B. Aspirin (Acetylsalicylate). Aspirin is a prototypical NSAID that is effective and inexpensive.
1. Mechanism of action. Aspirin elicits its effects via acetylation and irreversible inhibition of COX; hence, resulting in decreased PG synthesis. Irreversible inhibition of platelet COX-1 by aspirin is responsible for the blockade of TXA2 production and its associated anticoagulant effects. In contrast, inhibition produced by other NSAIDs are reversible.
2. Therapeutic uses
a. In general, aspirin is useful as an analgesic and an NSAID in dogs and cats, particularly in the control of osteoarthritis. However, it is not effective in treating colic. As an analgesic, aspirin is given orally in cats at 10 mg/kg, every 48 hours, and the same dose is given every 12 hours in dogs.
b. It can be an adjunct therapy for septic and endotoxic shocks in animals having a heavy infection.
c. Sulfasalazine, an oral salicylate-sulfonamide, is used to treat chronic inflammatory conditions of bowel, for example, ulcerative colitis. After oral administration, the intestinal flora metabolize it into sulfapyridine and 5-aminosalicylic acid; the latter stays in bowel to exerts its anti-inflammatory effect and the former is absorbed from the intestine (see Chapter 11).
3. Pharmacokinetics
a. Aspirin is readily absorbed from both the stomach and upper intestine. Gastric acidity enhances absorption by favoring deionization, while high blood flow through the upper intestine compromises the higher ionization of aspirin due to higher pH.
b. Buffered aspirin. Since the acidity of regular aspirin can irritate stomach, particularly in dogs and cats, buffered aspirin is preferred for these two species. Although buffered aspirin is more ionized, and thus less rapidly absorbed from the GI tract, the total GI absorption of buffered aspirin is similar to that of regular aspirin.
c. A total of 70–90% of circulating aspirin is bound by albumin.
d. Aspirin is inactive, but is rapidly metabolized to salicylic acid to elicit its effects.
e. In animals, salicylate metabolism is primarily through glucuronidation; there is extensive species variation, plasma t½ is 25–45 hours in cats, ~8 hours in dogs, 5 hours in horses, and 1.5 hours in humans.
f. Cats have very limited glucuronidation (by glucuronide transferase), and thus are most sensitive to aspirin toxicity. After the exhaustion of glucuronidation, salicylate then form conjugates with glutathione.
4. Adverse effects
a. Aspirin-induced signs of GI upset including vomiting, anorexia, GI ulceration, diarrhea may be seen even at therapeutic doses.
b. Aspirin-induced paradoxical hyperpyrexia is due to an increase in O2 consumption, leading to increased metabolic rate and increased heat production due to uncoupling of oxidative phosphorylation.
c. In the early phase aspirin-induced acid–base disturbances may be manifested as respiratory alkalosis due to direct stimulation of the medullary receptor center, leading to hyperventilation. This may be followed by respiratory acidosis as a result of CNS depression during the late phase.
Metabolic acidosis may arise from:
(1) Salicylic acid induced release of H+,
(2) Uncoupling of oxidative phosphorylation, may lead to build up of pyruvate and lactate,
(3) An increase in fat metabolism, leading to ketoacidosis,
(4) A depression of renal function, resulting in the accumulation of sulfuric and phosphoric acid.
d. Dehydration due to vomiting, sweating, and hyperpyrexia, may be life threatening.
e. Pulmonary edema is seen in sheep.
f. In animals that are placed on chronic aspirin therapy, drug treatment must be discontinued 7 days before surgery to minimize the risk of bleeding during surgery.
g. Caution must be exercised when placing dogs with joint diseases on long-term therapy. In particular, aspirin can inhibit PG synthesis by canine chondrocytes that may result in the aggravation of joint disease.
h. Drug interactions of aspirin happen most often due to salicylate-mediated displacement of other drugs that compete for the same albumin-binding site, for example, warfarin (in this case the end effect is aggravated due to the additive anticoagulant effects of both drugs).
i. Treatment of aspirin toxicity
(1) Induce emesis in the case of acute toxicity.
(2) Increase removal of the drug, for example, gastric lavage followed by administration of activated charcoal, and peritoneal dialysis.
(3) Increase urinary excretion of aspirin by administering an alkalinizing agent (e.g., NaHCO3), which may serve to correct the underlying metabolic acidosis.
(4) Initiate IV fluid therapy to address dehydration and metabolic acidosis that accompany drug overdose.
C. Meclofenamic acid
1. Mechanism of action. It is a derivative of anthranilic acid, which, in turn, is a salicylic acid analog. The human product is for extra-label use, since the veterinary product has become obsolete. Nonselective inhibition of both COX-1 and COX-2 is the primary mechanism of action. Additional effects may include prostaglandin receptor blockade.
2. Therapeutic uses. It is for oral use in the dog and horse. It is used in treatment of osteoarthritis in the horse as well as soft tissue inflammation, (e.g., laminitis) that affects the locomotor system. To a lesser extent, it is also used in dogs to improve mobility in hip dysplasia. It is effective in the control of anaphylaxis attributed to kinins, PGs, and leukotrienes in particular. For long-term use of the drug, the lowest effective dosage that maintains a satisfactory anti-inflammatory effect should be the objective. The onset of action is slow, taking from 36 to 96 hours to develop.
3. Pharmacokinetics. After oral dosing, plasma level peaks within 1–4 hours. The elimination t½ in horses is 1–8 hours. It can be detected in urine 96 hours after the final dose. It is metabolized in the liver primarily by oxidation to an active hydroxymethyl metabolite that may be further oxidized to an inactive carboxyl metabolite. The information for dogs is not available.
4. Adverse effects. In dogs, chronic administration (>48 hours) has been shown to be associated with increased incidence of GI events, including hemorrhage and diarrhea. Overdose in horses may induce buccal erosions, anorexia, GI disturbances, lower packed cell volume of blood. Therapeutic dose may induce colic and diarrhea in horses heavily infested with GI parasites. Chronic use of the drug in dogs can induce vomiting, tarry stools, leukocytosis, low hemoglobin levels, and small intestinal erosions.
E. Phenylbutazone. The safety and efficacy profile in addition to its affordability makes it the most commonly used NSAID in the horse.
1. Mechanism of action. Phenylbutazone, which belongs to the enolate class shows COX-2 inhibitory effects and COX-1 sparing effect in both horses and dogs.
2. Therapeutic uses. It is approved by the FDA for oral and IV administration in the dog and horse. One should avoid perivascular injection due to the risk of phlebitis. It is used to treat various forms of lameness as well as osteoarthritis and other painful conditions of the limbs including soft tissue or nonarticular rheumatism. It reduces nonspecific inflammation in other conditions, for example, thrombophlebitis, pericarditis, and pleurisy. Its misuse by unscrupulous individuals to mask lameness in horses has created serious ethical concerns in the racing industry.
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