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Sulindac; Indications, ContraIndications

Sulindac C0ntraindications/ Sulindac is a sulfinylindene derivative prodrug with potential antineoplastic activity. Converted in vivo to an active metabolite, sulindac, a nonsteroidal anti-inflammatory drug (NSAID), blocks cyclic guanosine monophosphate-phosphodiesterase (cGMP-PDE), an enzyme that inhibits the normal apoptosis signal pathway; this inhibition permits the apoptotic signal pathway to proceed unopposed, resulting in apoptotic cell death.

Sulindac is a sulfinylindene derivative prodrug whose sulfinyl moiety is converted in vivo to an active NSAID analgesic. Specifically, the prodrug is converted by liver enzymes to a sulfide which is excreted in the bile and then reabsorbed from the intestine. This helps to maintain constant blood levels with reduced gastrointestinal side effects.

Sulindac is a commonly used nonsteroidal anti-inflammatory drug (NSAID) that is available by prescription only and used predominantly to treat chronic arthritis. Sulidac is a rare, but the well-established cause of idiosyncratic, clinically apparent drug-induced liver disease.

Mechanism of Action of Sulindac

Sulindac’s exact mechanism of action is unknown. Its anti-inflammatory effects are believed to be due to inhibition of both COX-1 and COX-2 which leads to the inhibition of prostaglandin synthesis. Antipyretic effects may be due to action on the hypothalamus, resulting in increased peripheral blood flow, vasodilation, and subsequent heat dissipation.

Sulindac is a prodrug that is converted to an active sulfide metabolite, which is responsible for most of the pharmacologic activity. The active metabolite of sulindac competitively inhibits both cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, by blocking arachidonate binding resulting in analgesic, antipyretic, and anti-inflammatory pharmacologic effects. The parent drug has a minimal inhibitory effect on COX; the sulfide metabolite is 500 times more potent. The enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin G2 (PGG2), the first step of the synthesis prostaglandins and thromboxanes that are involved in rapid physiological responses. COX isoenzymes are also responsible for a peroxidase reaction, which is not affected by NSAIDs. In addition, NSAIDs do not suppress leukotriene synthesis by lipoxygenase pathways. COX-1 is constitutively expressed in almost all tissues, while COX-2 appears to only be constitutively expressed in the brain, kidney, bones, reproductive organs, and some neoplasms (e.g., colon and prostate cancers). COX-1 is responsible for prostaglandin synthesis in response to stimulation by circulating hormones, as well as maintenance of normal renal function, gastric mucosal integrity, and hemostasis. However, COX-2 is inducible in many cells in response to certain mediators of inflammation (e.g., interleukin-1, tumor necrosis factor, lipopolysaccharide, mitogens, and reactive oxygen intermediates).

FDA Level

Anti-inflammatory Activity – The anti-inflammatory mechanism of sulindac is due to decreased prostaglandin synthesis via inhibition of COX-1 and COX-2. It appears that the anti-inflammatory effects may be primarily due to inhibition of the COX-2 isoenzyme. However, COX-1 is expressed at some sites of inflammation. COX-1 is expressed in the joints of rheumatoid arthritis or osteoarthritis patients, especially the synovial lining, and it is the primary enzyme of prostaglandin synthesis in human bursitis. Sulindac is considered a non-selective NSAID; however, it is highly selective for the COX-1 isoenzyme.
Analgesic Activity – Sulindac is effective in cases where inflammation has caused the sensitivity of pain receptors (hyperalgesia). It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing the pain receptors; therefore, sulindac has an indirect analgesic effect by inhibiting the production of further prostaglandins and does not directly affect hyperalgesia or the pain threshold.
Antipyretic Activity – Sulindac promotes a return to a normal body temperature set point in the hypothalamus by suppressing the synthesis of prostaglandins, specifically PGE2, in circumventricular organs in and near the hypothalamus. Sulindac may mask fever in some patients, especially with high or chronic dosing.
GI Effects – Gastrointestinal side effects of sulindac are primarily contributed to COX-1 inhibition; however, the potential role of COX-2 inhibition in the GI tract has not been fully elucidated.
Platelet Effects – The inhibition of platelet aggregation seen with sulindac is due to a dose-dependent inhibition of COX-1 in platelets leading to decreased levels of platelet thromboxane A2 and an increase in bleeding time (see Adverse Reactions). The inhibition of platelet aggregation is reversible within 24 hours of discontinuation of sulindac. This differs from aspirin, which irreversibly binds to COX-1 in platelets inhibiting this enzyme for the life of the cell.
Renal Effects: In the kidney, prostaglandins, produced by both COX-1 and COX-2, are important regulators of sodium and water reabsorption through PGE2 and of renal function and hemodynamics via PGI2 in response to vasoconstrictive factors (e.g., endothelin-1, a factor that increases peripheral vascular resistance) and through effects on the renin-angiotensin system. In conditions where renal blood flow is dependent upon prostaglandin synthesis, administration of NSAIDs can result in significant decreases in renal blood flow leading to acute renal failure. In addition, alterations in sodium and water reabsorption may worsen increased blood pressure, which can be significant in selected individuals.

