مضادات الإلتهاب اللاستيروئيدية Anti-inflammatory Drugs

dr.Hazemdr.Hazem مدير عام
تم تعديل 2010/05/03 في علم الأدوية Pharmacology
(مقدمة عن آلية الإلتهاب)

It is a normal, protective response to tissue injury caused by
- tissue trauma,
- noxious chemicals or
- microbiological agents
Inflammation is the body’s effort to inactivate or destroy invading microorganisms, remove irritants and set the stage for tissue repair
When healing is complete, the inflammatory process usually subsides
Inflammation is sometimes inappropriately triggered by an innocuous agent or an autoimmune disease (e.g. pollen, asthma, rheumatoid arthritis)
Defense reactions themselves may cause progressive tissue injury
Inflammatory mediators
Inflammation is triggered by the release of chemical mediators
The specific mediators vary with the type of inflammatory process,
Include: amines (histamines, 5-HT), lipids (prostaglandins), small peptides (bradykinin), larger peptides (IL-1)
= unsaturated fatty acid derivatives containing 20 carbons that include a cyclic ring structure ‘eicosanoids’
All NSAIDS act by inhibition of the synthesis of prostaglandins

A. Role of prostaglandins as local mediators

Produced in minute amounts by virtually all tissues
Act locally on the tissues in which they are synthesized
Rapidly metabolized to inactive compounds at their sites of action
Do not circulate in blood in significant concentrations
Hydroperoxyeicosatetraenoic acid (HPETEs)

Hydroxyeicosatetraenoic acids (HETEs)

Related lipids, synthesized from the same precursors as PG are and using interrelated pathways
B. Synthesis of prostaglandins

1.Cyclooxygenase pathway

2.Lipoxygenase pathway

1. Cyclooxygenase pathway

All eicosanoids with ring structures(i.e. prostaglandins, thromboxanes and prostacyclins)
Two related isoforms of COX enzyme have been described

COX-1:physiologic production of prostanoids“house-keeping enzyme”- regulates normal cellular processes (gastric epithelial cytoprotection, platelet aggregation, vascular homeostasis and kidney function)

COX-2:causes elevated production of prostanoids in that occurs in sites of disease and inflammation(e.g. oxidative stress, injury, ischemia, seizures, neuro-degenerative diseases)

COX-2 is constitutively expressed in some tissues such as the brain, kidney and bone

Its expression at other sites is increased during states of inflammation

2. Lipoxygenase pathway

Several lipoxygenases can act on arachidonic acid to form leukotrienes or lipoxins depending on the tissue

Antileukotriene drugs (e.g. zileuton, zafirlukast and montelukast) à treatment of moderate to severe allergic asthma

C. Actions of prostaglandins

Many actions mediated by binding to a variety of cell receptors that operate via G proteinsà subsequently activate or inhibit adenylyl cyclase or stimulate phospholipase C

PGF2a, leukotrienes and TXA2 mediate certain actions by activating phosphatidylinositol metabolism and increase intracellular Ca2+

D. Functions in the body

PG and their metabolites produced endogenously act as local signals that fine-tune the response of a specific cell type

Functions vary widely depending on the tissue

- release of TXA-2 from plateletsà aggregation

- release of TXA-2 in some smooth musclesà contraction

- release of PG in some allergic and inflammatory reactions


  • dr.Hazemdr.Hazem مدير عام
    تم تعديل 2010/04/21

    A.Aspirin and other salicylates (last lec.)
    B.Propionic acid derivatives
    C.Acetic acid derivatives
    D.Oxicam derivatives
    F.Other agents (diclofenac, ketorolac, Tolmetin and nabumetone, diflunisal)

    NSAIDs: weak organic acids except nabumetone(ketone prodrug metabolized to acidic active drug).
    Most are well absorbed & food does not substantially change bioavaialbility.
    Renal excretion is the most important route for elimination,
    However, nearly all NSAIDs undergo enterohepatic circulation.
    The degree of lower GI irritation correlates with amount of enterohepatic circulation.

  • dr.Hazemdr.Hazem مدير عام
    تم تعديل 2010/04/23
    B. Propionic acid derivatives

    Ibuprofen, Naproxen, fenoprofen, ketoprofen, flurbiprofen and oxaprozin
    Analgesics, anti-inflammatory and antipyretics
    Wide acceptance in RA and OAà less GI irritation than ASA
    Oxaprozin: longest t1/2 (once daily)
    Hepatic metabolism, renal excretion
  • dr.Hazemdr.Hazem مدير عام
    تم تعديل 2010/04/25
    [FONT=&quot]C. Acetic acid derivatives[/FONT]
    [FONT=&quot]•[/FONT][FONT=&quot]Indomethacin, sulindac, and etodolac[/FONT]
    [FONT=&quot]•[/FONT][FONT=&quot]Generally not used to lower fever[/FONT][FONT=&quot]•[/FONT][FONT=&quot]Sulindac: prodrug[/FONT]à[FONT=&quot] less potent than indomethacin but useful in treatment fo RA, ankylosing spondylitis, OA and acute gout[/FONT]


    [FONT=&quot] •[/FONT][FONT=&quot]Toxicity limits its use for gout & ankylosing spondylitis. [/FONT]

