(مقدمة عن آلية الإلتهاب)
Inflammation
•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)
Prostaglandins
•= 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
•Thromboxanes
•Leukotrienes
•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
التعليقات
A.Aspirin and other salicylates (last lec.)
B.Propionic acid derivatives
C.Acetic acid derivatives
D.Oxicam derivatives
E.Fenamates
F.Other agents (diclofenac, ketorolac, Tolmetin and nabumetone, diflunisal)
Pharmacokinetics
•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.
•Wide acceptance in RA and OAà less GI irritation than ASA
•Oxaprozin: longest t1/2 (once daily)
•Hepatic metabolism, renal excretion
[FONT="]•[/FONT][FONT="]Indomethacin, sulindac, and etodolac[/FONT]
[FONT="]INDOMETHACIN[/FONT]
[FONT="] •[/FONT][FONT="]Toxicity limits its use for gout & ankylosing spondylitis. [/FONT]
[FONT="] •[/FONT][FONT="]used to treat patent ductusarteriosus (ibuprofen is as effective & < toxic)[/FONT]
[FONT="]At higher dosages, ~1/3 of patients have reactions requiring discontinuance: [/FONT]
[FONT="] •[/FONT][FONT="]HA in ~ 15-25% of patients + dizziness, confusion, depression. [/FONT][FONT="]
•[/FONT][FONT="]thrombocytopenia & aplastic anemia. [/FONT][FONT="]
[/FONT][FONT="]hyperkalemia.[/FONT]
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
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
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
Ketorolac
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.
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.
Diflunisal
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)
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
Celecoxib
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..