NSAID

• Antipyretic-Analgesic and Antiinflammatory Agents


  A kind of antipyretic and analgesic drugs, most have the effect of anti-inflammatory and anti-rheumatic. Also known as non steroidal anti-inflammatory drugs (NSAIDs).
• Drugs


  • Aspirin（阿司匹林）
  • Acetaminophen（⼄酰醋氨酚，扑热息痛）
  • Other non-narcotic nonsteroidal antiinflammatory drugs (NSAIDs)
• Treatment


  Pain, inflammation, hyperuricemia and gout
• Mechanism


  Inhibiting prostaglandin's(PGs) biosynthesis
• Prostaglandins (PGs)


  Relate to inflammation, thromboxane A (TXA) formation, etc. TXA can cause thrombosis and platelet aggregation.
• Cyclooxygenases(COX)


  • COX-1(structured type): major source of cytoprotective prostaglandin formation, which participate in the gastric mucosal blood flow, gastric juice secretion and regulation of renal function.
  • COX-2(induced type): Less commonly expressed in normal tissue, while is induced expression in arthritics, is the key enzyme of inflammatory mediators.
• Traditional NSAIDs (tNSAIDs)


  Inhibiting the prostaglandin synthase enzymes: COX-1: mediated large part of action including antipyretic, anagesic, antiinflammatory. COX-2: largly accounts for unwanted gastrointestinal adverse effects.
• Acetaminophen（对⼄酰氨基酚，扑热息痛）


  Effective as an antipyretic & analgesic agent and weak antiinflammatory action
• NSAIDs


  • Nonselective cyclooxygenase inhibitor (Aspirin, …….)
  • Selective cyclooxygenase inhibitor (Celecoxib, Nimesulide…)
• Inflammation


  The response to an injurious stimulus, be evoked by noxious agents: infections, antibodies, or physical injuries, response: calor (warmth), dolor (pain), rubor (redness), tumor (swelling)
• Inflammatory responses


  1. acute phase: transient local vasodilation and increased capillary permeability

  2. delayed, subacute phase: infiltration of leukocytes and phagocytic cells

  3. chronic proliferative phase: occur tissue degeneration and fibrosis
• Inflammatory Mechanisms


  • Adhesive interactions: adhesion of leukocytes and platelets to endothelium of inflammatory sites including E-, P-, and L-selectins, intercellular adhesion molecule-1 (ICAM-1), leukocyte integrins
  • Actived endothelial cells: A key role in "targeting" circulating cells to inflammatory sites
• Important mediator of inflammation


  • Histamme
  • Bradykinin and 5-hydroxytryptamine (serotonin, 5-HT)
  • Leukotrient (LT)-receptor anagonists
  • Autacoid, platelet-activating factor (PAF)
• Rheumatoid Arthritis


  An autoimmune disease driven primarily by activated T cells, giving rise to T cell-derived cytokines, such as IL-1 and tumor necrosis factor-α(TNF-α). Many cytolines, including IL-1 and TNF-α have been found in the rheumatoid synovium.
• NSAIDs


  • Antipyretic action
  • Analgesic action
  • Anti-inflammatory and anti rheumatism action
• Antipyretic action of NSAIDs


  • Patients with fever of hypothermia, almost no effect on normal human body temperature
  • The antipyretic effect does not vary with the outside temperature changes
  • Main effects on heat radiation
• Analgesic action of NSAIDs


  Effective on mild, moderate chronic pain, invalid on traumatic pain and visceral smooth muscle cramps. No tolerance, addiction and euphoria. Mainly in the peripheral analgesic effect.
• Anti-inflammatory and anti rheumatism action of NSAIDs


  • In addition to aniline, has anti-inflammatory effect. Only use as symptomatic treatment.
  • To inhibit the synthesis of inflammatory sites of PGs, decreased PGs in the inflammatory process in inflammation and sensitization, inhibited the activity of some cell adhesion molecules and anti-inflammatory, anti rheumatism.
• Other Clinical Uses of NSAIDs


  • Systemic Mastocytosis
  • Bartter's Syndrome
  • Cancer Chemoprevention
  • Niacin Tolerability
• Mechanisms of NSAIDs


  1. Inhibited the enzymatic production of prostaglandins(PGs) participated in the inflammation and fever

  2. Reduce production of superoxide radicals, apoptosis, expression of adhesion molecules, nitric oxide synthase, proinflammatory cytokines
• Classification of Nonsteroidal Analgesics


  • Salicylates: Aspirin, Diflunisal
  • Para-aminophenol derivative: Acetaminophen
  • Acetic acid derivatives: Indomethacin, Sulindac, Etodolac, Femanates, Mefenamic acid, Meclofenamate, Flufenamic acid, Tolmetin, Ketorolac, Diclofenac
  • Proprionic acid derivatives: Ibuprofen, Naproxen, Fenoprofen, Ketoprofen, Flurbiprofen, Oxaprozin
  • Enolic acid derivates: Piroxam, Meloxicam, Nabumetone
  • COX-2 selective inhibitoes: Celecoxib, Valdecoxib, Parecoxib, Etoricoxib, lumaricoxib
• Adverse Effects of NSAID Therapy