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Sulindac Indications

For acute or long-term use in the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), and acute gouty arthritis

Ankylosing Spondylitis
Tendonitis
Rheumatoid arthritis
Osteoarthritis
Acute and chronic rheumatoid arthritis,
Mild to moderate pain associated with musculotendinous trauma
sprains and strains
Postpartum pain.
Treatment of some pain, especially nerve pain such as
Sciatica,
Postherpetic neuralgia
Referred pain for radiculopathy.
Pauciarticular juvenile rheumatoid arthritis
Polyarticular juvenile rheumatoid arthritis, chronic or unspecified
Frozen shoulder
Pain with itching,
Tendonitis
Bursitis

Sulindac Contra-Indications

Systemic mastocytosis
Increased risk of bleeding due to a clotting disorder
Alcoholism
High blood pressure
Chronic heart failure
Disease of the heart and blood vessels
Stroke
Ulcer from stomach acid
Stomach or intestinal ulcer
Liver problems
Bleeding of the stomach or intestines
Kidney stone
Systemic lupus erythematosus
Visible water retention
Pregnancy
A mother who is producing milk and breastfeeding
A rupture in the wall of the stomach or intestine
Increased cardiovascular event risk
Time immediately after coronary bypass surgery
chronic kidney disease stage 4 (severe
A mother who is producing milk and breastfeeding

Dosages of Sulindac

Strengths: 150 mg; 200 mg

Rheumatoid Arthritis

Initial dose: 150 mg orally twice a day
Maximum dose: 400 mg orally per day

Osteoarthritis

Initial dose: 150 mg orally twice a day
Maximum dose: 400 mg orally per day

Ankylosing Spondylitis

Initial dose: 150 mg orally twice a day
Maximum dose: 400 mg orally per day

Acute Gout

Initial dose: 200 mg orally twice a day
Maximum dose: 400 mg orally per day
Duration of therapy: 7 days is usually adequate

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Bursitis

Initial dose: 200 mg orally twice a day
Maximum dose: 400 mg orally per day
Duration of therapy: 7 to 14 days is usually adequate

Tendonitis

Initial dose: 200 mg orally twice a day
Maximum dose: 400 mg orally per day
Duration of therapy: 7 to 14 days is usually adequate

Side Effects of Sulindac

The common

stomach pain
abdominal or stomach pain, cramping, or burning (severe)
bloody or black, tarry stools
blurred vision or any change in vision
chest pain
allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
convulsions (seizures)
fast or irregular breathing
fast, irregular heartbeat or pulse
indigestion
nausea, vomiting
diarrhea

More common

Less common

Rare

Anxiety
change in vision
seizures
abnormal or fast heart rate
weight loss
chest pain or tightness
confusion
cough
Agitation
arm, back, or jaw pain
blurred vision
chest pain or discomfort
convulsions
extra heartbeats
hallucinations
headache
irritability
muscle pain or cramps
pale or yellowed skin, dark colored urine, fever, confusion or weakness;
jaundice (yellowing of the skin or eyes);
sore throat, and headache with a severe blistering peeling, and red skin rash;
swelling, rapid weight gain, feeling short of breath (even with mild exertion); or
increased thirst , loss of appetite, urinating less than usual or not at all.

Drug Interactions of Sulindac

Sulindac may interact with following drugs, supplements & may change the efficacy of drugs

aminoglycoside antibiotics (e.g., amikacin, gentamicin, tobramycin)
angiotensin-converting enzyme (ACE) inhibitors (e.g., ramipril, enalapril, captopril, quinapril)
angiotensin receptor blockers (ARBs; e.g., candesartan, irbesartan, losartan)
“azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
beta-adrenergic blockers (e.g., atenolol, propranolol, sotalol)
bisphosphonates (e.g., alendronate, etidronate)
carbamazepine
celecoxib
cilostazol
clopidogrel
cyclosporine
dabigatran
dasatinib
diuretics (water pills; e.g., furosemide, hydrochlorothiazide, triamterene)
fluvastatin
haloperidol
heparin
ibrutinib
methotrexate
multivitamins (with vitamins A, E) with or without minerals
nilotinib
non-steroidal anti-inflammatory medications (NSAIDs; e.g., diclofenac, ibuprofen, naproxen)
omega-3 fatty acids
omeprazole
oral corticosteroids (e.g., dexamethasone, hydrocortisone, prednisone)
pentoxifylline
phenobarbital
phenytoin
quinolone antibiotics (e.g., ciprofloxacin, norfloxacin, ofloxacin)
selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine, paroxetine, sertraline)
serotonin/norepinephrine reuptake inhibitors (SNRIs; e.g., duloxetine, venlafaxine)
sulfasalazine
tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine, trimipramine

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Pregnancy & Lactation of Sulindac

Sulindac falls into category C before the 30th week of pregnancy, and category D after the 30th week.

Pregnancy

For Pregnancy Category C before the 30th week of pregnancy: Studies in animals have shown a harmful and undesired effect on the unborn baby, yet there are no adequate and well-controlled studies in pregnant women. This medication may be given to a pregnant woman if her healthcare provider believes that its benefits to the pregnant woman outweigh any possible risks to her unborn baby. For Pregnancy Category D after the thirtieth week of pregnancy: Sulindac should be avoided during the third trimester of pregnancy. There is evidence of risk to the unborn baby based on studies in humans or adverse reaction data.

Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if sulindac is excreted in human breast milk or if it will harm your nursing baby.