NSAIDs and Inflammation

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Guillermo Armaiz, Ph.D. can be contacted at [email protected] or 787-840-2575 ext. 3226.

Lecture Overview

• The lecture covers inflammation, rheumatoid arthritis, NSAIDs (COX1/2 inhibitors), and disease-modifying anti-rheumatic drugs.

Inflammation

• Inflammation involves a complex biological response to harmful stimuli.
• It eliminates the initial cause of cell injury and clears out necrotic/damaged tissue.
• Inflammation initiates tissue repair.
• Innate immunity provides a non-specific defense mechanism.
• Adaptive immunity provides the antigen-specific immune response.

Signs and Causes of Inflammation

• Signs include pain, heat, redness, and swelling.
• Loss of function can also be a sign.
• Exogenous causes include mechanical, physical, and chemical factors, as well as infections.
• Endogenous causes include autoimmune responses.

Inflammation Balance

• Too little inflammation leads to bacterial-derived diseases.
• Too much inflammation can result in conditions like hay fever, periodontitis, atherosclerosis, and rheumatoid arthritis.
• The body tightly regulates inflammation.

Inflammatory Process

• The inflammatory process can be acute or chronic.
• Acute inflammation occurs within seconds to minutes.
• Acute inflammation involves tissue injury and the release of autacoids like eicosanoids, which are locally synthesized.
• Acute inflammation has a vascular response including vasodilation and hyperemia.
• It has a cellular response involving neutrophils, platelets, and fibrinogen, along with an immune response that releases cytokines.
• Chronic inflammation lasts for months to years.
• It involves the infiltration of phagocytes and lymphocytes.
• Proinflammatory cytokines and chemokines, such as TNF-alpha and IL-1, are released in chronic inflammation.
• Simultaneous tissue destruction and healing occurs.

Chronic Inflammation Treatment

• Treatment aims for symptom relief and maintenance of function.
• It also focuses on slowing or preventing tissue-damaging processes.
• Treatment options include NSAIDs, Glucocorticoids, and DMARDs.

Rheumatoid Arthritis (RA)

• RA is an autoimmune, chronic inflammation disorder affecting joints.
• Systemic effects include shortened life, reduced mobility, and decreased quality of life.
• RA is caused by rheumatoid factor, which is an antibody against the Fc portion of IgG.
• Anti-citrullinated protein antibodies serve as biomarkers for RA.
• RA is uncommon under the age of 15.
• The incidence of RA rises with age, peaking around the 80s.
• Women are 3-5 times more likely to be diagnosed with RA.
• Women are commonly diagnosed between their 40s and 50s, while men are diagnosed later in life.

Effects of Rheumatoid Arthritis

• RA leads to pain, cartilage and bone damage.
• It causes immune complexes to become deposited in the joints.
• Lymphocytes and macrophages are present in the synovium, and PMNs are present in the synovial fluid.
• Cell membrane lysosomal enzymes and free radicals are seen in RA.
• Prostaglandins and leukotrienes are involved.
• Macrophages, T cell proliferation, and TNF-alpha contribute to RA.

Rheumatoid Arthritis Treatment

• Two primary goals for RA is to relieve pain using NSAIDs, and to slow tissue damage using DMARDs.
• The criteria used to define RA staging and response to treatment:
  • Disease Activity Index
  • AMR Response Index.
• New criteria include inflammatory cytokines.

NSAIDs

• NSAIDs are non-steroidal anti-inflammatory agents with diverse structures.
• They are anti-inflammatory, analgesic, and antipyretic.
• Most NSAIDs are weak organic acids.
• NSAIDs are gastric irritants, except for COX2 inhibitors.
• They inhibit platelet aggregation, except for COX2 inhibitors.
• Common side effects include nephrotoxicity, GI bleeding, hepatotoxicity, and hypersensitivity.
• NSAIDs are well absorbed.

