Non Steroidal Anti Inflammatory Drugs

University of duhok college of veterinary medicine Non-steroidal anti-inflammatory drugs

By Jivan Q Ahmad E-mail,[email protected]

Non-steroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, are drugs with analgesic, antipyretic and, in higher doses, with anti-inflammatory effects . The term "non-steroidal" is used to distinguish these drugs from steroids, which (among a broad range of other effects) have a similar eicosanoid-depressing, anti-inflammatory action. As analgesics, NSAIDs are .narcotic-unusual in that they are non

NSAIDs are among the oldest and most widely used drugs in human history. The ancient Greeks chewed the bark of willow trees to alleviate pain and fever, but it was not until the 1800s that the active ingredient in willow bark, salicin (which is metabolized to salicylate), was isolated. At the end of the nineteenth century, acetylsalicylic acid or aspirin was synthesized and marketed for its anti-pyretic, antiinflammatory and analgesic properties. Soon after, compounds with similar properties to aspirin were discovered and collectively named non-steroidal anti-inflammatory drugs (NSAIDs) to distinguish them from the anti-inflammatory activity of glucocorticoids. The connection between NSAIDs and the COX pathway was made in the early 1970s, when John Vane proposed that NSAIDs mediate their antiinflammatory effects by inhibiting the enzymatic activity of COX work for which he was subsequently awarded the Nobel .Prize for physiology or medicine

: Mode of Action Generally, the classification NSAID is applied to drugs that inhibit one or more steps in the metabolism of arachidonic acid (AA). 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.

Traditional NSAIDs can be grouped into three classes based on their inhibition of cox: 

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Class 1: simple, competitive reversible inhibitors that compete with arachidonic acid for binding to the cox active site.included in this class are ibuprofen, piroxican, sulindac sulfide, flufenamate, mefenamic acid and naproxen. Class 2: competitive, time dependent, reversible inhibitor that bind to the cox active site in a first phase to form reversible enzyme inhibitor complexthat if retained for sufficient time, cause non covalent conformational changes in protein. This class includes indumethacin, flubiprofen, meclofenamic acid and diclofenac. Class 3: competitive, time dependent, irreversible inhibitors that form an enzyme inhibitor complex after a covalent conformational change in the protein. Included in this class is aspirin

(Kinetics of NSAID (ADME Absorption: Since all NSAIDs are highly lipophilic substances,

Drug absorption after oral administration is generally rapid and complete. Distribution: The most significant aspect of NSAID distribution is plasma protein binding. Metabolism: Knowledge of the mechanism of action of NSAIDs, as competitive inhibitors for arachidonic acid binding to COX, provides a good tool to predict whether NSAID metabolites are active or not.

Metabolism and elimination is via hepatic conjugation with glucoronic acid. Excretion: small percentages of NSAIDs are excreted unchanged in urine. If the drug is excreted unchanged, its rate of excretion is expected to increase if the drug iscoadministered with agents that render the urine pH alkaline such as the antacids aluminum hydroxide and milk of magnesia.

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By mouth, they come in tablets, capsules or medicines. This is the most widely used form. Some NSAIDs are available as injections. This form is used for the pain after surgical operations and also is very effective for the treatment of pain produced by kidney stones (renal colic). Suppositories are available. These are often used for post operative pain and sometimes in chronic pain when the patient is unable to take medication by mouth. Creams, gels and foams to apply to the skin. These are not felt to be as effective, but some people do get considerable relief from their use.

Common types        

Aspirin carprofen Diclofenac Ketoprofen Naproxen Valdecoxib Indomethacin Ibuprofen

Aspirin Acetylsalicylic Acid, Aspirin is a non-selective, irreversible COX inhibitor.Aspirin was the first discovered member of the non-steroidal anti-inflammatory drugs (NSAIDs) Often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever , and as an anti-inflammatory medication.

