2. INFLAMMATION
• Inflammation is a defense reaction caused by tissue damage
or injury
• Can be elicited by numerous stimuli including:
• infectious agents
• antigen-antibody interaction
• ischemia
• thermal and physical injury
• Noxious chemicals
3. v)leukotrienes
- increase vascular permeability and leakiness
- increase mobilization of endogenous mediators of inflammation
vi)Prostaglandins
PGE2 - promote Vasodilation, Bronchodilation leukocyte infiltration,
Directly Cause Pain and Induces Fever
PGI2 - increase vascular permeability, enhance pain producing
properties of bradykinin
vii) Thromboxane A2 (TXA2)- Thromboxane is a member of the family of
lipids known as eicosanoids. The two major thromboxanes are thromboxane
A2 and thromboxane B2.
cause platelets to aggregate
causes vasoconstriction
causes smooth muscle contraction
enhances function of inflammatory cells
4. Prostaglandins
• Prostaglandins are unsaturated fatty acid
derivatives containing 20 carbons that include
a cyclic ring structure.
• Note: These compounds are sometimes
referred to as eicosanoids; whichrefers to the
20 carbon atoms.
5. Synthesis of prostaglandins
• Arachidonic acid, a 20-carbon fatty acid, is the primary
precursor of the prostaglandins and related
compounds.
• Arachidonic acid is present as a component of the
phospholipids of cell membranes ,primarily
phosphatidylinositol and other complex lipids.
• Free arachidonic acid is released from tissue
phospholipids by the action of phospholipase A2 and
other acyl hydrolases via a process controlled by
hormones and other stimuli.
• There are two major pathways in the synthesis of the
eicosanoids from arachidonic acid.
6. • Cyclooxygenase pathway:
• All eicosanoids with ring structures that is, the
prostaglandins, thromboxanes, and prostacyclins are
synthesized via the cyclooxygenase pathway.
• Two related isoforms of the cyclooxygenase enzymes have
been described. Cyclooxygenase-1 (COX-1) is responsible
for the physiologic production of prostanoids, whereas
cyclooxygenase-2 (COX-2) causes the elevated production
of prostanoids that occurs in sites of disease and
inflammation.
• COX-1 is described as a housekeeping enzyme• that
regulates normal cellular processes, such as gastric
cytoprotection, vascular homeostasis, platelet aggregation,
and kidney function.
• COX-2 is constitutively expressed in tissues such as the
brain, kidney, and bone.
7. • Lipoxygenase pathway:
• Alternatively, several lipoxygenases can act on
arachidonic acid to form 5-HPETE, 12-HPETE, and
15-HPETE,
derivatives
which are unstable peroxidated
that are
corresponding hydroxylated derivatives
converted to the
(the
HETEs) or to leukotrienes or lipoxins, depending
on the tissue .
• Antileukotriene drugs, such as zileuton,
zafirlukast, and montelukast, are useful for the
treatment of moderate to severe allergic asthma.
8.
9.
10. Two main forms of Cyclooxygenases (COX)
• Produces prostaglandins that
mediate homeostatic functions
• Constitutively expressed
• Homeostatic
Protection of gastric
mucosa
Platelet activation
Renal functions
Macrophage
differentiation
• Cyclooxygenase-1 (COX-1) • Cyclooxygenase-2 (COX-2)
• Produces prostaglandins that
mediate inflammation, pain, and
fever.
• Induced mainly in sites of
inflammation by cytokines
• Pathologic
Inflammation
Pain
Fever
Dysregulated
proliferation
12. NSAID
• The NSAIDs are a group of chemically
dissimilar agents that differ in their
antipyretic, analgesic, and anti-inflammatory
activities.
• They 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.
13.
14.
15. Disease-Modifying Antirheumatic
Agents
• Disease-modifying antirheumatic drugs (DMARDs) are used in
the treatment of RA .
• They have been shown-
- to slow the course of the disease by preventing further
destruction of the joints and involved tissues.
-induce remission,
When a patient is diagnosed with RA, the American College of
Rheumatology recommends initiation of therapy with
DMARDs within 3 months of diagnosis (in addition to NSAIDs,
low-dose corticosteroids, physical therapy).
Therapy with DMARDs is initiated rapidly to help stop the
progression of the disease at the earlier stages.
16. • Choice of drug
• No one DMARD is efficacious and safe in every patient, and trials of
several different drugs may be necessary.
