Sulindac dosing

Sulindac 90 93 (and high for metabolites) 7-8 (16.4 sulfide) <1% of sulindac dose appears as active sulfide metabolite Yes sulindac and sulfone undergo extensive enterohepatic circulation relative to sulfide Extensive in liver - oxidation to sulfone, reduction to sulfide and glucuronidation Sulindac sulfide (parent is prodrug)... 

Mattila J, Mantyla R, Vuorela A, et al. Pharmacokinetics of graded oral doses of sulindac in man. Arzneimittelforschung 1984 34(2) 226-229. 

Eideriy Age appears to increase the possibility of adverse reactions to NSAIDs. The risk of serious ulcer disease is increased this risk appears to increase with dose. Ketorolac is cleared more slowly by the elderly use caution and reduce dosage. Pregnancy Category B (ketoprofen, naproxen, naproxen sodium, flurbiprofen, diclofenac, fenoprofen, ibuprofen, indomethacin, meclofenamate, sulindac). 

Dimethyl Sulfoxide [DMSO] (Rimso-50) [GU Agent] Uses Interstitial cystitis Action Unknown Dose Intravesical, 50 mL, retain for 15 min repeat q2wk until relief Caution [C, ] Contra Component sensitivity Disp Soln SE Cystitis, eosinophilia, GI, taste disturbance Interactions -1-Effects OF sulindac EMS May cause garlic/onion taste in mouth OD Acute effects unlikely... 

Indomethacin and sulindac are slightly selective for COX-1. Meclofenamate and ibuprofen are approximately equipotent on COX-1 and COX-2, whereas celecoxib = diclofenac < rofecoxib = lumiracoxib < etoricoxib in inhibition of COX-2 (listed in order of increasing average selectivity). Aspirin acetylates and inhibits both enzymes covalently. Low doses (< 100 mg/day) inhibit preferentially, but not exclusively, platelet COX-1, whereas higher doses inhibit both systemic COX-1 and COX-2. 

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. 

The major urinary metabolites are sulindac and its glucuronide, sulfone and its glucuronide and in trace amounts the insoluble sulfide metabolite and its glucuronide. The major biotransformation involves irreversible oxidation of the sulfoxide group of sulindac to sulfone and a reversible reduction to the sulfide. Studies in healthy subjects revealed that after oral administration of sulindac at least 88% is absorbed. After a single 200 mg oral dose the peak plasma concentrations of sulindac and its sulfone and sulfide metabolites were 4, 2, and 3 mg/ml respectively, and were attained after 1 hour for the parent drug and after 2 hours for each of the metabolites. 

The sulfone and its conjugates are the major products excreted in urine, and account for 27.6 + 2.8% of the administered dose. Sulindac and its glucuronide accounted for 20.2 + 0o2% of the dose excreted in the urine. Mean renal clearance of sulindac and its sulfone metabolite was 45.1 + 16.2 and 33.2 + 12.2 ml/min respectively(16). The effective half-life for accumulation is about 7 hours for sulindac(17). The long half-life is due to extensive enterohepatic recirculation(18). 

Anandamide is rapidly hydrolysed enzymatically to arachidonic acid and ethanol-amine by a fatty acid amide hydrolase (FAAH) [50], The molecular characterization, cloning and expression of FAAH have been reported in a recent study [51]. FAAH can be blocked with either the general serine protease inhibitor phenyl methy(sulphonyl fluoride [38] or with the highly efficient methyl arachidonyl fluorophsphonate [52], The non-steroidal antiinflammatory ibuprofen in therapeutic doses, but not aspirin, sulindac or acetaminophen, also inhibits anandamide metabolism [53], This observation may have therapeutic implications. 

In a single-dose study examining the pharmacokinetics of sulindac and ibuprofen in 15 patients with alcoholic liver disease, no statistically significant effects were noted for ibuprofen elimination, half-life or AUC compared to the controls. However, there appeared to be delayed absorption in some patients [25]. 

