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Kinetics of NSAIDs

NSAIDs

Published on: 4/6/2010
Author/s : Dr. Puneet Agrawal, Dr. Amitraj Gupta
Non-steroidal anti-inflammatory drugs (NSAIDs) are, as a group, the most frequently consumed drugs worldwide. NSAIDs are the drugs with analgesic, antipyretic and anti-inflammatory effects so they reduce pain, fever and inflammation. The term "non-steroidal" is used to distinguish these drugs from steroids, which have a similar eicosanoid-depressing, anti-inflammatory action. As analgesics, NSAIDs are unusual in that they are non-narcotic.
NSAIDs - Image 1
Mode of action:
NSAIDs derive much of their anti-inflammatory properties from their capacity to inhibit the synthesis of prostaglandins (Figure 1). Prostaglandins have important roles in normal physiology that might best be described as protective in nature. Prostaglandins are released in response to injury and have the capacity to provoke vasodilatation, erythema, and hyperalgesia (1).
Prostaglandin formation is mediated by either one of two isoforms of cyclooxygenase (2&3). These are known as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Cyclooxygenase-1 (COX-1) mediates the formation of constitutive prostaglandins produced by many tissues, including gastrointestinal cells, platelets, endothelial cells and renal cells. Prostaglandins generated from COX-1 are constantly present and impart a variety of normal physiologic effects. These include protection of gastrointestinal mucosa, hemostasis and the kidney when subjected to hypotensive insults. Cyclooxygense-2 (COX-2) catalyzes the formation of inducible prostaglandins, which are needed only intermittently (Figure 2).
NSAIDs - Image 2
 
 
Fig 1: Pathways of pro-inflammatory mediators after cell membrane damage
 
 
NSAIDs - Image 3
 
 
Fig 2: Pathways and target tissues of COX-1 (Endogenous) and
COX-2 (Inducible) enzymes in arachidonic acid metabolism
 
 

