General Information

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Indications

• Arthritis
  • Acute Gout (see Gout)
  • Osteoarthritis (see Osteoarthritis)
  • Rheumatoid Arthritis (see Rheumatoid Arthritis)
• Dysmenorrhea (see Dysmenorrhea)
• Fever (see Fever)
• Pain
  • Post-Operative Pain
  • Soft Tissue/Musculoskeletal Injury
• Protective Role Against the Development of Malignancy
  • Breast Cancer (see Breast Cancer)
  • Colorectal Cancer (see Colorectal Cancer)
  • Prostate Cancer (see Prostate Cancer)

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Contraindications

• Chronic Kidney Disease (CKD) (see Chronic Kidney Disease)
  • Due to Risk of Worsening Chronic Kidney Disease
• Cirrhosis/Chronic Liver Disease (see Cirrhosis)
  • Due to Frequent Co-Existing Chronic Kidney Disease (and Risk of Hepatorenal Syndrome) (see Hepatorenal Syndrome)
  • Due to Risk of Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage)

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Agents

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Pharmacology

Genetics of Cyclooxgenases (COX-1, COX-2, and COX-3)

• Sequence Homology: COX-1 and COX-2 are 50-60% homologous
• Chromosomal Location of COX-1: chromosome 9
• Chromosomal Location of COX-2: chromosome 1

Tissue Expression of Cyclooxgenases (COX-1, COX-2, and COX-3)

• COX-1: constitutively expressed
  • Gastroduodenal Mucosa: COX-1 functions to produce mucosal-protective prostaglandins
  • Kidney: COX-1 is found in the collecting ducts, renal vasculature, and papillary interstitium
• COX-2: COX-2 is predominantly inducible (by endotoxin, TNF-Alpha, IL-1Beta, and mitogens)
  • However, constitutively expressed COX-2 can be found in normal human kidneys
  • Kidney: COX-2 is found in the arterial endothelial cells, arterioles and glomeruli of the cortex, cortical thick ascending limb of the loop of Henle, the endothelial lining of the vasa recta and collecting ducts

Physiologic Functions of Cyclooxgenases (COX-1, COX-2, and COX-3)

• COX-1
  • Renal Regulation of Natriuresis
  • Platelet Aggregation
  • Protection of Renal/Gastrointestinal Cell Function
• COX-2
  • Inflammatory Response: pain, fever, inflammation
  • Renal Protection: since the effects of renal ischemia are more pronounced in COX-2 knockout mice
• COX-3: unclear physiologic role
  • Effect of NSAID’s on COX-3 is unknown

NSAID’s Function as COX-1/COX-2 Inhibitors

NSAID Inhibition of COX-1

• NSAID Inhibition of COX-1: has been most associated with the cardiovascular protective effects and gastrointestinal toxicity of NSAID’s
• COX-1 Selectivity of Various NSAID’s (in Descending Order)
  • Ketorolac (Toradol) (see Ketorolac)
  • Flurbiprofen
  • Ketoprofen (Orudis, Oruvail) (see Ketoprofen)
  • Indomethacin (Indocin) (see Indomethacin)
  • Acetylsalicylic Acid (Aspirin) (see Acetylsalicylic Acid)
  • Naproxen (Naprosyn) (see Naproxen)
  • Tolemetin
  • Ibuprofen (Advil, Brufen, Motrin, Nurofen) (see Ibuprofen

NSAID Inhibition of COX-2

• NSAID Inhibition of COX-2: has been most associated with the anti-inflammatory effects of NSAID’s
• COX-2 Selectivity of Various NSAID’s (in Descending Order)
  • Lumiracoxib
  • Rofecoxib (Vioxx, Ceoxx, Ceeoxx) (see Rofecoxib)
  • Etoricoxib
  • Valdecoxib
  • Etodolac (Lodine, Eccoxolac) (see Etodolac)
  • Meloxicam (Mobic) (see Meloxicam)
  • Celecoxib (Celebrex) (see Celecoxib)
  • Diclofenac (Aclonac, Cataflam, Voltaren) (see Diclofenac)
  • Sulindac (Clinoril) (see Sulindac)
  • Piroxicam (Feldene) (see Piroxicam)
  • Diflunisal (Dolobid) (see Diflunisal)
  • Sodium Salicylate