NSAIDs Chemical Classification

• NSAIDs can be classified as propionic acid derivatives, indole derivatives, pyrrole acetic acid derivatives, phenylacetic acid derivatives, fenamates, oxicams, pyrazolone derivatives, salicylates, or para-aminophenols.
• Examples of each:
  • Propionic: Ibuprofen, ketoprofen, naproxen, oxaprozin
  • Indole: Indomethacin, sulindac
  • Pyrrole acetic acid: Ketorolac, tolmetin, nabumetone
  • Phenylacetic acid: Diclofenac
  • Fenamates: Meclofenamic acid, meclofenamate
  • Oxicams: Piroxicam
  • Pyrazolone: Phenylbutazone
  • Salicylates: Aspirin
  • Para-aminophenols: Acetaminophen

NSAIDs General Properties

• All, but one, are weak organic acids, nabumetone is the exception
• NSAIDs are strongly protein-bound, mainly to albumin
• They are mostly metabolized by P450 enzymes.
• The mechanism of action involves inhibition of prostaglandin biosynthesis.

NSAIDs Adverse Effects

• Gastrointestinal toxicity:
  • Dyspepsia
  • Gastroduodenal ulcers
  • GI bleeding and perforation
• Cardiovascular adverse effects:
  • Edema
  • Hypertension
  • Congestive heart failure
  • Myocardial infarction
  • Stroke and other thrombotic events
• Nephrotoxicity:
  • Electrolyte imbalance
  • Sodium retention
  • Edema
  • Reduced glomerular filtration rate
  • Nephrotic syndrome
  • Acute interstitial nephritis
  • Renal papillary necrosis
  • Chronic kidney disease

Non-Selective COX Inhibitors

• Examples include ibuprofen, naproxen (Aleve), fenoprofen (Nalfon), and ketoprofen (Orudis).
• These are proprionic acid derivates.
• There is no known interaction with anticoagulants.
• Fenoprofen can cause nephrotoxic syndrome.
• Oxaprozin has a longer half-life of 50-60 hours.

Non-Selective COX Inhibitors: Indomethacin, Sulindac, Tolmentin and Ketorolac

• Indomethacin (Indocin):
  • The frontline therapy for ankylosing spondylitis and Reiter syndrome.
  • It speeds closure of patent ductus arteriosus in premature infants.
  • It is rarely used for its analgesic or antipyretic effect.
  • Bleeding and ulceration are more likely than with other NSAIDs.
• Sulindac (Clinoril):
  • Tolmentin (Tolectin), ketorolac (Toradol) are pyrrole acetic acid derivatives.
  • Sulindac is given as a prodrug with an active metabolite that has a long half-life.
• Tolmentin:
  • It has a short half-life.
  • Demonstrates no effect on platelet aggregation.
  • It has a higher incidence of anaphylaxis.
• Ketorolac:
  • This is a potent analgesic with moderate anti-inflammatory properties.
  • Can be given as an IV or ophthalmic solution.

Non-Selective COX Inhibitors - Further Examples

• Meclofenamate (Meclomen), Mefenamic Acid (Ponstel):
  • They have short half lives.
  • They have a relatively high incidence of GI problems.
• Piroxicam (Feldene):
  • This is an oxicam derivative of enolic acid.
  • Has a long half-life.
  • Demonstrates a relatively higher incidence of bleeding and ulceration.

Selective COX2 Inhibitors

• They are sulfonyl phenyl derivates.
• Have the same anti-inflammatory, analgesic, and antipyretic effects as non-specific COX inhibitors.
• Results in less inhibition of platelet aggregation.
• Results in less GI side effects.
• Unlike aspirin, does not offer cardiovascular protection.
• It inhibits prostacyclin production at the site of inflammation.
• Side effects include renal toxicity, thrombosis, edema, and hypertension.

Selective COX2 Inhibitors Considerations

• Rationale: By inhibiting COX2, the inflammatory response and pain is reduced, without inhibiting the cytoprotective action of prostaglandins in the stomach (COX1).
• Problem: Its use showed increased incidence incidence of myocardial infarction among patients – long term use.
  • Rofecoxib and valdecoxib are out of the market.
  • Celecoxib and meloxicam are still available
• Black box warning regarding cardiovascular risks.
• It increases instances of blot clots.
  • A high profile case with Vioxx resulted in the FDA suing Merck.

Selective COX2 Inhibitors drugs

• Celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra).
• Only celecoxib remains in the market.
• The drug addresses osteoarthritis, rheumatoid arthritis, bone pain, dental pain and headache, and ankylosing spondylitis.
• Meloxicam (COX2 > COX1): for acute use at low doses.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

• DMARDs are drugs that are unrelated, but defined by their effect on slowing down RA.
• Most DMARDs are immunosuppressive drugs.
• DMARDs can be non-biologics (small molecule drugs) or biologics (usually proteins).
• It can take 2 weeks to 6 months to be effective.