Kinetics of NSAIDs
Absorption
The NSAIDs share similar absorption properties as all NSAIDs are highly lipophilic substances. Absorption occurs throughout the gastrointestinal tract, but particularly in the stomach of monogastric animals, the pH is normally more acidic than plasma pH. An acidic environment promotes the absorption of NSAIDs which, as weak acids, are less ionized in gastric juice and therefore absorbed by the mechanism of ionic or diffusion trapping. Most NSAIDs are given as oral tablets or capsules; others are given by injection to avoid gastric irritation (4&5).
Distribution
The most significant aspect of NSAIDs distribution is plasma-protein binding which is high (>95%) for most NSAIDs, although salicylate is an exception, with binding of ~50%. The major plasma protein component is albumin. The high degree of protein binding limits renal excretion of most NSAIDs. High plasma-protein binding may also limit the distribution of NSAIDs from plasma to body fluids and tissues. However, this does not necessarily limit and may even enhance therapeutic efficacy in acute inflammation because protein leaks from the vascular comparent into inflamed tissues and because drug concentrations in inflammatory exudates commonly exceed those in plasma (4&5). Protein binding does limit penetration into fluids such as milk. Flunixin and phenylbutazone have concentrations in milk that are ~1% of the plasma levels, corresponding approximately to the nonbound plasma concentration.
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. Generally, phase-I metabolism of NSAIDs produces more polar products. These polar metabolites are not efficient COX inhibitors because they lack the lipophilic properties to compete with arachidonic acid and prevent its binding to COX (5&6). Accordingly, it is easy to conclude that most of the NSAIDs are metabolized into inactive products, which is the case in reality.
Excretion
NSAIDs are mostly excreted as phase-II glucouronides and in a few cases as sulfate conjugates. In addition, 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 is coadministered with agents that render the urine pH alkaline such as the antacids aluminum hydroxide and milk of magnesia (5&6).
Adverse reactions to NSAIDs
There is a huge spectrum of reactions to NSAIDs, ranging from clinically common gastrointestinal problems to rare ones such as aseptic meningitis. Some of the more common adverse reactions to NSAIDs are described as follows:
System affected
Adverse reactions
Gastrointestinal (7&8)
Gastroesophageal reflex
Erosions
Peptic ulcers
Gastrointestinal hemorrhage
Small and large bowel ulceration
Hematopoietic (9,10&11)
Impaired blood clotting
Impaired platelet activity
Blood dyscrasias
Bone marrow dyscrasias
Renal (5)
Renal tubular nephritis
Renal papillary necrosis
Acute renal failure
Others (12.13,14&15)
Hepatotoxicity
Aseptic meningitis
Diarrhea
CNS depression
Currently available NSAIDs are indicated for the treatment of mild to moderately severe, acute and chronic pain, inflammation and pyrexia. Non-steroidal anti-inflammatory drugs differ widely in potency and therapeutic efficacy. Differences in efficacy can be explained by varying degrees of COX and cytokine inhibition, non-COX mechanisms, differing analgesia versus anti-inflammatory effects, and wide individual variation in response, within and between species.
A large number of non-steroidal anti-inflammatory drugs, of different chemical groups are available for veterinary use. For the Livestock sector Montajat Pharmaceuticals is providing safe and cost effective NSAIDs for the better management of diseases to ensure optimal production. Some of the known brands are discussed below. For more details, please visit www.montajat.biz.
1.  Flunixin Meglumine (FLUNIFLAM)
Flunixin meglumine is a non-steroidal anti-inflammatory drug (NSAID) and cyclooxygenase inhibitor. It is a potent analgesic, antipyretic and anti-inflammatory. NSAIDs work by inhibiting the body's production of prostaglandins and other chemicals that stimulate the body's inflammatory response (Vane, J.R. and Botting, R.M. (1996)16). Some of these actions may be dose-dependent. NSAIDs are quickly absorbed into the blood stream; pain relief and fever reduction usually starts within one to two hours.
FLUNIFLAM is available as 5% injection and it is indicated for use in horses to alleviate pain and inflammation associated with musculoskeletal disorders, and to alleviate the visceral pain associated with colic.
FLUNIFLAM is indicated for use in cattle to control pyrexia associated with bovine respiratory disease and endotoxemia, and to control inflammation in endotoxemia.
Dosage and administration:
Cattle: 2.2 mg/kg body weight (2 ml/45 kg bw), IV route, once daily for 5 days
Horse: 1.1 mg/kg body weight (1 ml/45 kg bw), IV route, for 5 days
Withdrawal time:
Meat: 5 days
Milk: 1 day
2.  Ketoprofen (KETAFLAM)
Ketoprofen is a propionic acid non-steroidal anti-inflammatory drug (NSAID) with analgesic, antipyretic and anti-inflammatory effects. It acts by inhibiting the body's production of prostaglandin. It is a nonselective inhibitor of COX-1 and COX-2.
KETAFLAM is available as 10% injection and it is used for treatment of pyrexia in dogs and cats. In horses, it is used for musculoskeletal inflammation and pain, abdominal pain and other inflammatory conditions. In cattle, it is used for fever, pain and inflammation, particularly during mastitis due to no withdrawal time.
Dosage and administration:
Cattle, Buffaloes, Camel, Sheep and Goats: 3 mg/kg body weight (1 ml/33 kg bw), IM, IV or SC route, once daily for 3 to 5 days
Horse: 2.2 mg/kg body weight (1 ml/45 kg bw), IV route, for 3 to 5 days
Dogs and Cats: 2 mg/kg body weight (1 ml/50 kg bw), once daily IM, SC or IV route, for 3 to 5 days
Withdrawal time:
Meat: 4 days (IM route); 1 day (IV route)
Milk: Nil
3.  Tolfenamic acid (TOLFENAC)
It is a non- steroidal anti-inflammatory agent (NSAID), which belongs to the fenamate group. It is a potent inhibitor of cyclooxygenase enzyme, thus inhibiting the synthesis of important inflammatory mediators such as thromboxane (Tx) B2 and prostaglandin (PG) E2. It acts not only by inhibiting prostaglandin synthesis, but it also has a direct antagonistic action on its receptors. The anti-inflammatory activity of Tolfenamic acid was evaluated in various animal models of inflammation.
TOLFENACis available as 4% injection and is used for reducing pain, inflammation and pyrexia due to infectious diseases, trauma, surgery and colic.
Dosage and administration:
By IM route- 1 ml per 20 kg bw to be repeated every 48 hrs
By IV route- 1 ml per 20 kg bw to be repeated every 24 hrs
 
