normal, protective response to tissue injury caused by physical trauma, noxious chemicals, or...

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.

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.

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 inflammationChemical mediator.

Vascular dilatationHistamine.ProstaglandinsComplement proteins (C3a, C5A).

Increased vascular permeabilityHistamine.Kinines.Prostaglandins.

Emigration of inflammatory cellsC5a.Leukotrienes.Cationic proteins of neutrophils

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.

Activation of T cells triggers a series of intercellular reactions

Lymphocytes, monocytes/ macrophages, and synovial fibroblasts are stimulated to release proinflammatory cytokines

Cytokines induce synovial proliferation and release of destructive enzymes

B Cell

T Cell

Macrophage

Pannus

Cartilage

TNF

IL-1

CD4+T lymphocyte

Macrophage

Endothelial cell

Osteoclasts

Bonedestruction

Jointerosion

Synoviocytes

Cartilagedestruction

Joint-spacenarrowing

Chondrocytes

Adhesion moleculeexpression

TNFIL-1

TNFIL-1

Adapted from Arend WP.  J Rheumatol Suppl. 2002;65:16-21. Permission to reproduce granted by Journal of Rheumatology and Dr WP Arend.

Inflammation

Activates monocytes/macrophages

Bone resorption and erosions

Activates osteoclasts, suppresses osteoblasts

Cartilage breakdown

Activates chondrocytes,

releasing collagenases

Activation of T cells

Production of auoantibodies .including RF

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.

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.

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.

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.

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.

Group of chemically dissimilar agents that differ in their antipyretic, analgesic, and anti-inflammatory 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

Prototype of traditional NSAIDs.

MOA: irreversibly acetylates (and, thus, inactivates) cyclooxygenases.

Antiinflammatory.

Antipyretic (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).

Analgesic: (by decreasing prostaglandin E2 synthesis, salicylate also prevents the sensitization of pain receptors to both mechanical and chemical stimuli).

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.

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.

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.

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.

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.

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.

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.

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.

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.

Ibuprofen. Naproxen. Ketoprofen. Fenoprofen. Flurbiprofen. Oxaprozin.

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.

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.

Indomethacin, sulindac, etodolac, diclofenac, tolmetin, keterolac.

All have antiinflammatory, antipyretic, and analgesic effects.

Mostly used to relieve symptoms in long-term 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.

Mefenamic acid, meclofenamate. No advantages over other NSAIDs. Associated with diarrhea and bowel

problems. Reported cases of hemolytic anemia.

Associated with low incidence of adverse effects.

Metabolized to an active metabolite first then this metabolite is deactivated.

Celecoxib: 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

Drug-drug interactions: Cyp2C9 inhibitors : fluconazole, fluvastatin. Substrates of Cyp2D6: amitryptylline,

risperidone

Actions: Inhibits prostaglandin

synthesis in the CNS. Has less effect on

cyclooxygenase in peripheral tissues, which accounts for its weak anti-inflammatory activity.

Does not affect platelet function or increase blood clotting time.

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 anti-inflammatory 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.

A/E: at therapeutic doses, no significant A/E.

Toxicity in overdose (due to n-acetyl-p-benzoquinoneimine NAPQI) : hepatic necrosis, (treated with N-acetylcystiene within 10 hrs of toxicity).renal tubular necrosis

Should be avoided in patients with liver impairment.

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)

Methotrexate. Leflunomide. Hydroxychloroquine. Sulfasalazine. D-penicillamine. Gold salts. Azathioprine. Cyclophosphamide.

MOA: 1- Inhibits

aminoimidazole carboxamide AICAR transformylase.

This leads to: Decrease chemotaxis. Decrease TNF alpha. Inhibits DHFR. Inhibits thymidylate

synthase.

Mucosal ulcertion. Cytopenias Liver abnormalities. Taking leucovorin

decreases the severity of S/Es

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.

Headache. Diarrhea. Wt loss. Flu like symptoms. Alopecia. Teratogenecity.

Hydroxychloroquine Sulfasalazine

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.

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

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.

Includes etanercept, adalimumab, and infliximab.

Decrease S&S. Reduce progression of structural damage. Improve physical function. Clinical benefits seen within 2 weeks of

therapy.

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.

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.

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.

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,

CD4+T lymphocyte

Macrophage

Endothelial cell

Osteoclasts

Bonedestruction

Jointerosion

Synoviocytes

Cartilagedestruction

Joint-spacenarrowing

Chondrocytes

Adhesion moleculeexpression

TNFIL-1

TNFIL-1

Adapted from Arend WP.  J Rheumatol Suppl. 2002;65:16-21. Permission to reproduce granted by Journal of Rheumatology and Dr WP Arend.

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.

Abatacept is a fusion protein made up of the extracellular domain of CTLA4 and competes with CD 28 in binding to CD80,

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..

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.

Metabolic disorder ch.ch. By high levels of uric acid in the blood and accumulation of urate crystals in joints and kidneys.

Treatment options: Interferring with uric acid synthesis. Increasing uric acid secretion. Inhibiting leukocyte entry in the affected

joints. Use NSAIDs for pain relief.

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.

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.

Used for the ttt of acute as well as chronic gout.

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

Weak organic acids that promote renal excretion of uric acid.

They inhibit urate-anion exchanger in the proximal tubule.

Propenicid: inhibits secretion of penicillin and some NSAIDs.