Pharmacokinetics

• NSAID’s are Acidic
• NSAID’s Have High Bioavailability
• NSAID’s are Highly Plasma Protein-Bound

Metabolism

• Hepatic: predominantly
• Renal: renal glucuronidation may be responsible for metabolism of some NSAID’s (naproxen, ibuprofen, ketoprofen), as well

Clinical Effects

• Analgesic, Anti-Pyretic, and Anti-Inflammatory Effects of NSAID’s are Attributed Predominantly to Decreased PGE2 and PGI2
  • Decreased PGE2 is Associated with Efficacy in Arthritis

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Administration

Discontinuation of NSAID’s Prior to Surgery/Procedure

• General Comments: NSAID drug elimination half-life correlates poorly with anti-platelet effects
• Aspirin: discontinue at least 7 days pre-operatively (since aspirin irreversibly inhibits platelet COX, and platelets are unable to synthesize additional COX)
• Most Other NSAID’s: discontinue at least 3 days pre-operatively
• Ibuprofen: discontinue at least 1 day pre-operatively

Use of NSAID’s in Patients with Concurrent Platelet Dysfunction/Thrombocytopenia

• Avoid NSAID’s in Disorders with Platelet Dysfunction (Uremia, Von Willebrand Disease, etc)/Thrombocytopenia: non-acetylated salicylates (salsalate, choline magnesium trisalicylate) or selective COX-2 inhibitor NSAID’s might be more safely used in these cases

Protective Effects of Non-Aspirin NSAID’s

• Non-Aspirin NSAID’s Have Not Been Evaluated for Protective Effects: therefore, they are not considered a substitute for aspirin
  • In addition, use of a non-salicylate NSAID in conjunction with aspirin may interfere with the beneficial protective effects of aspirin

Drug Interactions

• Anticoagulants (Coumadin, Factor Xa Inhibitors, Thrombin Inhibitors, etc)
  • NSAID’s Increase the Risk of Hemorrhage in Patients Anticoagulated with Coumadin/Factor Xa Inhibitors
    • There is an increased risk of serious hemorrhage after the start of aspirin/clopidogrel in patients with new onset atrial fibrillation, as compared to coumadin alone [MEDLINE]: increased risk of 2-2.5 bleeds per 1000 patients
  • Use of NSAID’s in Conjunction with Coumadin Derivatives May Increase the International Normalized Ratio (INR) [MEDLINE]: more vigilant INR monitoring may be required
• Selective Serotonin Reuptake Inhibitors (SSRI’s) (see Selective Serotonin Reuptake Inhibitors): independently increase the risk of gastrointestinal hemorrhage (possibly related to their effects on platelet serotonin)
  • Concomitant NSAID and SSRI Administration: further increases the risk of gastrointestinal hemorrhage over using each agent alone

