Transcript 931ca606dd9b884

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Normal, protective response to tissue injury
caused by physical trauma, noxious
chemicals, or microbiologic agents.
It is the body’s effort to inactivate or destroy
invading organisms, remove irritants, and set
the stage for tissue repair.
When healing is complete, the inflammatory
process usually subsides.
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Inflammation may cause progressive tissue
injury.
Associated pain may be severe and
intolerable.
Sometimes inflammation is caused by
inappropriate activation of our immune
system, NOT by injury:
 Autoimmune diseases.
 Hypersensitivity reactions.
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Dolar (pain).
Colar (heat).
Rubor (redness).
Oedema (swelling).
Functio Laesa (loss of function).
Four main events occur in sequence:
 Changes in vessel calibre: vasodilatation.
 Increased vascular permeability: vessels
became “leaky”.
 Leakage of plasma: fluid exudate rich in
protein.
 Emigration of inflammatory cells: mostly
neutrophils.
Phase of inflammation
Chemical mediator.
Vascular dilatation
Histamine.
Prostaglandins
Complement proteins (C3a, C5A).
Increased vascular permeability
Histamine.
Kinines.
Prostaglandins.
Emigration of inflammatory cells
C5a.
Leukotrienes.
Cationic proteins of neutrophils
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Ch.ch. By accumulation of macrophages and
lymphocytes in the site of injury with ongoing
chemotaxix.
Intense fibroblast accumulation with
replacement of part of the parenchymal
tissue.
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Activation of T cells
triggers a series of
B Cell
intercellular reactions
Lymphocytes, monocytes/ Macrophage
macrophages, and
T Cell
synovial fibroblasts are
Pannus
stimulated to release
proinflammatory
cytokines
IL-1
Cytokines induce synovial
TNF
proliferation and release
Cartilage
of destructive enzymes
Osteoclasts
Bone
destruction
TNFa
IL-1
CD4+
T lymphocyte
Joint
erosion
Synoviocytes
Macrophage
Cartilage
destruction
TNFa
IL-1
Chondrocytes
Endothelial cell
Adhesion molecule
expression
Adapted from Arend WP. J Rheumatol Suppl. 2002;65:16-21. Permission to reproduce
granted by Journal of Rheumatology and Dr WP Arend.
Joint-space
narrowing
Activates
monocytes/macrophages
Activates
chondrocytes,
releasing collagenases
Activates osteoclasts,
suppresses osteoblasts
Inflammation
Cartilage
breakdown
Bone resorption
and erosions
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Activation of
T cells
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Production of
auoantibodies
.including RF
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Cytokine
production TNF
alpha ,.
These
stimulate the
secretion of
MMP and
prostaglandins.
Derived, along with other related compounds,
from unsaturated fatty acid (Arachidonic
acid)through:
 Cyclooxygenase pathway (COX1, COX2)
◦ Cyclooxygenase-1 (COX-1) is responsible for the
physiologic production of prostanoids,
◦ Cyclooxygenase-2 (COX-2) causes the elevated
production of prostanoids that occurs in sites of
disease and inflammation.
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Mediated by binding to their receptors (G protein
linked receptors
Examples:
TXA2: vasoconstrictor, enhance platelet
aggregation.
PGI2: vasodilator, inhibit pltlt aggregation.
PGE1: gastric protection against HCL, increased
uterine contraction and induce labor.
PGF2 alpha: increase aqueous humor outflow.
PGE2: mediates pain and fever.
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PGI2, PGE1, PGD2: activate adenylcyclase,
increased cAMPs and phosphorylation of
internal calcium pump proteins and decrease
intracellular calcium concentrations.
TXA2: formation of IP3 leading to increase
free intracellular calcium.
MOA:
 PGE1 analog.
 Interacts with PG receptor on the parietal cells
and decrease HCL production.
 Stimulates mucus and bicarbonate production.
 Interact with PG receptors in the uterine SM and
induce contractions.
Adverse effects: black box warning (potential risk
to induce abortion, FDA pregnancy category X),
diarrhea and abdominal pain.
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Synthetic analog of prostacyclin.
Act on IP receptors in the lungs, increasing
cAMP and inhibit the production of TXA2
causing pulmonary vasodilatation .
Used for the treatment of pulmonary
hypertension.
Used by inhalation.
