COX Inhibitors

Article Author:
Owais Qureshi
Article Editor:
Anterpreet Dua
Updated:
7/10/2020 11:13:23 AM
PubMed Link:
COX Inhibitors

Indications

Cyclooxygenase (COX) inhibitors enjoy use in a wide variety of conditions and diseases for their analgesic, anti-inflammatory, and antipyretic properties. Diseases and conditions in which COX-inhibitors are indicated include but are not limited to osteoarthritis, rheumatoid arthritis, musculoskeletal injury, spondyloarthritis, migraines, and colon cancer (aspirin). According to the World Health Organization ladder, COX inhibitors are indicated for mild pain. Most professional societies, including the American College of Rheumatology, recommend the lowest dose and shortest duration regimen due to the risks associated with COX inhibitors.[1] Aspirin's indications include the secondary prevention of cardiovascular and cerebrovascular events.[2]

Mechanism of Action

COX inhibitors divide into non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 selective nonsteroidal anti-inflammatory drugs (c2s NSAIDs), and aspirin. NSAIDs include ibuprofen, naproxen, ketorolac, and indomethacin. C2s NSAIDs only include celecoxib. Meloxicam and diclofenac are cox-inhibitors that are not categorized.

The cox enzyme catalyzes the conversion of arachidonic acid into prostaglandin.[3] It has two known isoforms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). There are over 20 COX inhibitors, and each of them varies in the amount they inhibit each of the isoforms.

The COX-1 enzyme regulates many cellular processes, including platelet aggregation, kidney afferent arteriole vasodilation, and gastric mucosa acid protection.[4] The COX-2 enzyme is an inducible enzyme and increases during inflammatory processes. It is present in the brain, kidney, bone, and female reproductive system.[5]

C2s NSAIDs work by preferentially inhibiting COX-2. Aspirin irreversibly inhibits both COX-1 and COX-2 but, more so, inhibits COX-1 than COX-2. 

There have been several other mechanisms of action attributed to COX inhibitors. Amongst them is inhibition of neutrophil function and inhibition of the inducible nitric oxide synthetase.[6][7]

Administration

COX inhibitors are most commonly given orally by mouth. Ketorolac administration can be via the intramuscular or intravenous route. Several COX inhibitors are administered topically, as well. Topical NSAIDs have been shown to have the least amount of systemic side effects.[8]

Adverse Effects

Adverse effects vary depending on the COX-inhibitor used. 

Mortality Rate - Mortality rate associated with COX inhibitors is 21 per million and 24.8 per one million for NSAIDs and low dose aspirin, respectively.[2]

GI Effects

COX inhibitors can cause upper and lower gastrointestinal side effects ranging from mild irritation to more severe adverse events such as bleeding and perforation. Risk factors include patients who are older than 65 years old, have had a history of peptic ulcer disease, or are also on steroids or blood thinners. It is best to avoid NSAIDs in these patients.[9]

Upper GI side effects get reported more frequently.[2] Amongst the upper GI side effects, dyspepsia, heartburn, and nausea occur. Gastric or duodenal mucosal injury and ulceration may result as well. When ulceration develops into bleeding, endoscopic therapy and high dose proton pump inhibitor are recommended and decrease mortality [10]. 

Lower GI side effects are present within 75% of patients taking NSAIDs.[2] Patients can have ulceration, bleeding, strictures, or obstruction. Management always involves stopping the medication but can include endoscopic interventions as well.[10] In severe circumstances, laparotomy and bowel segment resection is necessary. Celecoxib has been found to correlate with fewer GI side effects, especially in combination with a proton pump inhibitor.[2] However, proton pump inhibitors have not been shown to decrease the risk of lower GI side effects, and their preventative effect does not occur beyond the stomach. Furthermore, the evidence is currently increasing regarding the concept that PPIs increase the risk of small bowel damage.[10]

Helicobacter pylori (H. pylori) is now implicated in increasing the risk of peptic ulcer disease in patients who are on NSAIDs and eradication of H.pylori before the initiation of NSAID use has been shown to reduce the risk of upper GI ulcers and can be useful as a preventative tool.[2]