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Adverse Effects

Allergic/Immunologic Adverse Effects

Pseudoallergic Reactions

• Type 1: NSAID-Induced Asthma and Rhinosinusitis
  • Epidemiology: may be caused by a multiple NSAID’s in a susceptible patient
  • Associated Diseases
    • Asthma: present in most cases
    • Chronic Rhinosinusitis with Nasal Polyposis
    • Aspirin-Exacerbated Respiratory Disease (AERD) (see Aspirin-Exacerbated Respiratory Disease): triad of asthma + chronic rinosinusitis with nasal polyposis + aspirin/NSAID-induced type I pseudoallergic reaction
  • Physiology: related to COX-1 inhibition
  • Timing of Onset: 30-180 min after administration
  • Common Clinical Findings
    • Angioedema (see Angioedema)
    • Bronchospasm (see Obstructive Lung Disease)
    • Conjunctival Injection
    • Facial Flushing (see Flushing)
    • Nasal Obstruction/Severe Rhinitis (see Rhinitis)
    • Peri-Orbital Edema
    • Urticaria (see Urticaria)
  • Uncommon Clinical Findings
    • Abdominal Pain (see Abdominal Pain)
    • Diarrhea (see Diarrhea)
    • Hypotension (see Hypotension)
    • Laryngospasm/Throat Constriction (see Laryngospasm)
    • Nausea/Vomiting (see Nausea and Vomiting)
• Type 2: NSAID-Induced Urticaria in Patient with Chronic Urticaria
  • Epidemiology: may be caused by a multiple NSAID’s in a susceptible patient
  • Associated Diseases
    • Chronic Urticaria
  • Physiology: related to COX-1 inhibition (usually dose-dependent)
  • Timing of Onset: 30-90 min after administration
  • Clinical
    • Angioedema (see Angioedema)
    • Urticaria (see Urticaria)
• Type 3: NSAID-Induced Urticaria and/or Angioedema in Otherwise Asymptomatic Patient
  • Epidemiology: may be caused by a multiple NSAID’s in a susceptible patient
  • Associated Diseases: none
  • Physiology: related to COX-1 inhibition
  • Timing of Onset: 30-90 min after administration
  • Clinical
    • Angioedema (see Angioedema): predominantly facial (periorbital skin, lips, mouth)
    • Urticaria (see Urticaria): predominantly facial (periorbital skin, lips, mouth)
  • Treatment: these patients usually usually tolerate highly-selective COX-2 inhibitor NSAID’s
• Type 4: Mixed NSAID-Induced Reaction in Otherwise Asymptomatic Patient (Involving Both Respiratory Tract and Skin)
  • Epidemiology: may be caused by a multiple NSAID’s in a susceptible patient
    • Includes patients with aspirin-intolerant asthma (aspirin-exacerbated respiratory disease, AERD)
  • Associated Diseases
    • Aspirin-Exacerbated Respiratory Disease (AERD): some cases
  • Physiology: related to COX-1 inhibition
  • Timing of Onset: 30-90 min after administration
  • Clinical
    • Dermal Symptoms
      • Angioedema (see Angioedema)
      • Urticaria (see Urticaria)
    • Respiratory Symptoms
      • Bronchospasm (see Obstructive Lung Disease)
      • Rhinitis (see Rhinitis)

Allergic Reactions

• Type 5: Cutaneous Allergic Reaction Due to a Specific NSAID
  • Epidemiology: caused by a specific NSAID (or by more than one NSAID with similar chemical structure) in a susceptible patient
    • Not reported with aspirin
  • Associated Diseases: none
  • Physiology: IgE-mediated (these patients usually have had at least one prior exposure to the implicated NSAID)
  • Timing of Onset: min-hrs after administration
  • Clinical
    • Angioedema (see Angioedema)
    • Pruritus (see Pruritus)
    • Urticaria (see Urticaria)
• Type 6: Anaphylaxis Due to a Specific NSAID (see Anaphylaxis)
  • Epidemiology: caused by a specific NSAID (or by more than one NSAID with similar chemical structure) in a susceptible patient
    • Interestingly, Anaphylaxis Has Not Been Reported with Aspirin Itself: for this reason, aspirin is used in challenge testing
    • Ibuprofen (see Ibuprofen): most commonly implicated NSAID in the US
    • Diclofenac (see Diclofenac): most commonly implicated NSAID in France
    • Celecoxib (see Celecoxib): cases have been reported
  • Associated Diseases: none
  • Physiology: IgE-mediated (these patients usually have had at least one prior exposure to the implicated NSAID)
  • Timing of Onset: min-hrs after administration
  • Clinical
    • Anaphylaxis (see Anaphylaxis)

Cardiovascular Adverse Effects

Increased Risk of Atrial Fibrillation (see Atrial Fibrillation)

