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Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Nonsteroidal antiinflammatory drugs ( NSAIDs NSAIDS Primary vs Secondary Headaches) are a class of medications consisting of aspirin, reversible NSAIDs NSAIDS Primary vs Secondary Headaches, and selective NSAIDs NSAIDS Primary vs Secondary Headaches. NSAIDs NSAIDS Primary vs Secondary Headaches are used as antiplatelet, analgesic, antipyretic Antipyretic Acetaminophen, 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.

Last updated: Nov 23, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Pharmacodynamics

Mechanism of action

Nonsteroidal antiinflammatory drugs ( NSAIDs NSAIDS Primary vs Secondary Headaches) exert their therapeutic effects by interrupting fatty acid metabolism Fatty acid metabolism Fatty acid metabolism includes the processes of either breaking down fatty acids to generate energy (catabolic) or creating fatty acids for storage or use (anabolic). Besides being a source of energy, fatty acids can also be utilized for cellular membranes or signaling molecules. Synthesis and beta oxidation are almost the reverse of each other, and special reactions are required for variations. Fatty Acid Metabolism, primarily the action of cyclooxygenase (COX) on arachidonic acid ( AA AA Amyloidosis). 

  •  Arachidonic acid is a phospholipid found in cell membranes that is released by a variety of stimuli to include cell membrane damage Membrane Damage Cell Injury and Death.
  • COX converts arachidonic acid into:
    • Thromboxanes Thromboxanes Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. Eicosanoids:
    • Prostaglandins Prostaglandins A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. Eicosanoids:
      • 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 Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation uterine contractions during menstruation Menstruation The periodic shedding of the endometrium and associated menstrual bleeding in the menstrual cycle of humans and primates. Menstruation is due to the decline in circulating progesterone, and occurs at the late luteal phase when luteolysis of the corpus luteum takes place. Menstrual Cycle
    • Prostacyclin Prostacyclin A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension. Eicosanoids (prostaglandin I2):
      • Inhibits platelet aggregation Platelet aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Hemostasis
      • Involved in vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs
  • There are 2 COX isoenzymes Isoenzymes Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics. Basics of Enzymes:
    • COX-1 is constitutively expressed in the body:
      • Involved in maintenance of GI mucosal lining
      • Involved in kidney vasoregulation
      • Involved in platelet aggregation Platelet aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Hemostasis
    • COX-2–induced expression occurs only during the inflammatory response 
  • Non–COX-selective NSAIDs NSAIDS Primary vs Secondary Headaches:
    • Irreversibly (aspirin) or reversibly (other NSAIDs NSAIDS Primary vs Secondary Headaches) inhibit both COX-1 and COX-2 
    • Decrease synthesis Synthesis Polymerase Chain Reaction (PCR) of:
      • Thromboxane A2 (TXA2)
      • Prostaglandins Prostaglandins A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. Eicosanoids
      • 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 NSAIDS Primary vs Secondary Headaches:

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

NSAIDs NSAIDS Primary vs Secondary Headaches are generally very similar:

  • Lipid-soluble weak acids Weak acids Acid-Base Balance
  • Nearly complete absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption from GI tract
    • Topical formulations are available (e.g., diclofenac)
    • IV formulations are available (e.g., 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
The arachidonic acid pathway

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

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Classification

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

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

Indications

  • Aspirin:
    • Low dose (< 325 mg/day):
      • Antiplatelet effect to prevent atherosclerotic ischemic events (usually at doses of 75–100 mg/day)
      • Note: per the USPSTF, initiation of daily low-dose aspirin is no longer recommended for primary prevention of cardiovascular disease in people > 60 yrs
    • High dose (4000–8000 mg/day):
      • Antiinflammatory effect
      • The usual maximal dose is 4500 mg/day due to concern for toxicity Toxicity Dosage Calculation (e.g., gastrointestinal bleeding Gastrointestinal bleeding Gastrointestinal bleeding (GIB) is a symptom of multiple diseases within the gastrointestinal (GI) tract. Gastrointestinal bleeding is designated as upper or lower based on the etiology’s location to the ligament of Treitz. Depending on the location of the bleeding, the patient may present with hematemesis (vomiting blood), melena (black, tarry stool), or hematochezia (fresh blood in stools). Gastrointestinal Bleeding and ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers, hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss, tinnitus Tinnitus A nonspecific symptom of hearing disorder characterized by the sensation of buzzing, ringing, clicking, pulsations, and other noises in the ear. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. Cranial Nerve Palsies)
    • Note: These are not necessarily hard cutoffs, and there is some overlap between these categories.
  • Reversible NSAIDs NSAIDS Primary vs Secondary Headaches:
  • Celecoxib:
    • Rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis
    • 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

Cardiovascular effects

  • Prostacyclin Prostacyclin A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension. Eicosanoids is a potent vasodilator and inhibitor of platelet aggregation Platelet aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Hemostasis.
  • NSAIDs NSAIDS Primary vs Secondary Headaches block prostacyclin Prostacyclin A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension. Eicosanoids:
  • 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: Histology 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:
  • Long-term COX-2 inhibitor use is associated with increased risk of cardiovascular complications. 
  • Nonselective NSAIDs NSAIDS Primary vs Secondary Headaches (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 Prostaglandins A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. Eicosanoids are involved in renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation 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: Anatomy.
  • NSAIDs NSAIDS Primary vs Secondary Headaches block prostaglandins Prostaglandins A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. Eicosanoids:
    • 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 Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage

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: Anatomy dysfunction and failure.