For patients with significant GI bleeding risk who require NSAID therapy, the current recommendation is the lowest possible dose celecoxib with a PPI.[2]

CV Effects

Non-aspirin cox inhibitors increase the risk of cardiovascular events, namely myocardial infarction, cardiovascular-related mortality, and stroke. The risk is small in patients without cardiovascular disease and slightly greater in patients with pre-existing cardiovascular disease.[5] The overall risk is less than the risk of GI side effects.[2] In 2015, the FDA strengthened its label warning regarding NSAIDs and the risk of heart attack and stroke. The risk of myocardial infarction has been observed to be at its peak with just 7 days of NSAID use. Celecoxib, however, requires 30 days of continuous use. This risk remained sustained for 3 weeks and 3.5 months after discontinuation of non-selective NSAIDs and celecoxib, respectively.[13] In 2016, the PRECISION trial demonstrated that moderate dose celecoxib was not inferior compared to ibuprofen and naproxen in cardiovascular safety.[11] Furthermore, in the safety analysis of six randomized controlled trials, the risk appears to be non-significant with low dose celecoxib, 400 mg daily. Therefore, in a patient with high cardiovascular risk requiring NSAID therapy, the current recommendation is celecoxib 200 mg daily. If a patient has low GI risk, naproxen is acceptable, as well. Diclofenac has been shown to have the highest cardiac risk.[8] Potential benefits such as improving quality of life should be carefully weighed with cardiovascular risks when deciding whether to start an NSAID on a patient.[5]

Renal Effects

The risk of renal effects with cox inhibitors is 1 to 5%.[11] COX inhibitors, non-specific NSAIDs and COX-2 specific NSAIDs both, can have adverse effects on the kidney. They are important players in vasoconstriction at the afferent arteriole level of the kidney. COX inhibitors should be avoided in patients with hypovolemia, prior kidney disease, or hypotension. COX-2, although generally thought to be an inducible enzyme,  is constitutively expressed in the kidney.

Acute renal failure, chronic renal failure, acute interstitial nephritis, sodium and fluid retention, and hypertension have all had reports as adverse effects of COX inhibitors. PGE2 and PGI2 both act as vasodilators in the kidney, and a decrease in them is thought to lead to adverse renal effects. Acute renal failure is dose-dependent, duration-dependent, and reversible and is believed to occur due to a decrease in PGE2 and PGI2.[12] Joint use of angiotensin receptor blockers or diuretics increases the risk of acute renal failure.[11]

NSAIDs may decrease blood flow to the papillae leading to destruction and renal papillary necrosis. There have been cases reported for both traditional NSAIDs as well as celecoxib. 

Acute interstitial nephritis occurs when there is inflammation within the interstitium of the kidney at the level of tubules; this can be due to a hypersensitivity reaction. Acute interstitial nephritis is reversible and occurs days after exposure. It commonly leads to nephrotic syndrome and can also lead to chronic renal failure.  At this time, the mechanism of how NSAIDs cause acute interstitial nephritis is unknown.[9]

NSAIDs can cause sodium retention leading to weight gain and edema. Hyperkalemia can occur as well. Celecoxib and diclofenac have a higher risk of causing hyperkalemia.[9]

Hematologic Effects

COX inhibitors have been known to cause platelet inhibition by inhibiting thromboxane A2 production. Aspirin causes irreversible inhibition of COX, and therefore, the duration of platelet inhibition lasts until 7 to 10 days after drug discontinuation. Patients who have other reasons for increased bleeding, such as alcohol, anticoagulants, or liver failure, have enhanced bleeding risk. 