Mechanism of action/Effect: The effectiveness of aspirin is largely due to its ability to inhibit prostaglandin synthesis. This is done by irreversibly blocking cyclooxygenase (prostaglandin synthase), which catalyzes the conversion of arachidonic acid to endoperoxide compounds; at appropriate doses, the drug decreases the formation of both the prostaglandins and thromboxane A2 but not the leukotrienes.

Indications There are three main indications:  Inflammation (treatment)1—Dogs and cats: Aspirin is used for the relief of inflammation associated with arthritis and joint problems.  Pain (treatment)—Cattle, dogs, pigs, and cats: Aspirin is used for relief from mild to moderate somatic pain, such as incisional pain following surgery, pain following dental procedures, and discomfort associated with cystitis.  Fever (treatment)—Cattle, dogs, pigs, and cats: Aspirin is used to reduce fever; however, the treatment of fever with antipyretic medications is controversial and specific therapy for the underlying disease should be sought.

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.

Side/Adverse Effects The most common side effect of aspirin at therapeutic doses is gastric or intestinal irritation with varying degrees of occult GI blood loss occurring. The resultant irritation may lead to vomiting and/or anorexia. Sever blood loss may result in secondary anemia or hypoprotienemia.In dogs , plain un coated aspirin may be more irritant to the gastric mucosa than either enteric coated tablets or buffered aspirin. hypersensitivity reaction have been reported in dogs, although they are thought to occur rarely. Salicylates are possible teratogenes and their use should be avoided during pregnancy, particularly during later stages. 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.

Dosage Recommended dosages  Dogs For analgesia: 10-25 mg/kg PO Q8-12h As anti-inflammatory/antirheumatic: 25 mg /kg PO q8h For antipyrexia: 10 mg/kg PO bid  Cats For analgesia and anti pyrexia: 10 mg/kg po q48h For treatment of arthritis/antirheumatic/anti-inflammatory: 10-20 mg/kg po q48h  Cattle For analgesia/antipyrexia: 50-100 mg/kg po q12h  horses For analgesia: 25 mg/kg po q12h initially then 10 mg/kg once daily For laminitis: 5-10 mg/kg, PO q24-48h

CARPROFEN. 2 This NSAID of the arylpropionic acid class ,Carprofen is approved to manage pain and inflammation associated with osteoarthritis and acute pain associated with soft-tissue and orthopedic surgery in dogs. 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,

mechanism of action 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.

Indications Carprofen has been used extensively in dogs since its introduction nflammation (treatment); or Pain (treatment)— Dogs: Carprofen caplets, chewable tablets, and ELCANinjectionEL are indicated in the control of inflammation and pain associated with osteoarthritis. Pain, postoperative (treatment)—Dogs:chewable tabletsEL, and injection are indicated in the control of postoperative pain associated with soft tissue or orthopedic surgery.Preoperative administration is recommended because it can be more effective than postoperative administration alone in the control of postoperative pain. Inflammation (treatment); or Pain (treatment)— Horses: Although the safety and efficacy have not been established, there is evidence to suggest that oral or parenteral carprofen can be effective in the treatment of pain and inflammation in horses.

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Side effects Gastrointestinal effects (vomiting, diarrhea, constipation, inappetence,

melena, hematemesis, gastrointestinal ulceration, gastrointestinal bleeding, pancreatitis);  hepatic effects(inappetence, vomiting, jaundice, acute hepatic toxicity,  hepaticenzyme elevation, abnormal liver function tests,hyperbilirubinemia, bilirubinuria, hypoalbuminemia);  neurologic effects(ataxia, paresis, paralysis, seizures, vestibular signs, disorientation);  urinary effects (hematuria, polyuria, polydipsia, urinary incontinence, urinary tract infection, azotemia, acute renal failure, tubular abnormalities, including acute tubular necrosis, renal tubular necrosis, glucosuria, glomerular disease, including glomerulonephritis);  behavioral effects(Sedation, lethargy, hyperactivity, restlessness, aggressiveness);  hematologic effects(immune-mediated hemolytic anemia, immunemediated Thrombocytopenia, blood loss anemia, epistaxis);  dermatologic effects(pruritis, increased shedding, alopecia, pyotraumatic moist dermatitis, necrotizing panniculitis/vasculitis, ventral ecchymosis);  immunologic effects or hypersensitivity (facial swelling, hives, erythema