Withdrawal time:
Meat: 12 days
Milk: Nil
4.  Metamizole sodium (MONTAGIN)
It is a non-steroidal anti-inflammatory drug, commonly used in the past as a powerful painkiller and fever reducer. It is better known under the names Dipyrone, Analgin and Novalgin. The mechanism is to prevent synthesis and release of PGE in anterior hypothalamic neurons, thus restoring body's normal response of heat production and dissipation, so that restore normal temperature.
MONTAGIN is available as 50% injection and it is used for the treatment of muscle pain, rheumatism, febrile diseases, colic etc.
Dosage and administration:
Cattle: 10 ml/100 kg body weight by IM or IV injection
Horse: 15-30 ml MONTAGIN injection by IV route only
Dogs: 0.1 ml/kg body weight by IM or IV route
Withdrawal time:
Meat:
Horses: 12 days
Cattle: 9 days after IV inj., 28 days after IM injection
5.  Aspirin
            It is a salicylic acid ester of acetic acid and is used as an analgesic, anti-inflammatory and antiplatelet drug.  Its anti-inflammatory action is caused by inhibition of prostaglandins. Aspirin binds irreversibly to the cyclooxygenase (COX) enzyme in tissue to inhibit synthesis of prostaglandins. At low doses it may be more specific for COX-1 than COX-2. In addition to inhibition of cyclooxygenase enzyme activity, salicylates inhibit the formation and release of kinins, stabilize lysosomes and remove energy necessary for inflammation by uncoupling oxidative phosphorylation (17).
Dosage and administration:
Small animals:
 
