Transcript nsaid

Vascular Phase
• Vasodilatation and separation of the cells of the
vascular endothelium. Leucotrienes appear to
mediate this response.
• Capillaries are damaged and become
permeable to plasma proteins causing focal
edema (swelling).
• Itch and heat and soreness and pain, mediated
by several powerful endogenous agents.
Function
Mediators
Increased vascular permeability
Histamine, serotonin, bradykinin,
C3a, C5a, PGE2, LTC4,
LTD4, prostacyclins, activated Hageman
factor, high-molecular-weight kininogen
fragments, fibrinopeptides
of small blood vessels
Vasoconstriction
TXA2, LTB4, LTC4, LTD4, C5a, N-formyl
peptides
Smooth muscle contraction
C3a, C5a, histamine, LTB4, LTC4, LTD4,
TXA2, serotonin, PAF, bradykinin
Increased endothelial cell
stickiness
IL-1, TNF-", MCP, endotoxin, LTB4
Mast cell degranulation
C5a, C3a
INFLAMMATION
Trauma
Proteolytic
Activation
Chemotaxis
Eicosanoid
Production
Acute Phase Protease
Regulatory Activity
Biochemical
Mediators
Vascular
Permeability
Phagocytosis
Damage by
Protease 02
Vascular
Dilatation
Cytosis
Systemic
Effects
Acute Phase Protease
Inhibitory Activity
Cellular Phase
• Swelling of damaged vascular endothelium
and adhesion of platelets.
• CHEMOTAXIS-- leukocytes functioning
anaerobically infiltrate and release
lysosomes.
• Sludging of blood (hyperemia, redness) lack
of adequate microcirculation.
• Decrease O2 tension and hypoxia, tissue
necrosis ensues.
Function
Mediators
Phagocytes
Stem cell proliferation
IL-3, G-CSF, GM-CSF, M-CSF
Recruitment from bone marrow
CSFs, IL-1
Adherence/aggregation
iC3b, IgG, fibronectin, lectins
Chemotaxis
C5a, LTB4, IL-8 and other chemokines,
PAF, histamine (for eosinophils), laminin,
N-formyl peptides, collagen fragments,
lymphocyte-derived chemotactic factor,
fibrinopeptides
Lysosomal granule release
C5a, IL-8, PAF, most chemoattractants,
phagocytosis
ARTHRITIS
• Rheumatoid arthritis is an inflammatory
condition.
• Acute and Chronic phases of
inflammation.
• Autoimmune in nature.
– Ab’s produced against IgG
– (The defective IgG molecules have
changes in microheterogeneity)
Adverse Effects of NSAIDs
• Gastrointestinal tract: gastric irritation, peptic ulcers,
bleeding, perforation
• Kidney: decreased renal blood flow, decreased
creatinine clearance rarely interstitial nephritis or
nephrotic syndrome
• CNS: headaches, confusion, tinnitus, aseptic
meningitis (rare)
• Hematopoietic system: bleeding, inhibited platelet
adhesion (irreversible effect with aspirin persisting 10-12
days)
Page et al. 1997
ADME/Side Effects of NSAIDs
• The T1/2 of the different NSAIDs vary from short, less
than 1 hr., to longer than 12 hrs.
• NSAIDs are heavily bound, 60%-90%, to plasma
proteins.
• NSAIDs are metabolized in the liver in a fashion
similar to ASA.
• Virtually all NSAIDs can cause dyspepsia and GI
toxicity including ulceration.
• All except the nonacetylated salycilates can effect
bleeding time. This is reversible except for aspirin
which lasts the life of the platelet.
ADME/Side Effects Continued
• NSAIDs decrease renal blood flow, cause fluid
retention, and may cause renal failure in some
patients, particularly the elderly.
• NSAIDs can cause central-nervous-system (CNS)
effects such as dizziness, anxiety, drowsiness, and
confusion; these symptoms may occur initially and
disappear with further use.
• NSAIDs frequently cause small increases in hepatic
enzyme activity, but life-threatening hepatic toxicity is
rare.
Protaglandins are always released
when cells are damaged and are
detected in increased concentrations
in inflammatory exudates
ASA & NSAIDs act here ------->
Intradermal, intravenous or intra-arterial
injections of prostaglandins give a
picture reminiscent of inflammation.
inflammatory stimuli
( heat, mechanical, chemical)
COX-2
inducible amounts  markedly
in response to stimuli
proteases
prostaglandin's
other inflammatory mediators
inflammation
Page et al. 1997
arachidonic acid
lipoxygenase
cyclooxygenase
2
1
leukotrienes
prostaglandins
thromboxane
phagocyte
mobilization,
changes in
vascular permeability,
inflammation
inflammation
DMARDs
• PENICILLAMINE (Depen, Cuprimine).
