Nonsteroidal Anti-inflammatory Drugs

من طرف **حازم شاهين** السبت 05 ديسمبر 2009, 6:07 am

Nonsteroidal Anti-inflammatory Drugs: Overview

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T he importance of pain management and the use of NSAID in animals has recently increased significantly. NSAID have the potential to relieve pain and inflammation without the immunosuppressive and metabolic side effects associated with corticosteroids. However, all NSAID have the potential for other adverse effects that should be considered in the overall management of the inflammatory process.

Mode of Action:

Generally, the classification NSAID is applied to drugs that inhibit one or more steps in the metabolism of arachidonic acid (AA). Unlike corticosteroids, which inhibit numerous pathways, NSAID act primarily to reduce the biosynthesis of prostaglandins (PG) by inhibiting cyclooxygenase (COX). In general, NSAID do not inhibit lipoxygenase (and hence leukotriene) formation, or the formation of other inflammatory mediators, although tepoxalin, a recently introduced NSAID does inhibit lipoxygenase.

The discovery of the 2 isoforms of COX (COX-1 and COX-2) has advanced understanding of the mechanism of action and potential adverse effects of NSAID. COX-1, expressed in virtually all tissues of the body, catalyzes the formation of constitutive PG, which mediate a variety of normal physiologic effects including hemostasis, GI mucosal protection, and protection of the kidney from hypotensive insult. In contrast, COX-2 is activated in damaged and inflamed tissues and catalyzes the formation of inducible PG, including PGE₂, associated with intensifying the inflammatory response. COX-2 is also involved in thermoregulation and the pain response to injury. Therefore, COX-2 inhibition by NSAID is thought to be responsible for the antipyretic, analgesic, and anti-inflammatory actions of NSAID. However, concurrent inhibition of COX-1 may result in many of the unwanted effects of NSAID including gastric ulceration and renal toxicity. Because NSAID vary in their ability to inhibit each COX isoform, a drug that inhibits COX-2 at a lower concentration than that necessary to inhibit COX-1 might be considered safer. This concept has propelled the development of the so-called “COX-2 selective” NSAID. Although ratios of COX-1:COX-2 activity for various NSAID in humans and animals have been reported, caution is advised when interpreting such ratios, as they vary greatly depending on the selectivity assay used. The COX selectivity of NSAID also varies by species; COX selectivity ratios reported for humans do not apply to other animals.

In general, drugs with ratios suggesting preferential activity against COX-2 may have fewer adverse effects due to COX-1 inhibition. In dogs, favorable ratios have been reported for carprofen, meloxicam, deracoxib, and firocoxib, while unfavorable ratios have been reported for aspirin, phenylbutazone, and piroxicam. COX-1-sparing drugs are associated with less GI ulceration and less platelet inhibition; however, it may be overly simplistic to assume that complete COX-2 inhibition is without potential risk. Recent research has suggested that COX-2 can be induced constitutively in various organs including the brain, spinal cord, ovary, and kidney. In dogs, COX-2 mRNA is present in the loop of Henle and the maculae densa and may play an important role in the protective response to hypotension. However, a recent study failed to demostrate COX-2 expression in canine kidneys, raising questions regarding its role.COX-2 also appears to be important in the healing of GI ulcers in humans, and certain COX-2-specific inhibitors delay ulcer healing experimentally. Although COX-1 plays a primary role in regulating homeostasis, it may play a more significant role in inflammation than originally proposed.

NSAID also vary in their mechanism of COX inhibition. Aspirin irreversibly acetylates a serine residue of COX, resulting in a complete loss of COX activity. The duration of the effect depends on the turnover rate of COX; activity is lost for the life of the platelet (7-10 days) following aspirin administration. Unlike aspirin, most other NSAID are reversible competitive COX inhibitors; their duration of inhibition is primarily determined by the elimination pharmacokinetics of the drug.

Pharmacologic Effects:

All NSAID, except for acetaminophen, are antipyretic, analgesic, and anti-inflammatory. They are routinely used for the relief of pain and inflammation associated with osteoarthritis in dogs and horses and for colic, navicular disease, and laminitis in horses. The use of NSAID for the relief of perioperative pain in companion animals is increasing. In general, NSAID provide only symptomatic relief from pain and inflammation and do not significantly alter the course of pathologic damage. As analgesics, they are generally less potent than opioids and are therefore more effective against mild to moderate pain.

As antipyretics, NSAID reduce body temperature in febrile states. Although the beneficial effects of the febrile response usually outweigh the negative effects, NSAID inhibition of PGE₂ activity in the hypothalamus may provide symptomatic relief and improve appetite. In Europe, NSAID have been used in conjunction with antibiotics for treatment of acute respiratory diseases in cattle and may reduce morbidity through their antipyretic and anti-inflammatory effects.