• Epidemiology
  • Class Effect: common to all NSAID’s
  • Meta-Analysis of 5 Studies Examining the Association Between NSAID’s Use and the Incidence of Atrial Fibrillation (Am J Cardiol, 2014): overall, non-aspirin NSAID use was associated with a 12% increased risk of atrial fibrillation [MEDLINE]
    • Relative risk was 1.53 (95% CI: 1.37-1.70) among new non-aspirin NSAID users
  • Selective COX-2 Inhibitors: also demonstrate an increased risk of atrial fibrillation
• Physiology: may be explained by the presence of congestive heart failure and/or renal disease

Increased Risk of Cardiovascular Death/Myocardial Infarction (see Coronary Artery Disease)

• Epidemiology
  • Class Effect: associated with both non-selective NSAID’s and selective COX-2 inhibitors (with the exception of naproxen, which does not appear to increase the risk)
  • Meta-Analysis of 280 Trials (Lancet, 2013) [MEDLINE]
    • Major vascular events were increased by coxibs with RR 1.37 (CI 1.14-1.66; p=0.0009) and diclofenac with RR 1.41 (CI: 1.12-1.78; p=0.0036)
    • Major vascular events were not increased by ibuprofen with RR 1.44 (CI: 0.89-2.33): however, ibuprofen increased major coronary events
    • Naproxen did not increase major vascular events with RR 0.93 (CI: 0.69-1.27)
    • Vascular death was increased by coxibs with RR 1.58 (CI: 1.00-2.49; p=0.0103) and diclofenac with RR 1.65 (CI: 0.95-2.85, p=0.0187), non-significantly by ibuprofen with RR 1.90 (CI: 0.56-6.41; p=0.17), but not by naproxen with RR 1.08 (CI: 0.48-2.47, p=0.80)
    • The proportional effects on major vascular events were independent of baseline characteristics of the patients (including vascular risk)
• Physiology

Dermatologic Adverse Effects

Morbilliform Rash

• Epidemiology: may occur

Pseudoporphyria

• Epidemiology: may occur

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (TEN) (see Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis)

• Epidemiology: uncommon

Endocrinologic Adverse Effects

Drug-Induced Hyporeninemic Hypoaldosteronism (see Hypoaldosteronism)

• Epidemiology
  • Class Effect: common to all NSAID’s
• Physiology: dose-dependent COX-inhibition -> decreased renal prostaglandin synthesis -> results in drug-induced hyporeninemic hypoaldosteronism
• Clinical
  • Hyperkalemia (see Hyperkalemia)
  • Type 4 Renal Tubular Acidosis (RTA) (see Type 4 Renal Tubular Acidosis)

Gastrointestinal/Hepatic Adverse Effects

General Comments

• NSAID-Induced Upper Gastrointestinal Complications
  • Meta-Analysis of 280 Trials Examining Upper Gastrointestinal Complications for Various NSAID’s (Lancet, 2013) [MEDLINE]
    • Coxibs: 1.81 (CI: 1.17-2.81, p=0.0070) -> while selective COX-2 inhibitors generally have less suppressive effects on gastroduodenal prostaglandin synthesis than non-selective NSAID’s, they may still inhibit COX-1 at clinically-relevant doses (therefore, they may still induce gastroduodenal mucosal injury)
    • Diclofenac: 1.89 (CI: 1.16-3.09, p=0.0106)
    • Ibuprofen: 3.97 (CI: 2.22-7.10, p<0.0001)
    • Naproxen: 4.22 (CI: 2.71-6.56, p<0.0001)
• NSAID-Associated Gastrointestinal Intolerance
  • Pooled Analysis of 21 Randomized Trials Examining Gastrointestinal Intolerance for Various NSAID’s (Curr Med Res Opin, 2011) [MEDLINE]: there is a lower incidence of gastrointestinal intolerance with the selective COX-2 inhibitor, celecoxib, as compared to non-selective COX inhibitors (naproxen, ibuprofen, diclofenac)

Colonic Ischemia (Ischemic Colitis) (see Colonic Ischemia)

