NSAIDs Piroxicam

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity, nie synthesis of this compound starts by a multi-step conversion of hydroxy thiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycinc ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22]. 

Mooney et al. [70] investigated the effect of pH on the solubility and dissolution of ionizable drugs based on a film model with total component material balances for reactive species, proposed by Olander. McNamara and Amidon [71] developed a convective diffusion model that included the effects of ionization at the solid-liquid surface and irreversible reaction of the dissolved species in the hydrodynamic boundary layer. Jinno et al. [72], and Kasim et al. [73] investigated the combined effects of pH and surfactants on the dissolution of the ionizable, poorly water-soluble BCS Class II weak acid NSAIDs piroxicam and ketoprofen, respectively. 

Significant research has centered on the preparation and investigation of oxicam derivatives as pharmaceutical agents. This interest was fueled by the successes of the nonsteroidal anti-inflammatory drugs (NSAIDs) piroxicam (Feldene ) 21, meloxicam (Mobic ) 22, and tenoxicam 23 (Figure 24). 

Benzene and thiophene rings can of course often be interchanged in biologically active agents. The very broad structural latitude consistent with NSAID activity is by now a familiar theme as well. Preparation of the fused thiophene counterpart of the NSAID piroxicam (Chapter 11) starts with the reaction of thiophene (25-1), itself the product of a multistep sequence, with ethyl A-methylglycinate to give the sulfonamide (25-2). Treatment of that intermediate with a base leads to intramolecular Claisen condensation and thus the formation of the 3-ketoester (25-3). An amide-ester interchange with 2-aminopyridme (25-4) completes the synthesis of tenoxicam (25-5) [25]. 

PROTEASE INHIBITORS NSAIDs - PIROXICAM Ritonavir t piroxicam levels Uncertain ritonavir is known to inhibit CYP2C9, for which NSAIDs are substrates Avoid co-administration... 

As another parameter to alter the pharmacodynamic prohle of desmopressin, a sex difference is most important. In 2004, Odeberg et al. demonstrated that there was a sex difference in a human pharmacokinetic (PK) and pharmacodynamic (PD) study [214], where desmopressin was administered intravenously as a single dose (for the PK study, a 2-pg dose for the PD study, a 0.2-pg dose), and parameters for urine flow and urine osmolality were estimated. The pharmacokinetics of desmopressin after a fixed bofus injection were influenced neither by piroxicam nor by sex of subjects. However, the pharmacodynamics of desmopressin showed a sex difference where females exhibited a more pronounced antidiuretic effect than males, which was statistically signihcant when the effects were submaximal (>4.5h after dose). The sex differences were diminished after pretreatment with an NSAID, piroxicam, indicating a prostaglandin PGE2-mediated mechanism. 

The simultaneous assay of six oxicam NSAIDs (piroxicam, tenoxicam, lornox-icam, cinnoxicam, isoxicam (ISX meloxicam) in pharmaceutical preparations was accomplished on a C g column (A = 320 nm for cinnoxicam and 360 nm for all others) using a 715/220/50/15 water (15/85 50mM Tris/50mM acetic acid)/ acetonitrile/THF/water (8.8 g ammonium phosphate with 25 mM tetrabutylammo-nium hydroxide to pH 7.5 with H3PO4) mobile phase [1333]. Good peak shape, excellent resolution, and elution complete in 25 min were obtained. The calibration curve was reported as 1-11 mg/L with detection limits of 3 ng/injection (S/N = 3) and quantitation limits of 10 ng/injection (S/N = 10). 

NSAIDs are of diverse chemical structures salicylates (aspirin, sulphasalazine), indole acetic acids (indomethacin, etodolac), heteroaryl acetic acids (diclofenac), arylpropionic acids (ibuprofen, naproxen), anthranilic acids (mefenamic acid) and enolic acids (piroxicam, meloxicam). 

Oxicams, e.g. piroxicam, tenoxicam, meloxicam and lornoxicam are non-specific inhibitors of COX. Like diclofenac, meloxicam inhibits COX-2 ten times more potently than COX-1. This property can be exploited clinically with doses up to 7.5 mg per day, but at higher doses COX-1-inhibition becomes clinically relevant. Since the dose of meloxicam commonly used is 15 mg daily, this agent cannot be regarded as a COX-2-selective NS AID and considerable caution needs to be exercised when making comparisons between the actions of meloxicam and those of other conventional NSAIDs. The average daily dose in anti-rheumatic therapy is 20 mg for piroxicam and tenoxicam, 7.5-15 mg for meloxicam and 12-16 mg for lornoxicam. Oxicams have long elimination half-lives (lornoxicam 3-5 h, meloxicam - 20 h, piroxicam 40 h and tenoxicam 70 h). 

Many NSAIDs inhibit both COX-1 and COX-2. Most NSAIDs are mainly COX-1 selective (eg, aspirin, ketoprofen, indomethacin, piroxicam, sulindac). Others are considered slightly selective for COX-1 (eg, ibuprofen, naproxen, diclofenac) and others may be considered slightly selective for COX-2 (eg, etodolac. 

Renai function impairment NSAID metabolites are eliminated primarily by kidneys use with caution in those with renal function impairment. In cases of advanced kidney disease, treatment with piroxicam and meloxicam is not recommended. Reduce dosage to avoid excessive accumulation. 

Category C (etodolac, ketorolac, mefenamic acid, meloxicam, nabumetone, oxaprozin, tolmetin, piroxicam, celecoxib). All NSAIDs are Category D if used in the third trimester or near delivery. Avoid during pregnancy, especially in the third trimester. 

