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Sulindac


Sulindac

Article Author:
Akul Munjal
Article Editor:
Roopma Wadhwa
Updated:
11/27/2020 9:04:52 AM
For CME on this topic:
Sulindac CME
PubMed Link:
Sulindac

Indications

Sulindac is a non-steroidal anti-inflammatory drug (NSAID). As with other NSAIDs, sulindac is used primarily to treat conditions characterized by acute or chronic inflammation. Per the manufacturer, the indications are broad. Sulindac is indicated for the acute treatment of musculoskeletal shoulder pain for a short duration. Sulindac also has FDA approval for the use of other forms of arthritis, including wear and tear osteoarthritis, as well as inflammatory arthritic conditions including both rheumatoid arthritis and ankylosing spondylarthritis. Sulindac also has approval for use in the treatment of acute gouty arthritis. Familial adenomatous polyposis (FAP) is a condition characterized by pediatric adenomas in the lower gastrointestinal tract and frequently results in colonic adenocarcinomas. Several chemopreventive strategies have been the object of research in an attempt to delay the development of colonic adenomas and subsequent adenocarcinomas. Sulindac has been one of the most extensively studied drug used in this chemopreventative strategy.[1][2]

Mechanism of Action

Sulindac is a non-selective COX (cyclooxygenase) inhibitor that inhibits both COX-1 and COX-2. The COX pathways are one of the two main pathways involved in arachidonic acid metabolism (the other involving leukotriene synthesis). The COX pathway results in the synthesis of both prostaglandins and thromboxanes. These are both critical mediators of inflammation and platelet aggregation. Prostaglandin E2 (PGE2) is often a trigger of the cardinal signs of inflammation: rubor (erythema), calor (warmth), tumor (swelling), and dolor (pain)- this is accomplished through increased blood flow and vascular permeability. PGE2 also triggers systemic fever through a hypothalamic mediated reaction. Sulindac and other NSAIDs are responsible for inhibiting the synthesis of this prostaglandin as well as others. Sulindac exists as a pro-drug that activates upon initial metabolism. Its metabolism forms both sulfide and sulfone derivatives; the sulfide derivative is the one that is responsible for inhibiting prostaglandin synthesis.[3][4][5] 

Administration

Per the manufacturer, sulindac administration is via the oral route. There are several strength tablets, and the maximum daily dose recommended is 400 mg.

Adverse Effects

Prostaglandins and thromboxanes have critical functions throughout the body. Unfortunately, the wide range of functions results in a host of side effects for NSAIDs like sulindac. Blood vessels, the gastrointestinal (GI) tract, and kidneys are a few examples of critical organ systems impacted by sulindac. The most common, most severe side effect of NSAID use involves ulceration of the GI tract, as GI mucosa appears to be protected by various prostaglandins. Sulindac is commonly thought to have associations with lower rates of GI-related complications when compared to other non-selective NSAIDs; however, this has come into question, and the GI side effects related to NSAID use appear to be primarily mediated through COX-1, as COX-2 selective NSAIDs are associated with lower risks of GI complications. These side effects appear to become exacerbated by simultaneous use with alcohol and or steroids. Sulindac also correlates with renal side effects. Certain prostaglandins are involved in dilation of the afferent arteriole- inhibition of this prostaglandin mediated mechanism may result in a reduced GFR; thus, the risk of acute kidney injury. Sulindac and other NSAIDs may also be nephrotoxic and may induce renal papillary necrosis and interstitial nephritis. This condition may become exacerbated with simultaneous use with other nephrotoxic agents.[6][7]

Sulindac is associated with various critical side effects, including changes in vision, hepatoxicity, pancreatitis, anemia, and steven-johnson syndrome.

Sulindac is also commonly associated with: nausea and vomiting, stomach pain, indigestion, diarrhea, constipation, gas, anxiety, dizziness, tinnitus, and urticaria. 

