NSAID salts

Kidney Function. Prostanoids influence a variety of kidney functions including renal blood flow, secretion of renin, glomerular filtration rate, and salt and water excretion. They do not have a critical role in modulating normal kidney function but play an important role when the kidney is under stress. Eor example, PGE2 and -I2 are renal vasodilators (70,71) and both are released as a result of various vasoconstrictor stimuli. They thus counterbalance the vasoconstrictor effects of the stimulus and prevent renal ischemia. The renal side effects of NSAIDS are primarily observed when normal kidney function is compromised. 

Flufenamic acid (162) is a reasonably well-established NSAID (Non Steroidal Anti Inflammatory Drug). Alkylation of its potassiuni salt with the hydroxyethyl ethyl ether of ethylenechlo-rohydrin affords the latendated derivative etofenamate (163) [41]. Antiinflammatory activity is apparently retained when both rings in the fenamate series carry carboxyl groups. Thus, condensation of dichlorobenzoic acid 164 with anthranilic acid (165) by means of nucleophilic aromatic... 

The sulfur analogue of the Hauser ortho-substitution rearrangement provides access to an arylacet-ic NSAID. Reaction of the aminobenzophenone 176 with ethyl methylthioacetate and tert-butyl hypochlorite gives the intermediate 178. The reaction probably proceeds by way of formation of the S-chlorinated sulfonium derivative 177 displacement on sulfur will lead to the salt 178. Treatment with triethylamine leads initially to the betaine 179. Electrocyelic rearrangement of that transient intermediate leads, after rearomatization, to the homoanthranilic acid 180. Internal ester-amine interchange leads then to indolone 181 [45]. The thiomethyl group is then removed with Raney niekel. Saponifieation of intermediate 182 affords bromfenac (183) [46J. 

Concurrent use of the fluoroquinolones with theophylline causes an increase in serum theophylline levels. When used concurrently with cimetidine, the cimetidine may interfere with the elimination of the fluoroquinolones. Use of the fluoroquinolones with an oral anticoagulant may cause an increase in the effects of the oral coagulant. Administration of the fluoroquinolones with antacids, iron salts, or zinc will decrease absorption of the fluoroquinolones. There is a risk of seizures if fluoroquinolones are given with the NSAIDs. There is a risk of severe cardiac arrhythmias when the fluoroquinolones gatifloxacin and moxifloxacin are administered with drains that increase the QT interval (eg, quini-dine, procainamide, amiodarone, and sotalol). 

Patients who have had multiple intestinal resections due to CD may have diarrhea related to the inability to reabsorb bile salts. Cholestyramine has been demonstrated to improve diarrheal symptoms in this population.8,15 NSAIDs should be avoided for pain management due to their ability to worsen IBD symptoms. Narcotic analgesics should be used with caution, as they may significantly reduce GI motility. 

Gold salts have had a long history of use in rheumatoid arthritis.269,270 The development of orally active auranofin (also known as Ridaura (50), Figure 23) was a major improvement over the early injectable gold preparations which were polymeric (e.g., (51)—(53)). However, use has declined with the popularity of nonsteroidal antiinflammatory drugs (NSAIDS) such as indo-methacin a recent estimate of the commercial value for auranofin was 6 million. The mechanism... 

NSAIDs are more likely to cause GI side effects. The salicylate salts cause fewer GI side effects than aspirin and do not inhibit platelet aggregation. 

Use in moderate pain Weak analgesic most effective when used with NSAIDs, aspirin, or acetaminophen This drug is not recommended in the elderly Will cause carbamazepine levels to increase 100 mg of napsylate salt = 65 mg of HCI salt Third-line agent for moderate-to-severe pain... 

For therapeutical purposes, a likewise frequently used group of drug compounds are the nonsteroidal anti-inflammatory drugs (NSAID). Among the best known representatives of the aryl acetic acid derivatives is diclofenac as well as ibuprofen, an aryl propionic acid derivative. As both have acidic properties, they dissociate while being dissolved and may form salts with amphiphilic properties. Together with appropriate counterions these amphiphilic organic acids may form lyotropic mesophases with water even at room or body temperature, for example, diclofenac diethylamine... 

Drugs that may affect beta blockers include aluminum salts, barbiturates, calcium salts, cholestyramine, cimetidine, colestipol, diphenhydramine, hydroxychloroquine, NSAIDs, penicillins (ampicillin), rifampin, salicylates, SSRIs, sulfinpyrazole, calcium blockers, oral contraceptives, flecainide, haloperidol, hydralazine, loop diuretics,... 

K /Na exchange in distal tubule Dose Adults. 5-10 mg PO daily Peds. 0.625 mg/kg/d X in renal impair Caution [B, ] Contra T K, SCr >1.5 mg/dL, BUN >30 mg/dL, diabetic neuropathy Disp Tabs SE T K HA, dizziness, dehydration, impotence Interactions T Risk of hyperkalemia W/ ACEI, K-sparing diuretics, NSAIDs, K salt substitutes T effects OF Li, digoxin, antihypertensives, amantadine T risk of hypokalemia W/ licorice EMS Monitor ECG for signs of hyperkalemia (peaked T waves) T effects of digoxin OD May cause bradycardia, light-headedness, and syncope symptomatic and supportive... 

Cardiovascular safety. Both drug types promote salt retention, can exacerbate heart failure and tend to raise blood pressure. COX-2 selective drugs also appear to raise the risks of thrombotic events, notably stroke and myocardial infarction, and recent evidence suggests that non-selective NSAIDs also raise these risks, though it is unclear whether to the same degree. For both drug types, dose and duration of treatment appear to affect risk. 

With the combination of traditional DMARDs complete remissions are obtained in 30% of early RA over a period of 5 years. These remissions last on average less than 10 months. After 5 years only half of the patients continue with MTX and less than 25% stay on other DMARDs. After 5 years non-compliance is mostly due to adverse effects and lack of efficacy of NSAIDs, hydroxychloroquine, sulfasalazine, prednisone, d-penicillamine, azafhio-prine, and gold salts. Only MTX retains some efficacy. With these therapeutic modalities joint erosions progress to permanent joint destruction, deformities and disability. 

The answer is b. (Hardman, p 448. Katzung, pp 493, 1130.) Some NSAIDs can increase proximal tubular reabsorption of lithium salts, which can create toxic levels of lithium in the plasma. 

Construction of the closely related NSAID bromefenac (46-8) depends on the Gassman indolone synthesis [46] for incorporation of the acetic acid chain. That reaction involves an anion-initiated electrocyclic rearrangement related conceptually to the little-known Hauser ortho substitution rearrangement. The simplest example of the latter depends on the formation of a carbanion by abstraction of one of the acidic protons from a benzyltrimethyl quaternary salt to give I (the... 

The large number of newly developed COX-2 inhibitors demonstrates how promising this field of anti-inflammatory agents is expected to be. More than 1000 COX-2 inhibitors have been described over the past few years (Prous database, March 2002). The chemical structures of COX-2 inhibitors are heterogenic. Contrary to the classical NSAIDs, this new class of enzyme inhibitors lacks a carboxylic acid group, thus effecting COX-2 affinity by a different orientation within the enzyme without formation of a salt bridge in the hydrophobic channel of the enzyme. 

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