Specific Nonsteroidal Anti-inflammatory Drugs

Specific Nonsteroidal Anti-inflammatory Drugs

[ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط]

[ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] [ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] [ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] [url=http://www.merckvetmanual.com/mvm/htm/bc/191606.htm#aMeclofenamic Acid:#aMeclofenamic Acid:]Meclofenamic Acid[/url] [url=http://www.merckvetmanual.com/mvm/htm/bc/191606.htm#aFlunixin Meglumine:#aFlunixin Meglumine:]Flunixin Meglumine[/url] [ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] [ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] [ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] [ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] [ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] [ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] [ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] [url=http://www.merckvetmanual.com/mvm/htm/bc/191606.htm#aOther NSAID:#aOther NSAID:]Other NSAID[/url]

Based on structure, most NSAID can be divided into 2 broad groups—carboxylic acid and enolic acid derivatives. The main subgroups of enolic acids are the pyrazolones (phenylbutazone, oxyphenbutazone, and ramifenazone) and the oxicams (meloxicam, piroxicam, and tenoxicam). Carboxylic acid subgroups include the salicylates (aspirin), proprionic acids (ibuprofen, naproxen, carprofen, ketoprofen, and vedaprofen), anthranilic acids (tolfenamic and meclofenamic acids), phenylacetic acids (acetaminophen), aminonicotinic acids (flunixin), and indolines (indomethacin). The newer coxib class of selective COX-2 inhibitors includes a diaryl-substituted furanone (rofecoxib), a diaryl-substituted pyrazole (celecoxib), and a diaryl-substituted isoxazole (valdecoxib), all available for human use. Two NSAID of the coxib class, deracoxib and firocoxib, have been introduced in veterinary medicine.

Aspirin:

By far the most widely used anti-inflammatory drug in humans, aspirin is frequently used in veterinary medicine. The salicylic ester of acetic acid, aspirin (acetylsalicylic acid) is available in several different pharmaceutical preparations including plain, buffered, and enteric-coated formulations as well as topical and rectal preparations. Following PO administration, aspirin is rapidly absorbed from the stomach and upper small intestine, reaching peak plasma concentrations in most species (except ruminants) within 1-2 hr. Most aspirin is absorbed directly, but is rapidly hydrolyzed to salicylic acid. After absorption, both aspirin and salicylic acid are widely distributed through most tissues and fluids and readily cross the placental barrier. About 80-90% of the absorbed salicylate is bound to plasma proteins. Metabolism and elimination is via hepatic conjugation with glucoronic acid, followed by renal excretion. Cats, which lack glucuronyl transferase, have difficulty metabolizing aspirin. The elimination half-life of aspirin in cats approaches 40 hr, compared with 7.5 hr in dogs. In veterinary medicine, aspirin is used primarily for the relief of mild to moderate pain associated with musculoskeletal inflammation or osteoarthritis. Because aspirin is not approved for veterinary use, definitive efficacy studies have not been performed to establish effective dosages. Recommended dosages in dogs are 10-40 mg/kg, PO, bid-tid. Aspirin has been used in the treatment of laminitis in horses at a dosage of 10 mg/kg, PO, sid. In cats, aspirin may be used for its anti-platelet effects in thromboembolic disease at a dosage of 10 mg/kg, PO, every 48 hr, to allow for prolonged metabolism. Adverse effects are common following aspirin administration and appear to be dosage dependent. Even at therapeutic dosages of 25 mg/kg, plain aspirin may induce mucosal erosion and ulceration in dogs. Vomiting and melena may be seen at higher doses. The PGE1 analog misoprostol may be effective in decreasing GI ulceration associated with aspirin and other NSAID. Aspirin overdose in any species can result in salicylate poisoning, characterized by severe acid-base abnormalities, hemorrhage, seizures, coma, and death.

Acetaminophen:

Acetaminophen is a para-aminophenol derivative with antipyretic and analgesic activity, but minimal anti-inflammatory effects. Acetaminophen does not inhibit neutrophil activation, has little ulcerogenic potential, and has no effect on platelets or bleeding time. The pharmacologic effect of acetaminophen may vary from that of other NSAID because acetaminophen is more effective in inhibiting COX in the brain rather than in the periphery. It has recently been suggested that acetaminophen may act by inhibiting COX-3, a splice variant of COX-1. The recommended dosage of acetominophen in dogs is 10-15 mg/kg, PO, tid. Dose-dependent adverse effects include depression, vomiting, and methemoglobinemia. Use in cats is contraindicated due to a lack of glucuronosyl transferase and the potential for hemolytic anemia and centrilobular hepatic necrosis.