DMARDs

• Methotrexate (Rheumatrex):
  • Most widely prescribed DMARD for roughly 50-70% of patients.
  • Its anti-inflammatory with immunosuppressive properties.
  • Results in the accumulation of AMP which leads to the secretion and conversion into adenosine.
  • Has hepatoxicity.
• Cyclophosphamide (Cytoxan)
  • Has an active metabolite of phosphoramide mustard
  • Suppresses B and T cell function

DMARDs - Azathioprine and Cyclosporine

• Azathioprine (Imuran)
  • synthetic DMARD
  • The major metabolite is 6-thioguanine
  • Action: Inhibits inosinic acid synthesis, inhibits T and B cell function, inhibits IL-2 secretion
  • Side effects include bone marrow suppression, GI toxicities
• Cyclosporine (Sandimmune)
  • Antibiotic
  • Inhibits IL-1, IL-2, macrophage-T cell interaction, T cell responsiveness and B cell function
  • Results in Leukopenia, thrombocytopenia, anemia
  • Chronic dosing can cause cardiotoxicity, sterility and bladder cancer (rare)

DMARDs - Leflunomide and Sulfasalazine

• Leflunomide (Arava):
  • Rapidly converts to active metabolite A77-1726.
  • Inhibits dihydroorotate dehydrogenase.
  • Decreases ribonucleotide synthesis, cell cycle arrest, T-cell proliferation and B cell function.
  • Side effects: diarrhea, mild alopecia, weight gain, and elevated blood pressure.
  • Contraindicated in pregnant women.
• Sulfasalazine (Azulfidine):
  • Metabolized to sulfapyridine and 5-aminosalicylic acid.
  • Decreases IgA and IgM production.
  • Decreases T and B cell function.
  • A third of patients discontinue use due to nausea, vomiting, headache, or rash.

Organic Gold Salts

• Include Aurothioglucose (Solganal), gold sodium, thiomalate (Myochrysine), and auranofin (Ridaura).
• Used to slow down the destruction of bone and joints.
• They suppress macrophages and reduces histamine release.
• Serious GI disturbances, dermatitis, and mucous membrane lesions.
• They are no longer used or recommended due to side effects, limited efficacy, and slow onset.

Antimalarials

• Include chloroquine (Aralen) and hydroxychloroquine (Plaquenil).
• They function as immunosuppressants, targeting T cells and impairing immune cell chemotaxis.
• Useful for joint pain associated with lupus and arthritis.
• Not widely used due to limited responses.

Penicillamine

• Penicillamine is a metabolite of penicillin.
• It demonstrates immunosuppressant activity.
• It has a long half-life.
• Common side effects are similar to gold compounds.
• It is rarely used.

Corticosteroids

• Prednisone is an example.
• Used only short term, they demonstrate quick effects.
• These are used orally for relief of severe arthritis involving many joints.
• Prolonged use, even at low doses, has serious toxicity issues.

Anakinra

• Anakinra (Kineret) blocks the IL-1 receptor.
• It decreases the pain and inflammation caused by IL-1.
• Administered via daily sub-cutaneous injection.
• Side effects include redness, burning pain, inflammation, and neutropenia.
• Limited effectiveness in RA and rarely used.

Infliximab

• Infliximab (Remicade) is a scavenger antibody to human TNF-alpha.
• Administered through IV infusion, which can be combined with other DMARDs. Half life of 8-12 days.
• Side effects include upper respiratory symptoms, nausea, headache, rash, and the production of antibodies against it (human anti-chimeric antibodies-~50%).

Adalimumab

• Adalimumab (Humira):
  • Acts as a fully human anti-TNF alpha monoclonal antibody.
  • Effective as monotherapy or when combined other DMARDs.
  • Administered weekly via SC injection.
  • Has a half life of 9-14 days.
  • Acts as a scavenger of TNF alpha and downregulates macrophage and T cell activity.
  • Side effects include infection and leukopenia.

Etanercept

• Etanercept is also known as Enbrel.
• It recombinantly fuses protein of two soluble TNF p75 receptors linked to the Fc portion of human IgG.
• Binds to TNF-alpha.
• Administered via twice a week SC injection.
• The half-life of 4-5 days.
• Is mostly used in combination with methotrexate.
• Side effects include erythema, pain, swelling, and anti-etanercept ab's.