    [FONT=&quot] •[/FONT][FONT=&quot]used to treat patent ductusarteriosus (ibuprofen is as effective & < toxic)[/FONT]
    [FONT=&quot]At higher dosages, ~1/3 of patients have reactions requiring discontinuance: [/FONT]
    [FONT=&quot]•[/FONT][FONT=&quot]GI effects may include abdominal pain, diarrhea, GI hemorrhage, & pancreatitis. [/FONT]

    [FONT=&quot] •[/FONT][FONT=&quot]HA in ~ 15-25% of patients + dizziness, confusion, depression. [/FONT][FONT=&quot]
    •[/FONT][FONT=&quot]thrombocytopenia & aplastic anemia. [/FONT][FONT=&quot]

  • nehadnehad مشرف منتدى التغذية و الطب البديل
    تم تعديل 2010/04/25
    جميل جدا يعطيك العافية
  • dr.Hazemdr.Hazem مدير عام
    تم تعديل 2010/04/25
    الله يعافيك دكتور..هي معلومات مبسطة و سهلة لكل من يغب بنظرة سريعة على مضادات الإلتهاب اللاستيروئيدية
  • ميرةميرة المشرفة العامة
    تم تعديل 2010/04/26
  • ميرةميرة المشرفة العامة
    تم تعديل 2010/04/26
  • dr.Hazemdr.Hazem مدير عام
    تم تعديل 2010/04/30
    D. Oxicam Derivatives

    Piroxicam and Meloxicam
    RA, OA and ankylosing spondylitis
    Long t1/2: administer once daily
    20% GIT disturbances with piroxicam
    Meloxicam is relativey COX-2 selective
    (less GIT irritation)- dose dependent
    Piroxicam: extensively metabolized to inactive metabolites → can be used in renal impairment
  • dr.Hazemdr.Hazem مدير عام
    تم تعديل 2010/05/01
    E. Fenamates
    Mefenamic acid and meclofenamate
    Have no advantages over other NSAIDs as anti-inflammatory agents
    Their side effects (e.g. diarrhea) can be severe and are associated with inflammation of bowel
    Cases of hemolytic anemia have been reported
    Mefenamic acid should not be used for > 1 week & should not be used in children < 14 years old
  • dr.Hazemdr.Hazem مدير عام
    تم تعديل 2010/05/02

    More potent than indomethacin or naproxen
    Ophthalmic, dermatologic, suppository and IM preparation are also available
    Approved for long-term use: RA, OA and ankylosing spondylistis


    significant analgesic efficacy → used to replace morphine in mild to moderate postsurgical pain (IM).
    use for > 5 days → peptic ulceration & renal impairment → withdrawal from some European markets.
  • dr.Hazemdr.Hazem مدير عام
    تم تعديل 2010/05/02
    Tolmetin and Nabumetone

    As potent as aspirin in treatment of adult or juvenile RA or OA, but
    They may have fewer side effects
    Tolmetin is not used in Gout
    Nabumetone May be < damaging to the stomach.
    May cause pseudoporphyria & photosensitivity.


    A diflurophenyl derivative of salicylic acid
    It is not metabolized to salicylate and therefore can’t cause salicylate intoxication
    3-4X more potent than ASA as analgesic and anti-inflammatory but has no antipyretic properties (does not cross BBB can’t relieve fever)
  • dr.Hazemdr.Hazem مدير عام
    تم تعديل 2010/05/03
    COX-2 Selective NSAIDs

    The structural differences between COX-1 and COX-2 allowed for the development of selective COX-2 inhibitors

    E.g. Celecoxib (Roficoxib and Valdecoxib withdrawn)

    Differ from most of traditional NSAIDs that inhibit both COX-1 and COX-2
    However, etodolac, meloxicam and numelsulide display some level of COX-2 selectivity

    Lower risk of the development of GI bleeding
    No significant effects on platelets

    Relative selectivity Figure (41.11) in Lippincott (pp.504)

    However, (like traditional NSAIDs) May cause renal insufficiency and increase risk of hypertension

    However, for patients who require chronic use of NSAIDs and are at high risk for NSAID—related gastroduodenal toxicity, primary therapy with a COX-2 selective inhibitor is a reasonable option


    Selective for COX-2.
    At in-vivo concentrations, does not inhibit COX-1
    Inhibition of COX-2 is time-dependent and reversible
    Readily absorbed from GIT (peak= 3 hrs)
    Extensively metabolised by liver. Excreted by feces and urine
    T1/2= 11 hrs (taken once daily)

    Adverse effects:
    The most common: Abdominal pain, diarrhea and dyspepsia

    Less gastroduodenal ulcer than naproxen, diclofenac or ibuprofen

    Kideny toxicity may occur (like with ither NSAIDs)

    Celecoxib is contraindicated in patients allergic to sulfonamides

    Selective COX-2 inhibitors should be avoided in patients with renal insufficiency, severe heart disease, volume depletion and/or hepatic failure

    Patients with HX of anaphylactoid reactions to aspirin or nonselective NSAIDs may have similar effects..
  • the-aspirantthe-aspirant المشرف العام
    تم تعديل 2010/05/03
    فعلاً موضوع مميز....مشكور دكتور
  • dr.Hazemdr.Hazem مدير عام
    تم تعديل 2010/05/03
    العفو أسبرينت...