A/E: dizziness, headache, flushing and
fainting.
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Stimulates the CL channels ( CIC-2) in the
luminal cells of the intestinal epithelium,
increasing intestinal fluid secretion.
This lead to stool softening and increase
intestinal motility.
Used mainly in chronic idiopathic
constipation and irritable bowel syndrome.
A/Es: nausea, diarrhea, abdominal pain and
headache.
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Group of chemically dissimilar agents that
differ in their antipyretic, analgesic, and antiinflammatory activities.
act primarily by inhibiting the cyclooxygenase
enzymes that catalyze the first step in
prostanoid biosynthesis.
This leads to decreased prostaglandin
synthesis with both beneficial and unwanted
effects
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Prototype of traditional
NSAIDs.
MOA: irreversibly
acetylates (and, thus,
inactivates)
cyclooxygenases.
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Antiinflammatory.
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Antipyretic
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Analgesic:
(antipyretic effects of salicylate are due
primarily to the blockade of prostaglandin synthesis at the
thermoregulatory centers in the hypothalamus and at
peripheral target sites).
(by decreasing prostaglandin E2 synthesis,
salicylate also prevents the sensitization of pain receptors to
both mechanical and chemical stimuli).
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At normal doses: Increases alveolar
ventilation due to uncoupling of oxidative
phosphorylation.
High doses work directly on the respiratory
center in the medulla, resulting in
hyperventilation and respiratory alkalosis that
usually is adequately compensated for by the
kidney.
At toxic levels, central respiratory paralysis
occurs, and respiratory acidosis ensues due
to continued production of CO2.
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PGI2 inhibits gastric acid secretion, whereas
PGE2 and PGF2 stimulate synthesis of
protective mucus in both the stomach and
small intestine.
Aspirin inhibits the synthesis of these
protective substances.
This results in increased gastric acid
secretion and diminished mucus protection.
Leading to epigastric distress, ulceration,
hemorrhage, and iron-deficiency anemia.
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TXA2 enhances platelet aggregation, while
PGI2 decreases platelet aggregation.
Low doses (60-81 mg daily) of aspirin can
irreversibly inhibit thromboxane production
in platelets via acetylation of cyclooxygenase.
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Cyclooxygenase inhibitors prevent the
synthesis of PGE2, PGI2 responsible for
maintaining renal blood flow, particularly in
the presence of circulating vasoconstrictors.
Decreased synthesis of prostaglandins can
result in retention of sodium and water and
may cause edema and hyperkalemia in some
patients.
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Anti-inflammatory, antipyretic, and analgesic
use:
 acute pain control, fever, rheumatic arthritis,
osteoarthritis, pulpitis (inflammation of the dental pulp),
abscesses.
 Higher doses are needed for the anti-inflammatory
actions compared to the antipyretic or analgesic dose.
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Cardiovascular applications: Low doses are
used prophylactically to
 reduce the risk of recurring transient ischemic attacks (TIAs)
 reduce the risk of death in those having an acute myocardial
infarction,
 Reduce risk of nonfatal MI.
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Well absorbed from the upper small intestine.
metabolized into salicylate and acetic acid
by tissue and blood esterases, then salicylate
is conjugated in the liver following saturable
kinetics.
Salicylate is secreted in the urine and affect
uric acid excretion.
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GI disturbances: microscopic bleeding, peptic
ulceration.
Prolonged bleeding time (aspirin should not
be taken for at least one week prior to
surgery).
Respiratory depression at toxic doses.
Hyperthermia at toxic doses.
Hypersensitivity reactions: urticaria,
bronchoconstriction, or angioedema.
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Reye’s syndrome: in children with viral
infections. Ch.ch. By cerebral edema and
fulminating hepatitis, may be fatal.
Pathogenesis: mitochondrial injury with
inhibition of oxidative phosphorylation and
fatty acid B-oxidation in a virus-infected
sensitized hosts.
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Ibuprofen.
Naproxen.
Ketoprofen.
Fenoprofen.
Flurbiprofen.
Oxaprozin.
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Possess anti-inflammatory,
analgesic, and antipyretic
activity.
Can alter platelet function
and prolong bleeding time.
Less intense GI effects
compared with aspirin.
Hepatic metabolism and
renal excretion.
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Long half lives, permits once daily dosing.