Platelet inhibition increases bleeding time. NSAIDs cause reversible COX inhibition, and therefore the duration of platelet inhibition depends on specific pharmacokinetics such as drug dosing and half-life.[13] Non-selective NSAIDs inhibit the anti-aggregate effect of aspirin and cause an increase in CV risk compared to low dose aspirin alone. COX-2 selective inhibitors do not impede the antiplatelet effect of aspirin.[2]

Malignancy

COX inhibitors have commonly shown favorable effects on cancer rather than adverse. Continuous aspirin use has demonstrated effectiveness in colorectal cancer prevention through a multitude of colorectal cancer pathways. It is recommended to select patients who are also at increased cardiovascular risk.[15] Aspirin and NSAIDs have been studied in prostate cancer as well, and results have shown that COX inhibitors could reduce the risk of prostate cancer, but currently, there are no clear guidelines or indications. Furthermore, long term use has to balance against the negative effects.[14] Intense non-aspirin COX inhibitors have correlated with increased survival with serous ovarian cancer.[15]

Hypersensitivity Reactions

NSAIDs are the most common medications that cause hypersensitivity reactions.  The number of hypersensitivity reactions caused by NSAIDs is extensive, complex, and classification is evolving. Hypersensitivity reactions vary widely in presentation and mechanism. They can be due to a specific drug, termed selective responder in the literature, or due to any NSAID, termed cross intolerant. Clinical manifestations include urticaria, rhinitis, asthma, angioedema, bullous or desquamating skin lesions, DRESS syndrome, or toxic epidermal necrolysis. Some reactions are organ-specific clinical entities, causing bile duct syndrome, meningitis, or vasculitis. Mechanisms can be IgE mediated, T cell-mediated, prostaglandin inhibition mediated, or are often unknown. Other possible causes are present as well, and clinicians may miss NSAIDs as the primary cause. Ibuprofen is the most common among all NSAIDs to cause a hypersensitivity reaction. 

The most described hypersensitivity reaction is NSAID exacerbated respiratory disease. It has a complex mechanism involving eosinophils and many other mediators. Chronic inflammation leads to symptoms such as rhinitis, nasal polyps, sinusitis, and asthma. It can result from an NSAID and has cross-intolerance. Single NSAID induced urticaria, angioedema, and anaphylaxis can occur, and symptoms usually occur in less than one hour.[16]

Contraindications

  • Allergy
  • History of ulcers
  • History of GI bleeding
  • History of coronary artery bypass
  • Renal impairment
  • Cirrhosis
  • Preexisting platelet defects

Monitoring

NSAIDs interact with anticoagulants, aspirin, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, and steroids and increased monitoring of kidney function, coagulation, and GI effects may be necessary. Kidney function may require monitoring in patients who are at risk for renal failure as well.

Toxicity

Overdose of COX inhibitors is rare and leads to minor symptoms or no symptoms at all, in adults and children. Severe symptoms have occurred, but those patients had taken multiple drugs at the same time.[17]

Enhancing Healthcare Team Outcomes

COX inhibitors are amongst the most commonly used medications in the world. Although they are available over the counter, they can have serious side effects and are associated with mortality. Patients need to speak to their physicians about taking COX inhibitors, especially if they plan to take them for an extended period. Clinicians should educate patients regarding having a list of medications, including over the counter medications with them available at all times. Patients at risk may require regular monitoring of kidney function as well as an endoscopy exam. The monitoring of renal function and/or coagulation has its basis on level III evidence.[8]

If planning a procedure for a patient on aspirin, communication is essential with the prescribing physician. 

When a patient does have an NSAID associated complication such as a GI bleed, all interprofessional healthcare team members must be aware of the contraindications and possible adverse effects. This involves excellent communication between gastroenterologists, primary care providers, nurses, and pharmacists. The contraindication should be communicated clearly with the patient and made clear in the patient's chart. Nursing will carry much of this responsibility since they have more frequent contact with the patient and can assess therapeutic effectiveness as well as monitor for adverse effects. The pharmacist can verify appropriate dosing and check for drug interactions, and communicate any concerns to the prescriber. All members of the interprofessional team need to communicate and collaborate to make COX inhibitor therapy successful, optimizing patient outcomes. [Level 5]