Dosage Dogs:  As anti-inflammatory/analgesic: 2.2mg/kg po twice daily  For surgical pain: 4mg/kg iv once  Cats:  For surgical pain: 4mg/kg iv once  Horses:  As anti-inflammatory/analgesic: 0.7mg/kg iiv one time

Diclofenac. 3 Diclofenac(voltaren)(2[(2,6-diclorophenyl)amino]phenylacetate) is relatively non selective cox inhibitor. used to reduce inflammation and as an analgesic reducing pain in conditions such as arthritis or acute injury. It can also be used to reduce menstrual pain, dysmenorrhea. Mechanism of action The exact mechanism of action is not entirely known, but it is thought that the primary mechanism responsible for its anti-inflammatory / antipyretic / analgesic action is inhibition of prostaglandin synthesis by inhibition of cyclooxygenase (COX).

Indications

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musculoskeletal complaints, especially arthritis gout attacks pain management in case of kidney stones and gallstones. acute migraines menstrual pain post-operative or post-traumatic pain Dc liposomal cream is used safely and effectively for symptomatic treatment of joint-associated lameness in horses It's also found very effectively in the treatment of clinical cases of myositis and arthritis in cattle and buffaloes. Dc in rectal suppository form is a drug of choice for preemptive analgesia. Ophthalmic preparation of Dc is used for prevention of postoperative ophthalmic inflammation

Side effects 

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in human include gastrointestinal distress, occult gastrointestinal bleeding, and gastric ulceration. Dc at dosage of l50mg\day appears to impair renal blood flow and glomerular filtration rate. In veterinary practice, Dc is reported to produce gastric ulcer and mild nephropathy. Hypersensitivity to Dc was also reported in calves .

Dipyrone Dipyrone (metamizole). The mechanism of action of dipyrone is thought to be similar to that of other NSAIDs: inhibition of the production of prostaglandins. It is commonly used in the horse as an antipyretic, analgesic, and anti-inflammatory. Dipyrone is a very mild NSAID. Because of its very mild analgesic properties it is unlikely to mask abdominal pain due to a surgical problem. Traditionally, dipyrone has been thought to also have antispasmodic properties on the smooth muscle of the gastro-intestinal tract, which has been the basis for its common use in cases of mild colic. Although research evidence does not support any claim of antispasmodic activity, many clinicians consider it a very useful drug precisely for this reason. Flunixin meglumine is a NSAID with stronger analgesic properties that is also used to treat GI pain. Dipyrone may be used in foals and in adult horses to reduce fevers. It is not commonly used for the treatment of musculoskeletal pain. Dipyrone may be given IM, IV, or subcutaneously.

Side Effects • The most common side effect for dipyrone is injection site reactions. These reactions usually respond to hot compresses and NSAIDs. • Prolonged use of dipyrone may cause bone marrow suppression (leukopenia, agranulocytosis). Animals receiving prolonged courses of dipyrone should be followed with regular CBCs.

Ketoprofen Ketoprofen is propionic acid derivative available as a 10% injectable solution for horses, and as tablets and a 1% injectable solution for dogs and cats. 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. 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.

Adverse effects 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

References 

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Dr. Miriam I. Yasin , The effectiveness of antibiotic, nsaids and glycerol in reducing post operative complications of rumonatomy in sheep's, Susan E. Aielo, B.S.,E.l.S ,The Merck Veterinary Manual . Donald C. Plumb, Veterinary drug hand book, Forth edition, 2002 Charles E.OPhardt ,Virtual chembook, Elmhurst college,, c.2003 (Veterinary—Systemic), The United States Pharmacopeial Convention Wedge wood Pharmacy http://www.wedgewoodpharmacy.com/monographs/dipyrone.asp Wikipedia, the free encyclopedia. http://www.drugs.com/vet/dipyrone-50-can.html