Mild analgesia
Anti-inflammatory
Antiplatelet
Dogs
10 mg/kg bw, twice daily, PO
20-25 mg/kg bw, twice daily, PO
5-10 mg/kg bw, to be repeated every 24-48 hrs, PO
Cats
10 mg/kg bw, once daily, PO
10-20 mg/kg bw, to be repeated every 48 hrs, PO
80 mg/cat, to be repeated every 48 hrs, PO
Large animals:
Ruminants: 100 mg/kg, twice daily, PO
Swine: 10 mg/kg, thrice daily, PO
Horses: 25-50 mg/kg, twice daily, PO
Withdrawal time:
Meat: 1 day
Milk: 1 day
6.  Naproxen
It is a propionic acid non-steroidal anti-inflammatory drug (NSAID) having analgesic, antipyretic and anti-inflammatory effects by inhibiting the synthesis of prostaglandin. It is a nonselective inhibitor of COX-1 and COX-2. It is used for treatment of musculoskeletal problems, such as myositis and osteoarthritis in dogs and horses.
Dosage and administration:
Small animal
Dogs: 5 mg/kg initially, then 2 mg/kg, to be repeated every 48 hrs, PO.
Large animal
Horses: 10 mg/kg, twice daily, PO.
7.  Carprofen
         It is a non-steroidal anti-inflammatory drug and it reduces inflammation by inhibiting the COX-2. The physiologic or protective actions of prostaglandins appear to be minimally inhibited with no loss of anti-inflammatory efficacy.
            It is used in dogs for joint pain or post-operative inflammation, or for the relief of the pain and inflammation associated with osteoarthritis, hip dysplasia, and other forms of joint deterioration (18). Effect of Carprofen on cartilage synthesis appears to be concentration dependent. At lower concentration (˂10 µg/ml), in vitro studies reveal no inhibitory effects of carprofen on cartilage synthesis and an increase in polysulfated glycosaminoglycan (GAG) synthesis. However, at 10 µg/ml carprofen inhibited GAG and protein synthesis (19).
Dosage and administration:
Dogs:  2.2 mg/kg, twice daily, PO or 4.4 mg/kg, once daily, PO
2.2 mg/kg, twice daily, SQ or 4.4 mg/kg, once daily, SQ
8.  Meclofenamic acid
            It is an anthranilic acid non-steroidal anti-inflammatory drug (NSAID), which inhibits cyclooxygenase as well as antagonizes certain actions of prostaglandins. It is used for the treatment of acute and chronic laminitis and skeletal conditions (20). Use in animals has diminished because of decrease availability and increase popularity of other NSAIDs.
Dosage and administration:
Small animal
Dogs: 1 mg/kg per day, up to 5 days PO.
Large animal
Horses: 2.2 mg/kg, once daily, PO.
9.  Phenylbutazone
It is a non-steroidal anti-inflammatory drug (NSAID) and a nonselective inhibitor of COX-1 and COX-2. It is used as analgesic, antipyretic and anti-inflammatory agent. In the horse, it is used commonly for musculoskeletal pain and inflammation, arthritis, soft tissue injury, muscle soreness, bone and joint problems, and laminitis. NSAIDs work by inhibiting the body's production of prostaglandins, thromboxane and other inflammatory mediators (21). Some of these actions may be dose-dependent. Phenylbutazone may be given intravenously or orally; pain relief and fever reduction usually starts within one to two hours.
It is used occasionally in dogs for the management of chronic pain particularly due to osteoarthritis. However the use in small animals is not common because of the availability of other drugs (Etodolac and Carprofen).
Dosage and administration:
Horse: 4.4-8.8 mg/kg/day, PO
2.2 -4.4 mg/kg/day for 48-96 hours by IV route only
Dogs: 15-22 mg/kg, every 8-12 hrs by PO or IV route
Pigs: 4 mg/kg once daily by IV route
Withdrawal time:
Meat:
Pigs: 15 days
10.  Meloxicam
       It selectively inhibits cyclooxygenase-2 (COX-2) enzyme so reducing the pain and inflammation by inhibiting the synthesis of prostaglandins. It is an effective anti-inflammatory and analgesic, generally free of significant gastrointestinal side effects. It is used for short term in acute pain and for long term in chronic pain for tolerant patients.
Dosage and administration:
Small animal
Dogs:  0.2 mg/kg IV, SC, PO on day one then 0.1 mg/kg IV, SC, PO once daily
Cats:
     Acute perioperative pain: 0.1 mg/kg SC, PO on day one followed by 0.05 mg/kg for up to 4 days if needed
     Chronic pain: 0.1 mg/kg SC, PO on day 1, followed by 0.05 mg/kg for up to 4 days, then reduce to lowest effective dose (0.025 mg/kg PO once every 48 to 72 hours)
Large animal
Horses: 0.6 mg/kg, once daily, IV or PO
Pigs: 0.4 mg/kg, once daily, IM
11.  Piroxicam
            Piroxicam is an NSAID of the oxicam class. It is a non-selective COX inhibitor possessing both analgesic and antipyretic properties. It undergoes entero-hepatic circulation. It is primarily used to treat arthritis and other musculoskeletal conditions. However, a common use in dogs and cats has been as an adjunct for treating cancer. This use is based on reports of its activity for treating or suppressing some tumors, including transitional cell carcinoma of bladder, squamous cell carcinoma and mammary adenocarcinoma (22).