Used for osteoarthritis, rheumatoid arthritis,
fever, injuries, etc
Meloxicam: less GI effects (preferential
binding to COX 2).
Metabolized and excreted in the urine and
feces.
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Indomethacin, sulindac, etodolac, diclofenac,
tolmetin, keterolac.
All have antiinflammatory, antipyretic, and
analgesic effects.
Mostly used to relieve symptoms in longterm treatment of rheumatoid arthritis,
osteoarthritis, ankylosing spondylitis, and
other musculoskeletal disorders
Indomethacin: severe GI effects, limited use.
Sulindac is a prodrug with less intense side
effects compared to other NSAIDs.
Keterolac is associated with very severe PU.
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Mefenamic acid, meclofenamate.
No advantages over other NSAIDs.
Associated with diarrhea and bowel
problems.
Reported cases of hemolytic anemia.
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Associated with low incidence of adverse
effects.
Metabolized to an active metabolite first then
this metabolite is deactivated.
Celecoxib:
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Reduce inflammation & pain with minimal GI
problems and reduced effect on platelet
aggregation,
Used for osteo- and rheumatoid arthritis, acute
pain, menstrual cramps, post dental or orthopedic
surgery
May cause allergic Rx
Elimination-T1/2 is 11 hours, hepatic metabolism
and excreted in the urine.
A/E: Headache, dyspepsia, diarrhea, and abdominal
pain
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Drug-drug interactions:
Cyp2C9 inhibitors : fluconazole, fluvastatin.
Substrates of Cyp2D6: amitryptylline,
risperidone
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Actions:
Inhibits prostaglandin
synthesis in the CNS.
Has less effect on
cyclooxygenase in
peripheral tissues, which
accounts for its weak antiinflammatory activity.
Does not affect platelet
function or increase blood
clotting time.
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Therapeutic uses:
substitute for the analgesic and antipyretic effects of
aspirin for those patients with gastric complaints, those
in whom prolongation of bleeding time would be a
disadvantage, or those who do not require the antiinflammatory action of aspirin.
Analgesic/antipyretic of choice for children with viral
infections or chickenpox.
Does not antagonize the uricosuric agents probenecid or
sulfinpyrazone and, therefore, may be used in patients with
gout who are taking these drugs.
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A/E: at therapeutic doses, no significant A/E.
Toxicity in overdose (due to n-acetyl-pbenzoquinoneimine NAPQI) : hepatic
necrosis, (treated with N-acetylcystiene
within 10 hrs of toxicity).renal tubular
necrosis
Should be avoided in patients with liver
impairment.
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Slow the course of the disease.
Induce remission.
Prevent further destruction of the joints and
involved tissue.
Many experts usually start with traditional
DMARDs (Methotrexate or
hydroxychloroquine).
Combination therapy are common
(methotrexate + other DMARDs)
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Methotrexate.
Leflunomide.
Hydroxychloroquine.
Sulfasalazine.
D-penicillamine.
Gold salts.
Azathioprine.
Cyclophosphamide.
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MOA:
1- Inhibits
aminoimidazole
carboxamide AICAR
transformylase.
This leads to:
Decrease chemotaxis.
Decrease TNF alpha.
Inhibits DHFR.
Inhibits thymidylate
synthase.
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Mucosal ulcertion.
Cytopenias
Liver abnormalities.
Taking leucovorin
decreases the severity
of S/Es
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Inhibits dihydroorotate
dehydrogenase
interfering with
pyrimidine synthesis
interfering with B cell
function and
proliferation.
Inhibits osteoclast
production.
Can be used as
monotherapy or in
combination with
methotrexate.
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Headache.
Diarrhea.
Wt loss.
Flu like symptoms.
Alopecia.
Teratogenecity.
Hydroxychloroquine
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An antimalarial drug.
Possible mechanisms:
Inhibition ofDNA nad
RNA synthesis.
antioxidant effects.
Decreased chemotaxis.
Decreased T
lymphocyte response
to mitogens.
Used for early-mild RA.
A/E: ocular toxicity.
Sulfasalazine
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Metabolized into
sulfapyridine and 5
aminosalicylic acid.
The sulfapyridine is
thought to be the
active moiety in RA.
Suppress T cell and B
cell responses.
Used for early mild RA
in combination with
hydroxychloroquine
and/or methotrexate.
S/E leukopenia
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The oral formulation auranofin.
