Nonsteroidal Antiinflammatory Drugs

Nonsteroidal antiinflammatory drugs (NSAIDs) are a class of medications consisting of aspirin, reversible NSAIDs, and selective NSAIDs. NSAIDs are used as antiplatelet, analgesic, antipyretic, and antiinflammatory agents. Common side effects include GI irritation, prolonged bleeding, and AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury.

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Pharmacodynamics

Mechanism of action

Nonsteroidal antiinflammatory drugs (NSAIDs) exert their therapeutic effects by interrupting fatty acid metabolism, primarily the action of cyclooxygenase (COX) on arachidonic acid (AA). 

  •  Arachidonic acid is a phospholipid found in cell membranes that is released by a variety of stimuli to include cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane damage.
  • COX converts arachidonic acid into: 
    • Thromboxanes: 
      • Involved in platelet adhesion
      • Involved in vasoconstriction
    • Prostaglandins:
      • Mediate inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
      • Increase hypothalamic temperature set-point
      • Involved in anti-nociception
      • Trigger uterine contractions during menstruation
    • Prostacyclin (prostaglandin I2): 
      • Inhibits platelet aggregation
      • Involved in vasodilation
  • There are 2 COX isoenzymes:
    • COX-1 is constitutively expressed in the body:
      • Involved in maintenance of GI mucosal lining
      • Involved in kidney vasoregulation
      • Involved in platelet aggregation
    • COX-2–induced expression occurs only during the inflammatory response 
  • Non–COX-selective NSAIDs:
    • Irreversibly (aspirin) or reversibly (other NSAIDs) inhibit both COX-1 and COX-2 
    • Decrease synthesis of: 
      • Thromboxane A2 (TXA2)
      • Prostaglandins
      • Prostacyclins
    • Therapeutic and adverse effects are attributed to diminution of these eicosanoids Eicosanoids Eicosanoids are cell-signaling molecules produced from arachidonic acid. With the action of phospholipase A2, arachidonic acid is released from the plasma membrane. The different families of eicosanoids, which are prostaglandins (PGs), thromboxanes (TXA2s), prostacyclin (PGI2), lipoxins (LXs), and leukotrienes (LTs), emerge from a series of reactions catalyzed by different enzymes. Eicosanoids
  • COX-2–selective NSAIDs:
    • Selectively inhibit COX-2
    • Decrease prostaglandin synthesis 
    • Spare COX-1 and, therefore, TXA2 synthesis
    • Have different side effect profiles from nonselective NSAIDs

Pharmacokinetics

NSAIDs are generally very similar:

  • Lipid-soluble weak acids
  • Nearly complete absorption from GI tract
    • Topical formulations are available (diclofenac)
    • IV formulations are available (ibuprofen)
  • Minimal 1st-pass hepatic metabolism
  • Highly protein-bound 
  • Small volume of distribution
  • Metabolized by CYP3A and CYP2C and /or glucuronidation.
  • Half-lives vary from < 2 to > 8 hours.
  • Excreted renally
Arachidonic acid pathway nonsteroidal anti-inflammatory drugs

Arachidonic acid pathway
HPETEs: hydroperoxyeicosatetraenoic acids
LOX: lipoxygenase
LT: leukotriene

Image by Lecturio. License: CC BY-NC-SA 4.0

Classification

NSAIDs can be divided into groups based on their ability to inhibit the isoforms of cyclooxygenase (COX-1 and COX-2).

  • Nonselective NSAIDs inhibit both COX-1 and COX-2.
    • Included in this category: 
      • Aspirin
      • Diclofenac
      • Ibuprofen
      • Naproxen
      • Mefenamic acid
      • Indomethacin
      • Ketoprofen
      • Piroxicam
      • Sulindac
  • Selective NSAIDs inhibit only the COX-2 isoform.
    • Included in this category:
      • Celecoxib
      • Meloxicam (at doses < 7.5 mg/day)

Indications

  • Aspirin:
    • Low dose (< 300 mg/day): antiplatelet effect to prevent atherosclerotic ischemic events
    • Medium dose (300–2400 mg/day): analgesic and antipyretic effects
    • High dose (2400–4000 mg/day): antiinflammatory effect
  • Reversible NSAIDs:
    • Analgesic
    • Antipyretic
    • Antiinflammatory
    • Closure of patent ductus arteriosus Patent ductus arteriosus The ductus arteriosus (DA) allows blood to bypass pulmonary circulation. After birth, the DA remains open for up to 72 hours and then constricts and involutes, becoming the ligamentum arteriosum. Failure of this process to occur results in patent ductus arteriosus (PDA), a condition that causes up to 10% of congenital heart defects. Patent Ductus Arteriosus (PDA) (indomethacin)
  • Celecoxib:
    • Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis
    • Osteoarthritis Osteoarthritis Osteoarthritis (OA) is the most common form of arthritis, and is due to cartilage destruction and changes of the subchondral bone. The risk of developing this disorder increases with age, obesity, and repetitive joint use or trauma. Patients develop gradual joint pain, stiffness lasting < 30 minutes, and decreased range of motion. Osteoarthritis