Apart from the salicylates NSAIDs include several classes of weak acids like propionic acid derivatives such as ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid and suprofen. Phenylbutazone is the most important representative of the pyrazolon derivatives which have a bad reputation for their risk of potentially fatal bone-marrow toxicity. To the acetic acid derivatives belong in-domethacin, diclofenac and sulindac. Sulindac is a pro-drug with less toxicity than indomethacin. The enolic acids include piroxicam, droxicam and tenoxicam. Meloxicam is an analog of piroxicam and has a high selectivity for COX-2. 

Treatment with COX-2 selective drugs has shown a lower likelihood of symptomatic ulcer or ulcer complications than treatment with non-selective NSAIDs, with non-selective NSAID risks varying dose-dependently and between drugs, with ibupro-fen lowest, and piroxicam and azapropazone amongst the highest. Whether COX-2 selective drugs pose no risk is unclear. 

Piroxicam (Feldene) is the prototypical oxicam derivative, with analgesic, antipyretic, and antiinflammatory properties. Its long half-life (45 hours) favors compliance, since only one dose per day is given. Side effects are similar to those encountered with other NSAIDs gastric disturbances, tinnitus, and headache. Piroxicam is indicated for inflammatory and rheumatoid conditions. 

Meloxicam (Mobic), recently introduced for the treatment of osteoarthritis, is also used for rheumatoid arthritis and certain acute conditions. Although meloxicam is sometimes reported to be a selective COX-2 inhibitor, it is considerably less selective than celecoxib or rofecoxib. Its adverse effects are similar to those of piroxicam and other NSAIDs however, the frequency of GI side effects is lower for meloxicam than for piroxicam and several other NSAIDs. 

Piroxicam is a new NSAID and has anti-inflammatory, analgesic and antipyretic activity. It provides effective and long-lasting relief of pain and stiffness. Its convenient once daily dosage provides round the clock relief of symptoms. 

CYP2C9 3 6-9 (W) 2-6% (W) population Isoniazid, Naproxen, Phenytoin, Piroxicam, Rifampin, Verapamil, Warfarin, NSAIDs... 

A benzazepine that includes the same (3-ketoamide array as piroxicam (Chapter 11) retains NSAID activity. Oxidation of benzothiapinone (5-1), obtainable by cycli-zation of 4-(4-chlorophenylthio)-butyric acid, with hydrogen peroxide gives the corresponding sulfone (5-2). This is then converted to its enamine (5-34) by reaction with pyrrolidine. Condensation of the intermediate with 3,4-dichorophenylisocyanate (5-4) leads to the amide (5-5). Hydrolysis with an aqueous acid cleaves the enamine function to give the keto-amide and thus enolicam (5-6) [6]. 

Selectivity for COX-1 versus COX-2 is variable and incomplete for the older NSAIDs, but many selective COX-2 inhibitors have been synthesized. The selective COX-2 inhibitors do not affect platelet function at their usual doses. In testing using human whole blood, aspirin, ibuprofen, indomethacin, piroxicam, and sulindac are somewhat more effective in inhibiting COX-1. The efficacy of -2-selective drugs equals that of the older NSAIDs, while gastrointestinal safety may be improved. On the other hand, selective COX-2 inhibitors may increase the incidence of edema and hypertension. As of December 2008, celecoxib and the less selective meloxicam are the only COX-2 inhibitors marketed in the USA. Rofecoxib and valdecoxib, two previously marketed, selective COX-2 inhibitors, have been withdrawn from the market due to their association with increased cardiovascular thrombotic events. Celecoxib has an FDA-initiated "black box" warning concerning cardiovascular risks. It has been recommended that all NSAID product labels be revised to include cardiovascular risks. 

Piroxicam can be used for the usual rheumatic indications. When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding is encountered. Epidemiologic studies suggest that this risk is as much as 9.5 times higher with piroxicam than with other NSAIDs (see common adverse effects above). 

Meloxicam is an enolcarboxamide related to piroxicam that has been shown to preferentially inhibit COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as the other coxibs. The drug is popular in Europe and many other countries for most rheumatic diseases and has recently been approved for treatment of osteoarthritis in the USA. Its efficacy in this condition and rheumatoid arthritis is comparable to that of other NSAIDs. It is associated with fewer clinical gastrointestinal symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, it appears that even at supratherapeutic doses its blockade of thromboxane A2 does not reach levels that result... 

Rheumatoid arthritis is a disease that involves inflammation in joints and causes severe pain and immobility. The worldwide scenario indicates that the elderly population suffers the most from this disease. The drugs of choice for treatment of this condition are nonsteroidal antiinflammatory drugs (NSAIDs), which include acetylsalicylic acid, diclofenac sodium, piroxicam, nimesulide, celecoxib, and refecoxib. Therapeutic doses, adverse effects, and precautions are given in the foifowing pages. 

BETA-BLOCKERS NSAIDS - INDOMETACIN, PIROXICAM, POSSIBLY IBUPROFEN, NAPROXEN 1 hypotensive efficacy of beta-blockers. There does not seem to be this effect with other NSAIDs Additive toxic effects on kidney, and sodium and water, retention by NSAIDs. NSAIDs can raise BP by inhibiting renal synthesis of vasodilating prostaglandins. It is uncertain why this effect is specific to these NSAIDs Watch for 1 response to beta-blockers... 

ANION EXCHANGE RESINS NSAIDs Colestyramine i absorption of NSAIDs Colestyramine binds NSAIDs in the intestine, reducing their absorption it also binds those NSAIDs with a significant entero-hepatic recirculation (meloxicam, piroxicam, sulindac, tenoxicam) Give the NSAID 1 hour before or 4-6 hours after colestyramine however, meloxicam, piroxicam, sulindac and tenoxicam should not be given with colestyramine... 

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