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Dyspepsia (see Dyspepsia)

• Epidemiology: common
  • Class Effect: common to all NSAID’s
• Physiology: inhibition of COX-1 -> decreased gastroduodenal mucosal-protective prostaglandin synthesis
  • Dyspeptic Symptoms Correlate Poorly with the Degree of Gastroduodenal Mucosal Injury: for this reason, dyspepsia and gastroduodenal mucosal injury should be viewed as separate processes
    • Example: acetaminophen/salsalate may induce dyspepsia, but minimally inhibit gastric COX activity and are not usually associated with gastroduodenal mucosal injury
    • Example: significant gastroduodenal mucosal injury may occur without any dyspeptic symptoms
• Clinical
  • Bloating
  • Epigastric Abdominal Pain (see Abdominal Pain)
  • Epigastric Fullness
  • Nausea (see Nausea and Vomiting)

Elevated Liver Function Tests (LFT’s)/Transaminitis with Acute Hepatocellular Injury (see Drug-Induced Hepatotoxicity)

• Epidemiology
  • Class Effect: common to all NSAID’s
    • In addition, diclofenac appears to induce a unique ANA-positive, autoimmune hepatitis-like syndrome (see Diclofenac) [MEDLINE]
  • Liver failure is rare
• Risk Factors [MEDLINE]
  • Concomitant Use of Other Hepatotoxic Medications
  • Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis): 10-fold increased risk of acute liver injury, as compared to osteoarthritis patients treated with NSAID’s
  • Use of Sulindac (see Sulindac): increased risk, as compared to other NSAID’s
• Physiology: elevation of hepatic transaminases with acute hepatocellular injury

Peptic Ulcer Disease (PUD)/Gastrointestinal Hemorrhage (see Peptic Ulcer Disease and Gastrointestinal Hemorrhage)

• Epidemiology
  • Class Effect: common to all NSAID’s
  • Timing of Onset: most gastroduodenal complications of NSAID’s occur within the first 3 mo of NSAID therapy
• Risk Factors
  • Advanced Age
  • Concurrent Anticoagulant Administration
  • Concurrent Bisphosphonate Administration (see Bisphosphonates): probable risk factor
  • Concurrent Clopidogrel Administration (see Clopidogrel)
  • Concurrent Glucocorticoid Administration (see Corticosteroids)
  • Concurrent Selective Serotonin Reuptake Inhibitor (SSRI) Administration (see Selective Serotonin Reuptake Inhibitors)
  • Higher NSAID Dose: however, even low-dose aspirin can induce gastroduodenal toxicity
  • Longer Duration of NSAID Therapy
  • Past History of NSAID-Related Gastroduodenal Toxicity
  • Past History of Peptic Ulcer Disease
• Physiology: inhibition of COX-1 -> decreased gastroduodenal mucosal-protective prostaglandin synthesis
  • Dyspeptic Symptoms Correlate Poorly with the Degree of Gastroduodenal Mucosal Injury: for this reason, dyspepsia and gastroduodenal mucosal injury should be viewed as separate processes
    • Example: acetaminophen/salsalate may induce dyspepsia, but minimally inhibit gastric COX activity and are not usually associated with gastroduodenal mucosal injury
    • Example: significant gastroduodenal mucosal injury may occur without any dyspeptic symptoms

Hematologic Adverse Effects

Aplastic Anemia (see Aplastic Anemia)

• Most Commonly-Associated NSAID’s
  • Indomethacin (see Indomethacin)
  • Phenylbutazone (see Phenylbutazone)

Neutropenia (see Neutropenia)

• Epidemiology
  • Class Effect: common to all NSAID’s
  • Incidence: occurs in <1% of cases
• Most Commonly-Associated NSAID’s
  • Indomethacin (see Indomethacin)
  • Phenylbutazone (see Phenylbutazone)

Hemorrhage (Due to Anti-Platelet Effects)