References

[1] Vargas-Schaffer G, Is the WHO analgesic ladder still valid? Twenty-four years of experience. Canadian family physician Medecin de famille canadien. 2010 Jun     [PubMed PMID: 20547511]
[2] Scarpignato C,Lanas A,Blandizzi C,Lems WF,Hermann M,Hunt RH, Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis--an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC medicine. 2015 Mar 19     [PubMed PMID: 25857826]
[3] Vane JR, Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature: New biology. 1971 Jun 23     [PubMed PMID: 5284360]
[4] Adelizzi RA, COX-1 and COX-2 in health and disease. The Journal of the American Osteopathic Association. 1999 Nov     [PubMed PMID: 10643175]
[5] Dubois RN,Abramson SB,Crofford L,Gupta RA,Simon LS,Van De Putte LB,Lipsky PE, Cyclooxygenase in biology and disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 1998 Sep     [PubMed PMID: 9737710]
[6] Díaz-González F,González-Alvaro I,Campanero MR,Mollinedo F,del Pozo MA,Muñoz C,Pivel JP,Sánchez-Madrid F, Prevention of in vitro neutrophil-endothelial attachment through shedding of L-selectin by nonsteroidal antiinflammatory drugs. The Journal of clinical investigation. 1995 Apr     [PubMed PMID: 7535797]
[7] Amin AR,Vyas P,Attur M,Leszczynska-Piziak J,Patel IR,Weissmann G,Abramson SB, The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase. Proceedings of the National Academy of Sciences of the United States of America. 1995 Aug 15     [PubMed PMID: 7544010]
[8] Hatt KM,Vijapura A,Maitin IB,Cruz E, Safety Considerations in Prescription of NSAIDs for Musculoskeletal Pain: A Narrative Review. PM & R : the journal of injury, function, and rehabilitation. 2018 Dec     [PubMed PMID: 29964214]
[9] Harirforoosh S,Asghar W,Jamali F, Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques. 2013     [PubMed PMID: 24393558]
[10] Guo CG,Leung WK, Potential Strategies in the Prevention of Nonsteroidal Anti-inflammatory Drugs-Associated Adverse Effects in the Lower Gastrointestinal Tract. Gut and liver. 2019 Sep 25     [PubMed PMID: 31547642]
[11] Curtis E,Fuggle N,Shaw S,Spooner L,Ntani G,Parsons C,Corp N,Honvo G,Baird J,Maggi S,Dennison E,Bruyère O,Reginster JY,Cooper C, Safety of Cyclooxygenase-2 Inhibitors in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis. Drugs & aging. 2019 Apr     [PubMed PMID: 31073922]
[12] Bally M,Beauchamp ME,Abrahamowicz M,Nadeau L,Brophy JM, Risk of acute myocardial infarction with real-world NSAIDs depends on dose and timing of exposure. Pharmacoepidemiology and drug safety. 2018 Jan     [PubMed PMID: 29171096]
[13] Schafer AI, Effects of nonsteroidal antiinflammatory drugs on platelet function and systemic hemostasis. Journal of clinical pharmacology. 1995 Mar     [PubMed PMID: 7608308]
[14] Hayashi T,Fujita K,Matsushita M,Nonomura N, Main Inflammatory Cells and Potentials of Anti-Inflammatory Agents in Prostate Cancer. Cancers. 2019 Aug 12     [PubMed PMID: 31408948]
[15] Verdoodt F,Dehlendorff C,Friis S,Kjaer SK, Non-aspirin NSAID use and ovarian cancer mortality. Gynecologic oncology. 2018 Aug     [PubMed PMID: 29960709]
[16] Blanca-Lopez N,Soriano V,Garcia-Martin E,Canto G,Blanca M, NSAID-induced reactions: classification, prevalence, impact, and management strategies. Journal of asthma and allergy. 2019     [PubMed PMID: 31496752]
[17] Kanabar DJ, A clinical and safety review of paracetamol and ibuprofen in children. Inflammopharmacology. 2017 Feb     [PubMed PMID: 28063133]