Aspirin Toxicity

Salicylate toxicity Toxicity Dosage Calculation 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 Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship, whereas purposeful exposure is more commonly observed in adolescents and young adults (i.e., suicide attempt Suicide attempt The unsuccessful attempt to kill oneself. Suicide).

  • Initial symptoms:
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • Tinnitus Tinnitus A nonspecific symptom of hearing disorder characterized by the sensation of buzzing, ringing, clicking, pulsations, and other noises in the ear. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. Cranial Nerve Palsies 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) VIII overactivation)
    • Diaphoresis
    • Hyperventilation Hyperventilation A pulmonary ventilation rate faster than is metabolically necessary for the exchange of gases. It is the result of an increased frequency of breathing, an increased tidal volume, or a combination of both. It causes an excess intake of oxygen and the blowing off of carbon dioxide. Respiratory Alkalosis
    • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
    • Hyperactivity Hyperactivity Attention Deficit Hyperactivity Disorder 
  • Symptoms of progressive toxicity Toxicity Dosage Calculation:
    • Agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus
    • 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 Convulsions Seizures
    • Lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia/stupor
    • Hyperthermia
  • Metabolic (acid–base) disturbance:
    • The early phase of respiratory alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis: due to the overactivation of the medullary respiratory center
    • The middle phase of combined respiratory alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis and metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
    • The late phase Late Phase Sepsis in Children of high anion gap Anion gap Metabolic Acidosis metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis: due to aspirin metabolite (salicylate)
  • Treatment:
    • Aspirin toxicity Toxicity Dosage Calculation treated with sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes (NaHCO3): sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes 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). Peritoneal Dialysis and Hemodialysis may be needed if sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes treatment is unsuccessful.

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Comparison of NSAIDs

Table: Comparison of NSAIDs NSAIDS Primary vs Secondary Headaches
Class Mechanism of action Clinical use Side effects
Reversible NSAIDs NSAIDS Primary vs Secondary Headaches (e.g., ibuprofen, ketorolac, indomethacin)
  • Analgesic
  • Antipyretic Antipyretic Acetaminophen
  • Antiinflammatory
  • Closure of patent ductus arteriosus Ductus arteriosus A fetal blood vessel connecting the pulmonary artery with the descending aorta. 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 Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage
  • Aspirin:
    • Reye syndrome Reye syndrome A form of encephalopathy with fatty infiltration of the liver, characterized by brain edema and vomiting that may rapidly progress to seizures; coma; and death. It is caused by a generalized loss of mitochondrial function leading to disturbances in fatty acid and carnitine metabolism. Varicella-Zoster Virus/Chickenpox in children with a viral infection
    • Asthma-like symptoms in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with nasal polyps or atopy Atopy Atopic Dermatitis (Eczema)
    • Tinnitus Tinnitus A nonspecific symptom of hearing disorder characterized by the sensation of buzzing, ringing, clicking, pulsations, and other noises in the ear. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. Cranial Nerve Palsies
    • Mixed respiratory alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis–metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
Aspirin
  • Low dose (< 300 mg/day): antiplatelet
  • Medium dose (300–2400 mg/day): analgesic and antipyretic Antipyretic Acetaminophen
  • High dose (2400–4000 mg/day): antiinflammatory
COX-2 inhibitors (e.g., celecoxib)
  • Rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis
  • 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 Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus:
    • Deep venous thrombosis Venous thrombosis The formation or presence of a blood clot (thrombus) within a vein. Budd-Chiari Syndrome
    • 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 Allergy An abnormal adaptive immune response that may or may not involve antigen-specific IgE Type I Hypersensitivity Reaction

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: 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 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 and 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/
  12. Vane, J.R. (1971). Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 231:232–235. https://pubmed.ncbi.nlm.nih.gov/5284360/
  13. Chaiamnuay, S., Allison, J.J., Curtis, J.R. (2006). Risks versus benefits of cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs. Am J Health Syst Pharm 63:1837–1851. https://pubmed.ncbi.nlm.nih.gov/16990630/
  14. Day, R.O., Graham, G.G. (2013). Nonsteroidal anti-inflammatory drugs (NSAIDs). 346:f3195. https://pubmed.ncbi.nlm.nih.gov/23757736/

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