In a single-dose study in patients with alcoholic liver disease (divided into fair or poor hepatic function) the activation of sulindac was delayed, and plasma concentration of the active sulfide metabolite was maximal about eight hours after an oral dose, compared to approximately two hours in healthy subjects. In addition, compared to controls, the AUC for the active metabolite was four times higher in those with the poorest hepatic function and almost double in those with fair hepatic function [25]. 

Following daily oral doses of 200 mg, twice a day to 12 subjects, mean maximum steady-state plasma concentrations were sulindac S.Opg/ml, sulphide 6.9 ig/ml, sulphone 2.6pg/ml a diurnal variation in plasma concentrations was reported with lower concentrations being attained after the evening dose. After oral administration of 400 mg once daily to 12 subjects, maximum steady-state plasma concentrations were sulindac 8.7 ig/ml, sulphide 8.8 pg/ml, sulphone 3.9 ig/ml (B. N. Swanson et al., Clin. Pharmac. Ther., 1982, 32, 397-403). 

Withdrawal of NSAIDs and acid suppression with standard doses of antisecretory drugs will allow prompt resolution of these ulcers, which should not recur unless the drugs are resumed. Many patients are prescribed NSAIDs inappropriately when their symptoms could be controlled by paracetamol or by local treatment. Topical NSAID creams applied over an affected joint may be helpful, but peptic ulcers can complicate therapy with NSAIDs administered as rectal suppositories. Prodrugs such as sulindac, which are metabolised to form antiinflammatory derivatives, can also produce ulcers. 

Several types of proven or suspected hypersensitivity have already been mentioned, for example in connection with the liver, but the exact mechanism of a particular adverse effect has not always been clear. One case of fever, pharyngitis, cervical lymphadenopathy, leukopenia, liver abnormalities, proteinuria, pulmonary infiltrates, and abdominal pain has been described. Another patient who previously took sulindac without problems developed pruritus, dyspnea, perioral edema, and lethargy after taking a single dose of sulindac 150 mg. 

Winde G, Schmid KW, Schlegel W, Fischer R, Osswald H, Bunte H. Complete reversion and prevention of rectal adenomas in colectomized patients with familial adenomatous polyposis by rectal low-dose sulindac maintenance treatment. Advantages of a low-dose nonsteroidal antiinflammatory drug regimen in reversing adenomas exceeding 33 months. Dis Colon Rectum 1995 38(8) 813-30. 

Careful monitoring of patients with a history of ulcers is recommended. Gastric bleeding, nau.sca. diarrhea, dizziness and other adverse effects have been noted, but with a lower frequency than with aspirin. Sulindac i.s recommended for RA. OA. and ankyUssing spondylitis in a ISO- to 200-mg dose, twice daily. - It is available as labIcLs (ISO-jmI 200 mg). 

Nevertheless, sulindac is the preferred compound for clinical applications an oral dosage of this inactive bioprecursor will circumvent initial exposure of gastric and intestinal mucosa to the active drug and might thus provide a therapeutic advantage in comparison with the sulfide dosing. 

Reversible inhibitors of COX 1 and COX 2, with analgesic, antipyretic, and anti-inflammatory actions, include ibuprofen, naproxen, indomethacin, ketorolac, and sulindac. When used as antiinflammatory agents, they are usually no more effective than ASA, but they may be better tolerated. All have antiplatelet actions (reversible) at moderate (not low) doses and cause bleeding tendencies. 

Little of the sulfide (or of its conjugates) is found in urine. The principal components excreted in the urine are the sulfone and its conjugates, which account for nearly 30% of an administered dose sulindac and its conjugates account for -20%. Up to 25% of an oral dose may appear as metabolites in the feces. 

Sulindac is Indicated for long-term use in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and acute gouty arthritis. The usual maximum dosage is 400 mg/day, with starting doses recommended at 150 mg twice a day. It is recommended that sulindac be administered with food. 

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