NSAIDs: Inflammation and Rheumatoid Arthritis

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

• Lecture by Guillermo Armaiz, Ph.D.
• Email: [email protected]; Phone: 787-840-2575 ext. 3226

Lecture Overview

• Covers inflammation and rheumatoid arthritis
• Discusses NSAIDs, including COX1 and 2 inhibitors, and COX2 inhibitors
• Explores disease-modifying anti-rheumatic drugs

What is Inflammation?

• Complex biological response of body tissues to harmful stimuli
• Eliminates initial cause of cell injury, clears necrotic cells and damaged tissue
• Initiates tissue repair
• Non-specific defense mechanism is innate immunity
• Antigen-specific immune response is adaptive immunity

Signs & Causes of Inflammation

• Pain, heat, redness, swelling, and loss of function are signs
• Exogenous causes include mechanical, physical, chemical factors, and infections
• Endogenous causes include autoimmune responses

The Balance of Inflammation

• Too little inflammation may result in bacterial-derived diseases
• Too much inflammation can cause hay fever, periodontitis, atherosclerosis, and rheumatoid arthritis
• Inflammation is tightly regulated by the body

Inflammatory Process

• Can be acute or chronic
• Acute inflammation occurs in seconds to minutes
• Tissue injury and release of autacoids (such as aa), eicosanoids synthesized locally occur
• Vascular Response involves vasodilation and hyperemia
• Cellular Response consists of neutrophils, platelets, and fibrinogen
• The immune response involves the release of cytokines

Chronic Inflammation

• Lasts from months to years
• Characterized by infiltration of phagocytes and lymphocytes
• Release of proinflammatory cytokines and chemokines occur, including TNF-alpha and IL-1
• Simultaneous destruction and healing of tissue

Chronic Inflammation Treatment

• Goals include symptom relief and maintenance of function
• Aims to slow or prevent tissue-damaging processes
• Treatment options include: NSAIDs, Glucocorticoids, DMARDs

Rheumatoid Arthritis

• An autoimmune, chronic inflammation disorder affects joints
• Systemic effects include shortening life, reducing mobility, and decreased quality of life
• Caused by rheumatoid factor: antibody against the Fc portion of IgG
• Anti-citrullinated protein antibodies serve as biomarkers
• Uncommon under age of 15
• Incidence rises with age to ~80's
• Women are 3X-5X more likely to be diagnosed
• Women are commonly diagnosed between their 40-50s; men later

Rheumatoid Arthritis Progression

• Causes pain, cartilage and bone damage
• Immune complexes deposited in joints
• Lymphocytes and macrophages in synovium and PMNs in synovial fluid
• Cell membrane lysosomal enzymes and free radicals are factors
• Prostaglandins and leukotrienes are involved
• Includes macrophages, T cell proliferation, chemotaxis, and TNF-alpha

Rheumatoid Arthritis - Therapeutic Goals

• Two primary goals are relief of pain (NSAIDs) and slowing tissue damage (DMADs)
• Several criteria used to define RA staging and response to treatment
• Disease Activity Index and AMR Response Index
• New criteria added includes inflammatory cytokines

NSAIDs

• Non-steroidal anti-inflammatory agents with diverse structures
• Anti-inflammatory, analgesic, and antipyretic
• Most are weak organic acids
• Gastric irritants, except COX2
• Inhibits platelet aggregation, except COX2
• Common side effects are nephrotoxicity, GI bleeding, hepatotoxic, and hypersensitivity
• Well absorbed

NSAIDs Classification

• Propionic acid derivatives: Ibuprofen, ketoprofen, naproxen, oxaprozin
• Indole derivatives: Indomethacin, sulindac
• Pyrrole acetic acid derivatives: Ketorolac, tolmetin, nabumetone
• Phenylacetic acid derivatives: diclofenac
• Fenamates Type: Meclofenamic acid, meclofenamate
• Oxicams Type: Piroxicam
• Pyrazolone derivatives: Phenylbutazone
• Salicylates: Aspirin
• Para-aminophenols: Acetaminophen

NSAIDs - General Properties

• All but one are weak organic acids, Nabumetone being the exception
• Protein bound - albumin
• Most metabolized by P450
• Mechanism of action: 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, reduce glomerular filtration rate, nephrotic syndrome, acute interstitial nephritis, renal papillary necrosis, and chronic kidney disease

Non-Selective COX Inhibitors

• Ibuprofen, naproxen (Aleve), fenoprofen (Nalfon), ketoprofen (Orudis)
• They're proprionic acid derivatives
• No known interaction with anticoagulants
• Fenoprofen causes nephrotoxic syndrome
• Oxaprozin has a longer half-life (50-60 hrs)
• Indomethacin (indocin) is frontline therapy for ankylosing spondylitis and Reiter syndrome
• Speeds closure of patent ductus arteriosus in premature infants
• Rarely used for analgesic or antipyretic effect; bleeding and ulceration are more likely than other NSAIDs
• Sulindac (clinoril), tolmentin (tolectin), ketorolac (toradol) are pyrrole acetic acid derivatives
• Sulindac is given as a prodrug and active metabolite has a long half-life
• Tolmentin has a short half-life; no effect on platelet aggregation; higher incidence of anaphylaxis
• Ketorolac is a potent analgesic, moderate anti-inflammatory properties; can be given as IV or ophthalmic solution
• Meclofenamate (Meclomen) and mefenamic acid (Ponstel) have a short half-life and relatively high incidence of GI problems
• Piroxicam (Feldene) is an oxicam derivative of enolic acid with a long half-life and relatively higher incidence of bleeding and ulceration