Phenylbutazone:

One of the earliest NSAID approved for use in horses and dogs, phenylbutazone is a pyrazolone derivative available in tablet, paste, gel, and parenteral formulations. The plasma half-life of phenylbutazone is 5-6 hr in horses and dogs and >30 hr in cattle. When given PO, phenylbutazone absorbs to hay in the diet, which may reduce GI absorption and bioavailability. Once absorbed, binding to plasma proteins is high (99% in horses, 93% in cattle). Phenylbutazone is metabolized by the liver to several active and inactive metabolites, which are excreted in urine. One of the major therapeutic uses of the drug is the treatment of acute laminitis in horses. Laminitis is treated initially with injectable phenylbutazone at dosages up to 8.8 mg/kg, followed by therapy PO at 2.2-4.4 mg/kg, bid . Because the therapeutic index for phenylbutazone is relatively narrow, dosage should be adjusted to the minimum possible to maintain comfort and avoid toxicity. The ulcerogenic potential of phenylbutazone in horses is greater than that of flunixin meglumine and ketoprofen. Phenylbutazone dosages of 3-7 mg/kg, PO, tid, are recommended in dogs. In dogs, phenylbutazone has been associated with bleeding dyscrasias, hepatopathies, nephropathies, and rare cases of irreversible bone marrow suppression.

Meclofenamic Acid:

This anthranilic NSAID is available for horses as a granular preparation and for dogs as an oral tablet. The recommended dosage is 2.2 mg/kg, sid for 5-7 days in horses and 1.1 mg/kg, sid, for 5-7 days in dogs. In cattle, administration of meclofenamic acid results in a biphasic pattern of absorption, with an initial peak plasma concentration reached at ~30 min and a secondary peak 4 hr after dosing. The second peak is presumed to be due to enterohepatic recirculation. In horses, meclofenamic acid is rapidly absorbed; however, the onset of action is slow, requiring 2-4 days of dosing for clinical effect. While it is effective in the treatment of chronic laminitis, meclofenamic acid has a therapeutic index that may be lower than that of other NSAID, possibly due to enterohepatic recirculation.

Flunixin Meglumine:

In the USA, the nicotinic acid derivative flunixin meglumine is approved for use in horses as PO and parenteral formulations. The recommended dosage is 1.1 mg/kg, IV or PO, sid for 5 days. Flunixin meglumine is rapidly absorbed following PO or IM administration, and the elimination half-life is short (~2-3 hr). Elimination is primarily by renal excretion. Flunixin meglumine is highly effective for treatment of visceral pain associated with equine colic and may have anti-endotoxic effects. The dosage recommended in horses is 1.1 mg/kg, bid, or 0.25 mg/kg, tid . Toxicity in horses is relatively uncommon, but GI ulceration and erosion may develop. Flunixin has been used to treat mastitis and acute pulmonary emphysema in cattle although it is not approved for these indications. Chronic administration of flunixin meglumine to dogs results in severe GI ulceration and renal damage and use in this species is not recommended.

Carprofen:

This NSAID of the arylpropionic acid class is available in the USA in caplet and chewable tablet formulations. An injectable formulation is also available in the USA and Europe. Carprofen is approved by the FDA to manage pain and inflammation associated with osteoarthritis and acute pain associated with soft-tissue and orthopedic surgery in dogs. The recommended dosage is 4.4 mg/kg, PO, sid or divided bid. In Europe and other countries, carprofen is also registered for use in cattle and for short-term therapy in cats. In dogs, oral bioavailability is high (90%) and plasma concentrations peak ~2-3 hr after dosing. The elimination half-life is ~8 hr. As with other NSAID, carprofen is highly (99%) protein bound. Elimination is via hepatic biotransformation with excretion of the resulting metabolites in feces and urine. Some enterohepatic recycling occurs. The exact mechanism of action of carprofen is unclear. Although it has greater selectivity for COX-2 over COX-1, carprofen is considered a weak COX inhibitor. In vitro canine cell line assays indicate that it is 129-fold selective for COX-2, whereas in vitro canine whole blood assays indicate it is 7- to 17-fold selective for COX-2, equine whole blood assays indicate it is 1.6-fold selective for COX-2, and feline whole blood assays indicate it is 5.5-fold selective for COX-2. Other mechanisms of action, including inhibition of PA2 may be responsible for its anti-inflammatory effects. Carprofen has been used extensively in dogs since its introduction, and adverse events have been comparable to those of other NSAID (ie, ~2 events/1,000 dogs treated). Approximately one fourth of the adverse reactions reported were GI signs, including vomiting, diarrhea, and GI ulceration. Renal and hepatic side effects are rare, as with other NSAID. Potentially serious idiosyncratic hepatopathies, characterized by acute hepatic necrosis, have been reported in some dogs. Approximately one third of the dogs developing hepatopathies while receiving carprofen were Labrador Retrievers, although a true breed predisposition has not been established. As with any NSAID therapy, clinical laboratory monitoring for hepatic damage is advised, especially in geriatric animals that may be predisposed to more serious complications.

Ketoprofen:

Ketoprofen is another propionic acid derivative available in the USA and other countries as a 10% injectable solution for horses, and in Europe and Canada as tablets and a 1% injectable solution for dogs and cats. Ketoprofen is recommended for acute pain (up to 5 days) in both dogs and cats. In horses, it is used for pain and inflammation associated with osteoarthritis and for visceral pain associated with colic. The recommended dosage is 1 mg/kg, IV or PO, sid for up to 5 days in dogs and cats, 2.2 mg/kg, IV, sid for up to 5 days in horses, and 3 mg/kg, IV or IM, sid for 1-3 days in cattle. Ketoprofen is a potent inhibitor of COX and bradykinin and may also inhibit some lipoxygenases. Its efficacy is comparable to that of opioids in the management of pain following orthopedic and soft-tissue surgery in dogs. Following administration PO, ketoprofen is rapidly absorbed and has a terminal half-life in cats and dogs of 2-3 hr. As with other NSAID, ketoprofen is metabolized in the liver to inactive metabolites that are eliminated by renal excretion. Adverse effects, including GI upset, are similar to those of other NSAID. Other side effects, including hepatopathies and renal disease, have been reported in animals. Due to potential antiplatelet effects, care should be exercised when using ketoprofen perioperatively.

Etodolac:

The pyranocarboxylic acid etodolac is approved for use in dogs in the USA. The elimination half-life is ~8-12 hr, allowing dosing at 10-15 mg/kg, PO, sid. Extensive enterohepatic recirculation has been reported in dogs, followed by elimination of etodolac and its metabolites in the liver and feces. In in vitro studies, etodolac was more selective in inhibition of COX-2 than COX-1, although in vitro canine whole blood assays have also shown it to be nonselective. Etodolac has been shown to inhibit macrophage chemotaxis and has demonstrated efficacy for the treatment of lameness associated with hip dysplasia. Although the risk of GI ulceration is low at therapeutic doses, administration of 3 times the label dosage resulted in GI ulceration, vomiting, and weight loss in toxicity studies. GI, hepatic, and renal adverse reactions have been reported after administration of etodolac, similar to other NSAID.

Vedaprofen:

The arylpropionic acid derivative vedaprofen is available in Europe in a gel formulation for horses and dogs and in an injectable formulation for horses. The drug is indicated for the treatment of pain and inflammation associated with musculoskeletal disorders in dogs (0.5 mg/kg, sid) and horses (1 mg/kg, bid) and for the treatment of pain associated with colic in horses (2 mg/kg, IV, as a single injection). Following administration PO, vedaprofen is rapidly absorbed. Biovailability is generally high, but may be reduced if the drug is administered with food. The terminal half-life is 10-13 hr in dogs and 6-8 hr in horses. Vedaprofen undergoes extensive biotransformation to hydroxylated metabolites, which are excreted in urine and feces.