• Most experts begin DMARD therapy with one of the traditional
drugs, such as methotrexate or hydroxychloroquine.
• These agents are efficacious and are generally well tolerated, with
well-known side-effect profiles.
• Inadequate response to the traditional agents may be followed by
use of newer DMARDs, such as leflunomide, anakinra, and TNF-
inhibitors (adalimumab, etanercept, and infliximab).
• Combination therapies are both safe and efficacious.
• In most cases, methotrexate is combined with one of the other
DMARDs.
• In patients who do not respond to combination therapy with
methotrexate plus TNF inhibitors, or other combinations, treatment
with rituximab or abatacept may be tried.
• Most of these agents are contraindicated for use in pregnant
women.
17. • Methotrexate
• Methotrexate [meth-oh-TREX-ate], used alone or in combination therapy, has
become the mainstay of treatment in patients with rheumatoid or psoriatic
arthritis.
• Methotrexate slows the appearance of new erosions within involved joints.
• Response to methotrexate occurs within 3 to 6 weeks of starting treatment.
• It is an immunosuppressant, and this may account for its effectiveness in an
autoimmune disease.
• The other DMARDs can be added to methotrexate therapy if there is partial or no
response to maximum doses of methotrexate.
• Doses of methotrexate required for this treatment are much lower than those
needed in cancer chemotherapy and are given once a week; therefore, the
adverse effects are minimized.
• The most common side effects observed after methotrexate treatment of RA are
mucosal ulceration and nausea.
• Cytopenias (particularly depression of the WBC count), cirrhosis of the liver, and
an acute pneumonia-like syndrome may occur on chronic administration.
• [Note: Taking leucovorin once daily after methotrexate reduces the severity of the
adverse effects.]
18. • Leflunomide
• The mechanism of action by which leflunomide works is by blocking the body's
ability to make certain nucleotide, which is a building block of DNA synthesis,
by blocking the enzyme dihydroorotate dehydrogenase.
• People who have rheumatoid arthritis have a type of immune cell (called a T
cell) that is overactive.
• T cells produce chemicals that cause inflammation and damage joint tissue.
• T cells need DNA to divide, or reproduce.
• By stopping the production of DNA, leflunomide prevents T cells from
reproducing, thereby reducing inflammation and preventing joint damage.
• Leflunomide has been approved for the treatment of RA.
• It not only reduces pain and inflammation associated with the disease but also
appears to slow the progression of structural damage.
20. • Hydroxychloroquine
• This agent is also used in the treatment of malaria.
• It is used for early, mild RA and has relatively few side effects.
• When used alone, it does not slow joint damage, therefore, it is often
used in combination with methotrexate.
• Its mechanism of action may include inhibition of phospholipase A2 and
platelet aggregation, membrane stabilization, effects on the immune
system, and antioxidant activity.
• It may cause renal toxicity
• Sulfasalazine
• Sulfasalazine [sull-fa-SAH-la-zeen] is also used for early, mild RA in
combination with hydroxycholoroquine and methotrexate.
• Onset of activity is 1 to 3 months, and it is associated with leukopenia.
• D-Penicillamine
• D-Penicillamine [pen-ih-SILL-a-meen], an analog of the amino acid
cysteine, slows the progression of bone destruction and RA.
• This agent is used as add-on therapy to existing NSAID/glucocorticoid
therapy.
21. • Gold salts
• Gold compounds, like the other drugs in this group,
cannot repair existing damage.
• They can only prevent further injury.
• The currently available gold preparation is auranofin
for oral administration.
• This agent will suppress phagocytosis and lysosomal
enzyme activity.
• This mechanism retards the progression of bone and
articular destruction, and beneficial effects may be
seen in 3 to 6 months.
• The gold compounds are being used infrequently by
rheumatologists because of the need for meticulous
monitoring for serious toxicity (for example,
myelosuppression) and the costs of monitoring.
22. • Other Therapies in Rheumatoid Arthritis
• Interleukin-1b and TNF- α are proinflammatory cytokines involved in the pathogenesis of RA.
• When secreted by synovial macrophages, IL-1b and TNF-α stimulate synovial cells to
proliferate and synthesize collagenase, thereby degrading cartilage, stimulating bone
resorption, and inhibiting proteoglycan synthesis.
• The TNF inhibitors (etanercept, adalimumab, and infliximab) have been shown to decrease
signs and symptoms of RA, reduce progression of structural damage, and improve physical
function; clinical response can be seen within 2 weeks of therapy.