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Adverse Effects

GI tract effects

  • Prostaglandins inhibit gastric acid secretion and promote protective mucus production. 
  • NSAIDs block prostaglandins:
    • → Dyspepsia
    • → GI erosion
    • → GI ulceration
    • → GI bleeding

Cardiovascular effects

  • Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation.
  • NSAIDs block prostacyclin:
    • → Vasoconstriction
    • → Platelet aggregation
  • Platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets contain only COX-1, which produces TXA2.
  • Thromboxane A2 is a potent vasoconstrictor and platelet aggregator and is thrombogenic.
  • Selective COX-2 inhibition results in unopposed COX-1 effects:
    • → Vasoconstriction
    • → Platelet aggregation
    • → Prothrombotic state
  • Long-term COX-2 inhibitor use is associated with increased risk of cardiovascular complications. 
  • Nonselective NSAIDs (except aspirin) also are associated with increased risk (though less than with selective COX-2). 
  • Safest NSAID/cardiovascular risk profile in this setting appears to be naproxen.

Renal effects

  • Prostaglandins are involved in renin release, regulation of vascular tone, and control of tubular function in the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys.
  • NSAIDs block prostaglandins:
    • AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury
    • → Interstitial nephritis
    • → Renal papillary necrosis

Miscellaneous effects

  • NSAID-associated bleeding risk significant only in combination with other anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants.
  • Diclofenac and sulindac have been associated with liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver dysfunction and failure.

Aspirin Toxicity

Salicylate toxicity is a series of symptoms and metabolic disturbances attributable to excessive ingestion of salicylic acid (e.g., aspirin and other over-the-counter (OTC) preparations). Accidental exposure is seen in pediatric patients, whereas purposeful exposure is more commonly observed in adolescents and young adults (i.e., suicide Suicide Suicide is one of the leading causes of death worldwide. Patients with chronic medical conditions or psychiatric disorders are at increased risk of suicidal ideation, attempt, and/or completion. The patient assessment of suicide risk is very important as it may help to prevent a serious suicide attempt, which may result in death. Suicide attempt).

  • Initial symptoms:
    • Nausea and vomiting
    • Tinnitus and vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo (cranial nerve (CN) VII overactivation)
    • Diaphoresis
    • Hyperventilation
    • Tachycardia
    • Hyperactivity 
  • Symptoms of progressive toxicity:
    • Agitation
    • Delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium
    • Convulsions
    • Lethargy/stupor
    • Hyperthermia
  • Metabolic (acid–base) disturbance:
    • The early phase of respiratory alkalosis Respiratory alkalosis The respiratory system is responsible for eliminating the volatile acid carbon dioxide (CO2), which is produced via aerobic metabolism. When hypoventilation occurs, excess carbon dioxide is blown off and respiratory alkalosis develops. The kidneys respond by decreasing serum bicarbonate (HCO3-) through increased HCO3- excretion or decreased excretion of H+. Respiratory Alkalosis: due to the overactivation of the medullary respiratory center
    • The middle phase of combined respiratory alkalosis Respiratory alkalosis The respiratory system is responsible for eliminating the volatile acid carbon dioxide (CO2), which is produced via aerobic metabolism. When hypoventilation occurs, excess carbon dioxide is blown off and respiratory alkalosis develops. The kidneys respond by decreasing serum bicarbonate (HCO3-) through increased HCO3- excretion or decreased excretion of H+. Respiratory Alkalosis and metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
    • The late phase of high anion gap metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis: due to aspirin metabolite (salicylate)
  • Treatment:
    • Aspirin toxicity treated with sodium bicarbonate (NaHCO3): sodium bicarbonate alkalinizes urine, facilitating salicylate excretion.
    • Dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of Dialysis may be needed if sodium bicarbonate treatment is unsuccessful.