Meloxicam:

Approved for use in Canada and Europe in dogs, cats, and cattle, the oxicam NSAID meloxicam is available as an oral syrup and injectable solution. Meloxicam is also approved for human use in the USA and Canada and was recently approved for use in dogs in the USA. A potent inhibitor of prostaglandin synthesis, meloxicam is used for the treatment of acute and chronic inflammation associated with musculoskeletal disease, and for the management of postoperative pain. In dogs, a one-time loading dosage of 0.2 mg/kg, PO, is recommended, followed by 0.1 mg/kg, PO, sid. Once a therapeutic effect is seen, the dosage can be titrated to the lowest possible dose. COX-1:COX-2 ratios reported for meloxicam suggest the drug is COX-2 selective, with in vitro canine whole blood assays indicating it is 2.7- to 10-fold selective for COX-2. Once absorbed, meloxicam is highly protein bound (97%) and has a relatively long elimination half-life (12+ hr). GI safety appears to be greater for meloxicam than for nonspecific NSAID, and meloxicam has been shown to be chondroneutral in rodent studies.

Deracoxib:

Deracoxib, the first NSAID of the coxib class approved for use in dogs, is available in a beef-flavored chewable tablet formulation in the USA. Deracoxib has been shown to inhibit COX-2-mediated PGE2 production. COX-1:COX-2 ratios reported for deracoxib in in vitro cloned canine cell assays indicate it is 1,275-fold selective for COX-2, whereas in in vitro canine whole blood assays it is 12- to 37-fold selective for COX-2. The drug is indicated for the control of postoperative pain and inflammation associated with orthopedic surgery at a dosage of 3-4 mg/kg, PO, sid for up to 7 days and for the control of pain and inflammation associated with osteoarthritis at a dosage of 1-2 mg/kg, PO, sid. Once absorbed, protein binding is >90%, and the elimination half-life is 3 hr.

Firocoxib:

Firocoxib is a coxib-class NSAID that was recently approved in the USA and Europe for the control of pain and inflammation associated with osteoarthritis in dogs. It is available in a chewable tablet formulation. Following administration PO, firocoxib is rapidly absorbed and then eliminated by hepatic metabolism and fecal excretion. The elimination half-life is ~8 hr, allowing dosing at 5 mg/kg, PO, sid. COX-1:COX-2 ratios from in vitro canine whole blood assays indicate it is 384-fold selective for COX-2. Like other NSAID, protein binding is high, at ~96%. GI safety appears to be greater than that of nonspecific NSAID.

Other NSAID:

A large number of prescription and nonprescription NSAID are available for human use. However, due to species differences in metabolism, efficacy, and toxicity, many are not recommended for use in animals. For example, in dogs, indomethacin is highly toxic to the GI tract and may result in severe ulceration, hematemesis, and melena at therapeutic doses. Piroxicam undergoes extensive enterohepatic recycling in dogs, resulting in a prolonged plasma half-life. GI ulceration and bleeding and renal papillary necrosis have been observed in dogs receiving piroxicam dosages of 0.3-1 mg/kg, sid. Ibuprofen is an arylpropionic acid derivative that has been used in dogs as an anti-inflammatory agent. However, dogs are much more sensitive to the development of GI side effects from ibuprofen administration than are humans. At therapeutic doses, adverse effects observed in dogs include vomiting, diarrhea, GI bleeding, and renal infection. Ibuprofen is not recommended for use in dogs or cats. Naproxen has been used in horses at a dosage of 5-10 mg/kg, sid-bid. Bioavailability is lower (~50%) for naproxen than for other NSAID, and the elimination half-life is ~5 hr in horses. In dogs, the elimination half-life of naproxen is 35-74 hr, presumably due to extensive enterohepatic recirculation. The pharmacokinetics in dogs also appear to be breed dependent. Due to the prolonged half-life of naproxen, dogs are extremely sensitive to its toxic effects. Coxib class drugs, including rofecoxib, celecoxib, and valdecoxib, recently introduced in human medicine, are COX-2 selective. The drugs are widely prescribed in humans because they do not inhibit COX-1 at therapeutic dosages. In clinical studies, the incidence of GI ulceration in patients receiving valdecoxib or celecoxib was significantly less than that of those receiving naproxen. The use of these drugs in animals has yet to be fully investigated. One pharmacokinetic study with celecoxib in Beagles demonstrated variability in drug elimination between dogs. In that study, one subgroup of Beagles metabolized celecoxib much more rapidly than the other, with elimination half-lives of ~2 and 18 hr, respectively. Until further data are available regarding the pharmacokinetics and safety of these drugs in animals, their use in veterinary medicine is not recommended.

they are antipyretic analgesics

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