The effects of some NSAID on chondrocyte metabolism have been investigated. Some, including aspirin, naproxen, and ibuprofen, are considered chondrotoxic because they inhibit the synthesis of cartilage proteoglycans. Others, including carprofen and meloxicam, may be considered chondroneutral, or depending on dose, actually stimulate the production of cartilage matrix. The potential beneficial or deleterious effects of NSAID on chondrocyte metabolism remain to be clarified.

A therapeutic area in which NSAID use may become important is in the treatment and prevention of cancer. Epidemiologic studies in humans show that aspirin use is associated with a significant reduction in the incidence of colon cancer. Newer evidence suggests that the therapeutic effect of NSAID on colon cancer is mediated by inhibition of COX-2, which may be up-regulated in many premalignant and malignant neoplasms. In veterinary medicine, piroxicam has been shown to reduce the size of tumors such as transitional cell carcinoma in dogs. Specific COX-2 inhibitors may prove useful as a primary or adjunctive therapy in the management of cancer.

Administration and Pharmacokinetics:

Most NSAID are weak organic acids that are well absorbed following PO administration. However, food can impair the oral absorption of some NSAID (eg, phenylbutazone, meclofenamate, flunixin meglumine) in horses and ruminants. Several NSAID are available as parenteral formulations for IV, IM, or SC administration. Some parenteral formulations are highly alkaline and may cause tissue necrosis if injected perivascularly. Once absorbed, most NSAID are extensively (up to 99%) bound to plasma proteins, with only a small proportion of unbound drug available to be active in the tissues. NSAID administration to animals with low serum albumin can result in higher than anticipated available drug levels and associated toxic effects. NSAID may also compete for binding sites with other highly protein-bound compounds.

Most NSAID are biotransformed in the liver to inactive metabolites that are excreted by the kidney via glomerular filtration and tubular secretion. Biotransformation and elimination half-lives vary significantly by species (and in some cases by breed), so it is not possible to safely extrapolate dosages from one species or animal to another. Some NSAID, including naproxen, etodolac, and meclofenamic acid, undergo extensive enterohepatic recirculation in some species, resulting in prolonged elimination half-lives.

Side Effects:

All NSAID have the potential to induce adverse reactions, some of which can be life threatening. Many reactions to NSAID are dose-related and are typically reversible with discontinuation of therapy and supportive care.

GI ulceration is the most common side effect. Loss of GI protective mechanisms results from inhibition of constitutive PG that regulate blood flow to the gastric mucosa and stimulate bicarbonate and mucus production. This disrupts the alkaline protective barrier of the gut, allowing diffusion of gastric acid back into the mucosa, injuring cells and blood vessels and causing gastritis and ulceration. As organic acids, NSAID, especially aspirin, may also cause direct chemical irritation of the GI mucosa. The enterohepatic recirculation of certain NSAID may result in high biliary concentrations that increase ulcerogenic potential in the gut. NSAID-induced GI bleeding may be occult, leading to iron-deficiency anemia, or more severe, resulting in vomiting, hematemesis, and hematochezia. Horses may develop oral, lingual, or gastric ulceration with accompanying signs of colic, weight loss, or loose manure. In addition, an idiosyncratic predisposition for ulceration of the right dorsal colon has been associated with NSAID therapy in horses.

GI blood loss may be further complicated by impaired platelet function. Platelet function is inhibited because NSAID prevent platelets from forming TXA₂, a potent aggregating agent. Because TXA₂ inhibition causes prolonged bleeding, evaluation of buccal mucosal bleeding time is advised in animals receiving NSAID for which surgery is anticipated. Blood dyscrasias after longterm NSAID therapy have been reported in cats, dogs, and horses. Acetaminophen administration in cats is associated with Heinz body anemia, methemoglobinemia, hepatic failure, and death. Bone marrow dyscrasias associated with phenylbutazone administration have also been reported.

Nephropathies associated with chronic NSAID use are common in humans. Animals with underlying renal compromise receiving NSAID could experience exacerbation or decompensation of their disease. It is important to maintain hydration and renal perfusion in animals receiving NSAID, especially those undergoing anesthesia or surgery.

Hepatopathies are relatively common in both humans and animals receiving NSAID. NSAID administration routinely induces mild hepatic changes characterized primarily by elevation in liver enzymes without clinical signs or hepatic dysfunction. Rare reports of idiosyncratic reactions resulting in hepatic dysfunction or failure have been reported in humans (acetaminophen and other), dogs (acetaminophen, carprofen, etodolac), and horses (phenylbutazone). Cytopathic (hepatocellular injury, necrosis), cholestatic, and mixed histopathologic patterns of injury have been documented. NSAID should be used with caution in animals with preexisting hepatic disease.

من طرف **حازم شاهين** السبت 05 ديسمبر 2009, 6:20 am

they are antipyretic analgesics

Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal Anti-inflammatory Drugs

رد: Nonsteroidal Anti-inflammatory Drugs