is also available commercially.

 

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