• Epidemiology
  • Class Effect: common to all COX-1 inhibitor NSAID’s
    • Highly selective COX-2 inhibitor NSAID’s do not affect platelet aggregation (since COX-2 is not found in platelets)
  • Risk Factors
    • Anticoagulation
    • Selective Serotonin Reuptake Inhibitors (SSRI’s) (see Selective Serotonin Reuptake Inhibitors)
• Physiology: due to COX-1 inhibition -> decreased production of thromboxane A2 (TXA2)
  • TXA2 is normally released from platelets, enhancing their function and inducing platelet aggregation
  • NSAID drug elimination half-life correlates poorly with platelet inhibitory effects

Increased International Normalized Ratio (INR) in Patients on Coumadin Derivatives

• Use of NSAID’s with Coumadin Derivatives May Increase the INR [MEDLINE]: more vigilant INR monitoring may be necessary

Neurologic Adverse Effects

Aseptic Meningitis (see Meningitis)

• Epidemiology: NSAID’s increase risk
  • More common in patients with systemic lupus erythematosus who are treated with phenylpropionic acid class NSAID’s (ibuprofen, naproxen)

Cognitive Dysfunction

• Epidemiology: NSAID’s increase risk (particularly with the use of indomethacin)

Increased Risk of Ischemic Cerebrovascular Accident (CVA) (see Ischemic Cerebrovascular Accident)

• Epidemiology
  • Class Effect: associated with both non-selective NSAID’s and selective COX-2 inhibitors (with the exception of naproxen, which does not appear to increase the risk)
  • Meta-Analysis of 280 Trials (Lancet, 2013) [MEDLINE]
    • Major vascular events were increased by coxibs with RR 1.37 (CI 1.14-1.66; p=0.0009) and diclofenac with RR 1.41 (CI: 1.12-1.78; p=0.0036)
    • Major vascular events were not increased by ibuprofen with RR 1.44 (CI: 0.89-2.33): however, ibuprofen increased major coronary events
    • Naproxen did not increase major vascular events with RR 0.93 (CI: 0.69-1.27)
    • Vascular death was increased by coxibs with RR 1.58 (CI: 1.00-2.49; p=0.0103) and diclofenac with RR 1.65 (CI: 0.95-2.85, p=0.0187), non-significantly by ibuprofen with RR 1.90 (CI: 0.56-6.41; p=0.17), but not by naproxen with RR 1.08 (CI: 0.48-2.47, p=0.80)
    • The proportional effects on major vascular events were independent of baseline characteristics of the patients (including vascular risk)
• Physiology

Psychosis (see Psychosis)

• Epidemiology: NSAID’s increase risk (particularly with the use of indomethacin)

Tinnitus (see Tinnitus)

• Epidemiology: can occur with all NSAID’s
  • More common with high-dose salicylates
• Treatment: reversible upon cessation of NSAID

Ophthalmologic Adverse Effects

Corneal Deposition of Drug Crystals/Corneal Edema

• Epidemiology: may occur

Optic Nerve Pathology

• Epidemiology: may occur

Pulmonary Adverse Effects

Aspirin-Exacerbated Respiratory Disease (AERD) (Aspirin-Intolerant Asthma, AIA) (see Aspirin-Exacerbated Respiratory Disease)

• Epidemiology
  • Class Effect: common to multiple NSAID’s
• Physiology: see above

Drug-Induced Pulmonary Eosinophilia (see Drug-Induced Pulmonary Eosinophilia)