Dosage and administration:
Dogs: 0.3 mg/kg, once in 48 hrs, PO. For cancer treaent: 0.3 mg/kg, once daily, PO.
Cats: 0.3 mg/kg, once daily, PO.
12.  Tepoxalin
            Tepoxalin is a non-steroidal anti-inflammatory drug (NSAID), like other drugs, it produces analgesic and anti-inflammatory effects by inhibiting the synthesis of prostaglandins. However, it also inhibits the action of lipoxygenase (LOX) to decrease the synthesis of inflammatory leukotrienes in dogs. This produces a "dual action" in dogs by inhibiting both prostaglandins and leukotrienes.
            It is used for acute and chronic treatment of pain and inflammation in dogs. One of the most common uses is osteoarthritis, but it is also used for pain associated with surgery.
Dosage and administration:
Dogs: 10 mg/kg, once daily, PO. It is safe to start with 20mg/kg initially and use a dose of 10-20 mg/kg because of safety margin.
Cats: Cats have tolerated 10 mg/kg as a single dose, but long term safety has not been evaluated.
13.  Deracoxib
            Deracoxib, the first NSAID of the coxib class approved for use in dogs. Deracoxib has been shown to inhibit COX-2-mediated PGE2 production. Deracoxib, using in vitro assay, is more COX-1 sparing compared to other NSAIDs and is a selective inhibitor of COX-2. The COX-1/COX-2 ratio is high compared to some other drugs registered for dogs.
            It is indicated for the control of postoperative pain and inflammation associated with orthopedic (bone) surgery and for the control of pain and inflammation (soreness) associated with osteoarthritis in dogs.
Dosage and administration:
Dogs:
Postoperative pain: 3-4 mg/kg, once daily for up to 7 days, PO.
Osteoarthritis: 1-2 mg/kg, once daily, PO.
14.  Firocoxib
            It is a non-steroidal anti-inflammatory drug with more than 350-fold selectivity in dogs for the inducible isoform of the enzyme cyclo-oxygenase-2 over cyclo-oxygenase-1. The COX-1/COX-2 ratio is greater than for other drugs registered for dogs (23).
            Firocoxib is indicated for the control of pain and inflammation associated with osteoarthritis and for the control of post operative pain and inflammation associated with soft-tissue surgery in dogs.
Dosage and administration:
Dogs:
Postoperative pain: 5 mg/kg, once daily for up to 3 days, PO.
Osteoarthritis: 5 mg/kg, once daily, PO.
15.  Etodolac
            It is a non-narcotic, non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, anti-pyretic, and analgesic activity (24). The mechanism of action of etodolac, like that of other NSAIDs, is believed to be associated with inhibition of cyclooxygenase activity. In vitro experiments have shown that etodolac selectively inhibits COX-2 activity (25). Etodolac also inhibits macrophage chemotaxis in vivo and in vitro (26). Because of the importance of macrophages in the inflammatory response, the anti-inflammatory effect of etodolac could be partially mediated through inhibition of the chemotactic ability of macrophages.
Etodoalc is indicated for treatment of osteoarthritis in dogs. It is also used as an analgesic and may be used for other painful conditions.
Dosage and administration:
Dogs: 10-15 mg/kg once daily, PO.
References
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4.      Swan, G.E. (1991) Non-steroidal anti-inflammatory drugs in domestic animals: I. Their classification, mechanism of action and pharmacological effects. J S Afr Vet Assoc. 62(1):35-8.
5.      http://www.merckveanual.com
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11.  Watson, A.D.J., Wilson, J.T. and Turner, D.M. (1980) Phenylbutazone induced blood dyscrasias suspected in three dogs. Vet Rec. 107:239-241.
12.  Lewis, J.H. (1984) Hepatic toxicity of non-steroidal anti-inflammatory drugs. Clin Pharm. 3:128-138.
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17.  Vane, J.R. (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature. 231:232-235.
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19.  Benton, H.P., Vasseur, P.B., Broderick-Villa, G.A. and Koolpe, M. (1997) Effect of carprofen on sulfated glycosaminoglycan metabolism, protein synthesis and prostaglandin release by cultured osteoarthritic canine chondrocytes. Am J Vet Res. 58:286-292.
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25.  Glaser, K.B. (1995) Cyclooxygenase selectivity and NSAIDs: cyclooxygenase-2 selectivity of etodolac (Lodine®). Inflammopharmacol. 3:335-345.
26.  Gervais, F., Martel, R.R. and Skamene, E. (1984) The effect of the non-steroidal anti-inflammatory drug Etodolac on macrophage migration in vitro and in vivo. J Immunopharmacol. 6:205-214.
 
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