• If a patient has failed therapy with one TNF inhibitor, a trial with a different TNF inhibitor is
appropriate.
• Many experts propose that a TNF inhibitor plus methotrexate be considered as standard
therapy for patients with rheumatoid and psoriatic arthritis.
• Indeed, TNF inhibitors can be administered with any of the other DMARDs, except for
anakinra, an IL-1 receptor antagonist.
• Patients receiving TNF inhibitors are at increased risk for infections (tuberculosis, and sepsis),
fungal infections, and pancytopenia.
• These agents should be used very cautiously in those with heart failure, because these agents
24. • Gout
• Gout is a metabolic disorder characterized by high levels
of uric acid (end product of purine metabolism) in the
blood.
• Hyperuricemia can lead to deposition of sodium urate
crystals in tissues, especially the joints and kidney.
• The cause of hyperuricemia is an overproduction of uric
acid relative to the patient's ability to excrete it.
• The deposition of urate crystals initiates an
infiltration of
urate crystals
inflammatory process involving the
granulocytes that phagocytize the
(Figure).
• This process generates oxygen metabolites, which
damage tissues, resulting in the release of lysosomal
enzymes that evoke an inflammatory response.
• In addition, there is increased production of lactate in
the synovial tissues.
• The resulting local decrease in pH fosters further
deposition of urate crystals.
26. • Most therapeutic strategies for gout involve lowering the uric
acid level below the saturation point (<6 mg/dL), thus
preventing the deposition of urate crystals.
• This can be accomplished by 1) interfering with uric acid
synthesis with allopurinol, 2) increasing uric acid excretion
with probenecid or sulfinpyrazone, 3) inhibiting leukocyte
entry into the affected joint with colchicine, or 4)
administration of NSAIDs.
27. • Treating acute gout
• Acute gouty attacks can result from a number of
conditions, including excessive alcohol
consumption, a diet rich in purines, or kidney
disease.
• Acute attacks are treated with indomethacin to
decrease movement of granulocytes into the
affected area;
• NSAIDs other than indomethacin
are also effective at decreasing pain and
inflammation.
• [Note: Aspirin is contraindicated, because it
competes with uric acid for the organic acid
secretion mechanism in the proximal tubule of
the kidney.]
28. • Treating chronic gout
• Chronic gout can be caused by 1) a genetic defect, such as one
resulting in an increase in the rate of purine synthesis; 2) renal
deficiency; 3) Lesch-Nyhan syndrome; or 4) excessive production of
uric acid associated with cancer chemotherapy.
• Treatment strategies for chronic gout include
-the use of uricosuric drugs : That increase the excretion of uric acid,
thereby reducing its concentration in plasma.
Uricosuric agents are first-line agents for patients with gout
associated with reduced urinary excretion of uric acid.
- inhibits uric acid production : Allopurinol, which is a selective
inhibitor of the terminal steps in the biosynthesis of uric acid.
Allopurinol is preferred in patients with excessive uric acid
synthesis, with previous histories of uric acid stones, or with renal
insufficiency.
29. • Colchicine
– Colchicine is an alkaloid
– It is used for relief of inflammation and pain in acute gouty
arthritis.
– Reduction of inflammation and relief from pain occur 12—
24 hours after oral administration.
– The mechanism of action in acute gout is unclear.
– Colchicine:
• Colchicine binds to tubulin, a microtubular protein,
causing its depolymerization. This disrupts cellular
functions, such as the mobility of granulocytes, thus
decreasing their migration into the affected area.
• Furthermore, colchicine blocks cell division by binding
to mitotic spindles.
• Colchicine also inhibits the synthesis and release of the
leukotrienes
30. – The adverse effects after oral administration, which occur
in 80% of patients at a dose near that necessary to relieve
gout, include nausea, vomiting, abdominal pain, and
particularly diarrhea.
– IV administration reduces the risk of gastrointestinal
disturbances and provides faster relief (6—12 h) but
increases the risk of sloughing skin and subcutaneous
tissue.
– Higher doses may (rarely) result in liver damage.
31. • Probenecid and sulfinpyrazone
• are organic acids
• reduce urate levels by preventing reabsorption of uric acid in
the renal tubule .
• These agents are used for chronic gout, often in combination
with colchicine.
• Probenecid and sulfinpyrazone undergo rapid oral absorption.
32. • These agents inhibit the excretion of other drugs that are actively
secreted by renal tubules, including penicillin, NSAIDs,
cephalosporins, and methotrexate.