Contraindications

Per the manufacturer, there are few absolute contraindications to the use of sulindac. The first is a previous hypersensitivity reaction to sulindac or other NSAIDs. NSAID hypersensitivity can present in a variety of ways. It can result in chronic respiratory disease because of the formation of nasal polyps. Cutaneously it can present with urticaria and angioedema, and in severe instances, it can even result in generalized anaphylaxis. The other absolute contraindication is in patients who are status post coronary artery bypass graft (CABG) operations.[7]

Monitoring

Sulindac use, as is the case with other NSAIDs, does not involve any routine monitoring. No regular blood work is necessary; however, it is essential to note that sulindac is not free from toxic side effects. Adhering to the dosing regiment is critical in preventing some of the side effects discussed above.[8]

Toxicity

It is essential to note that sulindac toxicity is rare; few cases are reported in the literature. It is also important to note that though sulindac is an NSAID, the toxicity does not present similarly to salicylate (aspirin) toxicity with metabolic acidosis, respiratory alkalosis, and tinnitus. Cases in the literature have demonstrated hepatic and renal toxicity associated with sulindac overdose; a case of granulocytosis has also been shown secondary to sulindac toxicity. One of the cases with hepatorenal toxicity further resulted in ischemic skin changes and ulceration. However, it is important to note that since there have been exceedingly few cases of sulindac toxicity reported, many of the implications of overdose have not had a thorough investigation. Other research has demonstrated the utility of activated charcoal in the acute treatment of sulindac toxicity. This agent can help minimize absorption, and some of the later sequelae associated with the drug's toxicity. However, other studies have demonstrated that once the drug has been in the system, the only true treatment protocol involves supportive care. One of the hallmarks of supportive care includes aggressive hydration and fluid replacement, and hemodialysis in certain cases.[9][10]

Enhancing Healthcare Team Outcomes

NSAIDs like sulindac are a common therapy. They are used for a wide variety of conditions and in a wide variety of situations. It is also important to note that while the side effect profile of NSAIDs like sulindac is favorable, and there are few long-term and toxic side effects associated with their use, they are not a benign medication that is free from toxicity. Understanding this, and understanding how toxicities can present and the importance of adhering to scheduled dosing regimens is critical in improving patient outcomes. Being able to implement treatment protocols in the case of emergencies rapidly is vital to advancing patient outcomes. 


References

[1] COX-Independent Mechanisms of Cancer Chemoprevention by Anti-Inflammatory Drugs., Gurpinar E,Grizzle WE,Piazza GA,, Frontiers in oncology, 2013     [PubMed PMID: 23875171]
[2] Karachalios GN,Donas G, Sulindac in the treatment of acute gout arthritis. International journal of tissue reactions. 1982;     [PubMed PMID: 7169301]
[3] Yin T,Wang G,Ye T,Wang Y, Sulindac, a non-steroidal anti-inflammatory drug, mediates breast cancer inhibition as an immune modulator. Scientific reports. 2016 Jan 18;     [PubMed PMID: 26777116]
[4] Saad J,Pellegrini MV, Nonsteroidal Anti-Inflammatory Drugs (NSAID) Toxicity 2020 Jan;     [PubMed PMID: 30252262]
[5] Strong HA,Warner NJ,Renwick AG,George CF, Sulindac metabolism: the importance of an intact colon. Clinical pharmacology and therapeutics. 1985 Oct;     [PubMed PMID: 4042521]
[6] Wongrakpanich S,Wongrakpanich A,Melhado K,Rangaswami J, A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly. Aging and disease. 2018 Feb;     [PubMed PMID: 29392089]
[7] Sánchez-Borges M,Caballero-Fonseca F,Capriles-Hulett A,González-Aveledo L, Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs: An Update. Pharmaceuticals (Basel, Switzerland). 2010 Jan 5;     [PubMed PMID: 27713240]
[8] Lione A,Scialli AR, The developmental toxicity of indomethacin and sulindac. Reproductive toxicology (Elmsford, N.Y.). 1995 Jan-Feb;     [PubMed PMID: 8520134]
[9] Vaughn JL,Shah KV,Ghossein MM,Meyer WL,Kirkpatrick RB, Acute kidney injury, hyperbilirubinemia, and ischemic skin necrosis due to massive sulindac overdose. Current drug safety. 2015;     [PubMed PMID: 25986039]
[10] Gross GE, Granulocytosis and a sulindac overdose. Annals of internal medicine. 1982 Jun;     [PubMed PMID: 7091952]