  • Gastrointestinal (G.I.)
  • Cardiovascular
  • Blood pressure, renal, and renovascular adverse events
  • Analgesic Nephropathy
  • Pregnancy and Lactation
  • Hypersensitivity
  • Aspirin Resistance
• Drug Interactions


  • Concomitant NSAIDs and Low-Dose Aspirin: Increase significantly gastrointestinal adverse events
  • Angiotensin-converting enzyme (ACE) inhibitors act, at least partly, by preventing the breakdown of kinins that stimulate prostaglandin production.
• Pharmacokinetics and Pharmacodynamics


  • Absorbed from gastrointestinal tract rapidly and completely
  • Peak concentration occurs within 1 to 4 hours
  • Extensively protein-bound (95%~99%)
  • Undergo hepatic metabolism and renal excretion
  • Metabolized by hepatic CYPs are subject to circadian variation in metabolic disposition
• Other Clinical Considerations in the Rational Selection of Therapy


  • All patients should be asked about previous hypersensitivity
  • Adverse effects usually become manifest in the first weeks of therapy, gastric ulceration and bleeding may present much later
  • Placebo-controlled trials established that at least three selective Cox-2 inhibitors confer an increased risk of heart attack and stroke: Rofecoxib, Valdecoxib, Celecoxib
  • Should be used at the lowest possible dose for the shortest period of time
  • Patients of cardiovascular disease or prone to thrombosis should avoid of these drugs
• Representative drugs


  • Aspirin(Acetyl salicylic acid)
  • Acetaminophen/ Paracetamol（扑热息痛）
  • Indomethacin（消炎痛）
• Aspirin(Acetyl salicylic acid)


  • 1. Analgesic, antipyretic and anti-rheumatism: Strong effect, Compound preparation--APC (aspirin, phenacetin, caffeine), Treat a cold fever and chronic dull pain, First choice for rheumatism and rheumatoid
  • 2. Effect on thrombosis: Small dose (40 ~ 80mg) can play anti-platelet aggregation and thrombosis, prevent myocardial infarction and cerebral thrombosis.
• Untoward effects of Aspirin


  • Gastrointestinal reaction
  • Coagulation disorders
  • Allergic reaction: Aspirin induced asthma (some patients taking aspirin or other antipyretic analgesic induced asthma)
  • Salicylic acid reaction: excessive dosage (≥ 5g/d) Headache, dizziness, nausea, vomiting, tinnitus and vision and hearing loss, excessive breathing, acid-base balance, and even psychosis, coma
  • Reye syndrome: serious liver function bad, acute brain edema
  • Effects on the kidney: on renal dysfunction can cause edema, polyuria, damage
• Drug interactions of Aspirin


  When Aspirin is used in combination with the urea and the adrenal cortex hormone, the plasma protein binding site can be competitive, then the free type concentration of these drugs can be improved, and the curative effect is enhanced. Combined with glucocorticoid, can aggravate gastrointestinal bleeding, induced ulcers.
• Acetaminophen/ Paracetamol（扑热息痛）


  Antipyretic and analgesic effects (inhibition of central PG synthesis), no effect of anti rheumatism and anti-inflammatory. Clinical use on antipyretic analgesic. At treatment dose, less adverse reaction; Excessive dose can cause liver necrosis.
• Indomethacin（消炎痛）


  One of the strongest PG synthase inhibitor, simultaneous inhibition of COX-1 and -2. Anti-inflammatory, anti rheumatism effect is stronger than aspirin (10 ~ 40 times). Antipyretic and analgesic effects is similar to aspirin. More adverse reactions. Use in the cases that other drug intolerance or curative effect.
• Butazone


  Antipyretic and analgesic effects is weaker than aspirin. Anti-inflammatory, anti rheumatism effect is stronger than aspirin. Promote uric acid excretion in a large dosage, used for acute gout. As second drug, use in rheumatism, rheumatoid and ankylosing spondylity. More adverse reactions.
• Celecoxib


  Selectively inhibite COX-2, no significant effect on COX-1. Little adverse reactions. Use for rheumatism, rheumatoid, osteoarthritis and chronic dull pain.
• Comparison


  • Drug - antipyretic - analgesic - antiinflammatory

  Aspirin - +++ - +++ - ++

  Acetaminophen - ++ - + - -

  Ibuprofen - ++ - ++ - +++

  Indomethacin - +++ - +++ - +++

  Butazone - + - + - +++

  Celecoxib - ++ - +++ - +++
• Analysis of Clinical Case


  Patient, male, 1 years ago without the incentive of wrist joint swelling, joint involvement increased after three months, the hands of the proximal interphalangeal joints, shoulders, knees were involved, and was associated with morning stiffness, cold stimulation condition is obviously increased.

  Admission: hands proximal interphalangeal joint, metacarpophalangeal joints and wrists joints moderate swelling and tenderness, wrists severe functional limitations, double elbow swelling, tenderness, about flexion deformity in 30 -45 degree deformity, with shoulders cannot lift, double knee joint moderate swelling, tenderness.

  Diagnosis: rheumatoid arthritis.

  Treatment: Aspirin daily 3~4g, 3~4 days, at the same time, given functional exercise guidance and careful nursing.

  8 days after admission, the lower limbs and the strength increased to 3 degree. 17 days later, the hands of joint swelling, tenderness significantly reduced, shoulders can lift, can get out of bed for activiting.