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Comparison of NSAIDs

Table: Comparison of NSAIDs
Class Mechanism of action Clinical use Side effects
Reversible NSAIDs (e.g., ibuprofen, ketorolac, indomethacin)
  • Reversibly inhibit COX-1 and COX-2
  • Decreased prostaglandin and thromboxane A2 (TXA2) synthesis
  • Analgesic
  • Antipyretic
  • Antiinflammatory
  • Closure of patent ductus arteriosus Patent ductus arteriosus The ductus arteriosus (DA) allows blood to bypass pulmonary circulation. After birth, the DA remains open for up to 72 hours and then constricts and involutes, becoming the ligamentum arteriosum. Failure of this process to occur results in patent ductus arteriosus (PDA), a condition that causes up to 10% of congenital heart defects. Patent Ductus Arteriosus (PDA) ( PDA PDA The ductus arteriosus (DA) allows blood to bypass pulmonary circulation. After birth, the DA remains open for up to 72 hours and then constricts and involutes, becoming the ligamentum arteriosum. Failure of this process to occur results in patent ductus arteriosus (PDA), a condition that causes up to 10% of congenital heart defects. Patent Ductus Arteriosus (PDA))
  • Gastric ulcers and GI bleeding
  • AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury
  • Interstitial nephritis
  • Renal papillary necrosis
  • Aspirin:
    • Reye syndrome in children with a viral infection
    • Asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma-like symptoms in patients with nasal polyps or atopy
    • Tinnitus
    • Mixed respiratory alkalosis Respiratory alkalosis The respiratory system is responsible for eliminating the volatile acid carbon dioxide (CO2), which is produced via aerobic metabolism. When hypoventilation occurs, excess carbon dioxide is blown off and respiratory alkalosis develops. The kidneys respond by decreasing serum bicarbonate (HCO3-) through increased HCO3- excretion or decreased excretion of H+. Respiratory Alkalosis metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
Aspirin
  • Irreversibly inhibits COX-1 and COX-2
  • Decreased prostaglandin and TXA2 synthesis
  • Low dose (< 300 mg/day): antiplatelet
  • Medium dose (300–2400 mg/day): analgesic and antipyretic
  • High dose (2400–4000 mg/day): antiinflammatory
COX-2 inhibitors (e.g., celecoxib)
  • Selectively inhibit COX-2
  • Decreased prostaglandin synthesis
  • Spared platelets and TXA2 synthesis
  • Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis
  • Osteoarthritis Osteoarthritis Osteoarthritis (OA) is the most common form of arthritis, and is due to cartilage destruction and changes of the subchondral bone. The risk of developing this disorder increases with age, obesity, and repetitive joint use or trauma. Patients develop gradual joint pain, stiffness lasting < 30 minutes, and decreased range of motion. Osteoarthritis
  • Increased risk of thrombosis:
    • Deep venous thrombosis
    • Pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism
  • Acute MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
  • Sulfa allergy

References

  1. Solomon, D.H. (2020). Nonselective NSAIDs: overview of adverse effects. UpToDate. Retrieved June 20, 2021, from https://www.uptodate.com/contents/nonselective-nsaids-overview-of-adverse-effects
  2. Solomon, D.H. (2019). NSAIDs: pharmacology and mechanism of action. UpToDate. Retrieved June 20, 2021, from https://www.uptodate.com/contents/nsaids-pharmacology-and-mechanism-of-action
  3. Solomon, D.H. (2021). Overview of COX-2 selective NSAIDs. UpToDate. Retrieved June 20, 2021, from https://www.uptodate.com/contents/overview-of-cox-2-selective-nsaids
  4. Phillips, W.J., Currier, B.L. (2004). Analgesic pharmacology: II. Specific analgesics. J Am Acad Orthop Surg 12:221–233. https://pubmed.ncbi.nlm.nih.gov/15473674/
  5. Dawood, M.Y. (2006). Primary dysmenorrhea: advances in pathogenesis and management. Obstet Gynecol 108:428–441. https://pubmed.ncbi.nlm.nih.gov/16880317/
  6. Shekelle, P.G., et al. (2017). Management of gout Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or "gout flare," followed later by chronic deforming arthritis. Gout: a systematic review in support of an American College of Physicians clinical practice guideline. Ann Intern Med 166:37–51. https://pubmed.ncbi.nlm.nih.gov/27802478/
  7. Oyler, D.R., et al. (2015). Nonopioid management of acute pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain associated with trauma: Focus on pharmacologic options. J Trauma Acute Care Surg 79:475–483. https://pubmed.ncbi.nlm.nih.gov/26307883/
  8. Zacher, J., et al. (2008). Topical diclofenac and its role in pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation: an evidence-based review. Curr Med Res Opin 24:925–950. https://pubmed.ncbi.nlm.nih.gov/18279583/
  9. Van den Bekerom, M.P.J., et al. (2015). Non-steroidal anti-inflammatory drugs (NSAIDs) for treating acute ankle sprains in adults: benefits outweigh adverse events. Knee Surg Sports Traumatol Arthrosc 23:2390–2399. https://pubmed.ncbi.nlm.nih.gov/24474583/
  10. May, J.J., Lovell, G., Hopkins, W.G. (2007). Effectiveness of 1% diclofenac gel in the treatment of wrist extensor tenosynovitis in long distance kayakers. J Sci Med Sport 10:59–65. https://pubmed.ncbi.nlm.nih.gov/16787761/
  11. Barkin, R.L. (2015). Topical nonsteroidal anti-inflammatory drugs: the importance of drug, delivery, and therapeutic outcome. Am J Ther 22:388–407. https://pubmed.ncbi.nlm.nih.gov/22367354/
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