The IM formulation aurothiomalate and
aurothioglucose .
MOA:
Alter the morphology and functionability of
macrophages, decrease lysosomal enzyme
activity and thus decrease bone and cartilage
damage.
s/e: myelosuppression, proteinuria.
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Includes etanercept, adalimumab, and
infliximab.
Decrease S&S.
Reduce progression of structural damage.
Improve physical function.
Clinical benefits seen within 2 weeks of
therapy.
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Fusion protein consists
of 2 TNF alpha
receptor moieties.
Given sc.
Used in patients with
moderate –severe RA
either alone or in
combination with
methotrexate.
Good s/e profile, can
produce local
inflammation at site of
injection.
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Monoclonal IgG antibody against TNF alpha.
Used in combination with methotrexate in
patients not showing enough response with
methotrexate alone.
If used alone: anti-infliximab antibodies.
Used as IV intermittent infusion over 2 hrs.
A/E: fever, chills, urticaria, infections, bone
marrow suppression.
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Recombinant monoclonal antibody that binds
TNF receptor sites interfering with
endogenous TNF activity.
Indicated as monotherapy or with
methotrexate in moderate to severe RA.
Administered SC weekly or every other week.
s/e: headache, rash, reaction at the injection
site.
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IL-1 receptor antagonist (interferes with the
effects of IL1 on the cartilage and bones.
Could be used alone or in combination with
other DMARDs.
Administered SC once daily in patients with
normal renal function or every other day in
those with renal impairment.
s/e: neutropenia,
Osteoclasts
Bone
destruction
TNFa
IL-1
CD4+
T lymphocyte
Joint
erosion
Synoviocytes
Macrophage
Cartilage
destruction
TNFa
IL-1
Chondrocytes
Endothelial cell
Adhesion molecule
expression
Adapted from Arend WP. J Rheumatol Suppl. 2002;65:16-21. Permission to reproduce
granted by Journal of Rheumatology and Dr WP Arend.
Joint-space
narrowing
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Activation of T lymphocytes needs binding of
a CD28 protein on its surface to the CD80/86
on the antigen-presenting cells.
If CTLA4 on the T lymphocyte binds with
CD80/86 on the T cells, the T cells become
inactivated.
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Abatacept is a
fusion protein
made up of the
extracellular
domain of
CTLA4 and
competes with
CD 28 in binding
to CD80,
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Administered as intermittent infusion over 30
min.at weeks 2 and 4 and every 4 weeks
thereafter.
A/E: headache, Nausea and upper respiratory
tract infections especially if used with TNF
alpha inhibitors and anakinra..
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Monoclonal AB directed against CD20 on the
surface of B lymphocytes resulting in B cell
depletion.
Used in combination with methotrexate to
reduce signs and symptoms in patients with
moderate to severe RA.
Administered as 2 infusions separated by 2
weeks.
s/e: infusion reactions (urticaria,
hypotension, angioedema) can be decreased
by methylprednisolone.
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Metabolic disorder ch.ch. By high levels of
uric acid in the blood and accumulation of
urate crystals in joints and kidneys.
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Treatment options:
Interferring with uric acid synthesis.
Increasing uric acid secretion.
Inhibiting leukocyte entry in the affected
joints.
Use NSAIDs for pain relief.
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Indomethacin can reduce leukocyte migration
to the joint, reduce pain and inflammation.
Intraarticular steroids can be used.
Chronic ttt is indicated when:
Patient has 2 or more attacks per year.
Attacks are severe an associated with renal
problems.
Serum urate is greater than 10 mg/dl.
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MOA:
◦ Binds to tubulin leading to depolymerization and
impairment of granulocyte mobility.
◦ Inhibits cell division by binding to mitotic spindles.
◦ Inhibits the synthesis and release of leukotrienes.
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Used for the ttt of acute as well as chronic
gout.
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Interfere with uric acid
biosynthesis.
Used for ttt of gout
and hyperuricemia of
malignancy.
Metabolized and the
drug and its
metabolites are
excreted in the urine.
S/E: skin rashes.GI
disturbances.
Febuxostat: new
xanthine oxidase
inhibitor
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Weak organic acids
that promote renal
excretion of uric acid.
They inhibit urateanion exchanger in the
proximal tubule.
Propenicid: inhibits
secretion of penicillin
and some NSAIDs.