Selective COX2 Inhibitors

• Sulfonyl Phenyl Derivates
• Same anti-inflammatory, analgesic, and antipyratic effects as non-specific COX inhibitors
• Less inhibition of platelet aggregation
• Less GI side effects due to less erosion of GI mucosa
• Does not offer cardiovascular protection, such as aspirin
• Inhibit prostacyclin production at site of inflammation
• Side effects: renal toxicity, thrombosis, edema, and hypertension

Selective COX2 Inhibitors Rationale & Problems

• The inhibition of COX2 leads to a reduced inflammatory response and pain
• Doesn't inhibit the cytoprotective action of prostaglandins in the stomach (COX1)
• Increased incidence of myocardial infarction among patients with long term use
• Rofecoxib and valdecoxib off the market; celecoxib and meloxicam still available
• Black box warning for cardiovascular risks
• Increased chance of blot clots
• Vioxx case resulted in the FDA suing Merck
• Celecoxib (celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra)
• Only celecoxib remains in the market and is indicated for osteoarthritis, rheumatoid arthritis, bone pain, dental pain and headache, and ankylosing spondylitis
• Meloxicam (COX2 > COX1) used acutely at low doses

Disease-Modifying Anti-Rheumatic Drugs

• DMARDs-unrelated drugs defined by their effect on slowing down RA
• Most are immunosuppressive drugs
• Non-biologics (small molecule drugs) and biologics (usually proteins)
• Takes 2 weeks to 6 months to be effective
• Methotrexate (Rheumatrex) is the most widely prescribed DMARD (~50-70% of patients)
• Anti-inflammatory with immunosuppressive properties
• Leads to accumulation of AMP that is secreted and converted into adenosine
• Can cause hepatoxicity
• Cyclophosphamide (Cytoxan) has an active metabolite: phosphoramide mustard
• Suppresses B and T cell function
• Azathioprine (Imuran) is a synthetic DMARD
• Its major metabolite is 6-thioguanine
• Inhibits inosinic acid synthesis, inhibits T and B cell function, inhibits IL-2 secretion
• Side effects: Bone marrow suppression, GI toxicities
• Cyclosporine (Sandimmune) is an antibiotic
• Inhibits IL-1, IL-2, macrophage-T cell interaction, T cell responsiveness, and B cell function
• Can cause Leukopenia, thrombocytopenia, and anema
• Chronic dosing can cause cardiotoxicity, sterility, and bladder cancer (rare)
• Leflunomide (Arava) is rapidly converted to its active metabolite: A77-1726
• Inhibits dihydroorotate dehydrogenase and decreases ribonucleotide synthesis
• Also causes cell cycle arrest, T-cell proliferation and B cell function
• Can cause diarrhea, mild alopecia, weight gain, and blood pressure and contraindicated in pregnant women
• Sulfasalazine (Azulfidine) is metabolized to sulfapyridine and 5-aminosalicylic acid
• IgA and IgM production is reduced with it
• Decreases T and B cell function
• One third discontinue use with a result of nausea, vomiting, headache, and rash

Organic Gold Salts & Antimalarials

• Aurothioglucose (Solganal), gold sodium thiomalate (Myochrysine), auranofin (Ridaura)
• It slows down the destruction of bone and joints
• Suppresses macrophages and reduces histamine release
• Serious GI disturbances, dermatitis, and mucous membrane lesions
• Not longer used or recommended due to side effects, limited efficacy, and slow onset
• Chloroquine (Aralen), Hydroxychloroquine (Plaquenil) are antimalarials
• Immunosuppressant of T cells and impairs immune cell chemotaxis
• Joint pain associated with lupus and arthritis
• Not widely used as they lead to limited responses

Penicillamine & Corticosteroids

• Penicillamine is a metabolite of penicillin
• It has immunosuppressant activity and a long half-life
• Side effects are common and similar to gold compounds
• Rarely used
• Prednisone is a corticosteroid
• Used only short term and effects are seen quickly
• Used orally for relief of severe arthritis involving many joints
• Prolonged use (even at low doses) causes serious toxicity issues

Anakinra

• Kinerect blocks IL-1 receptor
• Decreases pain and inflammation caused by IL-1
• Administered via daily sub-cutaneous injection
• Side effects: Redness, burning pain, inflammation, and neutropenia
• Limited effectiveness in RA and rarely used

Infliximab, Adalimunab & Etanercept

• Infliximab (Remicade) is a scavenger antibody to human TNF-alpha
• Given by IV infusion in 4-8 week intervals and can be combined with other DMARDs
• Half life: 8-12 days
• Side effect: Upper respiratory tract infections, nausea, headache, rash, antibodies against it (human anti-chimeric antibodies-~50%)
• Adalimunab (Humira) is a fully human anti-TNF alpha monoclonal antibody
• Effective as monotherapy or in combination with other DMARDs
• Weekly SC injection
• Half life: 9-14 days
• Scavenger of TNF alpha; downregulates macrophage and T cell activity
• Side effects: infection and leukopenia
• Etanercept (Enbrel) is recombinant fusion protein of two soluble TNF p75 receptors linked to the Fc portion of human IgG
• Binds to TNF-alpha
• Twice a week SC injection
• Half-life: 4-5 days
• Mostly used in combination with methotrexate
• Side effects: erythema, pain, swelling, anti-etanercept ab's