• Associated Agents
  • Acetylsalicylic Acid (Aspirin) (see Acetylsalicylic Acid)
  • Diclofenac (Aclonac, Cataflam, Voltaren) (see Diclofenac)
  • Diflunisal (Dolobid)
  • Fenbufen
  • Fenoprofen (see Fenoprofen): case reports
  • Ibuprofen (Advil, Brufen, Motrin, Nurofen) (see Ibuprofen): case reports
  • Indomethacin (Indocin) (see Indomethacin)
  • Loxoprofen
  • Meloxicam (Mobic) (see Meloxicam)
  • Naproxen (Naprosyn, Aleve) (see Naproxen): appears to be more frequent with naproxen than other NSAID’s
  • Nimesulide
  • Phenylbutazone (Butazolidine)
  • Piroxicam (Feldene) (see Piroxicam)
  • Pranoprofen
  • Sulindac (Clinoril) (see Sulindac): case reports
  • Tenidap
  • Tiaprofenic Acid
  • Tolfenamic Acid
• Diagnosis: lung biopsy demonstrates poorly defined granulomas with infiltrating eosinophils
• Clinical
  • Cough
  • Dyspnea
  • Fever
  • Peripheral Eosinophilia
  • Pulmonary Infiltrates
• Treatment: withdraw NSAID -> may require corticosteroids (see Corticosteroids)

Renal Adverse Effects

General Comments

• Incidence of Renal Adverse Effects: occur in 1-5% of NSAID-Treated Patients [MEDLINE]

Acute Interstitial Nephritis (see Acute Interstitial Nephritis)

• Epidemiology
  • Class Effect: common to multiple NSAID’s

Acute Kidney Injury (AKI) (see Acute Kidney Injury)

• Epidemiology
  • Class Effect: common to multiple NSAID’s (cases have been reported with selective COX-2 inhibitor administration, as well)
• Risk Factors
  • Advanced Age
  • Congestive Heart Failure (CHF) (see Congestive Heart Failure)
  • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease)
  • Cirrhosis (see Cirrhosis)
  • Diabetes Mellitus (see Diabetes Mellitus)
  • Hypovolemia (see Hypovolemic Shock)
  • Nephrotic Syndrome (see Nephrotic Syndrome)
• Mechanisms
  • Decreased Renal Blood Flow: due to inhibition of vasodilator prostaglandins
  • Acute Interstitial Nephritis (see Acute Interstitial Nephritis)

Chronic Kidney Disease (CKD) (see Chronic Kidney Disease)

• Analgesic Nephropathy: defined as renal papillary necrosis and chronic interstitial nephritis due to long-term NSAID use
  • Epidemiology: many of these cases were historically associated with aspirin/antipyrine in combination with phenacetin/paracetamol/salicylamide/caffeine/codeine in proprietary formulations
  • Physiology: aspirin potentiates the nephrotoxicity of phenacetin (and its primary metabolite, acetaminophen)
• Acetaminophen (see Acetaminophen)
  • Epidemiology: data suggesting that chronic acetaminophen use may result in chronic kidney disease is suggestive, but not conclusive [MEDLINE]
    • Physicians Health Study Data [MEDLINE]: acetaminophen use was not associated with chronic kidney disease
  • Physiology: may produce renal papillary necrosis
• Acetylsalicylic Acid (Aspirin) (see Acetylsalicylic Acid)
  • Epidemiology: although aspirin potentiates the nephrotoxicity of phenacetin (and it primary metabolite, acetaminophen), most studies indicate that chronic aspirin use is not associated with chronic kidney disease [MEDLINE]
  • Physiology: may produce renal papillary necrosis
• Other NSAID’s
  • Epidemiology: chronic use of large quantities of NSAID’s may be associated with the development of chronic kidney disease in some patients, but this effect appears to be small [MEDLINE]
  • Other Agents Associated with Renal Papillary Necrosis
    • Celecoxib (Celebrex) (see Celecoxib)
    • Flurbiprofen
    • Ibuprofen (Advil, Brufen, Motrin, Nurofen) (see Ibuprofen)
    • Indomethacin (Indocin (see Indomethacin)
    • Naproxen (Naprosyn, Aleve) (see Naproxen)

Hyperkalemia (see Hyperkalemia)