• SULFASALAZINE (Azuifidine).
• GOLD - Gold salts. Gold sodium thiomalate (Myochrysine) and
aurothioglucose (Solganal) injectable; Auranofin, oral.
• METHOTREXATE (Rheumatrex).
• HYDROXYCHLOROQUINE (Plaquenil).
• AZATHIOPRINE (Imuran).
• CYCLOPHOSPHAMIDE (Cytoxan)
• New treatment models for rheumatoid arthritis
suggests that more aggressive approaches earlier in
treatment can avoid or slow the progress of the
disease.
PENICILLAMINE
• Penicillamine is effective in acute, severe rheumatoid
arthritis in most patients able to tolerate the drug.
• Reductions in joint pain, edema, and stiffness are seen.
• Inhibits T-cell function and antigen presentation.
• Modification of trace metal metabolism and an effect on
macromolecules could contribute to its efficacy in
rheumatoid arthritis.
• It is readily absorbed from the gastrointestinal tract and is
rapidly excreted in the urine, largely as the intact
molecule.
• Toxicities include Aplastic anemia, thrombocytopenia,
obliterative bronchitis, polymyositis.
METHOTREXATE
• This antimetabolite drug, when administered in low
doses, is effective in the treatment of rheumatoid
arthritis.
• Decreases PMN chemotaxis, alters DNA synthesis.
• At low doses methotrexate appears to be acting more
as an antiinflammatory agent than as an
antimetabolite.
• Dose levels much be watched because of toxicity as
the drug accumulates. Toxicity includes, hepatic fibrosis,
acute interstitial pneumonia, bone marrow suppression.
• Toxicity threshold varies form organ to organ with
bone marrow and GI the most susceptible.
Azathioprine and Cyclophosphamide
• Cyclophosphamide and azathioprine, can reduce
arthritic signs and symptoms in a significant
proportion of patients able to tolerate the therapy.
• A reduction in new joint erosions were found in
patients receiving these agents.
• Interferes with DNA synthesis. Inhibits lymphocyte
proliferation.
• Side effects associated with the cytostatic-cytotoxic
drugs severely limit the use of such drugs.
• Twofold increase in non-Hodgkin's lymphoma.
HYDROXYCHLOROQUINE (Antimalarials)
• The aminoquinolines act on polymorphonuclear
leukocyte function which may be the key to their
antiinflammatory activity.
• The 4-aminoquinolines may “stabilize” lysosomal
membranes reducing the release of destructive
enzymes in the joints.
• The antimalarials are useful for the treatment of
rheumatoid disease showing long term antirheumatic
effects.
GOLD SALTS
• Gold salts suppress the function of t cells. Inhibit
PMN function and macrophage activation.
• Gold therapy suppresses the increased phagocytic
activity that occurs in patients with rheumatoid
arthritis.
• Aurothiomalate and aurothioglucose are given by
injection (i.m.) whereas aurafin is orally active.
• Aurothiomalate reduces the numbers of circulating
lymphocytes and aurafin inhibits the release of PGE2
from synovial cells and the release of LTB4 and LTC4
from polymorphonuclear leukocytes.
Gold Continued
• Gold is difficult to tolerate and can produce significant
toxicity. Serious reactions occur in 5% of patients.
• The most frequent ADRs with the oral agent aurafin
are-diarrhea, abdominal pain, neusea, anorexia. With
all agents pruritus and dermatitis.
• The therapeutic efficacy of gold salts is delayed 4-12
weeks after initiation of therapy.
Recent Progress in Arthritis Therapy
• New treatment models for rheumatoid arthritis
suggests that more aggressive approaches earlier in
treatment can avoid or slow progress of the disease.
• A new class of drugs called leumedins are identified
that could block the destructive inflammation in
diseases such as rheumatoid arthritis.
• Recent studies find that the body uses IL-1ra to turn
off the excessive inflammation typical of some forms
of arthritis.
GOUT
• Gout is an inflammatory reaction to crystals of
sodium urate.
• Sodium urate is the end product of purine
metabolism.
• Not everybody who is hyperuric has gout but
those with gout are hyperuric.
• 3-6.5 mg % in blood - gout pop 6-14 mg %.
• Blood concentration of 6.7 mg % is a
saturated solution. Less soluble in low
pH(e.g. joints).
Two Phases of Gout Treatment
• Treatment of the acute attacks where quick
relief from painful inflammation is highly
desirable.
• Long-term lowering of plasma urate
concentrations.
• For acute attacks: Indomethacin, Colchicine.
• Treatment of chronic hyperuricemia:
Probenecid, Allopurinol, Sulfinpyrazone
Uric Acid Formation
Goth’s Pharmacology