Nonsteroidal Anti-inflammatory Drugs


The nonsteroidal anti-inflammatory drugs (NSAIDs) discussed in this chapter fall under two classes, namely, inhibitors of prostaglandin (PG) synthesis and miscellaneous (locally applied) anti-inflammatory drugs. The PG inhibitors induce anti-inflammation and analgesia without affecting consciousness, while locally applied drugs exert their effects directly on the local lesions. The PG inhibitors have been used extensively to alleviate mild to moderate pain, and is also effective in treating cephalgia, myalgia, arthralgia, and other pain from the integument; although they do not relieve visceral (except flunixin), or sharp and intense pain.

A. Mechanisms of action of NSAIDs. Most of the NSAIDs act by inhibiting PG biosynthesis and in some instances leukotrienes. Hence, an understanding of PG biosynthesis and its physiological functions is essential to better comprehend the mechanism of drug action of the various NSAIDs listed below:
1. Prostaglandins, leukotrienes, and their synthesis (see Figure 3-3)
a. Prostaglandins are produced by a wide array of tissues including lungs, GI tract, kidney, and liver. They are metabolized primarily at the site of action hence resulting in decreased circulating levels of PGs.

b. Prostaglandins, prostacyclins, and thromboxanes collectively known as prostanoids are synthesized from the same precursor, arachidonic acid (AA).

c. AA is an important component of cell membrane and is released by the action of phospholipase A2 and other acyl hydrolases, which are subject to regulation by hormones and other stimuli. Subsequently, AA undergoes cyclization and oxygenation to prostanoids via the cyclooxygenase (COX) pathway; and to leukotrienes via the lipooxygenase (LOX) pathway.

d. Majority of the NSAIDs that are currently used elicit their potent anti-inflammatory, antipyretic, and analgesic effects through differential inhibition of COX-1 and COX-2 (see below) and to a lesser extent LOX.

2. Cyclooxygenase (COX) pathway. Prostanoids are synthesized primarily via the COX pathway; there are two COX isoforms, COX-1 and COX-2. In addition, the recently identified acetaminophen-inhibitable COX-3 isoform is found to be expressed in the canine brain. COX-3 participates in the pyresis processes.
a. COX-1 is constitutively expressed in several tissues and is termed “house keeping enzyme” because of its essential role in the maintenance of several homeostatic process including gastric mucosal cytoprotection, renal function, vascular homeostasis, platelet aggregation.

b. COX-2 is an inducible form because it is expressed at the site of injury, inflammation and in certain pathological states such as osteoarthritis. Interestingly, recent reports indicate that it may also be constitutively expressed in a tissue-specific manner including, bone, kidney, and brain and may promote delayed wound healing.

c. Both isoforms share 60% structural homology; yet they are distinct in several aspects. For example, COX-2 has a flexible and slightly wider active site in comparison to COX-1. This has led to the burgeoning interest in developing COX-2 selective inhibitors, but with COX-1 sparing action. Although, adopting such a strategy has raised great concerns regarding their adverse effects on the heart and kidneys in recent years.

3. Lipoxygenase (LOX) pathway. AA is converted by 5-LOX to 5-hydroperoxyeicosatetraenoic acid, which is eventually converted to leukotriene B4 (LTB4). LTB4 plays a central role in inflammation, increased microvascular permeability, and chemotactic properties involving neutrophil–endothelial adhesion, and neutrophil aggregation and degranulation.


All NSAIDs have proven efficacy in reducing pain and inflammation in animals. It is particularly useful in treating clinical conditions including osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout, and dental pain. Although NSAIDs provides effective short-term pain relief, chronic use of nonselective or traditional NSAIDs may increase the risk of GI complications.

A. Pharmacological consideration
1. All of them exert analgesic, anti-inflammatory and antipyretic actions by inhibiting PG synthesis via blocking COX. Some NSAIDs also inhibit LTB4 synthesis by blocking LOX.

2. Analgesic effects of NSAIDs are related to blockade of PGE2-mediated enhancement of pain sensitization produced by proinflammatory mediators such as bradykinin and substance P at the nerve endings in the CNS and at the sites of inflammation.

3. One should exercise caution when increasing the dose of an NSAID to induce analgesia in case of intense pain because of the emergence of their toxic effects at these levels.

4. Unlike, narcotic analgesics, NSAIDs do not produce tolerance or physical dependence with regards to analgesia.

5. The antipyretic effects or temperature-lowering action works only in the presence of a fever, because they impair the ability of pyrogens to raise the temperature set point of the thermoregulatory centers in the anterior hypothalamus, thereby promoting heat loss by sending signals through the descending system to cause cutaneous vasodilatation, sweating, and panting. The temperature-lowering action of NSAIDs do not influence normal body temperature.

6. The anti-inflammatory effect of NSAIDs is due to inhibition of PGE2 synthesis, stabilization of lysosomal membranes, inhibition of the complement system, phagocytosis, leukocyte accumulation, and synthesis of mucopolysaccharide and histamine, antagonism of bradykinin’s action, induction of oxygen radical scavenger action and uncoupling of oxidative phosphorylation to deprive inflammatory tissues of energy.