• Epidemiology
  • Class Effect: common to multiple NSAID’s (may occur with selective COX-2 inhibitors, as well)
  • Incidence: occurs in 10-46% of cases [MEDLINE]
  • Relative Frequency: indomethacin is the NSAID most associated with the development of hyperkalemia (even in healthy patients)
• Risk Factors [MEDLINE]
  • Chronic Kidney Disease (see Chronic Kidney Disease)
  • Congestive Heart Failure (see Congestive Heart Failure)
  • Diabetes Mellitus (see Diabetes Mellitus)
  • Multiple Myeloma (see Multiple Myeloma)
  • Use of Potassium Supplements/Potassium-Sparing Diuretics/Angiotensin Converting Enzyme (ACE) Inhibitors
• Mechanisms
  • Dose-Dependent COX-Inhibition with Decreased Renal Prostaglandin Synthesis: since PGI2 stimulates the juxtaglomerular cells in the kidney to release renin, NSAID inhibition of COX results in decreased renal renin secretion and drug-induced hyporeninemic hypoaldosteronism
  • Impaired Angiotensin II-Induced Release of Aldosterone
  • NSAID-Induced Decrease in Glomerular Filtration Rate: may also contribute

Hyponatremia Due to SIADH (see Syndrome of Inappropriate Antidiuretic Hormone Secretion)

• Epidemiology
  • Class Effect: common to all NSAID’s
    • More common with indomethacin (see Indomethacin)
• Physiology: NSAID’s inhibit renal PGE2 synthesis, potentiating the peripheral activity of vasopressin
  • Prostaglandins normally antagonize the action of antidiuretic hormone

Increased Renal Sodium Reabsorption

• Epidemiology
  • Most Common Renal Adverse Effect of NSAID’s: occurs in 25% of cases
  • Class Effect: common to all NSAID’s
• Risk Factors
  • Advanced Age
  • Diabetes Mellitus (see Diabetes Mellitus)
  • Volume Contraction
    • Cirrhosis (see End-Stage Liver Disease)
    • Congestive Heart Failure (CHF) (see Congestive Heart Failure)
    • Decreased Sodium Intake
    • Diuretics
• Physiology: dose-dependent decrease in PGE2 -> increased renal sodium reabsorption (and decreased water excretion)
  • PGE2 normally inhibits salt and water absorption in the thick ascending limb and collecting duct cells, promoting natriuresis
• Clinical: typically occurs during the first week of therapy
  • Exacerbation of Congestive Heart Failure (see Congestive Heart Failure)
    • Meta-Analysis of 280 Trials (Lancet, 2013) [MEDLINE]: all NSAID’s doubled the risk of CHF
  • Hypertension (see Hypertension): usually moderate
  • Peripheral Edema (see Peripheral Edema)
  • Weight Gain (see Weight Gain)

Increased Risk of Renal Cell Carcinoma

• Epidemiology
  • Nurses’ Health Study and the Health Professionals Follow-up Study (Arch Int Med, 2011) see Renal Cancer) [MEDLINE]: notably, this increased risk was not found with aspirin or acetaminophen

Progression of Existing Chronic Kidney Disease (see Chronic Kidney Disease)

• Epidemiology: NSAID’s may contribute to the progression of pre-existing chronic kidney disease [MEDLINE]
  • Class Effect: common to all NSAID’s

Type 4 Renal Tubular Acidosis (RTA) (see Type 4 Renal Tubular Acidosis)

• Epidemiology
  • Class Effect: common to all NSAID’s
• Physiology: due to NSAID-induced hyporeninemic hypoaldosteronism
• Clinical
  • Non-Anion Gap Metabolic Acidosis (NAGMA) (see Metabolic Acidosis-Normal Anion Gap)

Vascular Adverse Effects

Increased Risk of Venous Thromboembolism (see Deep Venous Thrombosis and Acute Pulmonary Embolism)

• Epidemiology
  • Class Effect: common to all NSAID’s
  • Systematic Review and Meta-analysis (Rheumatology, 2015) [MEDLINE]: NSAID’s increase risk of venous thromboembolism with RR of 1.80 (95% CI: 1.28-2.52)
• Physiology

Salicylate Intoxication

• See Salicylates

NSAID Intoxication

• xxx

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References

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