• Increased urinary concentration of uric acid may result in the
formation of urate stones (urolithiasis).
• This risk is decreased with:
1. the ingestion of large volumes of fluid or
2. alkalinization of urine with potassium citrate.
• Common adverse effects include gastrointestinal disturbances
and dermatitis; rarely, these agents cause blood dyscrasias
33. • Allopurinol
• Allopurinol inhibits the synthesis of uric acid by inhibiting
xanthine oxidase, an enzyme that converts hypoxanthine to
xanthine and xanthine to uric acid.
• Allopurinol is metabolized by xanthine oxidase to
alloxanthine, which also inhibits xanthine oxidase. Allopurinol also
inhibits de novo purine synthesis.
• Allopurinol commonly produces gastrointestinal disturbances and
dermatitis. This agent more rarely causes hypersensitivity, including
fever, hepatic dysfunction, and blood dyscrasias.
• Allopurinol should be used with caution in patients with liver
disease or bone marrow depression.
34. Mechanism of action:
Allopurinol inhibits xanthine oxidase enzyme
which is required for the synthesis of Uric acid.
This enzyme is required when purine is oxidized
to Uric acid.
35. 1. Anti-TNF- drugs
A. Infliximab:
• is a recombinant antibody with human constant and murine
variable regions that specifically binds TNF-α, thereby
blocking its action.
– Approved for use for rheumatoid arthritis, Crohn's
disease, psoriasis, and other autoimmune diseases
– Administered by IV infusion at 2-week intervals initially
and repeated at 6 and 8 weeks
36. •
•
B. Adalimumab
is approved for the treatment of rheumatoid arthritis.
It is a humanized (no murine components) anti-TNF-α antibody
administered subcutaneously every other week.
•
•
•
•
C. Etanercept
is a fusion protein composed of the ligand-binding pocket of a TNF-α
receptor fused to an IgG1 Fc fragment.
The fusion protein has two TNF-binding sites per IgG molecule and is
administered subcutaneously weekly.
The most serious adverse effect is infection including tuberculosis,
immunogenicity, and lymphoma.
Injection site infections are common.
37. 2. Anti-IL1 drugs
– Anakinra is a recombinant protein essentially identical to
IL-1 , a soluble antagonist of IL-1 that binds to the IL-1
receptor but does not trigger a biologic response.
– Anakinra is a competitive antagonist of the IL-1 receptor.
– It is approved for use for the treatment of rheumatoid
arthritis.
– It has a relatively short half-life and must be
administered subcutaneously daily.
38. Characterized by:
1. Redness (rubor): vasodilation of capillaries to increase
blood flow
2. Heat (calor): vasodilation
3. Pain (dolor): Hyperalgesia, sensitization of nociceptors
4. Swelling (tumor): Increased vascular permeability
(microvascular structural changes and escape of
plasma proteins from the bloodstream)
5. Loss of function (functio laesa)
• Inflammatory cell transmigration through endothelium
and accumulation at the site of injury
39. Other antiinflammatory drugs are used in the more advanced
stages of some rheumatoid diseases.
• Gold compounds:
– Aurothioglucose
– Gold sodium thiomalate
– Auranofin
– may retard the destruction of bone and joints by an
unknown mechanism.
– These agents have long latency.
– Aurothioglucose and gold sodium thiomalate are
administered intramuscularly.
– Auranofin is administered orally and is 95% bound to
plasma proteins.
40. Side effects: Gold compounds
Serious:
• gastrointestinal disturbances, dermatitis, and mucous membrane
lesions.
Less common effects:
• aplastic anemia
• proteinuria
Occasional:
• nephrotic syndrome.
41. Penicillamine
– Penicillamine is a chelating drug (will chelate gold) that is a
metabolite of penicillin.
– Penicillamine has immunosuppressant activity, but its
mechanism of action is unknown.
– This agent has long latency.
– The incidence of severe adverse effects is high; these
effects are similar to those of the gold compounds.
42. • Methotrexate
– Methotrexate is an antineoplastic drug used for
rheumatoid arthritis that does not respond well to NSAIDs
or glucocorticoids.
– Methotrexate commonly produces hepatotoxicity.
• Chloroquine and hydrochloroquine
– Chloroquine and hydrochloroquine are antimalarial drugs.
– These agents have immunosuppressant activity, but their
mechanism of action is unknown.
– Used to treat joint pain associated with lupus and arthritis
• Adrenocorticosteroids