7. The COX-1 inhibitors decrease blood clotting by inhibiting platelet aggregation (they inhibit synthesis of thromboxane A2(TXA2), which are proaggregatory). Since platelets cannot synthesize new COX, the inhibition is irreversible in these cells. This could result in prolonged bleeding time.

8. The COX-2 inhibitors at the recommended dosages exhibit minimal GI damaging effects, since COX-1 mediates the maintenance of GI mucosa.

B. Pharmacokinetics consideration
1. As weak acids, NSAIDs usually are readily absorbed following oral administration.

2. Injectable solutions tend to be alkaline and can cause pain and necrosis in cases of extravasation.

3. Circulating NSAIDs are bound vividly by albumin, which decreases volume of distribution. Unbound drugs can reach target tissues for actions and metabolism. Displacement from albumin due to competition by other drugs for the albumin binding sites or hypoalbuminemia can lead to higher plasma levels of unbound drugs, which can predispose the patient to drug-induced adverse effects.

4. Drug elimination rates of NSAIDs are variable, depending on drugs and species. Most NSAIDs are eliminated primarily via hepatic phases I and II metabolisms. Conjugate metabolites are then excreted in the urine/feces. However, a small amount may be excreted in their unchanged form in the urine/feces as well.

5. The use of NSAIDs in cats is a great challenge to clinicians, since there are no FDA-approved drugs available for use in this species, except the injectable meloxicam. In addition, very little pharmacokinetics information is available for cats. Since cats have inefficient cytochrome P450 and glucuronidation conjugation system; the extrapolation of NSAIDs dosages from other species needs to be carefully validated.

6. Young and old patients may require smaller doses of NSAIDs due to weak liver and kidney status, which may result in lower elimination rates.

C. Adverse effects
1. All NSAIDs can cause adverse effects particularly at large doses and when used for longer periods. The ones that are used most commonly in human medicine can cause poisoning in animals, for example, aspirin, acetaminophen, ibuprofen, indomethacin, and naproxen. Cats and dogs are more vulnerable to adverse effects of NSAIDs than humans.

2. The following are the commonly seen adverse effects of NSAIDs in animals: vomiting, diarrhea, GI ulceration, hepatotoxicity, renal toxicity, CNS depression, and circulatory disturbances. The GI ulceration is the most common and serious adverse effect of NSAIDs. Underlying nephrotoxicity, hepatotoxicity, or impaired cardiac conditions may exaggerate the adverse effects associated with NSAIDs.

4. NSAID-induced renal toxicity reflects inhibition of vasodilatory PGs. The prostanoids PGE2 and PGI2 play a key role in the regulation of renal blood flow since their Gs-coupled receptors mediate vasodilatation. They promote natriuresis and diuresis in the kidney. These mechanisms are critical especially when the systemic levels of vasoconstrictors, renin, angiotensin, and norepinephrine are elevated under stress. NSAID-mediated inhibition of PGE2 and PGI2 biosynthesis may cause edema, hyperkalemia, and acute renal failure. Patients with compromised renal function could be seriously affected.

5. NSAID-induced hepatotoxicity. The mechanisms underlying the hepatotoxic effects of NSAIDs are presently unclear.

D. Drug interactions
1. Concurrent use of glucocorticoids and other NSAIDs should be avoided due to increased risk of GI adverse effects.

2. Concurrent use of high protein-binding drugs or drugs that share the same metabolic pathway including anticonvulsant drugs, behavior-modifying drugs, and warfarin requires careful monitoring.

3. Concurrent use of aminoglycosides warrants careful monitoring, due to increased risk of nephrotoxicity.

E. Guidelines for the safe use of NSAIDs
1. Individualized dosing based on the drug’s efficacy, age of the animal, and duration of action.

2. Screen patients for underlying renal and hepatic dysfunction by performing routine diagnostic procedures.

3. Monitor the hydration status of patients. Hypovolemic animals should not be placed on NSAIDs before improving the hydration status.

4. An adequate wash out period should be allowed prior to administering a new NSAID.

5. Administer the lowest possible effective dose for the shortest period to minimize risk of injury.

6. Concurrent use of glucocorticoids and NSAIDs should be avoided due to increased risk of GI complications.


A. Classification of NSAIDs
1. Nonselective COX inhibitors:
a. Enolic acids

Oxicams: Meloxicam
Pyrazolones: Phenylbutazone

b. Carboxylic acid

Nicotinic acid: Flunixin meglumine
Fenamates: Meclofenamic acid
Salicylates: Aspirin
Propionates: Ibuprofen, Naproxen, Ketoprofen, Carprofen
Acetic acid: Etodolac

2. COX-2 selective inhibitors:

Coxibs: Deracoxib, Firocoxib

3. Dual inhibitors: (COX/and 5-LOX):

Propanamide: Tepoxalin

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.

D. Acetaminophen. This drug is unsafe in small animals.

May 28, 2017 | Posted by in GENERAL | Comments Off on Nonsteroidal Anti-inflammatory Drugs
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